Method for treating pediatric eosinophilic esophagitis by administering an IL-4R antagonist

Abstract

A method for treating eosinophilic esophagitis in pediatric subjects is provided. In one aspect, the method includes administering to the subject an IL-4R antagonist, such as an anti-interleukin-4 receptor (IL-4R) antibody or an antigen-binding fragment thereof, one or more times.

Description

Technical Field

[0001] Cross - reference to Related Applications This application is filed on July 7, 2023, as a PCT international patent application claiming the priority and benefit of U.S. Provisional Application No. 63 / 359,577, filed on July 8, 2022, which is incorporated herein by reference.

Background Art

[0002] Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by esophageal dysfunction and eosinophilic inflammation of the esophagus, and is thought to be triggered by an abnormal type 2 immune response to food allergens (Non - Patent Document 1; Non - Patent Document 2). Although it is considered a rare disease, the current prevalence is estimated to be 22.7 per 100,000 worldwide (Non - Patent Document 3), and it appears to be on the rise (Non - Patent Document 4). Eosinophilic esophagitis has been reported in all age groups; however, most cases are in children and adults under 50 years old. Children under 18 years old account for approximately 30% of the EoE patient population (see, for example, Non - Patent Document 5).

[0003] The main clinical symptoms of EoE in adults and children over 10 years old are dysphagia and food impaction (Non-Patent Document 6). In fact, the clinical features of young children are non-specific and vary greatly depending on the age of the patient and whether the patient can describe prominent symptoms. Infants often present with breastfeeding difficulties, vomiting, and reflux, and there is also a possibility of growth retardation, while school-age children complain of abdominal pain and heartburn (Non-Patent Document 7). In addition, older children with symptomatic EoE may modify their diet and eating behavior, such as taking smaller bites, chewing well, eating slowly, consuming large amounts of fluids, and avoiding foods that are sticky, which is an eating behavior reported in adults as an attempt to prevent food impaction in the esophagus, strongly suggesting dysphagia. Such symptoms significantly impair QOL (see, for example, Non-Patent Document 8). Endoscopic findings are associated with esophageal inflammation and consist of fixed or transient concentric rings, longitudinal furrows, white plaques, decreased mucosal vessels, friable mucosa or crepe-like mucosa, and strictures. Grooves and white plaques are thought to be the most common findings in children, while rings are not common in children (Non-Patent Document 9). In some patients (especially pediatric patients), the esophagus may appear normal, but histologically, it may be active EoE (Non-Patent Document 10).

[0004] Current standard treatments for EoE are dietary modifications (e.g., elimination diets), as well as off-label proton pump inhibitors (PPIs), off-label use of topical corticosteroids for swallowing, and esophageal dilation. However, standard treatments for EoE have limitations in terms of variable efficacy, recurrence after treatment discontinuation, and adverse effects on QOL. Esophageal dilation is frequently performed to relieve symptoms of dysphagia due to esophageal stricture, but stricture is less common in children, so esophageal dilation is less commonly performed in pediatric EoE patients compared to adult EoE patients (Non-Patent Document 11). Furthermore, emergency endoscopy for obstruction due to retained and / or painful food boluses or esophageal dilation to relieve stricture is associated with a risk of severe esophageal injury and does not change the underlying pathology or disease progression. Dietary therapy that eliminates specific foods is effective in a significant proportion of patients; however, 30 - 40% of patients do not have their disease cured even with dietary improvement (Non-Patent Document 12). Proton pump inhibitors result in histological remission in approximately 50% of EoE patients (Non-Patent Document 6), and the remaining patients do not respond. Topical corticosteroids for swallowing have been reported to induce partial clinical response and histological remission in clinical trials; however, their effects are not uniform, they may be associated with local fungal infections, and there is a risk of growth suppression and hypothalamic-pituitary-adrenal axis suppression after systemic absorption (Non-Patent Document 13), and their use is limited to a short period. Therefore, there remains a high unmet medical need for a safe and effective treatment for pediatric EoE.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non - Patent Document 4

Non - Patent Document 5

Non - Patent Document 6

Non - Patent Document 7

Non - Patent Document 8

Non - Patent Document 9

Non - Patent Document 10

Non - Patent Document 11

Non - Patent Document 12

Non - Patent Document 13

Summary of the Invention

Means for Solving the Problems

[0006] In one aspect, a method is provided for treating, preventing, or ameliorating at least one symptom of eosinophilic esophagitis (EoE) in pediatric subjects under 12 years of age. In some embodiments, the method comprises administering to the subject an interleukin-4 receptor (IL-4R) antagonist one or more times. In some embodiments, the IL-4R antagonist specifically binds to IL-4 and / or IL-13. In some embodiments, the IL-4R antagonist specifically binds to IL-4Rα (e.g., human IL-4Rα).

[0007] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0008] In some embodiments, the subject is 1 year of age or older and under 12 years of age. In some embodiments, the subject weighs 5 kg or more. In some embodiments, the subject weighs less than 60 kg.

[0009] In some embodiments, the subject is under 12 years of age and weighs 5 kg or more and less than 15 kg. In some embodiments, the subject is under 12 years of age and weighs 15 kg or more and less than 30 kg. In some embodiments, the subject is under 12 years of age and weighs 30 kg or more and less than 60 kg. In some embodiments, the subject is under 12 years of age and weighs 40 kg or more.

[0010] In some embodiments, the subject is 1 year of age or older and has a weight of at least 5 kg and less than 15 kg. In some embodiments, the subject is 1 year of age or older and has a weight of at least 15 kg and less than 30 kg. In some embodiments, the subject is 1 year of age or older and has a weight of at least 30 kg and less than 60 kg. In some embodiments, the subject is 1 year of age or older and has a weight of at least 40 kg.

[0011] In some embodiments, prior to initiation of treatment with an IL-4R antagonist, the subject has a peak number of intraepithelial eosinophil infiltrating cells of 15 eos / hpf or greater as measured by endoscopic biopsy in at least two of the proximal esophageal region, the middle esophageal region, and the distal esophageal region.

[0012] In some embodiments, the subject has been previously treated with a topical corticosteroid for swallowing and / or a proton pump inhibitor (PPI). In some embodiments, the subject does not respond, responds inadequately, or is intolerant to treatment with a topical corticosteroid for swallowing and / or a PPI, or standard treatment is contraindicated. In some embodiments, the subject has a concurrent atopic disease. In some embodiments, the concurrent atopic disease is food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis.

[0013] In some embodiments, prior to initiation of treatment, the subject: has a baseline peak intraepithelial eosinophil cell count of 70 eos / hpf or greater; has a baseline mean intraepithelial eosinophil cell count of 50 eos / hpf or greater; has a baseline EoE endoscopic reference score (EoE-EREFS) of at least a score of 6; and / or has a baseline serum total IgE value of at least 400 IU / L.

[0014] In some embodiments, the subject (a) has a weight of less than 5 kg; (b) has a weight of 60 kg or greater; (c) being eosinophilic gastroenteritis, eosinophilia syndrome, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome); (d) having a history of Crohn's disease, ulcerative colitis, celiac disease, or esophageal surgery; (e) having an esophageal stricture that cannot be passed through with a standard diagnostic upper endoscope or having an esophageal stricture that requires dilation; (f) having been treated with topical corticosteroids for swallowing within the past 8 weeks; (g) having been treated with subcutaneous immunotherapy (SCIT), except when not treated with a stable maintenance dose for at least one year; (h) having received pretreatment with sublingual immunotherapy (SLIT), transcutaneous immunotherapy (EPIT), or oral immunotherapy (OIT); (i) having been treated with systemic immunosuppressive drugs or immunomodulatory drugs within the past 3 months; (j) having started or changed a food elimination diet regimen within the past 6 weeks; (k) having started, stopped, or changed the administration regimen of PPI, leukotriene inhibitor, intranasal corticosteroid, or inhaled corticosteroid within the past 8 weeks; (l) having been vaccinated with a live vaccine (attenuated vaccine) within the past 4 weeks; (m) having active Helicobacter pylori (H. pylori), helminth infection, active parasitic infection, or having a chronic or acute infectious disease that requires treatment with systemic antibiotics, antiviral drugs, or antifungal drugs; (n) having a known or suspected immunodeficiency disorder; (o) having liver disease; and (p) having a platelet value of less than 100×10 3 / μL, a neutrophil level of 1.5×10 3 / μL or less, or an estimated glomerular filtration rate (eGFR) of less than 30 mL / min / 1.73 m 2 2; is selected based on not showing one or more exclusion criteria selected from the group consisting of.

[0015] In some embodiments, the anti-IL-4R antibody or an antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab.

[0016] In some embodiments, the IL-4R antagonist is administered at a dose of about 50 mg to about 600 mg. In some embodiments, the IL-4R antagonist is administered once a week or once every two weeks at a dose of about 100 mg to about 300 mg. In some embodiments, the IL-4R antagonist is administered subcutaneously.

[0017] In some embodiments, the subject weighs 5 kg or more: For subjects weighing 5 kg or more but less than 15 kg, the IL-4R antagonist is administered at a dose of about 100 mg Q2W, about 200 mg Q3W, or about 200 mg Q4W; For subjects weighing 15 kg or more but less than 30 kg, the IL-4R antagonist is administered at a dose of about 200 mg Q2W, or about 300 mg Q4W; For subjects weighing 30 kg or more but less than 60 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W, or about 200 mg Q2W; and / or For subjects weighing 60 kg or more, the IL-4R antagonist is administered at a dose of about 300 mg QW or about 300 mg Q2W.

[0018] In some embodiments, the subject weighs 5 kg or more: For subjects weighing 5 kg or more but less than 15 kg, the IL-4R antagonist is administered at a dose of about 100 mg Q2W, or about 200 mg Q3W; For subjects weighing 15 kg or more but less than 30 kg, the IL-4R antagonist is administered at a dose of about 200 mg Q2W; For subjects weighing more than 30 kg and less than 60 kg, the IL-4R antagonist is administered at a dose of approximately 300 mg Q2W; and / or For subjects weighing 60 kg or more, the IL-4R antagonist is administered at a dose of approximately 300 mg QW.

[0019] In some embodiments, the subject weighs 5 kg or more: For subjects weighing 5 kg or more and less than 15 kg, the IL-4R antagonist is administered at a dose of approximately 200 mg Q3W; For subjects weighing 15 kg or more and less than 30 kg, the IL-4R antagonist is administered at a dose of approximately 200 mg Q2W; For subjects weighing 30 kg or more and less than 40 kg, the IL-4R antagonist is administered at a dose of approximately 300 mg Q2W; and / or For subjects weighing 40 kg or more, the IL-4R antagonist is administered at a dose of approximately 300 mg QW.

[0020] In some embodiments, the subject weighs 5 kg or more and less than 15 kg. In some embodiments, the subject weighs 5 kg or more and less than 15 kg, and the IL-4R antagonist is administered at a dose of approximately 100 mg Q2W. In some embodiments, the subject weighs 5 kg or more and less than 15 kg, and the IL-4R antagonist is administered at a dose of approximately 200 mg Q3W. In some embodiments, the subject weighs 5 kg or more and less than 15 kg, and the IL-4R antagonist is administered at a dose of approximately 200 mg Q4W.

[0021] In some embodiments, the subject weighs 15 kg or more and less than 30 kg. In some embodiments, the subject weighs 15 kg or more and less than 30 kg, and the IL-4R antagonist is administered at a dose of approximately 200 mg Q2W. In some embodiments, the subject weighs 15 kg or more and less than 30 kg, and the IL-4R antagonist is administered at a dose of approximately 300 mg Q4W.

[0022] In some embodiments, the subject weighs at least 30 kg and less than 60 kg. In some embodiments, the subject weighs at least 30 kg and less than 60 kg, and the IL-4R antagonist is administered at a dose of about 300 mg Q2W. In some embodiments, the subject weighs at least 30 kg and less than 60 kg, and the IL-4R antagonist is administered at a dose of about 200 mg Q2W.

[0023] In some embodiments, the subject weighs at least 60 kg. In some embodiments, the subject weighs at least 60 kg, and the IL-4R antagonist is administered at a dose of about 300 mg QW. In some embodiments, the subject weighs at least 60 kg, and the IL-4R antagonist is administered at a dose of about 300 mg Q2W.

[0024] In some embodiments, the subject weighs at least 40 kg. In some embodiments, the subject weighs at least 40 kg, and the IL-4R antagonist is administered at a dose of about 300 mg QW.

[0025] In some embodiments, the IL-4R antagonist is administered in combination with a second therapeutic agent or treatment. In some embodiments, the second therapeutic agent or treatment is an IL-1β inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNFα inhibitor, an eotaxin-3 inhibitor, an IgE inhibitor, a prostaglandin D2 inhibitor, an immunosuppressive agent, a topical corticosteroid, an oral corticosteroid, a systemic corticosteroid, an inhaled corticosteroid, a glucocorticoid, a PPI, a blood-removing agent, an antihistamine, a non-steroidal anti-inflammatory drug (NSAID), esophageal dilation, a nutritional tube, allergen removal, or diet management. In some embodiments, the second therapeutic agent or treatment is diet management. In some embodiments, the second therapeutic agent or treatment is a PPI.

[0026] In some embodiments, treatment with the IL-4R antagonist for at least 16 weeks results in: a decrease in peak esophageal intraepithelial eosinophil count; Reduction in the severity and / or extent of the disease as measured by the histological scoring system for eosinophilic esophagitis (EoE-HSS); Improvement in esophageal anatomical features as measured by the endoscopic reference score for eosinophilic esophagitis (EoE-EREFS); Increase in the percentile of body weight for age; and / or Decrease in the normalized enrichment score (NES) for the type 2 inflammation panel and / or the EoE diagnostic panel of genes resulting in.

[0027] In some embodiments, 16 weeks of treatment with an IL-4R antagonist results in a peak esophageal intraepithelial eosinophil count of 6 eos / hpf or less and / or a reduction in the peak esophageal intraepithelial eosinophil count of at least 75%.

[0028] In some embodiments, the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an auto-injector device. In some embodiments, the IL-4R antagonist is contained in a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose pre-filled syringe. In some embodiments, the IL-4R antagonist is contained in an auto-injector device. In some embodiments, the IL-4R antagonist is contained in a pen delivery device.

[0029] In another aspect, the present disclosure provides a pharmaceutical composition comprising an IL-4R antagonist for use in treating, preventing, or ameliorating at least one symptom of EoE in pediatric subjects under 12 years of age (e.g., subjects from 1 year of age up to but not including 12 years of age), or pediatric or adolescent subjects weighing less than 40 kg at baseline (e.g., weighing 5 kg or more and less than 40 kg at baseline). In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof comprising an HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, an HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, an HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, an LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, an LCDR2 comprising or consisting of the amino acid sequence of LGS, and an LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-IL-4R antibody or an antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab. In some embodiments, the pharmaceutical composition is formulated to administer from about 50 mg to about 600 mg of the IL-4R antagonist per dose, such as about 100 mg, about 200 mg, or about 300 mg.

[0030] In another aspect, the present disclosure provides the use of an IL-4R antagonist in the preparation of a medicament for treating, preventing, or ameliorating at least one symptom of EoE in pediatric subjects less than 12 years of age (e.g., subjects from 1 year of age up to but not including 12 years of age), or pediatric or adolescent subjects having a body weight of less than 40 kg at baseline (e.g., having a body weight of 5 kg or more and less than 40 kg at baseline). In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof comprising an HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, an HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, an HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, an LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, an LCDR2 comprising or consisting of the amino acid sequence of LGS, and an LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-IL-4R antibody or an antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab. In some embodiments, the medicament is formulated to administer from about 50 mg to about 600 mg of the IL-4R antagonist per dose, e.g., about 100 mg, about 200 mg, or about 300 mg.

[0031] In another aspect, the present disclosure provides a therapeutic dosage form of a pharmaceutical composition comprising an IL-4R antagonist for use in treating, preventing, or ameliorating at least one symptom of EoE in pediatric subjects less than 12 years of age (e.g., subjects 1 year of age or older and less than 12 years of age), or pediatric or adolescent subjects having a body weight of less than 40 kg at baseline (e.g., having a body weight of 5 kg or more and less than 40 kg at baseline). In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof comprising an HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, an HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, an HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, an LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, an LCDR2 comprising or consisting of the amino acid sequence of LGS, and an LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-IL-4R antibody or an antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab. In some embodiments, the therapeutic dosage form is formulated to administer from about 50 mg to about 600 mg of the IL-4R antagonist per dose, such as about 100 mg, about 200 mg, or about 300 mg.

[0032] In another aspect, the present disclosure provides a kit, a pharmaceutical composition, or a medicament comprising an IL-4R antagonist for use in treating, preventing, or ameliorating at least one symptom of EoE in pediatric subjects under 12 years of age (e.g., subjects from 1 year to less than 12 years of age), or pediatric or adolescent subjects having a body weight of less than 40 kg at baseline (e.g., having a body weight of 5 kg or more and less than 40 kg at baseline). In some embodiments, the kit also includes a label or instructions for use.

[0033] Other embodiments will be apparent from the overview of the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0034] Definitions Before describing the present invention, it is to be understood that the invention is not limited to the specific methods and experimental conditions described, as such methods and conditions may vary. Also, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present invention is limited only by the appended claims.

[0035] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0036] As used herein, the term "about," when used in connection with a particular recited numerical value, means that the value may vary by up to 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101, as well as all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0037] As used herein, the terms "treat", "treating", etc. mean alleviating symptoms, removing the cause of symptoms temporarily or permanently, or preventing or delaying the appearance of symptoms of a specified disorder or condition.

[0038] "Eosinophilic esophagitis" or "EoE" refers to an inflammatory disease characterized by abnormal eosinophilic inflammation in the esophagus and esophageal dysfunction. The main symptoms of EoE include, but are not limited to, chest pain, abdominal pain, dysphagia, heartburn, feeding refusal, vomiting, food impaction, and failure to thrive. The histopathological features of EoE are related to esophageal inflammation and may include fixed or transient concentric rings, longitudinal furrows, white plaques, decreased mucosal vessels, friable mucosa or cobblestone mucosa, and strictures. Furrows and white plaques are more common in children, and rings are more common in adults than in children. EoE is usually diagnosed by endoscopy of the esophagus with biopsy followed by microscopic and biochemical analysis of the inner layer of the esophageal mucosa. The current consensus-based recommendation for the diagnosis of EoE is a peak esophageal intraepithelial eosinophil count of 15 eos / hpf or more.

[0039] As used herein, the term "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms or signs of eosinophilic esophagitis, and / or a human or non-human animal diagnosed with eosinophilic esophagitis. In certain embodiments, the term includes a subject that exhibits elevated levels of one or more EoE-related biomarkers (described elsewhere herein), and / or a subject having a gene expression profile related to EoE (the "EoE disease transcriptome"). For example, in some embodiments, a subject treated according to the methods of the present disclosure is a subject having elevated levels of IgE, serum TARC, and / or eotaxin-3, a subject having a gene expression profile that matches a published EoE gene expression signature (Dellon et al., Clin Transl Gastroenterol, 2017, 8(2):e74), or a subject in which the expression level of one or more genes of a published EoE gene expression signature has changed. As used herein, the terms "subject" and "patient" are used interchangeably.

[0040] Also, the term "subject in need thereof" may include, for example, a subject that exhibits (or has exhibited) one or more signs of EoE, such as esophageal overexpression of pro-inflammatory mediators such as mast cells, esophageal eosinophil infiltration, esophageal wall thickening, dysphagia, occlusion by food bolus, chest pain and abdominal pain, and / or elevated EoE-related biomarkers, prior to treatment. The term also includes subjects having an elevated peripheral eosinophil count (e.g., 100 cells / μL or more, 150 cells / μL or more, 200 cells / μL or more, 300 cells / μL or more) or an elevated serum IgE (e.g., greater than 150 kU / L).

[0041] The term "eosinophil infiltration" refers to the presence of eosinophils in organs or tissues including the subject's blood, esophagus, stomach, duodenum, and ileum. In the context of the present disclosure, the term "eosinophil infiltration" refers to the presence of eosinophils in the inner mucosal layer of regions of the gastrointestinal tract including, but not limited to, the esophagus and stomach. Eosinophil infiltration is analyzed, for example, in esophageal tissue biopsies from subjects with EoE. According to some embodiments, "eosinophil infiltration" refers to the presence of 15 or more eosinophils per high-power field in the esophagus or in two or more of the proximal, middle, and distal regions of the esophagus. The term "high-power field" refers to a standard total magnification of 400x of a microscope used to observe eosinophils in tissue, such as eosinophils from the subject's esophagus. Thus, in some embodiments, "a subject in need thereof" refers to a subject showing the presence of 15 or more eosinophils ("eos") per high-power field ("hpf") in the esophagus, for example, in two or more of the proximal, middle, and distal regions of the esophagus. In certain embodiments, "eosinophil infiltration" includes infiltration of tissues by white blood cells such as lymphocytes, neutrophils, and mast cells. For example, leukocyte infiltration into esophageal tissue can be detected by cell surface markers such as eosinophil-specific markers (e.g., CD11c Low / Neg , SiglecF + , F4 / 80 + , EMR1 + , Siglec8 + , and MBP2 + ), macrophage-specific markers (e.g., CD11b + , F4 / 80 + , CD14 + , EMR1 + , and CD68 + ), neutrophil-specific markers (e.g., CD11b + , Ly6G + , Ly6C + , CD11b + , and CD66b + ), and T cell-specific markers (e.g., CD3 + , CD4 + , and CD8 + ).

[0042] In some embodiments, the subject does not respond, responds inadequately, or is intolerant to treatment with standard treatments (e.g., topical corticosteroids or PPIs for swallowing). As used herein, for example, as measured using the EoE-related parameters disclosed herein (e.g., the number of eosinophils in the esophageal epithelium, changes in the severity and / or extent of histological features of the esophagus, or changes in one or more esophageal features measured by EoE-EREFS), a subject who "does not respond" to treatment is one in whom the disease symptoms do not improve, do not significantly improve, or worsen over a defined period of time with treatment by standard therapy. As used herein, for example, as measured using the EoE-related parameters disclosed herein (e.g., the number of eosinophils in the esophageal epithelium, changes in the severity and / or extent of histological features of the esophagus, or changes in one or more esophageal features measured by EoE-EREFS), a subject who is "inadequately responsive" to treatment is one in whom the disease symptoms may improve partially with treatment by standard therapy but do not improve to a level indicating disease control, or in whom the disease symptoms improve initially but do not achieve, for example, stable long-term disease control. As used herein, a subject who is "intolerant" to treatment is one who cannot tolerate the side effects of the treatment, for example, at a therapeutic or sub-therapeutic dose.

[0043] Any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, but representative methods and materials are described. All publications mentioned herein are hereby incorporated by reference in their entirety.

[0044] Treatment methods In one aspect, a method is provided for treating, preventing, or ameliorating one or more symptoms of eosinophilic esophagitis (EoE) in a subject. In some embodiments, the subject is a pediatric or adolescent subject under 18 years of age. In some embodiments, the subject is a pediatric subject under 12 years of age. In some embodiments, the subject is 1 year or older and under 12 years of age. In some embodiments, the subject is 1 year or older and under 4 years of age. In some embodiments, the subject is 1 year or older and under 5 years of age. In some embodiments, the subject is 2 years or older and under 8 years of age. In some embodiments, the subject is 5 years or older and under 12 years of age. In some embodiments, the subject is 8 years or older and under 12 years of age.

[0045] In some embodiments, a subject treated according to the methods disclosed herein has a documented diagnosis history of EoE by endoscopic biopsy as indicated by intraepithelial eosinophil infiltration from at least one esophageal region. In some embodiments, the subject has a baseline peak eosinophil count of 15 eos / hpf or greater. As used herein, "peak esophageal intraepithelial eosinophil count" refers to, for example, the number of eosinophils contained within one high power field (hpf) at 400x magnification. In some embodiments, the subject has a peak number of intraepithelial eosinophil infiltrating cells measured by endoscopic biopsy of 15 eos / hpf or greater in at least two, or all three, of the proximal esophageal region, the mid-esophageal region, and the distal esophageal region. In some embodiments, the subject's mean peak esophageal intraepithelial eosinophil count is 20 eos / hpf or greater, 25 eos / hpf or greater, 30 eos / hpf or greater, 35 eos / hpf or greater, 40 eos / hpf or greater, 45 eos / hpf or greater, 50 eos / hpf or greater, 55 eos / hpf or greater, 60 eos / hpf or greater, 65 eos / hpf or greater, 70 eos / hpf or greater, 75 eos / hpf or greater, 80 eos / hpf or greater, 85 eos / hpf or greater, or 90 eos / hpf or greater.

[0046] In some embodiments, the subject to be treated according to the methods disclosed herein has a history of one or more symptoms of EoE, such as abdominal pain, chest pain, heartburn, food reflux, dysphagia, vomiting, obstruction by food bolus, eating disorder, feeding refusal, or failure to thrive, but is not limited thereto. In some embodiments, the subject has a history of one or more symptoms of EoE for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 50 weeks, or more. In some embodiments, the subject has a history of one or more symptoms of EoE for at least 6 months, at least 1 year, at least 2 years, or more. In some embodiments, the subject has a weight below the average of the age percentile.

[0047] In some embodiments, the subject to be treated according to the methods disclosed herein has a pretreatment history of one or more standard treatment therapies for EoE, such as, but not limited to, dietary modification (e.g., food elimination diet), topical corticosteroids for swallowing, glucocorticoids, proton pump inhibitor (PPI) therapy (e.g., high-dose PPI regimen), or esophageal dilation. In some embodiments, the subject to be treated is a subject who is non-responsive, insufficiently responsive, intolerant, or resistant to one or more current standard treatment therapies for EoE. In some embodiments, the subject to be treated has a contraindication to one or more standard treatment therapies.

[0048] In some embodiments, the subject to be treated has a body weight of 5 kg or more at baseline. In some embodiments, the subject to be treated has a body weight of less than 60 kg at baseline. In some embodiments, the subject to be treated has a body weight of 5 kg or more and less than 60 kg at baseline. In some embodiments, the subject to be treated has a body weight of 5 kg or more and less than 15 kg at baseline. In some embodiments, the subject to be treated has a body weight of 15 kg or more and less than 30 kg at baseline. In some embodiments, the subject to be treated has a body weight of 30 kg or more and less than 60 kg at baseline.

[0049] In some embodiments, the subject to be treated is a pediatric or adolescent patient with a body weight of less than 40 kg at baseline. In some embodiments, the subject to be treated has a body weight of 5 kg or more and less than 40 kg at baseline.

[0050] In some embodiments, the subject to be treated has a change in one or more biomarker levels of EoE, or exhibits or has a gene signature profile of an EoE-related gene that matches the published gene signature profile of an EoE patient. EoE-related biomarkers and gene expression panels for diagnosing EoE are described in the art, for example, Sherrill et al., Genes Immun, 2014, 15(6):361-369; Dellon et al., Clin Transl Gastroenterol, 2017, 8(2):e74; and U.S. Patent Publication No. 2017 / 0067111. In some embodiments, the subject has elevated levels of eotaxin-3, serum TARC, and / or total IgE. In some embodiments, the subject to be treated has elevated levels of one or more EoE-related genes such as TNFAIP6, LRRC31, SLC26A4-AS1, ALOX15, CCL26, TGM6, NRXN1, PMCH, SLC26A4, CXCL1, CCR3, TREML2, POSTN, LURAP1L, or CXCL6. In some embodiments, the subject to be treated has decreased levels of one or more EoE-related genes such as CRTAC1, BC107108, SFTA2, C2orf16, KRTAP3-2, PLNIPRP3, CIDEA, FLG, SLC8A1-AS1, SPINK5, SPINK7, SPINK8, DPCR1, MUC22, CRISP2, DSG1, GYS2, or CRISP3.

[0051] In some embodiments, the subject to be treated has or had at least one co-existing disorder. In some embodiments, the co-existing disorder is asthma, atopic dermatitis, hand and food eczema, allergic rhinitis, oral allergy syndrome, or food allergy (e.g., peanut allergy).

[0052] In some embodiments, the subject to be treated has or had a type 2 inflammatory state concurrent with. As used herein, "type 2 inflammatory state" refers to T helper 2 (T H2) A disease, disorder, or condition associated with a type 2 inflammatory response (Gandhi et al., Nat Rev Drug Discov., 2016, 15(1):35-50). Non-limiting examples of type 2 inflammatory conditions include asthma, chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), unified airway disease, eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), gastroesophageal reflux disease (GERD), atopic conjunctivitis, atopic dermatitis, vasculitis, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps (CRSwNP), aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity (e.g., NSAID-intolerant respiratory disease, or NSAID-ERD), perennial allergic rhinitis (PAR), chronic eosinophilic pneumonia (CEP), and exercise-induced bronchospasm. In some embodiments, the subject has a comorbid atopic disease or condition selected from the group consisting of food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis.

[0053] In some embodiments, the subject to be treated is a subject sensitive to allergens, e.g., a subject having food allergy or oral allergy syndrome. For example, in some embodiments, the subject exhibits one of the following characteristics: (a) likely to have an allergic reaction or response when exposed to one or more allergens; (b) having previously shown an allergic reaction or response to one or more allergens; (c) having a known allergy history; and / or (d) showing signs or symptoms of an allergic response or anaphylaxis. As used herein, terms such as "allergic response", "allergic reaction", "allergic symptom" include one or more signs or symptoms selected from the group consisting of urticaria (e.g., hives), angioedema, rhinitis, asthma, vomiting, sneezing, nasal discharge, sinusitis, watering eyes, wheezing, bronchospasm, decreased expiratory flow (PEF), gastrointestinal disorders, flushing, swelling of the lips, swelling of the tongue, decreased blood pressure, anaphylaxis, and organ dysfunction / failure. "Allergic response", "allergic reaction", "allergic symptom", etc. also include immunological responses and reactions such as increased IgE production, increased allergen-specific immunoglobulin production, and / or eosinophilia. In certain embodiments, the subject is allergic to an allergen associated with EoE, or an allergen that renders the subject sensitive to EoE and / or predisposes the subject to developing EoE. In some embodiments, the allergen is contained in or derived from foods such as dairy products (e.g., milk), eggs, wheat, soybeans, corn, rye, fish, shellfish, peanuts, nuts, or is contained in or derived from non-foods such as dust (e.g., containing house dust mites), pollen, insect venom (e.g., venom of bees, wasps, mosquitoes, etc.), mold, animal dander, latex, pharmaceuticals, drugs, mugwort, Gramineae plants, birch, etc.

[0054] In some embodiments, the subject to be treated is selected based on exhibiting one or more inclusion criteria disclosed in Example 1. In some embodiments, the subject to be treated is further selected based on not exhibiting one or more exclusion criteria disclosed in Example 1.

[0055] Interleukin-4 receptor antagonist In some embodiments, the methods of the disclosure involve administering to a subject in need thereof (e.g., a subject having EoE under 12 years of age, or a subject having EoE 1 year of age or older and under 12 years of age), an interleukin-4 receptor (IL-4R) antagonist or a pharmaceutical composition comprising an IL-4R antagonist. As used herein, an “IL-4R antagonist” (also referred to herein as an “IL-4R inhibitor,” “IL-4R blocker,” or “IL-4Rα antagonist”) is any agent that binds or interacts with IL-4Rα or an IL-4R ligand and inhibits or attenuates the normal biological signaling function of the type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. The type 1 IL-4 receptor is a dimer receptor that includes an IL-4Rα chain and a γc chain. The type 2 IL-4 receptor is a dimer receptor that includes an IL-4Rα chain and an IL-13Rα1 chain. The type 1 IL-4 receptor interacts with and is stimulated by IL-4, while the type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, the IL-4R antagonists used in the methods of the disclosure function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4-mediated signaling and IL-13-mediated signaling. Thus, the IL-4R antagonists of the disclosure can prevent the interaction of IL-4 and / or IL-13 with the type 1 or type 2 receptors.

[0056] Non-limiting examples of the category of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor bodies" (e.g., engineered molecules containing the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0057] Anti-IL-4Rα antibodies and antigen-binding fragments thereof In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. The term "antibody" as used herein includes immunoglobulin molecules comprising four polypeptide chains of two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H for short) and a heavy chain constant region. The heavy chain constant region comprises three domains, C H 1, C H 2 and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L for short) and a light chain constant region. The light chain constant region comprises one domain, C L 1. The V H and V L regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each V H and V LIt is composed of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences. In some embodiments, one or more of the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) are naturally or artificially modified.

[0058] As used herein, the term "antibody" includes antigen-binding fragments of a complete antibody molecule. As used herein, terms such as "antigen-binding portion of an antibody," "antigen-binding fragment of an antibody," etc., include naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptides or glycoproteins that specifically bind to an antigen to form a complex. Antigen-binding fragments of an antibody can be derived from a complete antibody molecule using any suitable standard techniques, such as proteolytic digestion or recombinant genetic engineering techniques including manipulation and expression of DNA encoding antibody variable domains and optionally constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including phage antibody libraries), or synthesized. The DNA is sequenced and manipulated using chemical or molecular biological techniques, for example, to arrange one or more variable domains and / or constant domains in an appropriate conformation, or to introduce codons, create cysteine residues, modify, add, or delete amino acids.

[0059] Non-limiting examples of antigen-binding fragments include the following: (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 tethered FR3-CDR3-FR4 peptides. Domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other engineered molecules such as shark variable IgNAR domains are also encompassed by the term “antigen-binding fragment” as used herein.

[0060] Antigen-binding fragments of an antibody generally contain at least one variable domain. The variable domain can be of any size and amino acid composition and generally contains at least one CDR adjacent to or at the same position as one or more framework sequences. The V L domain that associates with the V H domain in an antigen-binding fragment having a V H domain and a V L domain can be positioned relative to each other in any suitable arrangement. For example, the variable region can be dimeric and can contain a dimer of V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody can contain a monomeric V H or V L domain.

[0061] In certain embodiments, the antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting and exemplary configurations of the variable and constant domains found within the antigen-binding fragments of the antibodies of the present disclosure are: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C LIt includes. In any three-dimensional arrangement of the variable domain and the constant domain including any of the above exemplary three-dimensional arrangements, the variable domain and the constant domain are directly connected to each other or are connected by a complete or partial hinge or linker region. The hinge region is composed of at least 2 (for example, 5, 10, 15, 20, 40, 60 or more) amino acids, resulting in a flexible or semi-flexible connection between adjacent variable domains and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragment of the antibody of the present disclosure can include any homodimer or heterodimer (or other multimer) of the above variable domain and constant domain three-dimensional arrangements, non-covalently to each other, and / or one or more monomeric V H or V L domains and (for example, by disulfide bonds).

[0062] The constant region of the antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, in some embodiments, the isotype of the antibody is selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0063] As used herein, the term "antibody" includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies typically include at least two different variable domains, each of which can specifically bind to a separate antigen or a different epitope of the same antigen. Any multispecific antibody format can be adapted for use in the context of the antibodies or antigen-binding fragments of antibodies of the present disclosure using conventional techniques available in the art. For example, in some embodiments, the methods of the present disclosure include the use of bispecific antibodies in which one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof and the other arm of the immunoglobulin is specific for a second therapeutic target or conjugated to a therapeutic site. Exemplary bispecific formats used in the context of the present disclosure include, but are not limited to, for example, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, Quadroma, knob-in-hole, common light chain (e.g., common light chain with knob-in-hole, knob-in-hole, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, Duobody, IgG1 / IgG2, dual action Fab (DAF)-IgG, Mab 2 Bispecific formats are included (see, for example, Klein et al., 2012, mAbs, 4:6, 1-11, and references cited therein for an overview of the above formats). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation. For example, here non-natural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates, which are self-assembled to generate multimeric complexes with defined composition, valency, and geometry. (See, for example, Kazane et al., J. Am. Chem. Soc., [Epub: Dec. 4, 2012].)

[0064] In some embodiments, the antibodies used in the methods of the present disclosure are human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Notwithstanding, the human antibodies of the present disclosure may, for example, in the CDRs and particularly CDR3, contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random mutagenesis or site-directed mutagenesis in vitro, or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of other mammalian species, such as mice, have been grafted onto human framework sequences.

[0065] The antibodies used in the methods of the present disclosure may be recombinant human antibodies. As used herein, the term "recombinant human antibody" refers to any antibody prepared, expressed, produced, or isolated by recombinant means, such as an antibody expressed using a recombinant expression vector transfected into a host cell (described further below), an antibody isolated from a recombinant combinatorial human antibody library (described further below), an antibody isolated from an animal (e.g., a mouse) into which a human immunoglobulin gene has been introduced (see, e.g., Taylor et al., (1992) Nucl. Acids Res. 20:6287-6295), or an antibody prepared, expressed, produced, or isolated by any other means involving splicing of human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if transgenic animals with human Ig sequences are used, in vivo somatic mutagenesis), and thus the amino acid sequences of the V H and V L regions of the recombinant antibody are different from the V H and VL An array-derived and related array that may not naturally exist in the human antibody germline repertoire in vivo.

[0066] "Isolated antibody" refers to an antibody that has been identified and separated and / or recovered from at least one component of the natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody". Isolated antibodies also include in situ antibodies within recombinant cells. An isolated antibody is an antibody that has undergone at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular materials and / or chemical substances.

[0067] According to certain embodiments, the antibodies used in the methods of the present disclosure specifically bind to IL-4Rα. The term "specifically binds" as used herein means that an antibody or an antigen-binding fragment thereof forms a relatively stable complex with an antigen 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. In some embodiments, an antibody that "specifically binds" to IL-4Rα has an equilibrium dissociation constant (K D) are conjugated. In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) can also specifically bind to another antigen, e.g., an ortholog of the target antigen. For example, in some embodiments, an isolated antibody that specifically binds to human IL-4Rα exhibits cross-reactivity to other antigens such as IL-4Rα molecules from other (non-human) species.

[0068] In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof that comprises a complementarity-determining region (CDR) that comprises any of the amino acid sequences of the heavy chain variable region (HCVR), the light chain variable region (LCVR), and / or the anti-IL-4R antibody described in U.S. Patent No. 7,608,693, which is incorporated herein by reference. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof that comprises the heavy chain complementarity-determining regions (HCDRs) of the heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity-determining regions (LCDRs) of the light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof that comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0069] In some embodiments, the anti-IL-4R antibody or an antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 3, 4, 5, 6, 7, and 8, respectively, and an HCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 1, and an LCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody or an antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2.

[0070] In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0071] An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 is the fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present disclosure include the use of dupilumab. As used herein, "dupilumab" also includes biological equivalents of dupilumab. The term "biological equivalent" as used herein with respect to dupilumab refers to an anti-IL-4R antibody or IL-4R binding protein or fragment thereof that is a pharmaceutical equivalent or alternative that, when administered at the same molar dose under similar experimental conditions, either single or multiple dosing, does not show a significant difference in the rate and / or extent of absorption compared to that of dupilumab. In some embodiments, the term refers to an antigen-binding protein that binds to IL-4R and has no clinically meaningful difference from dupilumab in terms of safety, purity, and / or efficacy.

[0072] Other anti-IL-4Rα antibodies used in the context of the methods of the present disclosure include, for example, the antibody known as AMG317 in the art (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or MEDI9314, or any of the anti-IL-4Rα antibodies described in U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, U.S. Patent No. 8,877,189, U.S. Patent No. 10,774,141, or International Patent Publications WO2020 / 096381, WO2020 / 182197, WO2020 / 239134, WO2021 / 213329, WO2022 / 052974, WO2022 / 136669, or WO2022 / 136675, the contents of each of which are incorporated herein by reference.

[0073] In some embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof for use in the methods of the present disclosure comprises one or more of the CDR, HCVR, and / or LCVR sequences set forth in Table 7 below.

[0074] In some embodiments, the anti-IL-4Rα antibody has an HCVR comprising the amino acid sequence of SEQ ID NO: 32 (SCB-VH-59), SEQ ID NO: 33 (SCB-VH-60), SEQ ID NO: 34 (SCB-VH-61), SEQ ID NO: 35 (SCB-VH-62), SEQ ID NO: 36 (SCB-VH-63), SEQ ID NO: 37 (SCB-VH-64), SEQ ID NO: 38 (SCB-VH-65), SEQ ID NO: 39 (SCB-VH-66), SEQ ID NO: 40 (SCB-VH-67), SEQ ID NO: 41 (SCB-VH-68), SEQ ID NO: 42 (SCB-VH-69), SEQ ID NO: 43 (SCB-VH-70), SEQ ID NO: 44 (SCB-VH-71), SEQ ID NO: 45 (SCB-VH-72), SEQ ID NO: 46 (SCB-VH-73), SEQ ID NO: 47 (SCB-VH-74), SEQ ID NO: 48 (SCB-VH-75), SEQ ID NO: 49 (SCB-VH-76), SEQ ID NO: 50 (SCB-VH-77), SEQ ID NO: 51 (SCB-VH-78), SEQ ID NO: 52 (SCB-VH-79), SEQ ID NO: 53 (SCB-VH-80), SEQ ID NO: 54 (SCB-VH-81), SEQ ID NO: 55 (SCB-VH-82), SEQ ID NO: 56 (SCB-VH-83), SEQ ID NO: 57 (SCB-VH-84), SEQ ID NO: 58 (SCB-VH-85), SEQ ID NO: 59 (SCB-VH-86), SEQ ID NO: 60 (SCB-VH-87), SEQ ID NO: 61 (SCB-VH-88), SEQ ID NO: 62 (SCB-VH-89), SEQ ID NO: 63 (SCB-VH-90), SEQ ID NO: 64 (SCB-VH-91), SEQ ID NO: 65 (SCB-VH-92), or SEQ ID NO: 66 (SCB-VH-93);and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO: 12 (SCB-VL-39), SEQ ID NO: 13 (SCB-VL-40), SEQ ID NO: 14 (SCB-VL-41), SEQ ID NO: 15 (SCB-VL-42), SEQ ID NO: 16 (SCB-VL-43), SEQ ID NO: 17 (SCB-VL-44), SEQ ID NO: 18 (SCB-VL-45), SEQ ID NO: 19 (SCB-VL-46), SEQ ID NO: 20 (SCB-VL-47), SEQ ID NO: 21 (SCB-VL-48), SEQ ID NO: 22 (SCB-VL-49), SEQ ID NO: 23 (SCB-VL-50), SEQ ID NO: 24 (SCB-VL-51), SEQ ID NO: 25 (SCB-VL-52), SEQ ID NO: 26 (SCB-VL-53), SEQ ID NO: 27 (SCB-VL-54), SEQ ID NO: 28 (SCB-VL-55), SEQ ID NO: 29 (SCB-VL-56), SEQ ID NO: 30 (SCB-VL-57), or SEQ ID NO: 31 (SCB-VL-58). In some embodiments, the anti-IL-4Rα antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 64 (SCB-VH-91), and an LCVR comprising the amino acid sequence of SEQ ID NO: 17 (SCB-VL-44), SEQ ID NO: 27 (SCB-VL-54), or SEQ ID NO: 28 (SCB-VL-55).;

[0075] In some embodiments, the anti-IL-4Rα antibody comprises an amino acid sequence pair selected from the group consisting of: SEQ ID NO: 67 / 68 (MEDI-1-VH / MEDI-1-VL); SEQ ID NO: 69 / 70 (MEDI-2-VH / MEDI-2-VL); SEQ ID NO: 71 / 72 (MEDI-3-VH / MEDI-3-VL); SEQ ID NO: 73 / 74 (MEDI-4-VH / MEDI-4-VL); SEQ ID NO: 75 / 76 (MEDI-5-VH / MEDI-5-VL); SEQ ID NO: 77 / 78 (MEDI-6-VH / MEDI-6 / VL); SEQ ID NO: 79 / 80 (MEDI-7-VH / MEDI-7-VL); SEQ ID NO: 81 / 82 (MEDI-8-VH / MEDI-8-VL); SEQ ID NO: 83 / 84 (MEDI-9-VH / MEDI-9-VL); SEQ ID NO: 85 / 86 (MEDI-10-VH / MEDI-10-VL); SEQ ID NO: 87 / 88 (MEDI-11-VH / MEDI-11 / VL); SEQ ID NO: 89 / 90 (MEDI-12-VH / MEDI-12-VL); SEQ ID NO: 91 / 92 (MEDI-13-VH / MEDI-13-VL); SEQ ID NO: 93 / 94 (MEDI-14-VH / MEDI-14-VL); SEQ ID NO: 95 / 96 (MEDI-15-VH / MEDI-15-VL); SEQ ID NO: 97 / 98 (MEDI-16-VH / MEDI-16 / VL); SEQ ID NO: 99 / 100 (MEDI-17-VH / MEDI-17-VL); SEQ ID NO: 101 / 102 (MEDI-18-VH / MEDI-18-VL); SEQ ID NO: 103 / 104 (MEDI-19-VH / MEDI-19-VL); SEQ ID NO: 105 / 106 (MEDI-20-VH / MEDI-20-VL); SEQ ID NO: 107 / 108 (MEDI-21-VH / MEDI-21-VL); SEQ ID NO: 109 / 110 (MEDI-22-VH / MEDI-22-VL); SEQ ID NO: 111 / 112 (MEDI-23-VH / MEDI-23-VL); SEQ ID NO: 113 / 114 (MEDI-24-VH / MEDI-24-VL); SEQ ID NO: 115 / 116 (MEDI-25-VH / MEDI-25-VL); SEQ ID NO: 117 / 118 (MEDI-26-VH / MEDI-26-VL); SEQ ID NO: 119 / 120 (MEDI-27-VH / MEDI-27-VL); SEQ ID NO: 121 / 122 (MEDI-28-VH / MEDI-28-VL);Array numbers 123 / 124 (MEDI-29-VH / MEDI-29-VL); array numbers 125 / 126 (MEDI-30-VH / MEDI-30-VL); array numbers 127 / 128 (MEDI-31-VH / MEDI-31-VL); array numbers 129 / 130 (MEDI-32-VH / MEDI-32-VL); array numbers 131 / 132 (MEDI-33-VH / MEDI-33-VL); array numbers 133 / 134 (MEDI-34-VH / MEDI-34-VL); array numbers 135 / 136 (MEDI-35-VH / MEDI-35-VL); array numbers 137 / 138 (MEDI-36-VH / MEDI-36-VL); array numbers 139 / 140 (MEDI-37-VH / MEDI-37-VL); array numbers 141 / 142 (MEDI-38-VH / MEDI-38-VL); array numbers 143 / 144 (MEDI-39-VH / MEDI-39-VL); array numbers 145 / 146 (MEDI-40-VH / MEDI-40-VL); array numbers 147 / 148 (MEDI-41-VH / MEDI-41-VL); array numbers 149 / 150 (MEDI-42-VH / MEDI-42-VL); and array numbers 151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).;

[0076] In some embodiments, the anti-IL-4Rα antibody comprises: (i) an HCVR comprising the amino acid sequence of SEQ ID NO: 153 (AJOU-1-VH), SEQ ID NO: 154 (AJOU-2-VH), SEQ ID NO: 155 (AJOU-3-VH), SEQ ID NO: 156 (AJOU-4-VH), SEQ ID NO: 157 (AJOU-5-VH), SEQ ID NO: 158 (AJOU-6-VH), SEQ ID NO: 159 (AJOU-7-VH), SEQ ID NO: 160 (AJOU-8-VH), SEQ ID NO: 161 (AJOU-9-VH), SEQ ID NO: 162 (AJOU-10-VH), SEQ ID NO: 163 (AJOU-69-VH), SEQ ID NO: 164 (AJOU-70-VH), SEQ ID NO: 165 (AJOU-71-VH), SEQ ID NO: 166 (AJOU-72-VH), or SEQ ID NO: 167 (AJOU-83-VH); and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO: 168 (AJOU-33-VL), SEQ ID NO: 169 (AJOU-34-VL), SEQ ID NO: 170 (AJOU-35-VL), SEQ ID NO: 171 (AJOU-36-VL), SEQ ID NO: 172 (AJOU-37-VL), SEQ ID NO: 173 (AJOU-38-VL), SEQ ID NO: 174 (AJOU-39-VL), SEQ ID NO: 175 (AJOU-40-VL), SEQ ID NO: 176 (AJOU-41-VL), SEQ ID NO: 177 (AJOU-42-VL), SEQ ID NO: 178 (AJOU-77-VL), SEQ ID NO: 179 (AJOU-78-VL), SEQ ID NO: 180 (AJOU-79-VL), SEQ ID NO: 181 (AJOU-80-VL), SEQ ID NO: 182 (AJOU-86-VL), SEQ ID NO: 183 (AJOU-87-VL), SEQ ID NO: 184 (AJOU-88-VL), SEQ ID NO: 185 (AJOU-89-VL), SEQ ID NO: 186 (AJOU-90-VL), or SEQ ID NO: 187 (AJOU-91-VL).

[0077] In some embodiments, the anti-IL-4Rα antibody comprises: (i) an HCVR comprising the amino acid sequence of SEQ ID NO: 188 (REGN-VH-3), SEQ ID NO: 189 (REGN-VH-19), SEQ ID NO: 190 (REGN-VH-35), SEQ ID NO: 191 (REGN-VH-51), SEQ ID NO: 192 (REGN-VH-67), SEQ ID NO: 193 (REGN-VH-83), SEQ ID NO: 194 (REGN-VH-99), SEQ ID NO: 195 (REGN-VH-115), SEQ ID NO: 196 (REGN-VH-147), or SEQ ID NO: 197 (REGN-VH-163); and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO: 198 (REGN-VL-11), SEQ ID NO: 199 (REGN-VL-27), SEQ ID NO: 200 (REGN-VL-43), SEQ ID NO: 201 (REGN-VL-59), SEQ ID NO: 202 (REGN-VL-75), SEQ ID NO: 203 (REGN-VL-91), SEQ ID NO: 204 (REGN-VL-107), SEQ ID NO: 205 (REGN-VL-123), SEQ ID NO: 206 (REGN-VL-155), or SEQ ID NO: 207 (REGN-VL-171).

[0078] In some embodiments, the anti-IL-4Rα antibody has an HCVR comprising the amino acid sequence of (i) SEQ ID NO: 208 (STSA-C27-VH), SEQ ID NO: 209 (STSA-C27-6-33-VH), SEQ ID NO: 210 (STSA-C27-7-33-VH), SEQ ID NO: 211 (STSA-C27-24-56-VH), SEQ ID NO: 212 (STSA-C27-47-56-VH), SEQ ID NO: 213 (STSA-C27-33-33-VH), SEQ ID NO: 214 (STSA-C27-56-56-VH), SEQ ID NO: 215 (STSA-C27-78-78-VH), SEQ ID NO: 216 (STSA-C27-82-58-VH), SEQ ID NO: 217 (STSA-C27-54-54-VH), SEQ ID NO: 218 (STSA-C27-36-36-VH), SEQ ID NO: 219 (STSA-C27-53-53-VH), SEQ ID NO: 220 (STSA-C27-67-67-VH), SEQ ID NO: 221 (STSA-C27-55-55-VH), SEQ ID NO: 222 (STSA-C27-59-59-VH), SEQ ID NO: 223 (STSA-C27-58-58-VH), SEQ ID NO: 224 (STSA-C27-52-52-VH), or SEQ ID NO: 225 (STSA-C27-Y2-Y2-VH);and (ii) an LCVR comprising an amino acid sequence of SEQ ID NO: 226 (STSA-C27-VL), SEQ ID NO: 227 (STSA-C27-6-33-VL), SEQ ID NO: 228 (STSA-C27-7-33-VL), SEQ ID NO: 229 (STSA-C27-24-56-VL), SEQ ID NO: 230 (STSA-C27-47-56-VL), SEQ ID NO: 231 (STSA-C27-33-33-VL), SEQ ID NO: 232 (STSA-C27-56-56-VL), SEQ ID NO: 233 (STSA-C27-78-78-VL), SEQ ID NO: 234 (STSA-C27-82-58-VL), SEQ ID NO: 235 (STSA-C27-54-54-VL), SEQ ID NO: 236 (STSA-C27-36-36-VL), SEQ ID NO: 237 (STSA-C27-53-53-VL), SEQ ID NO: 238 (STSA-C27-67-67-VL), SEQ ID NO: 239 (STSA-C27-55-55-VL), SEQ ID NO: 240 (STSA-C27-59-59-VL), SEQ ID NO: 241 (STSA-C27-58-58-VL), SEQ ID NO: 242 (STSA-C27-52-52-VL), or SEQ ID NO: 243 (STSA-C27-Y2-Y2-VL).;

[0079] In some embodiments, the anti-IL-4Rα antibody is (i) SEQ ID NO: 244 (Y0188-1 VH), SEQ ID NO: 245 (Y0188-2 VH), SEQ ID NO: 246 (Y0188-3 VH), SEQ ID NO: 247 (Y0188-4 VH), SEQ ID NO: 248 (Y0188-6 VH), SEQ ID NO: 249 (Y0188-8 VH), SEQ ID NO: 250 (Y0188-9 VH), SEQ ID NO: 251 (Y0188-10 VH), SEQ ID NO: 252 (Y0188-14 VH), SEQ ID NO: 253 (HV3-15-14 VH), SEQ ID NO: 254 (HV3-48-14 VH), SEQ ID NO: 255 (HV3-73 *an HCVR comprising the amino acid sequence of SEQ ID NO: 255 (2-14 VH), SEQ ID NO: 256 (HV3-72-14 VH), SEQ ID NO: 257 (Y01-14 VH), SEQ ID NO: 258 (162-14 VH), or SEQ ID NO: 259 (VH73-14 VH); and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO: 260 (Y0188-1 VL), SEQ ID NO: 261 (Y0188-2 VL), SEQ ID NO: 262 (Y0188-3 VL), SEQ ID NO: 263 (Y0188-4 VL), SEQ ID NO: 264 (Y0188-6 VL), SEQ ID NO: 265 (Y0188-8 VL), SEQ ID NO: 266 (Y0188-9 VL), SEQ ID NO: 267 (Y0188-10 VL), SEQ ID NO: 268 (Y0188-14 VL), SEQ ID NO: 269 (Y01-14 VL), SEQ ID NO: 270 (164-14 VL), SEQ ID NO: 271 (KV4-14 VL), SEQ ID NO: 272 (KV1-27-14 VL), SEQ ID NO: 273 (KV1-9-14 VL), SEQ ID NO: 274 (KV1-NL1-14 VL), or SEQ ID NO: 275 (KV1D-43-14 VL).

[0080] In some embodiments, the anti-IL-4Rα antibody used in the methods of the disclosure can have pH-dependent binding properties. For example, an anti-IL-4Rα antibody for use as disclosed herein may exhibit a decrease in binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody for use as disclosed herein may exhibit an increase in binding to its antigen at acidic pH compared to neutral pH. The expression “acidic pH” includes pH values of less than about 6.2, such as, for example, less than about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0. As used herein, the expression “neutral pH” means a pH of from about 7.0 to about 7.4. The expression “neutral pH” includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0081] In certain examples, "decreased binding to IL-4Rα at acidic pH compared to neutral pH" is represented by the ratio of the K D value of an antibody that binds to IL-4Rα at acidic pH to the K D value of an antibody that binds to IL-4Rα at neutral pH (or the inverse thereof). For example, if an antibody or an antigen-binding fragment thereof exhibits an acidic / neutral K D ratio of about 3.0 or greater, for the purposes of the present disclosure, the antibody or antigen-binding fragment thereof is considered to "exhibit decreased binding to IL-4Rα at acidic pH compared to neutral pH". In certain exemplary embodiments, the acidic / neutral K D ratio of the antibodies or antigen-binding fragments of the present disclosure is about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or greater.

[0082] Antibodies having pH-dependent binding properties can be obtained, for example, by screening a population of antibodies that exhibit decreased (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. Additionally, antibodies having pH-dependent properties can be obtained by modifying the antigen-binding domain at the amino acid level. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues, an antibody with decreased antigen binding at acidic pH compared to neutral pH can be obtained.

[0083] Preparation of Human Antibodies Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used in the context of the present disclosure to produce human antibodies that specifically bind to human IL-4R.

[0084] Using the VELOCIMMUNE (trademark) technology (see, e.g., US 6,596,541, Regeneron Pharmaceuticals) or other known methods for making monoclonal antibodies, a high-affinity chimeric antibody against IL-4R is first isolated to have human variable regions and mouse constant regions. The VELOCIMMUNE (registered trademark) technology involves creating transgenic mice having a genome containing human heavy and light chain variable regions operably linked to the endogenous mouse constant region locus such that, in response to antigen stimulation, the mouse produces antibodies containing human variable regions and mouse constant regions. DNA encoding the variable regions of the heavy and light chains of the antibody is isolated and operably linked to DNA encoding the constant regions of the human heavy and light chains. This DNA is then expressed in cells capable of expressing a fully human antibody.

[0085] Generally, the antigen of interest is administered to VELOCIMMUNE (registered trademark) mice, and lymphoid cells (such as B cells) are recovered from the mice expressing the antibody. These lymphoid cells are fused with a myeloma cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific for the antigen of interest. DNA encoding the variable regions of the heavy and light chains may be isolated and linked to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can also be produced in cells such as CHO cells. Alternatively, antigen-specific chimeric antibodies or DNA encoding the variable regions of the light and heavy chains can be isolated directly from antigen-specific lymphocytes.

[0086] First, a high-affinity chimeric antibody having a human variable region and a mouse constant region is isolated. This antibody is characterized and selected by standard procedures known to those skilled in the art for desirable properties such as affinity, selectivity, epitope, etc. The mouse constant region is replaced with the desired human constant region to generate the fully human antibodies of the present disclosure, such as wild-type or modified IgG1 or IgG4. The constant region selected can vary depending on the particular use, but the features of high-affinity antigen binding and target specificity are attributed to the variable region.

[0087] Generally, the antibodies usable in the methods of the present disclosure have high affinity as measured by binding to an antigen immobilized in either the solid phase or the solution phase. The mouse constant region is replaced with the desired human constant region to generate the fully human antibodies of the present disclosure. The constant region selected can vary depending on the particular use, but the features of high-affinity antigen binding and target specificity are attributed to the variable region.

[0088] In one embodiment, a human antibody or an antigen-binding fragment thereof that specifically binds to IL-4R and can be used in the methods disclosed 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, and three light-chain CDRs (LCVR1, LCVR2, and 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 specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to specify 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 variability, the Chothia definition is based on the positions of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, for example, 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 for identifying CDR sequences in antibodies are also available.

[0089] Pharmaceutical Compositions and Kits In one aspect, the present disclosure provides a method comprising administering an IL-4R antagonist to a subject, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is included within a pharmaceutical composition comprising one or more pharmaceutically acceptable vehicles, carriers, and / or excipients. Various pharmaceutically acceptable carriers and excipients are well known in the art. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. In some embodiments, the carrier is suitable for intravenous administration, intramuscular administration, oral administration, intraperitoneal administration, intrathecal administration, transdermal administration, topical administration, or subcutaneous administration.

[0090] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by absorption through epithelial or mucocutaneous linings (such as, for example, oral mucosa, rectal mucosa, and intestinal mucosa) by any convenient route, for example, by injection or bolus injection, and can be administered together with other biologically active agents. In some embodiments, the pharmaceutical composition as disclosed herein is administered intravenously. In some embodiments, the pharmaceutical composition as disclosed herein is administered subcutaneously.

[0091] In some embodiments, the pharmaceutical composition includes injectable preparations such as dosage forms for intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, infusion, etc. These injectable preparations can be prepared by known methods. For example, an injectable preparation can be prepared by dissolving, suspending, or emulsifying the above-described antibody or a salt thereof in a sterile aqueous medium or an oily medium commonly used for injection. Examples of the injectable aqueous medium include physiological saline, isotonic solutions containing glucose and other adjuvants, etc., and it can also be used in combination with a suitable solubilizing agent such as alcohol (e.g., ethanol), polyhydric alcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. As the oily medium, for example, sesame oil, soybean oil, etc. are adopted, and it can also be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is filled into a suitable ampoule.

[0092] The dosage of the antibody administered to a subject according to the method of the present disclosure may vary depending on the age and build of the subject, symptoms, condition, route of administration, etc. The dosage is typically 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. An effective dosage and schedule for administering a pharmaceutical composition containing an anti-IL-4R antibody can be determined empirically; for example, the progression of the subject can be monitored by regular evaluations, and the dosage can be adjusted accordingly. Furthermore, interspecies scaling of the dosage can be carried out using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res., 8:1351). Specific exemplary dosages of anti-IL-4R antibodies that can be used in the context of the present disclosure, and dosing regimens containing the same, are disclosed elsewhere in this specification.

[0093] In some embodiments, the IL-4R antagonist or pharmaceutical composition of the present disclosure is contained in a container. Thus, in another aspect, a container containing the IL-4R antagonist or pharmaceutical composition disclosed herein is provided. For example, in some embodiments, the pharmaceutical composition is contained in a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an autoinjector.

[0094] In some embodiments, the pharmaceutical composition of the present disclosure is delivered, for example, subcutaneously or intravenously using a standard needle and syringe. In some embodiments, the syringe is contained in a pre-filled syringe. In some embodiments, a pen delivery device or autoinjector is used to deliver the pharmaceutical composition of the present disclosure (e.g., for subcutaneous delivery). The pen delivery device can be reusable or disposable. Typically, a reusable pen delivery device utilizes a replaceable cartridge containing the pharmaceutical composition. Once 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, the disposable pen delivery device is pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the pharmaceutical composition is emptied from the reservoir, the entire device is discarded.

[0095] Examples of suitable pens and delivery devices of autoinjectors include, but are not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOGMIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen delivery devices having use in subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to, SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.), and HUMIRA™ Pen (Abbott Labs, Abbott Park IL).

[0096] In some embodiments, the pharmaceutical composition is delivered using a controlled release system. In one embodiment, a pump is used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, a polymeric material is used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system is placed in the vicinity of the target of the composition and thus requires only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, Vol. 2, pp. 115-138). Other controlled release systems are described in the review by Langer, 1990, Science, 249:1527-1533. Other delivery systems are known and can be used to administer the pharmaceutical composition. For example, encapsulation into liposomes, microparticles, microcapsules, recombinant cells that can express mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem., 262:4429-4432).

[0097] In some embodiments, a pharmaceutical composition comprising an anti-IL-4R antibody is administered using a drug delivery device that is a needle-based injection system as described in Table 1 of Section 5.2 of ISO11608-1:2014(E). As described in ISO11608-1:2014(E), needle-based injection systems can be broadly classified into multiple-dose container systems and single-dose (with partial or complete discharge) container systems. The container may be an exchangeable container or an integral non-exchangeable container.

[0098] As further described in ISO11608-1:2014(E), a multiple-dose container system may include a needle-based injection device with an interchangeable container. In such a system, each container holds a multiple-dose volume, which may be of fixed or variable size (predetermined by the user). Another multiple-dose container system may include an injection needle-based injection device with a non-interchangeable integrated container. In such a system, each container holds a multiple-dose volume, which may be of fixed or variable size (predetermined by the user).

[0099] As further described in ISO11608-1:2014(E), a single-dose container system may include a needle-based injection device with an interchangeable container. In one example of such a system, each container holds a single-dose volume, whereby the entire deliverable volume is discharged (complete discharge). In a further example, each container holds a single-dose volume, whereby a portion of the deliverable volume is discharged (partial discharge). As also described in ISO11608-1:2014(E), a single-dose container system may include a needle-based injection device with a non-interchangeable integrated container. In one example of such a system, each container holds a single-dose volume, whereby the entire deliverable volume is discharged (complete discharge). In a further example, each container holds a single-dose volume, whereby a portion of the deliverable volume is discharged (partial discharge).

[0100] An exemplary sleeve-triggered automatic injection device with manual needle insertion is described in International Publication WO2015 / 004052. Exemplary audible administration end feedback mechanisms are described in International Publications WO2016 / 193346 and WO2016 / 193348. An exemplary needle safety mechanism after use of an automatic injection device is described in International Publication WO2016 / 193352. An exemplary needle sheath removal mechanism for a syringe automatic injection device is described in International Publication WO2016 / 193353. An exemplary support mechanism for supporting the axial position of a syringe is described in International Publication WO2016 / 193355.

[0101] In some embodiments, the pharmaceutical composition for use described herein is formulated into unit dosage forms suitable for accommodating the dosage of the active ingredient. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, and the like.

[0102] Exemplary pharmaceutical compositions containing anti-IL-4R antibodies that can be used in the context of the present disclosure are disclosed, for example, in U.S. Patent No. 8,945,559.

[0103] In another aspect, a kit comprising an IL-4R antagonist or a pharmaceutical composition disclosed herein is provided. In some embodiments, the kit comprises an anti-IL-4R antibody, or a pharmaceutical composition comprising an anti-IL-4R antibody, and instructions for their use in the treatment of eosinophilic esophagitis in pediatric subjects less than 12 years of age (e.g., subjects 1 year of age or older and less than 12 years of age), or pediatric or adolescent subjects with a body weight less than 40 kg at baseline. In some embodiments, the instructions for use include administering the anti-IL-4R antibody or pharmaceutical composition in an amount, dosing frequency, and / or dosing period as disclosed elsewhere herein.

[0104] Dosage and Administration In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered at a therapeutically effective amount to a subject (e.g., a subject from 1 year of age up to, but not including, 12 years of age) according to the methods of the present disclosure. As used herein with respect to an IL-4R antagonist, the phrase "therapeutically effective amount" means an amount of the IL-4R antagonist that results in one or more of the following: (a) a decrease in the severity or duration of symptoms of eosinophilic esophagitis; (b) a decrease in the number of eosinophils in the esophagus; (c) an improvement in one or more anatomical, endoscopic, or histological features of the esophagus; (d) an increase in the distensibility of the esophagus; (e) a decrease in the episodes or intensity of dysphagia; (f) normalization of one or more EoE-related biomarkers or gene expression signatures; and / or (g) a decrease in the use or need for concomitant or rescue treatment with other agents (e.g., a decrease or discontinuation in the use of systemic and / or topical corticosteroids, PPIs, etc.).

[0105] In the case of an anti-IL-4R antibody, a therapeutically effective amount is from about 0.05 mg to about 600 mg, from about 50 mg to about 600 mg, from about 50 mg to about 300 mg, or from about 100 mg to about 300 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 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, or about 600 mg of the anti-IL-4R antibody. In some embodiments, the therapeutically effective amount is from about 50 mg to about 600 mg, or from about 100 mg to about 600 mg, from about 50 mg to about 400 mg, or from about 100 mg to about 300 mg. In certain embodiments, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 300 mg of the anti-IL-4R antibody is administered to the subject.

[0106] The amount of the IL-4R antagonist (e.g., anti-IL-4R antibody) contained within an individual dosage is expressed in milligrams of antibody per kilogram of the subject's body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to the subject at a dosage of about 0.0001 to about 10 mg / kg of the subject's body weight, such as a dosage of about 1 mg / kg to about 10 mg / kg, a dosage of about 2 mg / kg to about 9 mg / kg, or a dosage of about 3 mg / kg to about 8 mg / kg. In some embodiments, the IL-4R antagonist can be administered to the subject at a dosage of about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg.

[0107] In some embodiments, the methods disclosed herein include administering the IL-4R antagonist to the subject at a frequency of about 4 times per week, 2 times per week, 1 time per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently, as long as a therapeutic response is achieved. In some embodiments, the methods disclosed herein include administering the IL-4R antagonist to the subject once per week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. In some embodiments, the IL-4R antagonist (e.g., the anti-IL-4R antibody disclosed herein) is administered once per week (QW), once every 2 weeks (Q2W), once every 3 weeks (Q3W), or once every 4 weeks (Q4W) in an amount of about 50 mg to about 600 mg, such as about 75 mg, about 100 mg, about 150 mg, about 200 mg, or about 300 mg.

[0108] In some embodiments, multiple doses of the IL-4R antagonist are administered to a subject over a defined period of time. In some embodiments, the methods of the disclosure include sequentially administering multiple doses of the IL-4R antagonist to a subject. As used herein, "sequentially administering" means that each dose of the IL-4R antagonist is administered to the subject on different days separated by different time points, e.g., at predetermined intervals (e.g., several hours, several days, several weeks, or several months). In some embodiments, the methods of the disclosure include sequentially administering to a patient a single initial dose of the IL-4R antagonist, then one or more secondary doses of the IL-4R antagonist, and optionally then one or more tertiary doses of the IL-4R antagonist.

[0109] The terms "first dose", "second dose", and "third dose" refer to the chronological order of administration of the IL-4R antagonist. Thus, the "first dose" is the dose administered first in the treatment regimen (also referred to as the "loading dose"), the "second dose" is the dose administered after the first dose; and the "third dose" is the dose administered after the second dose. The first dose, second dose, and third dose may all contain the same amount of the IL-4R antagonist, but generally may differ from each other in terms of dosing frequency. However, in certain embodiments, the amount of the IL-4R antagonist contained in the first dose, second dose, and / or third dose may differ from each other during the course of the treatment (e.g., adjusted up or down as appropriate). In some embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the start of the treatment regimen as a "loading dose", followed by subsequent doses (e.g., "maintenance doses") administered at a less frequent rate. In some embodiments, the first dose or loading dose, and one or more second doses or maintenance doses each contain the same amount of the IL-4R antagonist. In other embodiments, the first dose contains a first amount of the IL-4R antagonist and each of the one or more second doses contains a second amount of the IL-4R antagonist. For example, the first amount of the IL-4R antagonist can be 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times or more greater than the second amount of the IL-4R antagonist. In some embodiments, one or more maintenance doses of the IL-4R antagonist are administered without a loading dose.

[0110] In some embodiments, the loading dose is a "split dose" administered as two or more doses (e.g., 2, 3, 4, or 5 doses) administered on separate days. In some embodiments, the loading dose is administered as a split dose in which two or more doses are administered at intervals of at least about one week. In some embodiments, the loading dose is administered as a split dose in which two or more doses are administered at intervals of about one week, two weeks, three weeks, or four weeks. In some embodiments, the loading dose is evenly divided over two or more doses (e.g., half of the loading dose is administered as a first portion and half of the loading dose is administered as a second portion). In some embodiments, the loading dose is unevenly divided over two or more doses (e.g., more than half of the loading dose is administered as a first portion and less than half of the loading dose is administered as a second portion).

[0111] In some embodiments, each secondary dose and / or tertiary dose is administered 1 to 14 (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2, or more) weeks after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" means, in the context of multiple dosing sequences, the dose of the IL-4R antagonist that is administered to the patient without intervening doses and immediately prior to the next administration in the dosing sequence.

[0112] The methods of the present disclosure may include administering to a patient any number of secondary doses and / or tertiary doses of an IL-4R antagonist. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0113] In some embodiments that include a plurality of secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose can be administered to the patient 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose. Similarly, in some embodiments that include a plurality of tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose is administered to the patient 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary dose and / or the tertiary dose is administered to the patient can be changed during the course of the treatment regimen. The dosing frequency can also be adjusted by the physician during the course of treatment according to the needs of the individual patient after clinical examination.

[0114] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 100 mg administered every two weeks (Q2W) when the subject weighs more than 5 kg and less than 15 kg. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a loading dose of 200 mg, is administered.

[0115] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 200 mg administered every three weeks (Q3W) when the subject weighs more than 5 kg and less than 15 kg. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a loading dose of 400 mg, is administered.

[0116] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 200 mg administered every four weeks (Q4W) when the subject weighs more than 5 kg and less than 15 kg. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a loading dose of 400 mg, is administered.

[0117] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 200 mg administered every two weeks (Q2W) if the subject weighs 15 kg or more but less than 30 kg. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a 400 mg loading dose, is administered.

[0118] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 300 mg administered every four weeks (Q4W) if the subject weighs 15 kg or more but less than 30 kg. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a 400 mg loading dose, is administered.

[0119] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 300 mg administered every two weeks (Q2W) if the subject weighs 30 kg or more but less than 40 kg. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a 600 mg loading dose, is administered.

[0120] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 200 mg administered every two weeks (Q2W) if the subject weighs 30 kg or more but less than 40 kg. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a 400 mg loading dose, is administered.

[0121] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 300 mg administered once a week (QW) if the subject weighs 40 kg or more. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a 600 mg loading dose, is administered.

[0122] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 300 mg administered every two weeks (Q2W) when the subject weighs 40 kg or more. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a 600 mg loading dose, is administered.

[0123] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 300 mg administered every two weeks (Q2W) when the subject weighs more than 30 kg and less than 60 kg. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a 600 mg loading dose, is administered.

[0124] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 200 mg administered every two weeks (Q2W) when the subject weighs more than 30 kg and less than 60 kg. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a 400 mg loading dose, is administered.

[0125] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 300 mg administered once a week (QW) when the subject weighs 60 kg or more. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a 600 mg loading dose, is administered.

[0126] In some embodiments, for a subject having eosinophilic esophagitis, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) includes 300 mg administered every two weeks (Q2W) when the subject weighs 60 kg or more. In some embodiments, a loading dose is not administered. In some embodiments, a loading dose, e.g., a loading dose of 600 mg, is administered.

[0127] Therapeutic dosage form In another aspect, the present disclosure provides a therapeutic dosage form of an IL-4R antagonist (e.g., an anti-IL-4R antibody or an antigen-binding fragment thereof) for use in treating a subject having eosinophilic esophagitis as disclosed herein.

[0128] In some embodiments, when the subject weighs 5 kg or more and less than 15 kg, the therapeutic dose is 100 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody) and is administered every two weeks (Q2W).

[0129] In some embodiments, when the subject weighs 5 kg or more and less than 15 kg, the therapeutic dose is 200 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody) and is administered every three weeks (Q3W).

[0130] In some embodiments, when the subject weighs 5 kg or more and less than 15 kg, the therapeutic dose is 200 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody) and is administered every four weeks (Q4W).

[0131] In some embodiments, when the subject weighs 15 kg or more and less than 30 kg, the therapeutic dose is 200 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody) and is administered every two weeks (Q2W).

[0132] In some embodiments, when the subject weighs 15 kg or more and less than 30 kg, the therapeutic dose is 300 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody) and is administered every four weeks (Q4W).

[0133] In some embodiments, when the subject's weight is 30 kg or more and less than 40 kg, the therapeutic dose is 300 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody), and the administration is once every two weeks (Q2W).

[0134] In some embodiments, when the subject's weight is 30 kg or more and less than 40 kg, the therapeutic dose is 200 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody), and the administration is once every two weeks (Q2W).

[0135] In some embodiments, when the subject's weight is 40 kg or more, the therapeutic dose is 300 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody), and the administration is once a week (QW).

[0136] In some embodiments, when the subject's weight is 40 kg or more, the therapeutic dose is 300 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody), and the administration is once every two weeks (Q2W).

[0137] In some embodiments, when the subject's weight is 30 kg or more and less than 60 kg, the therapeutic dose is 300 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody), and the administration is once every two weeks (Q2W).

[0138] In some embodiments, when the subject's weight is 30 kg or more and less than 60 kg, the therapeutic dose is 200 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody), and the administration is once every two weeks (Q2W).

[0139] In some embodiments, when the subject's weight is 60 kg or more, the therapeutic dose is 300 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody), and the administration is once a week (QW).

[0140] In some embodiments, when the subject's weight is 60 kg or more, the therapeutic dose is 300 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody), and the administration is once every two weeks (Q2W).

[0141] EoE-related parameters In some embodiments, the treatment methods disclosed herein result in the improvement of one or more endpoints or EoE-related parameters used to assess the presence or severity of EoE in a subject. Examples of EoE-related parameters include, but are not limited to: (a) changes (e.g., decreases) in the number of eosinophils in the esophageal epithelium; (b) changes in the severity and / or extent of histological features of the esophagus, measured, for example, using the histological scoring system for eosinophilic esophagitis (EoE-HSS); (c) changes in one or more esophageal features, e.g., the absence, presence, or severity of edema, rings, exudate, furrows, and / or strictures, measured using EoE-EREFS; (d) levels of one or more biomarkers associated with EoE, or changes (e.g., normalization) in the gene expression signature of EoE; (e) changes (e.g., decreases) in the frequency and / or intensity of dysphagia, measured, for example, using the Dysphagia Symptom Questionnaire (DSQ), the Straumann Dysphagia Instrument (SDI), the Patient Global Impression of Change (PGIC) for dysphagia, or the Patient Global Impression of Severity (PGIS); or (f) changes in the frequency and / or severity of other symptoms of EoE, such as the Pediatric EoE Signs / Symptoms Questionnaire (PESQ) patient version (PESQ-P) or caregiver version (PESQ-C), the Pediatric EoE Impact Scale (PEIS) patient version (PEIS-P) or caregiver version (PEIS-C), the Global Impression of Change (GIC) patient version (GIC-P) or caregiver version (GIC-C), or clinician version (GIC-Clin), the Global Impression of Severity (GIS) patient version (GIS-P), caregiver version (GIS-C), or clinician version (GIS-Clin), or the Pediatric Esophagitis Symptom Score (PEESS). Methods for assessing these and other EoE-related parameters are described in the items of the following examples and are also disclosed in WO2019 / 028367 and WO2021 / 237110, which are incorporated herein by reference.

[0142] To determine whether the EoE-related parameters have "improved", the parameters are quantified at baseline (e.g., before the start of treatment with an IL-4R antagonist) and at one or more time points after administration of the IL-4R antagonist. For example, the EoE-related parameters may be measured on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85; or, after the first treatment with the pharmaceutical composition of the present disclosure, at the end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or more. The difference between the value of the parameter at a specific time point after the start of treatment and the value of the parameter at baseline is used to confirm whether there has been an improvement in the EoE-related parameters.

[0143] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement (e.g., a decrease) in the peak esophageal intraepithelial eosinophil count. The "peak esophageal intraepithelial eosinophil count" refers to the number of eosinophils contained within one high power field (hpf). In some embodiments, treatment with an IL-4R antagonist results in a decrease in the peak esophageal intraepithelial eosinophil count relative to a baseline (e.g., the peak count of the subject prior to initiation of treatment). In some embodiments, treatment with an IL-4R antagonist results in a peak esophageal intraepithelial eosinophil count that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to the baseline. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the peak esophageal intraepithelial eosinophil count to less than 10 eos / hpf or less than 6 eos / hpf. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the peak esophageal intraepithelial eosinophil count to 6 eos / hpf or less, 5 eos / hpf or less, 4 eos / hpf or less, 3 eos / hpf or less, 2 eos / hpf or less, or 1 eos / hpf or less. In some embodiments, treatment with an IL-4R antagonist results in remission of the histological disease, as measured by a peak esophageal intraepithelial eosinophil count of 6 eos / hpf or less. In some embodiments, the change in the peak esophageal intraepithelial eosinophil count is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later after administration of the IL-4R antagonist, or 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, or 24 weeks after treatment with the IL-4R antagonist.

[0144] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of one or more histological features of EoE. In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of the EoE-HSS score. EoE-HSS is a validated instrument that generates separate severity (grade) and extent (stage) disease scores. This score is used to measure eight histological features (parameters) of EoE from three different regions of the esophagus (proximal, mid, distal) (Collins et al., Dis Esophagus, 2017, 30:1-8). The eight parameters include: eosinophil density, basal zone hyperplasia, eosinophil abscess, eosinophil surface layering, dilation of the intercellular space, changes in the surface epithelium, abnormal keratinocytes, and lamina propria fibrosis. For each parameter, a scale of 0-3 is used for both grade and stage (0 being least inflamed and normal). In some embodiments, treatment with an IL-4R antagonist results in at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more decrease in the EoE-HSS score relative to baseline (e.g., the subject's EoE-HSS score prior to initiation of treatment). In some embodiments, treatment with an IL-4R antagonist results in a decrease in the EoE-HSS composite score, grade score, and / or stage score. In some embodiments, the change in the EoE-HSS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later after administration of the IL-4R antagonist, or 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks after treatment with the IL-4R antagonist.

[0145] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of one or more endoscopic features of EoE. In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of the EoE-EREFS score. EoE-EREFS (Edema, Rings, Exudates, Furrows, Strictures) is a valid scoring system for the inflammatory and remodeling features of the disease, used to measure the inflammatory and remodeling features of endoscopically identified EoE esophageal mucosa (Hirano et al., Gut, 2013, 62:489-495). This instrument includes a total of 17 items regarding the presence and severity of esophageal features. Specific esophageal features are: Rings (concentric rings around the esophagus - none, mild, moderate, severe, not applicable); Strictures (narrowing of the esophagus - present, absent, not applicable); diameter of the stricture (if applicable); Exudates (referred to as white plaques - none, mild, severe); Furrows (vertical lines in the esophagus - absent, present); Edema (loss of mucosal vascular pattern - absent, present); Crepe paper esophagus (absent, present); overall appearance incorporating all endoscopically identified EoE findings (i.e., fixed rings, strictures, white exudates, furrows, edema, crepe paper mucosa, etc.). In addition, mucosal changes associated with gastroesophageal reflux disease are recorded using the Los Angeles classification system for erosions (no erosions or Los Angeles classification A, B, C, D). In some embodiments, treatment with an IL-4R antagonist results in a decrease in the EoE-EREFS score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline (e.g., the subject's EoE-EREFS score prior to treatment initiation). In some embodiments, the change in the EoE-EREFS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later after administration of the IL-4R antagonist, or 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks after treatment with the IL-4R antagonist.In some embodiments, treatment with an IL-4R antagonist results in improvement of one or more of the EoE-EREFS subscores.

[0146] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of symptoms of dysphagia. In some embodiments, the treatment results in a change (e.g., a decrease) in the frequency and / or intensity of dysphagia in the subject, as measured, for example, using a Dysphagia Symptom Questionnaire (DSQ), the Straumann Dysphagia Instrument (SDI), the Patient Global Impression of Change in Dysphagia (PGIC), or the Patient Global Impression of Severity (PGIS). In some embodiments, the treatment results in a decrease in the frequency of dysphagia episodes per week, e.g., at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more decrease relative to baseline (e.g., the average frequency of dysphagia episodes per week in the subject prior to treatment initiation). In some embodiments, the treatment results in improvement of the DSQ score or SDI. The DSQ is a validated PRO that has been used in clinical studies to measure the frequency and intensity of dysphagia. See Hudgens et al., J Patient Rep Outcomes, 2017, 1(1):3, doi:10.1186 / s41687-017-0006-5. The SDI is an unvalidated patient-reported outcome (PRO) that has been used in clinical studies to determine the frequency and intensity of dysphagia (Straumann, Gastroenterology, 2010, 139:1526-1537). In some embodiments, treatment with an IL-4R antagonist results in a decrease in the DSQ score of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 points or more relative to baseline. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the DSQ score or SDI score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline.In some embodiments, the change in score is measured on the 8th, 15th, 22nd, 25th, 29th, 36th, 43rd, 50th, 57th, 64th, 71st, 85th, 113th day or later after administration of the IL-4R antagonist, or 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, or 24 weeks after treatment with the IL-4R antagonist. In some embodiments, treatment with the IL-4R antagonist reduces the symptoms of dysphagia in the subject (e.g., measured by the absolute change in the DSQ score or the rate of decrease in the DSQ score or SDI score relative to the baseline value of the subject) within about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks after starting treatment with the IL-4R antagonist.

[0147] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in normalization of the normalized enrichment score (NES) calculated for one or more EoE-related biomarkers, an EoE gene signature, a type 2 inflammatory gene signature, and / or a set of EoE-related genes. In some embodiments, treatment of a subject with an IL-4R antagonist suppresses the NES calculated for an EoE gene signature, a type 2 inflammatory gene signature, and / or a set of EoE-related or type 2 inflammatory genes. As used herein, the term "EoE-related biomarker" refers to a biological response, cell type, parameter, protein, polypeptide, enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or other biomolecule that is present or detectable in EoE patients at a level or amount that is different (e.g., greater or less) than the level or amount of the marker that is present or detectable in non-EoE patients. In some embodiments, the EoE-related biomarker is a gene associated with fibrosis, tissue remodeling, or epithelial barrier function. Exemplary EoE-related biomarkers include, for example, esophageal eosinophils, eotaxin-3 (CCL26), periostin (POSTN), serum IgE (total and allergen-specific), serum IgG (total and allergen-specific), arachidonic acid 15-lipoxygenase (ALOX15), IL-13, IL-5, serum thymus and activation-regulated chemokine (TARC; CCL17), thymic stromal lymphopoietin (TSLP), serum eosinophil cationic protein (ECP), collagen genes (e.g., COL4A3, COL4A4, COL4A6, COL8A2, COL14A1, and COL21A1), calpain 14, desmoglein-1 (DSG1), filaggrin (FLG), signal transducer and activator of transcription 6 (STAT6), serine peptidase inhibitor Kazal type 5 (SPINK5), SPINK7, SPINK8, interleukin 4 receptor (IL-4R), eosinophil-related genes (e.g., CLC and SIGLEC8), anoctamin-1 (ANO1), cathepsin C (CTSC), C-C chemokine receptor type 3 (CCR3), and eosinophil-derived neurotoxin (EDN), but are not limited thereto.The "EoE gene signature" refers to the difference in gene expression profiles in esophageal biopsies of EoE patients compared to healthy controls, and is also referred to as the "EoE disease transcriptome" (Sherrill et al., Genes Immun, 2014, 15:361 - 369). In some embodiments, the EoE gene signature is a smaller gene set of a published EoE disease transcriptome, such as the EoE Diagnostic Panel (EDP, clinically available as EoGenius™, Inform Diagnostics, USA). The "type 2 inflammation gene signature" refers to the transcriptome of a gene set associated with type 2 inflammation. Exemplary type 2 inflammation-related genes include, but are not limited to, CCL26, ALOX15, CCR3, and IL1RL1. An exemplary gene list of the type 2 inflammation gene signature is shown in WO2021 / 237110. The normalized enrichment score (NES) reflects the extent to which the activity level of a set of transcripts occupies a large proportion at the extremes (upper or lower end) of the ranked list of all transcripts in a sample, and is normalized taking into account the number of transcripts in the set (Subramanian et al., Proc Natl Acad Sci USA, 2005, 102:15545 - 50) (Barbie et al., Nature, 2009, 462:108 - 112).

[0148] In some embodiments, an EoE-related biomarker, an EoE gene signature, a type 2 inflammation gene signature, and / or a NES is determined using a tissue sample from a subject (e.g., an esophageal pinch biopsy sample from a proximal, middle, and / or distal region). In some embodiments, treatment of a subject with an IL-4R antagonist results in normalization of one or more EoE-related biomarkers, an EoE gene signature, a type 2 inflammation gene signature, and / or a NES relative to a baseline (e.g., the expression level of the EoE-related biomarker, EoE gene signature, or NES in the subject prior to initiation of treatment), e.g., measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later after administration of the IL-4R antagonist, or 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks after treatment with the IL-4R antagonist. In some embodiments, treatment of a subject with an IL-4R antagonist results in suppression of the NES of one or more EoE-related biomarkers, an EoE gene signature, or a type 2 inflammation gene signature relative to a baseline (e.g., the NES of the subject prior to initiation of treatment), e.g., measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later after administration of the IL-4R inhibitor, or 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks after treatment with the IL-4R antagonist.

[0149] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of one or more other signs or symptoms of EoE, or health-related QOL.

[0150] In some embodiments, treatment results in an improvement in the PESQ score. The PESQ has a patient version (PESQ-P) intended for use in EoE patients aged 8 - 12 years and a caregiver version (PESQ-C) intended for use by caregivers of EoE patients aged 1 - 11 years. Both questionnaires measure the same concept; PESQ-P assesses symptom frequency, duration, and / or severity, and PESQ-C assesses the presence / absence of signs / symptoms. These symptoms include stomach pain, heartburn, acid regurgitation, reflux, vomiting, feeding refusal, swallowing trouble, food getting stuck in the throat, etc. See Kamat et al., J Allergy Clin Immunol: In Practice, 2022, ISSN: 2213 - 2198. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the PESQ score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline. In some embodiments, the change in the PESQ score is measured on the 8th, 15th, 22nd, 25th, 29th, 36th, 43rd, 50th, 57th, 64th, 71st, 85th, 113th day or later after administration of the IL-4R antagonist, or 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, or 24 weeks after treatment with the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the number of days with one or more EoE signs as measured by PESQ-P or PESQ-C, or the number of whole intervals (e.g., night, morning, afternoon, evening) in a day. In some embodiments, treatment with an IL-4R antagonist results in an improvement in one or more signs / symptoms as measured by PESQ.

[0151] In some embodiments, treatment results in an improvement in the PEIS score. The PEIS has a patient version (PEIS-P) intended for use by pediatric EoE patients aged 8 - 12 years to fill out alone, and a caregiver version (PEIS-C) intended for use by caregivers of EoE patients aged 1 - 11 years. The PEIS-P assesses the impact of EoE on the patient's health-related over the past week, and the PEIS-C assesses the impact of the pediatric patient's EoE on the caregiver's anxiety, social and occupational activities, activities of daily living, and relationships over the past week. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the PEIS score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline. In some embodiments, the change in the EoE-PEIS score is measured on the 8th, 15th, 22nd, 25th, 29th, 36th, 43rd, 50th, 57th, 64th, 71st, 85th, 113th day or later after administration of the IL-4R antagonist, or 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, or 24 weeks after treatment with the IL-4R antagonist.

[0152] In some embodiments, the treatment results in an improvement in the GIC score. The GIC is a single-item outcome measure that has a patient version (GIC-P) intended to be completed alone by pediatric EoE patients aged 8 - 12 years, a caregiver version (GIC-C) intended to be completed alone by caregivers of EoE patients aged 1 - 11 years, and a clinician version (GIC-Clin) intended to be completed alone by physicians of EoE patients aged 1 - 11 years. All measure the same concept: GIC-P assesses the patient's impression of the overall change (improvement or worsening) in their EoE condition since the start of the test treatment, while GIC-C and GIC-Clin assess the caregiver's or physician's impression of the overall change (improvement or worsening) in the pediatric patient's EoE condition since the start of the test treatment, respectively. In some embodiments, treatment with an IL-4R antagonist results in an improvement (e.g., a decrease) in the GIC score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline. In some embodiments, the change in the GIC score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later after administration of the IL-4R antagonist, or 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, or 24 weeks after treatment with the IL-4R antagonist.

[0153] In some embodiments, treatment results in an improvement in the GIS score. The GIS is a single-item outcome measure that has a patient version (GIS-P) intended to be completed alone by pediatric EoE patients aged 8 - 12 years, a caregiver version (GIS-C) intended to be completed alone by caregivers of EoE patients aged 1 - 11 years, and a clinician version (GIS-Clin) intended to be completed alone by physicians of EoE patients aged 1 - 11 years. All measure the same concept: GIS-P assesses the patient's impression of the overall severity of his / her EoE condition over the past week, while GIS-C and GIS-Clin assess the caregiver's or physician's impression of the overall severity of the pediatric patient's EoE condition over the past week, respectively. In some embodiments, treatment with an IL-4R antagonist results in an improvement (e.g., a decrease) in the GIS score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline. In some embodiments, the change in the GIS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later after administration of the IL-4R antagonist, or 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 or 24 weeks after treatment with the IL-4R antagonist.

[0154] In some embodiments, treatment results in an improvement in the PEESS score. PEESS v2.0 is a caregiver-reported outcome measure that assesses the frequency and severity of EoE symptoms in pediatric patients (Franciosi, 2011). The caregiver version of PEESS v2.0 consists of 20 items and has a 1-month recall period. The total score of PEESS v2.0 ranges from 0 to 100; a higher score indicates a greater symptom burden in pediatric EoE patients. In some embodiments, treatment with an IL-4R antagonist results in a reduction in the PEESS score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline. In some embodiments, treatment with an IL-4R antagonist results in a reduction in the PEESS score of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 points or more relative to baseline. In some embodiments, the change in the PEESS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later after administration of the IL-4R antagonist, or 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 or 24 weeks after treatment with the IL-4R antagonist.

[0155] In some embodiments, treatment with an IL-4R antagonist results in improved weight gain compared to a control (e.g., a placebo-treated patient) and compared to the patient's baseline weight. In some embodiments, treatment with an IL-4R antagonist results in a weight gain of at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3% or more relative to baseline. In some embodiments, the change in weight is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later after administration of the IL-4R antagonist, or 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 or 24 weeks after treatment with the IL-4R antagonist.

[0156] Combination therapy In some embodiments, the methods of the present disclosure comprise administering an IL-4R antagonist (e.g., an anti-IL-4R antibody) described herein to a subject (e.g., a subject 1 year of age or older and less than 12 years of age) in combination with one or more additional therapeutic agents. As used herein, the expression "combining" means that the additional therapeutic agent is administered before, after, or simultaneously with the pharmaceutical composition comprising the IL-4R antagonist. Also, the term "combining" includes sequential or co-administration of the IL-4R antagonist with a second therapeutic agent or therapy.

[0157] For example, when administered "before" the pharmaceutical composition comprising the IL-4R antagonist, the additional therapeutic agent may be administered about 72 hours before, about 60 hours before, about 48 hours before, about 36 hours before, about 24 hours before, about 12 hours before, about 10 hours before, about 8 hours before, about 6 hours before, about 4 hours before, about 2 hours before, about 1 hour before, about 30 minutes before, about 15 minutes before, or about 10 minutes before administration of the pharmaceutical composition comprising the IL-4R antagonist. For example, when administered "after" the pharmaceutical composition comprising the IL-4R antagonist, the additional therapeutic agent may be administered about 10 minutes after, about 15 minutes after, about 30 minutes after, about 1 hour after, about 2 hours after, about 4 hours after, about 6 hours after, about 8 hours after, about 10 hours after, about 12 hours after, about 24 hours after, about 36 hours after, about 48 hours after, about 60 hours after, or about 72 hours after administration of the pharmaceutical composition comprising the IL-4R antagonist. "Simultaneous" or co-administration with the pharmaceutical composition comprising the IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within about 10 minutes (before, after, or simultaneously) from the administration of the pharmaceutical composition comprising the IL-4R antagonist, or that both the additional therapeutic agent and the IL-4R antagonist are administered to the subject as a single combined dosage form.

[0158] In some embodiments, the second therapeutic agent or treatment is an IL-1β inhibitor, an IL-5 or IL-5R inhibitor (e.g., an anti-IL-5 or anti-IL-5R antibody such as benralizumab, mepolizumab, or reslizumab), an IL-9 inhibitor, an IL-13 inhibitor (e.g., an anti-IL-13 antibody such as tralokinumab, RPC4046, or QAX576), an IL-17 inhibitor, an IL-25 inhibitor, a TNFα inhibitor (e.g., an anti-TNFα antibody such as infliximab or adalimumab), an eotaxin-3 inhibitor, an IgE inhibitor (e.g., an anti-IgE antibody such as omalizumab), a TSLP inhibitor (e.g., an anti-TSLP antibody such as tezepelumab), a CRTH2 inhibitor, a Siglec-8 inhibitor, a prostaglandin D2 inhibitor, an integrin inhibitor (e.g., an integrin α4β7 inhibitor such as vedolizumab), an eotaxin inhibitor, an immunosuppressant, a topical corticosteroid, an oral corticosteroid, a systemic corticosteroid, an inhaled corticosteroid, a glucocorticoid, a PPI, a hemostatic agent, an antihistamine, a non-steroidal anti-inflammatory drug (NSAID), esophageal dilation, a feeding tube, allergen removal, or diet management. In some embodiments, the IL-4R antagonist is used in combination with diet management, allergen removal, or a feeding tube. In some embodiments, the IL-4R antagonist is used in combination with a corticosteroid (e.g., a swallowed topical corticosteroid). In some embodiments, the IL-4R antagonist is used in combination with a PPI, e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole.

[0159] In some embodiments, administration of an IL-4R antagonist reduces dependence on concomitant therapies (e.g., PPIs, corticosteroids, glucocorticoids, or feeding tubes) or reduces the need to use concomitant therapies. In some embodiments, administration of an IL-4R antagonist in combination with a second therapy (e.g., PPI, corticosteroid, glucocorticoid, or feeding tube) reduces the amount of the second therapy used by the patient by at least 20%, at least 30%, at least 40%, or at least 50% compared to the amount used by the subject prior to treatment with the IL-4R antagonist. In some embodiments, administration of the IL-4R antagonist eliminates the need for the second therapy.

Example

[0160] The following examples are set forth to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions of the disclosure, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure the accuracy of the numerical values (e.g., amounts, temperatures, etc.) used, but some experimental errors and deviations 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.

Example

[0161] Clinical trial to examine the efficacy and safety of dupilumab in pediatric patients with eosinophilic esophagitis Study design and objectives This is a Phase 3, multicenter, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy, safety, tolerability, pharmacokinetics, and immunogenicity of dupilumab in pediatric patients (aged 1 year and older but less than 12 years) with active eosinophilic esophagitis (EoE). The trial consists of a screening period of up to 85 days, a 16-week double-blind treatment period (Part A), a 36-week open-label extension treatment period (Part B), a 108-week open-label extension period (Part C), and a 12-week follow-up period. Dupilumab is a fully human anti-IL-4R antibody that includes a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair containing SEQ ID NO: 1 / 2; and heavy and light chain CDR sequences containing SEQ ID NOs: 3-8.

[0162] The primary objective of this trial is to demonstrate the efficacy of dupilumab treatment compared to placebo in pediatric patients with active EoE based on histological improvement meeting validated histological criteria. The secondary objectives are: to demonstrate the efficacy of dupilumab compared to placebo in pediatric patients with active EoE by visual measurement of endoscopic disease activity using the Eosinophilic Esophagitis Endoscopic Reference Score (EoE-EREFS) and measurement of histological abnormalities using the Eosinophilic Esophagitis Histological Scoring System (EoE-HSS) after 16 weeks of treatment; to evaluate the safety, tolerability, and immunogenicity of dupilumab treatment up to 16 weeks in pediatric patients with active EoE; to evaluate the effect of dupilumab on the transcriptome signature associated with EoE and type 2 inflammation; to test the effect of dupilumab on the type 2 inflammation gene expression signature; to evaluate the concentration-time profile of functional dupilumab in serum in this population; to evaluate the efficacy of long-term (up to 160 weeks) dupilumab treatment; to evaluate the effect of dupilumab treatment on changes in weight and growth during the extension and open-label extension periods of this trial; to evaluate the safety, tolerability, and immunogenicity of long-term (up to 160 weeks) dupilumab treatment; and to evaluate the effect of dupilumab treatment on the signs and symptoms of EoE.

[0163] This study was conducted in accordance with the Helsinki Declaration, the International Conference on Harmonization Guidelines for Good Clinical Practice, and the provisions of the applicable regulatory requirements. The protocol was reviewed and approved by the institutional review board / ethics committee at all sites. Written informed consent was obtained from the parent or legal guardian for all patients.

[0164] Number of patients This trial included pediatric patients (aged 1 year or older and less than 12 years at screening visit) with active EoE.

[0165] To be eligible for inclusion in the reference trial, patients had to meet the following criteria: (1) male or female, 1 year of age or older and less than 12 years of age; (2) a diagnosis of EoE diagnosed by endoscopic biopsy prior to screening. Proven by intraepithelial eosinophil infiltration (peak eosinophil count of 15 eos / hpf or more) (400x magnification) in at least one esophageal region, performed after at least 8 weeks of treatment with a PPI regimen. If the patient discontinued PPI therapy, a biopsy had to be performed within 2 weeks of the discontinuation date. If past (documented) endoscopic biopsies meeting these criteria were not available (or if past biopsies were not available), patients meeting other clinical and laboratory eligibility criteria were treated with a PPI regimen for at least 8 weeks during the screening period prior to baseline endoscopy / biopsy. (3) Baseline endoscopic biopsy when intraepithelial eosinophil infiltration (peak eosinophil count of 15 eos / hpf or more) was confirmed by central reading in at least 2 of the 3 esophageal regions biopsied (proximal, mid, distal); (4) History of symptoms (reported by the patient or caregiver) determined by the treating physician to be the result of EoE (e.g., abdominal pain, chest pain, heartburn, food regurgitation, dysphagia, vomiting, or feeding refusal) during the month prior to screening; (5) Patients 8 years of age or older and less than 12 years of age, and caregivers or legal guardians of all patients had to understand and complete the trial requirements and trial-related questionnaires. At least 8 of 14 days of the PESQ-C eDiary had to be completed prior to baseline / visit 3. (6) Parent or legal guardian had to provide signed informed consent. If applicable, consent had to be obtained from the patient in accordance with regional regulatory (jurisdiction / ethics) guidelines based on the patient's age and maturity.

[0166] Exclusion Criteria: The following were the exclusion criteria for Part A of this trial: (1) Body weight at screening was less than 5 kg or 60 kg or more; (2) had participated in a dupilumab clinical trial or had received treatment with dupilumab in the past or currently; (3) had initiated or changed a food elimination diet regimen within 6 weeks before screening, or had reintroduced a previously eliminated food group; patients on a food elimination diet must continue the same diet during the trial period; (4) other causes of esophageal eosinophilia or the following conditions: eosinophilic gastroenteritis, eosinophilic syndrome, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome); (5) active Helicobacter pylori infection; (6) helminth infection; (7) a history of Crohn's disease, ulcerative colitis, celiac disease, or esophageal surgery; (8) there was an esophageal stricture that could not be passed with a standard diagnostic upper endoscope or a severe esophageal stricture requiring dilation at screening; (9) treatment with topical corticosteroids for swallowing within 8 weeks before the baseline standard treatment endoscopy; (10) pretreatment with subcutaneous immunotherapy (SCIT) if not treated with a stable maintenance dose for at least 1 year; (11) pretreatment with sublingual immunotherapy (SLIT), transcutaneous immunotherapy (EPIT), or oral immunotherapy (OIT); (12) initiation, discontinuation, or change in the administration method of the following drugs within 8 weeks before the baseline endoscopy: PPI, leukotriene inhibitor, nasal and / or inhaled corticosteroids; (13) treatment with systemic immunosuppressive / immunomodulatory drugs including but not limited to systemic corticosteroids, mepolizumab, omalizumab, cyclosporine, mycophenolate mofetil, interferon-γ [IFN-γ], Janus kinase inhibitors, azathioprine, and methotrexate within 3 months before screening (note: the use of corticosteroids once as part of the anesthesia preparation used during each endoscopy procedure is permitted); (14) treatment with the investigational drug within the longer of the period within 2 months before the first visit or 5 half-lives (if known); (15) a history of bleeding disorder or esophageal varix that, in the opinion of the attending physician, would expose the patient to an excessive risk of serious complications due to the endoscopy procedure; (16) use of prohibited drugs and procedures planned or predicted during the trial period;(17) Large-scale surgical procedures planned or anticipated during the study period; (18) Treatment with live vaccines (attenuated vaccines) within 4 weeks before baseline visit; (19) Active parasitic infections or suspected parasitic infections, except when active infections are excluded by clinical examinations and (if necessary) laboratory evaluations before randomization; (20) Chronic or acute infections requiring systemic administration of antibiotics, antiviral agents, or antifungal agents within 2 weeks before baseline visit (Note: After the infection has resolved, the patient may be retested); (21) Known or suspected immunodeficiency disorders, including a history of invasive opportunistic infections (such as tuberculosis [TB], nontuberculous mycobacterial infections, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis), or infections that recur at an abnormal frequency, or long-term infections suggesting immunodeficiency, as determined by the attending physician; (22) History of human immunodeficiency virus (HIV) infection, or positive for hepatitis B antigen or hepatitis C antigen; (23) Treatment for liver diseases including, but not limited to, acute or chronic hepatitis, cirrhosis, and liver failure, or evidence of liver disease indicated by persistent elevation (confirmed by repeated testing at intervals of more than 2 weeks) of transaminases (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) above 3 times the upper limit of normal [ULN] during the screening period; (24) Any of the following abnormal test values at screening: platelets less than 100 × 10; 3 / μL, neutrophils less than 1.5 × 10 3 / μL, or estimated glomerular filtration rate (eGFR) less than 30 mL / min / 1.73 m 2Less than; (25) Severe complications that, in the judgment of the attending physician, adversely affect the patient's participation in the trial. Examples include, but are not limited to, short life expectancy, uncontrolled diabetes, cardiovascular conditions (e.g., heart failure of NYHA class III or IV), severe renal conditions (e.g., dialysis patients), hepatobiliary conditions (e.g., Child-Pugh class B or C), neurological conditions (e.g., demyelinating diseases), active major autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrine, digestive, metabolic, pulmonary, and lymphatic diseases. (26) History of malignant tumors within 5 years prior to screening; (27) History of alcohol or drug abuse within 6 months prior to screening, as per the opinion of the attending physician; (28) Other medical or psychological conditions, including abnormal relevant clinical test values at the time of screening, that suggest a new and / or insufficiently understood disease, that may pose an unreasonable risk to the trial patient by participating in this clinical trial, that may make the patient's participation untrustworthy, or that may interfere with the trial evaluation; (29) A close relative of the patient is a member of the trial team; (30) The patient is female and pregnant, breastfeeding, or planning to become pregnant or breastfeed during the trial period; (31) The patient may be pregnant and has no intention of using effective contraception before the first dose / first treatment start, during the trial period, and for at least 12 weeks after the last dose; (32) Female patients who have no intention of following the precautions for women of childbearing potential (WOCBP) who have reached menarche and may be pregnant; (33) Known systemic allergies to dupilumab or the excipients of the formulation.

[0167] The following are the exclusion criteria for Part B (Extended Active Treatment) of this trial: (1) Patients who developed an SAE and / or AE considered to be related to the investigational drug during the double-blind treatment period and whose administration of the investigational drug was discontinued (patients whose administration of the investigational drug was prematurely discontinued due to lack of efficacy are eligible to participate in Part B); (2) Patients who were prematurely discontinued during the double-blind treatment period for reasons such as protocol violation, poor compliance, or inability to complete the required test evaluations; (3) Patients who did not undergo an endoscopy with biopsy before week 16 or before receiving life-saving treatment; (4) Female patients who had their first menstruation and had no intention of following the precautions for WOCBP.

[0168] The following are the exclusion criteria for patients who participated in this trial without interruption regarding Part C (OLE) of this trial: (1) Patients who developed an SAE and / or AE considered to be related to the investigational drug during the extended active treatment period and whose administration of the investigational drug was discontinued (patients whose administration of the investigational drug was prematurely discontinued due to lack of efficacy are eligible to participate in Part C); (2) Patients who were prematurely discontinued during the extended active treatment period for reasons such as protocol violation, poor compliance, or inability to complete the required test evaluations; (3) Patients who did not undergo an endoscopy with biopsy before week 52 or before receiving life-saving treatment; (4) Female patients who had their first menstruation and had no intention of following the precautions for WOCBP.

[0169] Study Treatment The treatment with the investigational drug is as follows: · Dupilumab 150 mg / mL: Each 2.25 mL, pre-filled glass syringe with a single-use snap-off cap delivers 300 mg of the investigational drug (2.0 mL of 150 mg / mL solution). · Dupilumab 175 mg / mL: Each 1.14 mL, pre-filled glass syringe with a single-use snap-off cap delivers 200 mg of the investigational drug (1.14 mL of 175 mg / mL solution). · Dupilumab 150 mg / mL: Each 0.67 mL, pre-filled glass syringe with a single-use snap-off cap delivers 100 mg of the investigational drug (0.67 mL of 150 mg / mL solution). · The placebo-matched dupilumab is prepared in the same formulation without the addition of protein (i.e., the anti-IL-4Rα monoclonal antibody, the active substance). Three types of matching placebo formulations are used: 2 mL of placebo-matched 300 mg dupilumab formulation 1.14 mL of placebo-matched 200 mg dupilumab formulation 0.67 mL of placebo-matched 100 mg dupilumab formulation

[0170] Part A is part of a double-blind placebo-controlled trial. In Part A, patients are randomly assigned in a 1:1:1 ratio to receive high-exposure dupilumab, low-exposure dupilumab (a stepwise, weight-based dosing schedule based on baseline weight), or placebo by subcutaneous (SC) injection over 16 weeks.

[0171] The dosing regimen for Part A is as follows: High-exposure regimen of dupilumab (Part A): · 100 mg Q2W for patients weighing more than 5 kg and less than 15 kg · 200 mg Q2W for patients weighing more than 15 kg and less than 30 kg · 300 mg Q2W for patients weighing more than 30 kg and less than 60 kg Low-exposure regimen of dupilumab (Part A): · 200 mg Q4W for patients weighing more than 5 kg and less than 15 kg · 300 mg Q4W for patients weighing more than 15 kg and less than 30 kg · 200 mg Q2W for patients weighing more than 30 kg and less than 60 kg Note: In Part A, patients receive dupilumab injections at a frequency of Q2W or Q4W, and the matching placebo is administered alternately with dupilumab administration. For the purpose of blinding the regimen based on the treatment assignment in Part A, the injection frequency is Q2W for both groups. Placebo in Part A: The dose-matched placebo is administered either Q2W or alternately with dupilumab Q4W. For the purpose of blinding the regimen in Part A, the frequency is Q2W for both groups.

[0172] Part B is the extended active treatment portion of this trial. All patients (active and placebo in Part A) will receive dupilumab based on their weight at the 8th visit (week 16, end of the double-blind treatment period or start of the extension treatment period) for each of the high-exposure and low-exposure groups assigned at randomization. If the weight increases at the 12th visit / week 32, the patient will be re-assigned to the extended active treatment regimen based on the following weight-stratified dosing regimens: High-exposure regimen of dupilumab (Part B): · 100 mg Q2W for patients weighing 5 kg or more and less than 15 kg · 200 mg Q2W for patients weighing 15 kg or more and less than 30 kg · 300 mg Q2W for patients weighing 30 kg or more and less than 60 kg · 300 mg QW for patients weighing 60 kg or more Low-exposure regimen of dupilumab (Part B): · 200 mg Q4W for patients weighing 5 kg or more and less than 15 kg · 300 mg Q4W for patients weighing 15 kg or more and less than 30 kg · 200 mg Q2W for patients weighing 30 kg or more and less than 60 kg · 300 mg Q2W for patients weighing 60 kg or more Note: In Part B, the study drug or matching placebo will be administered Q2W to all patients in the group weighing less than 60 kg and QW to all patients in the group weighing 60 kg or more. For regimen blinding, dupilumab or placebo will be administered alternately Q2W to patients weighing less than 60 kg assigned to the Q4W regimen and QW to patients weighing 60 kg or more assigned to the Q2W regimen. Placebo in Part B: The dose-matching placebo will be administered alternately Q2W or Q4W with dupilumab, with the frequency being Q2W for the group weighing less than 60 kg and QW for the group weighing 60 kg or more for the purpose of regimen blinding in Part B.

[0173] Part C is the open-label extension period of this trial. All patients (Part C) will be administered a higher-exposure dupilumab regimen based on body weight at the 17th visit (52 weeks, end of the extended active treatment period) or at the start of the open-label period (re-entry patients). All patients who received low-exposure dupilumab in Part B will be re-randomized to the higher-exposure dupilumab regimen at the start of the open-label period (Part C). If a patient transitions to a higher weight category at the 17th visit / 52 weeks (or at the start of the open-label period for re-entry patients) or at the designated clinical visit in Part C due to weight gain, the patient will be re-randomized to the open-label treatment regimen based on the weight-category-specific dosing regimen specified below. Higher-exposure regimen of dupilumab (Part C): · 200 mg Q3W for patients weighing 5 kg or more and less than 15 kg · 200 mg Q2W for patients weighing 15 kg or more and less than 30 kg · 300 mg Q2W for patients weighing 30 kg or more and less than 60 kg · 300 mg QW for patients weighing 60 kg or more Note: In Part C, only the active study drug (dupilumab) is administered. In Part C, matching placebo is not administered. In Part C, patients located in countries where dupilumab for the treatment of EoE in patients 12 years of age and older is commercially available will receive treatment with the study drug until they meet both (1) at least 12 years of age and (2) a body weight of at least 40 kg or the lowest weight approved as an indication for EoE. These patients will, upon meeting both criteria, make a treatment-ending visit at the next scheduled study visit and then make a post-trial follow-up visit 12 weeks later.

[0174] Background treatment: Patients who undergo a PPI therapy test before screening or during the screening period of Part A may choose to continue the PPI regimen throughout the entire study period or discontinue the PPI regimen before baseline; then, they must refrain from taking PPI during the study period.

[0175] Life-saving treatment: If medically necessary (e.g., for the treatment of intractable EoE symptoms), life-saving medications (systemic and / or topical corticosteroids for swallowing) or emergency esophageal dilation are permitted for the study patients. Endoscopy with biopsy is performed before the start of life-saving therapy. Patients who undergo endoscopy with biopsy at the start of life-saving treatment will not undergo the scheduled endoscopy / biopsy at week 16 and / or week 52 thereafter. Patients who receive life-saving treatment during the double-blind period of this study will not be eligible for the extended active treatment period unless endoscopy with biopsy is performed before the start of life-saving treatment. Patients receiving life-saving therapy can continue to receive the study drug. Patients are required to return to the clinic for all remaining study visits during the double-blind treatment period and follow-up period while remaining blinded. For the purpose of efficacy analysis, patients who receive life-saving treatment during the study period are considered treatment failures.

[0176] Results evaluated The primary endpoint is the percentage of patients who achieved a peak esophageal intraepithelial eosinophil count of 6 eos / hpf (400x) or less at week 16.

[0177] The main secondary endpoints were: the percentage of patients with a peak esophageal intraepithelial eosinophil count of less than 15 eos / hpf at week 16; the rate of change in the peak esophageal intraepithelial eosinophil count (eos / hpf) from baseline to week 16; the absolute change in the mean EoE grade score from EoE-HSS from baseline to week 16; the absolute change in the mean EoE stage score from EoE-HSS from baseline to week 16; the absolute change in EoE EREFS from baseline to week 16; the change from baseline in the type 2 inflammation transcript signature score at weeks 16 and 52; the change from baseline to week 16 in the percentage of days with one or more EoE symptoms as measured by the Pediatric EoE Symptom / Questionnaire-Caregiver Version (PESQ-C) (for patients aged 1 year and older and less than 12 years); the change from baseline to week 16 in the percentage of all intervals with one or more EoE symptoms on one day (night, morning, afternoon, evening) as measured by the PESQ-C (for patients aged 1 year and older and less than 12 years); the change from baseline to week 16 in the percentage of days with one or more EoE symptoms as measured by the PESQ-P (Patient Version) (for patients aged 8 years and older and less than 12 years); the change from baseline to week 16 in the percentage of all intervals with one or more EoE symptoms on one day (night, morning, afternoon, evening) as measured by the PESQ-P (for patients aged 8 years and older and less than 12 years); the change in the total score from baseline to week 16 as measured by the PEESSv2.0-Caregiver Version Questionnaire (for patients aged 1 year and older and less than 12 years); the normalized enrichment score (NES) for the relative change in the EoE diagnostic panel (EDP) transcriptome signature from baseline to week 16; the NES for the relative change in the type 2 inflammation transcriptome signature from baseline to week 16.

[0178] Other endpoints include safety endpoints, clinical pharmacology endpoints, and exploratory endpoints such as the overall impression of change and the impact of dupilumab treatment on disease severity, and the impact of dupilumab treatment on changes in weight and growth. The procedures for evaluating efficacy are described below and are also described in WO2019 / 028367 and WO2021 / 237110, which are incorporated herein by reference.

[0179] Pediatric Eosinophilic Esophagitis Symptom Questionnaire (PESQ): The PESQ is a new 8-item symptom questionnaire that measures the diverse symptom experiences of children. There are a patient version (PESQ-P) and a caregiver version (PESQ-C) of the PESQ. The PESQ-P is a patient-reported outcome measure intended to be completed independently by EoE patients aged over 8 and under 12 years. The PESQ-P measures the occurrence and severity of EoE symptoms and is completed once daily via an electronic diary. Data for the 14 days prior to baseline visit and the 14 days prior to the 16-week visit are used to calculate the proportion of days or entire intervals in which one or more EoE symptoms are seen in a day (night, morning, afternoon, evening). The PESQ-C is an observer-reported outcome measure intended to be completed independently by the caregivers of all pediatric EoE patients participating in this trial. The PESQ-C measures the occurrence of EoE signs and is completed once daily via an electronic diary. Data for the 14 days prior to baseline visit and the 14 days prior to the 16-week visit are used to calculate the proportion of days or entire intervals in which one or more EoE signs are seen in a day (night, morning, afternoon, evening).

[0180] Pediatric EoE Impact Scale (PEIS): The Pediatric EoE Impact Scale (PEIS) has a patient version (PEIS-P) and a caregiver version (PEIS-C). The PEIS-P is a patient-reported outcome measure intended to be completed independently by pediatric EoE patients aged over 8 and under 12 years. The PEIS-P assesses the impact of EoE on the patient's health over the past week. The PEIS-C is intended to be completed independently by caregivers of pediatric EoE patients aged over 1 and under 12 years. The PEIS-C assesses the impact of the pediatric patient's EoE on the caregiver's anxiety, social and occupational activities, activities of daily living, and relationships over the past week.

[0181] Global Impression of Change (GIC): The GIC has a patient version (GIC-P), a caregiver version (GIC-C), and a clinician version (GIC-Clin). The GIC-P is a single-item patient-reported outcome measure intended to be completed independently by pediatric EoE patients aged over 8 and under 12 years. The GIC-P assesses the patient's impression of the overall change (improvement or worsening) in their EoE status since the start of the study treatment. The GIC-C is a single-item observer-reported outcome measure intended to be completed independently by caregivers of pediatric EoE patients aged over 1 and under 12 years. The GIC-C assesses the caregiver's impression of the overall change (improvement or worsening) in the pediatric patient's EoE status since the start of the study treatment. The GIC-Clin is a single-item observer-reported outcome measure intended to be completed independently by the treating physician - physician for all pediatric EoE patients participating in this study. The GIC-Clin assesses the treating physician / clinician's impression of the overall change (improvement or worsening) in the pediatric patient's EoE status since the start of the study treatment.

[0182] Global Impression of Severity (GIS): There are patient (GIS-P), caregiver (GIS-C), and clinician (GIS-Clin) versions of the GIS. The GIS-P is a single-item patient-reported outcome measure intended for use by pediatric EoE patients over 8 years and under 12 years old to complete alone. The GIS-P assesses the patient's impression of the overall severity of their EoE condition over the past week. The GIS-C is a single-item observer-reported outcome measure intended for use by caregivers of pediatric EoE patients over 1 year and under 12 years old to complete alone. The GIS-C assesses the caregiver's impression of the overall severity of the pediatric patient's EoE condition over the past week. The GIS-Clin is a single-item observer-reported outcome measure intended for use by the attending physician - physician of all pediatric EoE patients participating in this trial to complete alone. The GIS-Clin assesses the treating physician / clinician's impression of the overall severity of the pediatric patient's EoE condition over the past week.

[0183] Pediatric Eosinophilic Esophagitis Symptom Score (PEESS): The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 - caregiver version is an observer-reported outcome measure that assesses the frequency and severity of EoE symptoms in pediatric patients. The PEESS v2.0 caregiver version consists of 20 items and has a 1-month recall period. The total score of the PEESS v2.0 ranges from 0 to 100; a higher score indicates a greater symptom burden in pediatric EoE patients.

[0184] EoE-EREFS: The esophageal features of EoE are analyzed based on a validated scoring system called EoE-EREFS that assesses the features of inflammation and remodeling of the disease, using both the overall score and the scores for each feature (Hirano, 2013). The proximal and distal esophageal regions are scored separately, with scores for each site ranging from 0 to 9 and the overall score ranging from 0 to 18. The main features regarding the esophagus include: edema (absent, present); rings (absent, mild, moderate, severe); exudate (absent, mild, severe); furrows (absent, mild, severe); stricture (absent, present). In addition to these main features, data regarding the following secondary features are also collected by the physician performing the endoscopic procedure: crepe paper esophagus (vulnerability or laceration of the mucosa with passage of the diagnostic endoscope): absent, present; narrow esophagus (decrease in the diameter of the lumen in most of the tubular esophagus): absent, present; stricture diameter. Mucosal changes associated with gastroesophageal reflux disease are also recorded using the Los Angeles classification system for erosions (absent or grade A, B, C, D).

[0185] Biopsy: Biopsies are taken by endoscopy at the second screening visit (second visit), at 16 weeks, at 52 weeks, and immediately before the start of rescue medications or procedures during the double-blind treatment period. Esophageal 3 regions: A total of 9 mucosal pinch biopsies are taken at each time point from 3 proximal sites, 3 middle sites, and 3 distal sites. Two samples from each region are used for histological examination (required for study inclusion criteria and endpoint evaluation), and the other samples are used for RNA extraction and exploratory research. To participate in this study, patients must have a peak intraepithelial eosinophil count of 15 eos / hpf or more (400x) in at least 2 of the 3 esophageal regions sampled. Additionally, to rule out other causes of esophageal eosinophilia, gastric and / or duodenal biopsy specimens are taken from all patients at the second visit. Biopsy samples for histopathological analysis are evaluated for the peak eosinophils per hpf, and an EoE grade score and stage score are assigned. The EoE grade score and stage score evaluate 8 features: eosinophil density, basal zone hyperplasia, eosinophilic abscess, eosinophil surface stratification, intercellular space dilation, surface epithelial changes, abnormal keratinized epithelial cells, and lamina propria fibrosis (absent / present).

[0186] Pharmacokinetic and Exploratory Biomarker Procedures In this study, research evaluations are conducted to investigate how EoE, dupilumab, may modify predictors of the underlying disease process of EoE, type 2 inflammation, and the safety and efficacy of dupilumab. Samples may also be used to evaluate markers related to toxicity as needed. Samples of total IgE, serum, and eotaxin-3 (heparinized plasma) are taken at specific time points. The biomarkers of interest are related to the pathophysiology of EoE, treatment response (i.e., evaluation of type 2 inflammation), and the mechanism of action of dupilumab.

[0187] EoE Diagnostic Panel and Type 2 Inflammation Transcriptomics The differences in gene expression profiles compared to healthy controls in esophageal biopsies of EoE patients are the EoE disease transcriptome (Sherrill et al., Genes Immun 2014, 15(6):361 - 369). The gene expression signature of this disease has been further refined into a smaller gene set for use as an EoE diagnostic panel (EDP) (Dellon et al., Clin Transl Gastroenterol 2017, 8(2):e74). The gene signature representing type 2 inflammation was selected from the literature, pre - clinical experiments conducted at Regeneron, and the dupilumab response signature from phase 2 trials of atopic dermatitis and EoE.

[0188] The normalized enrichment score (NES) reflects the degree to which the active level of a set of transcripts occupies a large proportion at both extremes (upper or lower end) of the ranked list of all transcripts within a sample, and is normalized considering the number of transcripts within the set (Subramanian, 2005; Barbie, 2009). The NES score was calculated for each transcriptome signature of each sample.

Example

[0189] Results of Clinical Trial Part A Part A of this trial was a double - blind 16 - week treatment period. As disclosed above, according to a step - wise, weight - based dosing schedule based on baseline weight, patients were randomly assigned 1:1:1 to groups receiving either placebo, high - exposure dupilumab, or low - exposure dupilumab. A total of 102 patients were randomly assigned (34 received placebo, 31 received low - exposure dupilumab, and 37 received high - exposure dupilumab). Almost all of these patients completed week 16 (32 / 34 (94.1%) in placebo; 29 / 31 (93.5%) in low - exposure dupilumab; 37 / 37 (100%) in high - exposure dupilumab; 98 / 102 (96.1%) in total).

[0190] The baseline demographic characteristics are summarized in Table 1. The baseline demographic characteristics were generally comparable across treatment groups. The baseline disease characteristics are summarized in Table 2. In general, patients were highly symptomatic, with a high proportion (about 80%) of patients having a history of using topical corticosteroids for swallowing, and about 50% of patients were taking PPIs at randomization. Patients in the dupilumab high-exposure group had a higher mean peak eosinophil count on average, but were less symptomatic compared to other groups in terms of the PESQ-C score. As shown in Table 3, the patient population had a high incidence of comorbid atopic diseases, highlighting the presence of a type 2 pathophysiology common to these diseases.

[0191]

Table 1

[0192]

Table 2

[0193]

Table 3

[0194] Efficacy The efficacy results of Part A for the primary endpoint and secondary endpoints are shown in Table 4 below. Both dupilumab exposure regimens (high-exposure dupilumab and low-exposure dupilumab) showed significant improvement in achieving histological remission. The primary endpoint was to evaluate the proportion of patients whose peak eosinophil count reached 6 eos / hpf (400x) or less at week 16. Only 2.9% (n = 1 / 34) of placebo patients reached 6 eos / hpf or less at week 16, while 67.6% of patients in the high-exposure dupilumab regimen (n = 25 / 37) and 55.1% of patients in the low-exposure dupilumab regimen (n = 18 / 31) reached 6 eos / hpf or less at week 16.

[0195] The high-exposure dupilumab regimen met all predefined secondary efficacy endpoints related to histology, endoscopy, and transcriptome (all p-values < 0.0001) (Table 4). In children administered the high-exposure dupilumab regimen, the following changes were observed at week 16: · The peak esophageal intraepithelial eosinophil count decreased by 86% from baseline, whereas it increased by 21% in the placebo (p < 0.0001). · The decrease in disease severity and disease extent at the microscopic level from baseline (measured by the EoEHSS mean grade score and mean stage score, respectively) was 0.88 and 0.84, respectively, whereas in the placebo, it was an increase of 0.02 and 0.05 (both p < 0.0001). · Endoscopic abnormalities decreased by 3.5 points from baseline (measured by the EoE-EREFS score), whereas in the placebo, it increased by 0.3 points (p < 0.0001).

[0196] The high-exposure dupilumab regimen also showed improvement compared to the placebo, although no statistically significant difference was obtained in the absolute change (LS mean value) from baseline to week 16 in the proportion of days with one or more EoE symptoms measured by the secondary symptom endpoint PESQ-C (placebo: -0.17; high-exposure dupilumab regimen: -0.28; Δ -0.10 (p = 0.15); this corresponds to approximately 1.5 fewer days with EoE symptoms compared to the placebo). As shown in Table 4, the low-exposure dupilumab regimen was equivalent or numerically lower in predefined secondary efficacy endpoints (histology, endoscopy, transcriptome, symptoms) compared to the high-exposure dupilumab regimen. Furthermore, the high-exposure dupilumab regimen showed greater improvement than the low-exposure dupilumab regimen in other patient-reported outcomes, overall impression, and QOL.

[0197]

Table 4

[0198] Body weight The exploratory endpoint was the change from the baseline of the body weight percentile for age at week 16. In all dupilumab treatment groups, the change from the baseline of the body weight percentile for age at week 16 was greater compared to placebo (placebo: mean change 0.29; high-exposure dupilumab: mean change 3.09; low-exposure dupilumab: mean change 2.88).

[0199] Safety In both the high-exposure dupilumab regimen and the low-exposure dupilumab regimen, the tolerability was good, showing an acceptable safety profile, and no new safety concerns were identified. The safety results were generally consistent with the known safety profile of Dupixent approved for pediatric and adult patients 12 years of age and older. During the 16-week treatment period, the overall percentage of adverse events (AEs) was 79% for Dupixent and 91% for placebo. AEs that were more commonly (≥5%) observed with Dupixent compared to placebo were COVID-19 (21% for Dupixent and 0% for placebo; all cases were mild or moderate and did not lead to treatment discontinuation), rash (9% for Dupixent and 6% for placebo), headache (8% for Dupixent and 3% for placebo), viral gastroenteritis (6% for Dupixent and 3% for placebo), diarrhea (6% for Dupixent and 3% for placebo), and nausea (6% for Dupixent and 0% for placebo). The treatment discontinuation rate due to AEs before week 16 was 0% for Dupixent and 6% for placebo.

[0200] There was no need for life-saving treatment in any of placebo, low-exposure dupilumab, or high-exposure dupilumab.

[0201] Conclusion In Part A of this two-part trial evaluating the efficacy and safety of dupilumab in EoE patients aged 1 year or older and less than 12 years, treatment with either high-exposure dupilumab or low-exposure dupilumab according to a stepwise, weight-based dosing schedule based on baseline weight resulted in meeting the primary histological endpoint at week 16. High-exposure dupilumab met all secondary endpoints related to histological examination, endoscopy, and transcriptome. High-exposure dupilumab treatment in pediatric patients resulted in numerically higher or equivalent results compared to 300 mg QW dosing in adults and adolescents in histological, endoscopic, and transcriptome efficacy endpoints. The tolerability of dupilumab was good, showing a safety profile similar to the known safety profile of dupilumab in adult and adolescent EoE patients.

Example

[0202] Results of Clinical Trial Part B Part B of this trial is a 36-week open-label extension treatment period for patients who participated in Part A. A total of 98 patients (out of 102) from Part A were enrolled in Part B. All patients were informed that they were receiving active treatment in Part B, but the dosing regimen was blinded. The treatment groups in Part B are shown in Table 5 below:

[0203]

Table 5

[0204] Efficacy As shown in Table 6 below, it was found that the treatment effect of dupilumab on histological effects, endoscopic effects, symptoms, and transcriptome effects observed at week 16 persisted until week 52. When placebo-treated patients from Part A were switched to dupilumab treatment in Part B, the efficacy was generally similar to that observed in dupilumab-treated patients in Part A.

[0205]

Table 6

[0206] Safety The overall incidence of TEAE was similar among the treatment groups, and most of them were mild or moderate in intensity. The incidence of SAE and AE leading to treatment discontinuation was low. All SAEs were judged to be unrelated to the investigational drug.

[0207] The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are intended to be included within the scope of the appended claims.

[0208]

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

Table 7-7

Table 7-8

Table 7-9

Table 7-10

Table 7-11

Table 7-12

Table 7-13

Table 7-14

Claims

1. A method for treating, preventing or ameliorating at least one symptom of eosinophilic esophagitis (EoE) in a subject less than 12 years of age, comprising administering to the subject an interleukin-4 receptor (IL-4R) antagonist one or more times, wherein the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof comprising three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

2. The method according to claim 1, wherein the subject is 1 year or older and less than 12 years of age.

3. Before initiation of treatment with the IL-4R antagonist, the subject has a peak number of intraepithelial eosinophil infiltrating cells of 15 eos / hpf or more as measured by endoscopic biopsy in at least two of the proximal esophageal region, the middle esophageal region, and the distal esophageal region. The method according to claim 1 or 2.

4. The method according to any one of claims 1 to 3, wherein the subject has been previously treated with a topical corticosteroid for swallowing and / or a proton pump inhibitor (PPI).

5. The method according to any one of claims 1 to 4, wherein the subject does not respond, responds inadequately, or is intolerant to treatment with a topical corticosteroid for swallowing and / or a PPI, or standard treatment is contraindicated.

6. The method according to any one of claims 1 to 5, wherein the subject has a concurrent atopic disease.

7. The method according to claim 6, wherein the concurrent atopic disease is food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis.

8. The method according to any one of claims 1 to 7, wherein the subject weighs 5 kg or more.

9. The method according to any one of claims 1 to 8, wherein the subject weighs less than 60 kg.

10. Before initiation of treatment, the subject has: A baseline peak of intraepithelial eosinophil cell count of 70 eos / hpf or more; A baseline mean value of intraepithelial eosinophil cell count of 50 eos / hpf or more; The baseline endoscopic reference score for eosinophilic esophagitis (EoE-EREFS) is at least 6; and / or The baseline total serum IgE value is at least 400 IU / L, The method according to any one of claims 1 to 9.

11. The subject is (a) having a body weight of less than 5 kg; (b) having a body weight of 60 kg or more; (c) having eosinophilic gastroenteritis, eosinophilia syndrome, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome); (d) having a history of Crohn's disease, ulcerative colitis, celiac disease, or esophageal surgery; (e) having an esophageal stricture that cannot be passed through with a standard diagnostic upper endoscope or having an esophageal stricture that requires dilation; (f) having been treated with topical corticosteroids for swallowing within the past 8 weeks; (g) having received pretreatment with subcutaneous immunotherapy (SCIT), except when not being treated with a stable maintenance dose of SCIT for at least one year; (h) having received pretreatment with sublingual immunotherapy (SLIT), epicutaneous immunotherapy (EPIT), or oral immunotherapy (OIT); (i) having been treated with systemic immunosuppressive drugs or immunomodulatory drugs within the past 3 months; (j) having started or changed a food elimination diet regimen within the past 6 weeks; (k) having started, stopped, or changed the administration regimen of a PPI, leukotriene inhibitor, intranasal corticosteroid, or inhaled corticosteroid within the past 8 weeks; (l) having been vaccinated with a live vaccine (attenuated vaccine) within the past 4 weeks; (m) having active Helicobacter pylori, helminth infection, active parasitic infection, or a chronic or acute infection that requires treatment with systemic antibiotics, antiviral drugs, or antifungal drugs; (n) having a known or suspected immunodeficiency disorder; (o) having a liver disease; and (p) Platelet count less than 100 × 10 ３ / μL, neutrophil level 1.5 × 10 ３ / μL or less, or estimated glomerular filtration rate (eGFR) less than 30 mL / min / 1.73 m ２ having The method according to any one of claims 1 to 10, selected based on not showing one or more exclusion criteria selected from the group consisting of

12. The anti-IL-4R antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2, the method according to any one of claims 1 to 11.

13. The anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10, and the method according to any one of claims 1 to 12.

14. The method according to any one of claims 1 to 13, wherein the IL-4R antagonist is dupilumab.

15. The method according to any one of claims 1 to 14, wherein the IL-4R antagonist is administered at a dose of about 50 mg to about 600 mg.

16. The subject has a body weight of 5 kg or more: For subjects with a body weight of 5 kg or more and less than 15 kg, the IL-4R antagonist is administered at a dose of about 100 mg Q2W, about 200 mg Q3W, or about 200 mg Q4W; For subjects with a body weight of 15 kg or more and less than 30 kg, the IL-4R antagonist is administered at a dose of about 200 mg Q2W, or about 300 mg Q4W; For subjects with a body weight of 30 kg or more and less than 60 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W, or about 200 mg Q2W; and / or For subjects with a body weight of 60 kg or more, the IL-4R antagonist is administered at a dose of about 300 mg QW or about 300 mg Q2W, The method according to any one of claims 1 to 15.

17. The subject has a body weight of 5 kg or more, For subjects with a body weight of 5 kg or more and less than 15 kg, the IL-4R antagonist is administered at a dose of about 100 mg Q2W, or about 200 mg Q3W; For subjects with a body weight of 15 kg or more and less than 30 kg, the IL-4R antagonist is administered at a dose of about 200 mg Q2W; For subjects with a body weight of 30 kg or more and less than 60 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W; and / or For subjects with a body weight of 60 kg or more, the IL-4R antagonist is administered at a dose of about 300 mg QW, The method according to any one of claims 1 to 15.

18. The subject has a body weight of 5 kg or more, For subjects with a body weight of 5 kg or more and less than 15 kg, the IL-4R antagonist is administered at a dose of about 200 mg Q3W; For subjects with a body weight of 15 kg or more and less than 30 kg, the IL-4R antagonist is administered at a dose of about 200 mg Q2W; For subjects with a body weight of 30 kg or more and less than 40 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W; and / or For subjects weighing 40 kg or more, the IL-4R antagonist is administered at a dose of approximately 300 mg QW. The method according to any one of claims 1 to 15.

19. The method according to any one of claims 1 to 16, wherein the subject weighs 5 kg or more and less than 15 kg.

20. The method according to claim 19, wherein the IL-4R antagonist is administered at a dose of approximately 100 mg Q2W.

21. The method according to claim 19, wherein the IL-4R antagonist is administered at a dose of approximately 200 mg Q3W.

22. The method according to claim 19, wherein the IL-4R antagonist is administered at a dose of approximately 200 mg Q4W.

23. The method according to any one of claims 1 to 16, wherein the subject weighs 15 kg or more and less than 30 kg.

24. The method according to claim 23, wherein the IL-4R antagonist is administered at a dose of approximately 200 mg Q2W.

25. The method according to claim 23, wherein the IL-4R antagonist is administered at a dose of approximately 300 mg Q4W.

26. The method according to any one of claims 1 to 16, wherein the subject weighs 30 kg or more and less than 60 kg.

27. The method according to claim 26, wherein the IL-4R antagonist is administered at a dose of approximately 300 mg Q2W.

28. The method according to claim 26, wherein the IL-4R antagonist is administered at a dose of approximately 200 mg Q2W.

29. The method according to any one of claims 1 to 16, wherein the subject weighs 60 kg or more.

30. The method according to claim 29, wherein the IL-4R antagonist is administered at a dose of approximately 300 mg QW.

31. The method according to claim 29, wherein the IL-4R antagonist is administered at a dose of approximately 300 mg Q2W.

32. The method according to any one of claims 1 to 15 or 18, wherein the subject weighs 30 kg or more and less than 40 kg, and the IL-4R antagonist is administered at a dose of approximately 300 mg Q2W.

33. The method according to any one of claims 1 to 15 or 18, wherein the subject weighs 40 kg or more, and the IL-4R antagonist is administered at a dose of approximately 300 mg QW.

34. The method according to any one of claims 1 to 15, wherein the IL-4R antagonist is administered at a dose of approximately 100 mg to approximately 300 mg once a week or once every two weeks.

35. The IL-4R antagonist is administered every three weeks at a dose of from about 100 mg to about 300 mg, by the method according to any one of claims 1 to 15.

36. The IL-4R antagonist is administered subcutaneously, by the method according to any one of claims 1 to 35.

37. The IL-4R antagonist is administered in combination with a second therapeutic agent or treatment method, by the method according to any one of claims 1 to 36.

38. The second therapeutic agent or treatment method is dietary management, by the method according to claim 37.

39. The second therapeutic agent or treatment method is a proton pump inhibitor (PPI), by the method according to claim 37.

40. Treatment with the IL-4R antagonist for at least 16 weeks results in: A decrease in the peak number of esophageal intraepithelial eosinophils; A decrease in the severity and / or extent of the disease measured by the histological scoring system for eosinophilic esophagitis (EoE-HSS); Improvement in the esophageal anatomical features measured by the endoscopic reference score for eosinophilic esophagitis (EoE-EREFS); An increase in the percentile of body weight for age; and / or A decrease in the normalized enrichment score (NES) for the type 2 inflammation panel and / or the EoE diagnostic panel of genes by the method according to any one of claims 1 to 39.

41. Treatment with the IL-4R antagonist for 16 weeks results in a peak number of esophageal intraepithelial eosinophils of 6 eos / hpf or less and / or a decrease in the peak number of esophageal intraepithelial eosinophils of at least 75%, by the method according to claim 40.

42. The IL-4R antagonist is contained in a container selected from the group consisting of glass vials, syringes, pre-filled syringes, pen delivery devices, and auto-injectors, by the method according to any one of claims 1 to 41.

43. The IL-4R antagonist is contained in a pre-filled syringe, by the method according to claim 42.

44. The pre-filled syringe is a single-dose pre-filled syringe, by the method according to claim 43.

45. The IL-4R antagonist is contained in an auto-injector, by the method according to claim 42.

46. The IL-4R antagonist is contained in a pen delivery device, by the method according to claim 42.

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