A method for treating eosinophilic esophagitis with the administration of IL-4R inhibitors.

Abstract

The present disclosure provides methods for treating, preventing, or ameliorating one or more symptoms of eosinophilic esophagitis in an adolescent or adult subject by administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) inhibitor, e.g., an anti-IL-4R antibody or antigen-binding fragment thereof.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 029,085, filed May 21, 2021; No. 63 / 066,705, filed August 17, 2020; No. 63 / 071,264, filed August 27, 2020; No. 63 / 088,147, filed October 6, 2020; No. 63 / 121,088, filed December 3, 2020; and No. 63 / 144,939, filed February 2, 2021; and European Patent Application No. 21315068.3, filed April 21, 2021; the entire contents of each of which are incorporated by reference.

[0002] The present disclosure relates to the use of an interleukin - 4 (IL - 4) receptor inhibitor for treating or preventing eosinophilic esophagitis in a subject that needs it.

Background Art

[0003] Eosinophilic esophagitis (EoE) is a chronic, inflammatory, allergic / immune - mediated disease of the esophagus characterized by local eosinophilic inflammation leading to symptoms of esophageal dysfunction. Although considered a rare disease, the current prevalence is estimated to be 22.7 per 100,000 worldwide (Non - Patent Document 1) and appears to be on the increase (Non - Patent Document 2). Eosinophilic esophagitis has been reported in all ages; however, most cases are recognized in children and adults younger than 50 years old (see, for example, Non - Patent Document 3). In EoE, there is no gender - related difference in clinical symptoms, but gender differences have been consistently reported, and men are affected at a frequency 3 - 4 times higher than women (see, for example, Non - Patent Document 4).

[0004] In both adults and children over 10 years of age, the primary clinical signs of esophageal ulceration (EoE) are dysphagia and food impaction (Non-Patent Literature 5). These symptoms lead to a substantial deterioration of quality of life (QOL) (see Non-Patent Literature 6; Non-Patent Literature 7; and Non-Patent Literature 8). Endoscopic findings are associated with esophageal inflammation and consist of fixed or transient concentric annular grooves, longitudinal grooves, white patches, reduced mucosal vascular distribution, fragile or crepe-like mucosa, and stenosis.

[0005] Growing evidence suggests that type 2 cytokine-mediated immune responses play a crucial role in the development of esophageal eosinophilia (EoE). This is thought to occur through the induction of eosinophil-induced, mast cell-induced, T cell-induced, and lymphocyte-induced chronic inflammation via cytokines known to regulate eosinophil accumulation in the esophagus, such as interleukin (IL)-4, IL-5, IL-13, and eotaxin-1, eotaxin-2, and eotaxin-3 (see, e.g., Non-Patent Documents 9; 10; 11; and 12). Consistent with the type 2-mediated inflammation observed in esophageal tissue, EoE patients have a high prevalence of co-existing allergic diseases, particularly food allergies, atopic dermatitis (AD), asthma, and allergic rhinitis, which are also associated with enhanced signaling of IL-4 and IL-13 (see, e.g., Non-Patent Documents 13; and 14). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Arias et al., Aliment Pharmaco Ther 2016, 43:3~15 [Non-Patent Document 2] Dellon, Gastroenterology Clinics of North America 2014, 43:201~218 [Non-Patent Document 3] Dellon et al., Clinical Gastroenterology and Hepatology 2014, 12:589~596 [Non-Patent Document 4] Kapel et al., Gastroenterology 2008, 140:82~90 [Non-Patent Document 5] Lucendo et al., United European Gastroenterol J, 2017, 5:335–358 [Non-Patent Document 6] DeBrosse et al., Journal of Allergy and Clinical Immunology 2011, 128:132–138 [Non-Patent Document 7] Falk, Gastrointestinal Endoscopy Clinics of North America 2014, 43:231~242 [Non-Patent Document 8] Straumann, Gastrointestinal Endoscopy Clinics of North America 2008, 18:99~118 [Non-Patent Document 9] Abonia and Rothenberg, Annual Review of Medicine 2012, 63:421-434. [Non-Patent Document 10] Blanchard et al., Journal of Clinical Investigation, 2006, 116:536-547 [Non-Patent Document 11] Blanchard et al., Gastrointestinal Endoscopy Clinics of North America, 2008, 18:133–43 [Non-Patent Document 12] Mishra, Immunology and Allergy Clinics of North America, 2009, 29:29–40. [Non-Patent Document 13] Assa'ad, Gastrointestinal Endoscopy Clinics of North America, 2008, 18:119~132 [Non-Patent Document 14] Weinbrand-Goichberg et al., Immunologic Research, 2013, 56:249~260 [Overview of the project] [Problems that the invention aims to solve]

[0007] Current treatment approaches include long-term food restriction, topical corticosteroid swallowing preparations (not approved for the treatment of EoE outside the European Union [EU]), and esophageal dilation. Emergency endoscopy for prolonged and / or painful food impaction is associated with a risk of severe esophageal injury and does not alter the underlying etiology or disease progression. Topical corticosteroid swallowing has been reported to induce partial clinical response and histological remission in clinical trials, but it is not uniformly effective and can be associated with disease relapse after discontinuation as well as fungal infections. Therefore, safe and effective therapies for treating EoE remain needed. [Means for solving the problem]

[0008] In one embodiment, a method is provided for treating, preventing, or relieving at least one symptom of eosinophilic esophagitis (EoE) in subjects aged 12 years or older. In some embodiments, the method comprises administering one or more doses of an interleukin-4 receptor (IL-4R) inhibitor to a subject having a Dysphagia Symptom Questionnaire (DSQ) score of 10 or more prior to the initiation of treatment, wherein the IL-4R inhibitor is an antibody or antigen-binding fragment thereof that binds to IL-4Rα and comprises a heavy chain complementarity-determining region (HCDR) 1 containing the amino acid sequence of SEQ ID NO: 3, an HCDR 2 containing the amino acid sequence of SEQ ID NO: 4, an HCDR 3 containing the amino acid sequence of SEQ ID NO: 5, a light chain complementarity-determining region (LCDR) 1 containing the amino acid sequence of SEQ ID NO: 6, an LCDR 2 containing the amino acid sequence of SEQ ID NO: 7, and an LCDR 3 containing the amino acid sequence of SEQ ID NO: 8.

[0009] In some embodiments, the subjects are adults. In some embodiments, the subjects are young people between the ages of 12 and 18.

[0010] In some embodiments, the subject has an intraepithelial eosinophil infiltration peak cell count of 15 eos / hpf or higher as measured by endoscopic biopsy in at least two of the proximal, middle, and distal esophageal regions prior to the initiation of treatment. In some embodiments, the subject has a history of at least two episodes of dysphagia per week on average for at least four weeks. In some embodiments, the subject is refractory to or poorly responding to treatment with topical corticosteroids and / or proton pump inhibitors (PPIs) for swallowing.

[0011] In some embodiments, the subject has a comorbid atopic condition. In some embodiments, the comorbid atopic condition is food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis. In some embodiments, the subject has eosinophilic gastroenteritis. In some embodiments, the subject has a current or previous comorbidity selected from the group consisting of asthma, atopic dermatitis, hand eczema and food eczema, allergic rhinitis, oral allergy syndrome, and food allergy (e.g., peanut allergy).

[0012] In some embodiments, the subjects have a co-occurring type 2 inflammatory disease. In some embodiments, the subjects have one or more of the following conditions: asthma, chronic rhinosinusitis, allergic rhinitis, allergic fungal sinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), integrated airway disease, eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), gastroesophageal reflux disease (GERD), atopic conjunctivitis, vasculitis, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps (CRSwNP), aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (e.g., NSAID-exacerbated respiratory disease, or NSAID-ERD), perennial allergic rhinitis (PAR), atopic dermatitis (AD), chronic eosinophilic pneumonia (CEP), or exercise-induced bronchospasm.

[0013] In some embodiments, the IL-4R inhibitor comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-4R inhibitor comprises 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. In some embodiments, the IL-4R inhibitor is dupilumab or its bioequivalent.

[0014] In some embodiments, the IL-4R inhibitor is administered in doses of approximately 50 mg to approximately 600 mg. In some embodiments, the IL-4R inhibitor is administered in doses of approximately 300 mg. In some embodiments, the IL-4R inhibitor is administered once a week or once every two weeks.

[0015] In some embodiments, IL-4R inhibitors are administered in combination with a second therapeutic agent or therapy. In some embodiments, the second therapeutic agent or therapy 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 immunosuppressant, a topical corticosteroid, an oral corticosteroid, a systemic corticosteroid, an inhaled corticosteroid, a glucocorticoid, a PPI, a decongestant, an antihistamine, a nonsteroidal anti-inflammatory drug (NSAID), an esophageal dilator, an allergen elimination, or a dietary regimen.

[0016] In some embodiments, IL-4R inhibitors are administered in combination with PPIs. In some embodiments, PPIs are administered as high-dose regimens selected from the group consisting of omeprazole in doses of 40 mg QD or 20 mg BID, esomeprazole in doses of 40 mg QD or 20 mg BID, lansoprazole in doses of 60 mg QD or 30 mg BID, dexlansoprazole in doses of 60 mg QD, rabeprazole in doses of 40 mg QD or 20 mg BID, and pantoprazole in doses of 80 mg QD or 40 mg BID. In some embodiments, treatment with an IL-4R inhibitor reduces the need for treatment with a PPI.

[0017] In some embodiments, treatment with an IL-4R inhibitor normalizes the expression of one or more EoE-related genes and / or type 2 inflammation-related genes (e.g., normalizing the expression of one or more type 2 inflammation-related genes shown in Figure 3, and / or normalizing the expression of one or more EoE-related genes shown in Figure 6). In some embodiments, treatment with an IL-4R inhibitor reduces dysphagia in subjects (e.g., improves the subject's ability to swallow food). In some embodiments, treatment with an IL-4R inhibitor reduces the subject's DSQ score by at least 30% compared to baseline after 24 weeks of treatment; and / or reduces the subject's DSQ score by at least 10 points compared to baseline after 24 weeks of treatment. In some embodiments, treatment with an IL-4R inhibitor reduces symptoms of dysphagia compared to baseline values ​​in subjects within approximately 4 weeks, 6 weeks, or 8 weeks of the start of treatment. In some embodiments, treatment with an IL-4R inhibitor reduces esophageal intraepithelial eosinophils in subjects. In some embodiments, the subject's peak esophageal eosinophil count is reduced by at least 50% compared to baseline after 24 weeks of treatment; and / or the subject's peak esophageal eosinophil count is reduced to 6 eos / hpf or less after 24 weeks of treatment. In some embodiments, treatment with an IL-4R inhibitor reduces the subject's peak esophageal eosinophil count to 1 eos / hpf or less after 24 weeks of treatment. In some embodiments, treatment with an IL-4R inhibitor improves the presence or severity of one or more endoscopic characteristics of the esophagus, e.g., edema, cricoid sulcus, exudate, longitudinal grooves, and / or strictures in the proximal and / or distal parts of the esophagus. In some embodiments, treatment with an IL-4R inhibitor reduces the subject's EoE-EREFS score by at least 25% compared to baseline after 24 weeks of treatment. In some embodiments, treatment with an IL-4R inhibitor reduces the expression of a biomarker selected from the group consisting of TARC, eotaxin-3, and IgE (e.g., total IgE).In some embodiments, treatment with an IL-4R inhibitor normalizes the expression of genes (e.g., CTSC, CCL26, CCR3, ANO1, and / or SPINK8) that correlate with clinical measures of disease severity.

[0018] In another embodiment, a method for improving the ability to swallow food is provided. In some embodiments, this method is: The treatment involves administering one or more doses of interleukin-4 receptor (IL-4R) inhibitors to subjects with eosinophilic esophagitis (EoE), wherein the IL-4R inhibitor is an antibody or antigen-binding fragment that binds to IL-4Rα and comprises a heavy chain complementarity-determining region (HCDR)1 containing the amino acid sequence of SEQ ID NO: 3, an HCDR2 containing the amino acid sequence of SEQ ID NO: 4, an HCDR3 containing the amino acid sequence of SEQ ID NO: 5, an LCDR1 containing the amino acid sequence of SEQ ID NO: 6, an LCDR2 containing the amino acid sequence of SEQ ID NO: 7, and an LCDR3 containing the amino acid sequence of SEQ ID NO: 8.

[0019] In some embodiments, the subjects are adults. In some embodiments, the subjects are young people between the ages of 12 and 18.

[0020] In some embodiments, the subject has a Dysphagia Symptom Questionnaire (DSQ) score of 10 or higher prior to the initiation of treatment. In some embodiments, the subject has an intraepithelial eosinophil infiltration peak cell count of 15 eos / hpf or higher as measured by endoscopic biopsy in at least two of the proximal, middle, and distal esophageal regions prior to the initiation of treatment. In some embodiments, the subject has a history of at least two episodes of dysphagia per week on average over a period of at least four weeks. In some embodiments, the subject is unresponsive or poorly responding to treatment with topical corticosteroids and / or proton pump inhibitors (PPIs) for swallowing.

[0021] In some embodiments, the subject has a comorbid atopic condition. In some embodiments, the comorbid atopic condition is food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis. In some embodiments, the subject has eosinophilic gastroenteritis.

[0022] In some embodiments, the subjects have a co-occurring type 2 inflammatory disease. In some embodiments, the subjects have one or more of the following conditions: asthma, chronic rhinosinusitis, allergic rhinitis, allergic fungal sinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), integrated airway disease, eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), gastroesophageal reflux disease (GERD), atopic conjunctivitis, vasculitis, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps (CRSwNP), aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (e.g., NSAID-exacerbated respiratory disease, or NSAID-ERD), perennial allergic rhinitis (PAR), atopic dermatitis (AD), chronic eosinophilic pneumonia (CEP), or exercise-induced bronchospasm.

[0023] In some embodiments, the IL-4R inhibitor comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-4R inhibitor comprises 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. In some embodiments, the IL-4R inhibitor is dupilumab or its bioequivalent.

[0024] In some embodiments, the IL-4R inhibitor is administered in doses of approximately 50 mg to approximately 600 mg. In some embodiments, the IL-4R inhibitor is administered in doses of approximately 300 mg. In some embodiments, the IL-4R inhibitor is administered once a week or once every two weeks.

[0025] In some embodiments, IL-4R inhibitors are administered in combination with a second therapeutic agent or therapy. In some embodiments, the second therapeutic agent or therapy 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 immunosuppressant, a topical corticosteroid, an oral corticosteroid, a systemic corticosteroid, an inhaled corticosteroid, a glucocorticoid, a PPI, a decongestant, an antihistamine, a nonsteroidal anti-inflammatory drug (NSAID), an esophageal dilator, an allergen elimination, or a dietary regimen.

[0026] In some embodiments, IL-4R inhibitors are administered in combination with PPIs. In some embodiments, PPIs are administered as high-dose regimens selected from the group consisting of omeprazole in doses of 40 mg QD or 20 mg BID, esomeprazole in doses of 40 mg QD or 20 mg BID, lansoprazole in doses of 60 mg QD or 30 mg BID, dexlansoprazole in doses of 60 mg QD, rabeprazole in doses of 40 mg QD or 20 mg BID, and pantoprazole in doses of 80 mg QD or 40 mg BID. In some embodiments, treatment with an IL-4R inhibitor reduces the need for treatment with a PPI.

[0027] In some embodiments, treatment with an Il-4R inhibitor is: The target DSQ score will be reduced by at least 30% compared to baseline after 24 weeks of treatment; The target DSQ score is reduced by at least 10 points compared to baseline after 24 weeks of treatment; and / or, To improve the Patient Global Impression of Change (PGIC) score regarding changes in swallowing difficulties in the target patient.

[0028] In some embodiments, treatment with an Il-4R inhibitor results in the patient's Global Impression (PGIC) score regarding changes in the subject's dysphagia outcome being "significantly improved" or "moderately improved" after 24 weeks of treatment.

[0029] In some embodiments, the IL-4R inhibitor is contained in a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an auto-injector. In some embodiments, the IL-4R inhibitor is contained in a glass vial. In some embodiments, the IL-4R inhibitor is contained in a syringe. In some embodiments, the IL-4R inhibitor is contained in an auto-injector. In some embodiments, the IL-4R inhibitor is contained in a pen delivery device. In some embodiments, the pen delivery device is pre-filled.

[0030] Other embodiments will become clear when you examine the detailed description below. [Brief explanation of the drawing]

[0031] [Figure 1] Dupilumab treatment significantly and rapidly reduced the severity of dysphagia in EoE patients, as measured by the change in total DSQ score over a 24-week treatment period. DSQ scores range from 0 to 84, with lower scores indicating less frequent or severe dysphagia. Placebo = diamond (upper line of the graph); Dupilumab 300 mg QW = circle (lower line of the graph). LS: least squares; SE: standard error. *P<0.05; **P<0.01; ***P<0.001. [Figure 2A]Dupilumab treatment reduced the endoscopic features of EoE at week 24, as measured by the EREFS score. The EREFS score ranges from 0 to 18, with higher scores indicating greater severity / prevalence. Figure 2A: Absolute change from baseline in total EREFS score. Figure 2B: Change from baseline to week 24 in key features of EREFS in the proximal and distal esophageal regions. **P<0.01;***P<0.001. P values ​​are nominal. EREFS, Eosinophilic Esophagitis-Endoscopic Reference Score; LS, least squares; SD, standard deviation; SE, standard error. a Five patients in the placebo group received rescue treatment; data after rescue treatment were set to missing, and these week 24 data were imputed. Other reasons for missing data include early termination of the trial in Part A, endoscopy at week 24 occurring after patients had received their first dose of the Part C study drug, or delayed week 24 visits due to restrictions imposed by the COVID-19 pandemic. [Figure 2B]Dupilumab treatment reduced the endoscopic features of EoE at week 24, as measured by the EREFS score. The EREFS score ranges from 0 to 18, with higher scores indicating greater severity / prevalence. Figure 2A: Absolute change from baseline in total EREFS score. Figure 2B: Change from baseline to week 24 in key features of EREFS in the proximal and distal esophageal regions. **P<0.01;***P<0.001. P values ​​are nominal. EREFS, Eosinophilic Esophagitis-Endoscopic Reference Score; LS, least squares; SD, standard deviation; SE, standard error. a Five patients in the placebo group received rescue treatment; data after rescue treatment were set to missing, and these week 24 data were imputed. Other reasons for missing data include early termination of the trial in Part A, endoscopy at week 24 occurring after patients had received their first dose of the Part C study drug, or delayed week 24 visits due to restrictions imposed by the COVID-19 pandemic. [Figure 3] Dupilumab treatment normalized type 2 inflammatory signatures (T2INFGS) in esophageal biopsies of adult and adolescent EoE patients in Example 1. The rows show the genes of type 2 inflammatory signatures: IL13RA1, FCER1A, CCL17, ARG1, IL4R, STAT6, CCR4, TSLP, DPP4, SIGLEC8, GATA1, PTGDR2, CCR3, CLC, HRH1, CCL24, ALOX15, CCL26, IL1RL1, HDC, TPSAB1, CMA1, IL25, IL4, GATA3, IL13, IL5, POSTN, CCL13, CCL18, IL33, CCL11, MUC5B, MUC5AC, PTGDS, and FCER2. Each column represents the mean gene expression from one patient (a maximum of three samples per patient per time point are available). Gene expression signatures are shown for placebo-treated patients at screening and week 24 of treatment, dupilumab-treated patients at screening and week 24 of treatment, healthy controls, and EoE controls. [Figure 4] Dupilumab treatment normalized the 96-gene EoE diagnostic panel (EDPGS) in esophageal biopsies of adult and adolescent EoE patients in Example 1. The rows show the genes from the EoE diagnostic panel (Wen et al., Gastroenterology 2013;145(6):1289-1299). Each column represents the mean gene expression for one patient (up to three samples per patient per time point). Gene expression signatures are shown for placebo-treated patients at screening and week 24 of treatment, dupilumab-treated patients at screening and week 24 of treatment, healthy controls, and EoE controls. [Figure 5] The effect of dupilumab 300 mg QW versus placebo on 1,302 genes with modified expression ("DpxOme-EoE" trademark) at week 12, and their enrichment scores (NES_EoE) in each individual sample. Gene expression signatures are shown for placebo-treated patients (n=19) at baseline and week 12 of treatment, dupilumab-treated patients (n=22) at baseline and week 12 of treatment, healthy controls, and EoE controls. Rows indicate the genes of DpxOme-EoE (trademark). [Figure 6] The top 30 genes showing the greatest change in expression at week 12 after treatment with dupilumab 300 mg QW compared to placebo. [Figure 7A]Effect of dupilumab 300 mg QW versus placebo on median change from baseline to weeks 4, 12, and 24 of serum TARC (Figure 7A), plasma eotaxin-3 (Figure 7B), and serum total IgE (Figure 7C), biomarkers of type 2 inflammation, in patients with EoE. ***P-value <0.0001 for dupilumab versus placebo. The difference between dupilumab and placebo in change from baseline was analyzed using a rank-based ANCOVA model with baseline measurements as covariates, and treatment as a stratification factor and fixed factor. Values ​​after the first rescue treatment used were censored, and missing data at each visit were imputed using the last observation carried forward (LOCF) method. [Figure 7B] Effect of dupilumab 300 mg QW versus placebo on median change from baseline to weeks 4, 12, and 24 of serum TARC (Figure 7A), plasma eotaxin-3 (Figure 7B), and serum total IgE (Figure 7C), biomarkers of type 2 inflammation, in patients with EoE. ***P-value <0.0001 for dupilumab versus placebo. The difference between dupilumab and placebo in change from baseline was analyzed using a rank-based ANCOVA model with baseline measurements as covariates, and treatment as a stratification factor and fixed factor. Values ​​after the first rescue treatment used were censored, and missing data at each visit were imputed using the last observation carried forward (LOCF) method. [Figure 7C]Effect of dupilumab 300 mg QW versus placebo on median change from baseline to weeks 4, 12, and 24 of serum TARC (Figure 7A), plasma eotaxin-3 (Figure 7B), and serum total IgE (Figure 7C), biomarkers of type 2 inflammation, in patients with EoE. ***P-value <0.0001 for dupilumab versus placebo. The difference between dupilumab and placebo in change from baseline was analyzed using a rank-based ANCOVA model with baseline measurements as covariates, and treatment as a stratification factor and fixed factor. Values ​​after the first rescue treatment used were censored, and missing data at each visit were imputed using the last observation carried forward (LOCF) method. [Modes for carrying out the invention]

[0032] Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, as the methods and experimental conditions can vary. Furthermore, since the scope of the present invention is limited only by the appended claims, it should be understood that the terms used herein are intended solely to describe specific embodiments and are not intended to limit them.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention pertains.

[0034] As used herein, the term “approximately” means that, when used in reference to a particular numerical value, that value may vary by no more than 1% from the stated value. For example, as used herein, the expression “approximately 100” includes 99 and 101, as well as all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0035] As used herein, terms such as “to treat” and “to treat” mean to alleviate the symptoms of the disorder or condition mentioned, to temporarily or permanently eliminate the cause of the symptoms, or to prevent or slow the appearance of the symptoms.

[0036] "Eosinophilic esophagitis," or "EoE," as used herein, refers to an inflammatory disease characterized by abnormal eosinophilic inflammation and esophageal dysfunction in the esophagus. Primary symptoms of EoE include, but are not limited to, chest and abdominal pain, dysphagia, heartburn, food refusal, vomiting, and food impaction. The clinicopathology of EoE is characterized by the presence of elevations or tracheal cricoid grooves in the esophageal wall and eosinophilic infiltration in the esophageal mucosa. EoE is currently diagnosed by microscopic and biochemical analysis of the endoscopic esophageal mucosa following esophageal endoscopy with biopsy. EoE can be classified as atopic or non-atopic (see Mulder et al., Histopathology 2012, 61:810-822). This disclosure includes methods for treating both atopic and non-atopic forms of EoE.

[0037] As used herein, the term “subject requiring it” refers to a human or non-human mammal exhibiting one or more symptoms or signs of eosinophilic esophagitis and / or being diagnosed with eosinophilic esophagitis. In certain embodiments, this term includes subjects exhibiting elevated levels of one or more EoE-related biomarkers (as described elsewhere herein) and / or subjects having an EoE-related gene expression profile (“EoE disease transcriptome”). For example, in some embodiments, subjects treated according to the methods of this disclosure are subjects with elevated levels of IgE, serum TARC, and / or eotaxin-3, subjects having a gene expression profile consistent with a published EoE gene expression signature (Dellon et al., Clin Transl Gastroenterol 2017, 8(2):e74), or subjects with altered expression levels of one or more genes in a published EoE gene expression signature. As used herein, the terms “subject” and “patient” are used synonymously.

[0038] The term “subjects requiring it” may also include subjects who, prior to treatment, exhibit (or have exhibited) one or more signs of EoE, such as overexpression of pro-inflammatory mediators such as mast cells in the esophagus, eosinophilic infiltration of the esophagus, thickening of the esophageal wall, dysphagia, food impaction, and chest and abdominal pain, as well as / or elevated levels of EoE-related biomarkers. This term also includes subjects with elevated peripheral eosinophil counts (e.g., ≥100, ≥150, ≥200, or ≥300 cells / μL) or elevated serum IgE (>150 kU / L).

[0039] 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 (hpf) of the esophagus, or in two or more of the proximal, mid, and distal regions of the esophagus. The term "high-power field" refers to a standard total magnification of 400x by microscope, for example, used to view eosinophils in tissue from the subject's esophagus. Thus, in some embodiments, "a subject who needs it" refers to a subject who shows the presence of 15 or more eosinophils (eos) per high-power field ("hpf") in two or more of, for example, the proximal, mid, 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. Infiltration of white blood cells, such as into esophageal tissue, can be detected by cell surface markers such as eosinophil-specific markers (e.g., CD11c + , SiglecF<00 and F4 / 80 + + EMR1 + Siglec 8 + 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 + ).

[0040] Treatment method In one embodiment, a method is provided for treating, preventing, or relieving one or more symptoms of eosinophilic esophagitis (EoE) in a subject. In some embodiments, the subject is 12 years of age or older. In some embodiments, the subject is an adult. In some embodiments, the subject is a young adult between 12 and 18 years of age. In some embodiments, the subject is a young adult weighing more than 40 kg before the start of treatment.

[0041] In some embodiments, the subjects being treated have a history of frequent and / or severe dysphagia. For example, in some embodiments, the subjects have a Dysphagia Symptom Questionnaire (DSQ) score of 10 or higher, e.g., 15 or higher, 20 or higher, 25 or higher, 30 or higher, or 35 or higher, prior to the initiation of treatment. In some embodiments, the subjects have experienced at least two, three, four, five or more dysphagia episodes on average per week prior to the initiation of treatment. In some embodiments, the subjects have experienced multiple dysphagia episodes per week (e.g., at least two dysphagia episodes on average) over a period of at least four weeks, at least eight weeks, at least twelve weeks, at least sixteen weeks, or at least twenty weeks, or over a period of at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, or longer. In some embodiments, the subject has experienced multiple (e.g., two or more) episodes of dysphagia requiring medical intervention, such as liquid, cough, or dry vomiting, vomiting, or dysphagia, prior to the initiation of treatment.

[0042] In some embodiments, the subject being treated has altered levels of one or more EoE biomarkers or has a genetic signature profile of EoE-related genes that exhibits or matches a publicly available genetic signature profile for EoE patients. EoE-related biomarkers and gene expression panels for the diagnosis of EoE have been described in the Art, for example, in 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, total IgE, allergen-specific IgE, and / or allergen-specific IgG4. In some embodiments, the treated subject 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 treated subject 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.

[0043] In some embodiments, the subject being treated has or has had at least one comorbidity. In some embodiments, the comorbidity is asthma, atopic dermatitis, hand eczema and food eczema, allergic rhinitis, oral allergy syndrome, or food allergy (e.g., peanut allergy).

[0044] In some embodiments, the subject being treated has a co-existing atopic condition. In some embodiments, the co-existing atopic condition may be a food allergy, atopic dermatitis, asthma, chronic sinusitis, allergic rhinitis, or allergic conjunctivitis.

[0045] In some embodiments, the subject being treated has or has had a co-existing type 2 inflammatory condition. Non-specific examples of type 2 inflammatory conditions include asthma, chronic rhinosinusitis, allergic rhinitis, allergic fungal sinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), stoichiasis, 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, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (e.g., NSAID-exacerbated respiratory disease, or NSAID-ERD), perennial allergic rhinitis (PAR), chronic eosinophilic pneumonia (CEP), and exercise-induced bronchospasm.

[0046] In some embodiments, the subject being treated is a subject sensitive to allergens, for example, a subject with a food allergy. For example, in some embodiments, the subject may exhibit one of the following characteristics: (a) susceptible to allergic reactions or responses upon exposure to one or more allergens; (b) previously exhibited allergic reactions or responses to one or more allergens; (c) have a history of allergies; and / or (d) exhibit signs or symptoms of an allergic reaction or anaphylaxis. As used herein, terms such as “allergic response,” “allergic reaction,” and “allergic symptoms” include one or more signs or symptoms selected from the group consisting of urticaria (e.g., hives), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinusitis, watery eyes, wheezing, bronchospasm, reduced maximum expiratory flow (PEF), gastrointestinal distress, flushing, lip distension, tongue distension, hypotension, anaphylaxis, and organ dysfunction / failure. "Allergic response," "allergic reaction," and "allergic symptoms" also include immunological responses and reactions, such as increased IgE production, increased allergen-specific immunoglobulin production, and / or eosinophilia. In certain embodiments, a subject is allergic to allergens associated with EoE, or to allergens that make the subject susceptible to and / or prone to developing EoE. In some embodiments, allergens are contained in or derived from food products, such as dairy products (e.g., milk), eggs, wheat, soy, corn, rye, fish, shellfish, peanuts, and tree nuts. In some embodiments, allergens are contained in or derived from non-food products, such as dust (e.g., house dust mites), pollen, insect toxins (e.g., venom from bees, wasps, mosquitoes, etc.), mold, animal scales, latex, pharmaceuticals, drugs, ragweed, grass, or birch trees.

[0047] In some embodiments, the subject being treated presents with or has been diagnosed with a chronic esophageal disorder, including gastroesophageal reflux disease (GERD). In some embodiments, the subject being treated presents with or has been diagnosed with a chronic esophageal disorder, including a chronic gastroesophageal disorder.

[0048] In some embodiments, the subject being treated is unresponsive, poorly responsive, or resistant to one or more of the current standard treatments for EoE (e.g., elimination diets, topical corticosteroids for swallowing, glucocorticoids, PPI therapy such as high-dose PPI regimens, or esophageal dilation). In some embodiments, the subject is receiving a high-dose PPI regimen at the start of treatment with an IL-4R inhibitor. In some embodiments, the subject has previously received one or more esophageal dilations.

[0049] Anti-IL-4Rα antibody and its antigen-binding fragment According to certain exemplary embodiments of this disclosure, an IL-4R inhibitor is an anti-IL-4Rα antibody or its antigen-binding fragment. The term "antibody," as used herein, includes an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as its polymer (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (HCVR or V) as herein defined. H It includes the heavy chain steady region (abbreviated as C). The heavy chain steady region is C H 1. C H 2, and C H It contains three domains. Each light chain has a light chain variable region (LCVR or V in this specification). L It includes a light chain steady region (abbreviated as C). The light chain steady region consists of one domain (C L Includes 1). V H Region and V LThe region can be further subdivided into highly variable regions called complementary decision regions (CDRs), which are interspersed with highly conserved regions called framework regions (FRs). H and V L It consists 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 various embodiments of this disclosure, the FRs of the anti-IL-4R antibody (or its antigen-binding moiety) may be identical to the human germline sequence or may be naturally or artificially modified. The amino acid consensus sequence can be defined based on a parallel analysis of two or more CDRs.

[0050] The term “antibody,” as used herein, also includes the antigen-binding fragment of a complete antibody molecule. Terms such as “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from a complete antibody molecule using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding the variable and optionally constant domains of the antibody. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. DNA can be manipulated, for example, by sequencing, chemically, or by using molecular biological techniques to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, etc.

[0051] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv(scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated complementarity-determining regions (CDRs) such as the CDR3 peptide), or constrained FR3-CDR3-FR4 peptides. Domain-specific antibodies, single-domain antibodies, domain deletion antibodies, chimeric antibodies, CDR graft 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 included in the expression “antigen-binding fragment” as used herein.

[0052] Antigen-binding fragments of antibodies typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and generally contains at least one CDR adjacent to, or in-frame with, one or more framework sequences. L V related to the domain H In antigen-binding fragments having a domain, V H Domain and V L The domains may be positioned in any preferred arrangement relative to one another. For example, the variable region is a dimer, V H -V H , V H -V L , or V L -V L It may contain a dimer of the monomer. Alternatively, the antigen-binding fragment of the antibody may contain a monomer of V. H or V L It may also include a domain name.

[0053] In certain embodiments, the antigen-binding fragment of an antibody may include at least one variable domain covalently bound to at least one constant domain. Non-limiting and exemplary configurations of variable and constant domains that may be found within the antigen-binding fragment of an antibody of this disclosure include: (i)V H -C H 1;(ii)V H -C H 2; (iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)V L -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv)V L -C LIn any configuration of the variable domain and constant domain, including all of the exemplary configurations listed above, the variable domain and constant domain may be directly bound to each other, or they may be bound by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that result in mobile or semi-mobile binding between adjacent variable domains and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragments of the antibodies of this disclosure are bound to each other and / or one or more monomer V H Or V L The structure may include a homodimer or heterodimer (or other polymer) of any of the variable domain and constant domain configurations listed above, which are non-covalently associated with the domain (for example, by disulfide bonds).

[0054] The term “antibody,” as used herein, also includes polyspecific (e.g., bispecific) antibodies. A polyspecific antibody or antigen-binding fragment of an antibody typically comprises at least two distinct variable domains, each of which can specifically bind to a separate antigen or to a different epitope on the same antigen. Any polyspecific antibody format can be adapted for use in association with the antibodies or antigen-binding fragments of antibodies of this disclosure using standard techniques available in the art. For example, this disclosure includes a method comprising the use of a bispecific antibody, wherein one arm of the immunoglobulin is specific to IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific to a second therapeutic target or is conjugated to a therapeutic portion. Exemplary bispecificity formats that can be used in connection with this disclosure include, but are not limited to, scFv-based or diabody bispecificity formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadromas, knob-into-holes, common light chains (e.g., common light chains with knob-into-holes), CrossMab, CrossFab, (SEED) bodies, leucine zippers, duobodies, IgG1 / IgG2, dual-acting Fab(DAF)-IgG, and Mab 2 This includes bispecificity formats (for an overview of the aforementioned formats, see, for example, Klein et al., 2012, mAbs 4:6, 1-11, and the references cited therein). Bispecificity antibodies can also be constructed, for example, using peptide / nucleic acid conjugations, in which site-specific antibody-oligonucleotide conjugates are generated using non-natural amino acids with orthogonal chemical reactivity, which then self-assemble into a multimeric complex with a defined composition, titer, and geometric shape. (See, for example, Kazane et al., J.Am.Chem.Soc. [Epub: December 4, 2012]).

[0055] In some embodiments, the antibodies used in the methods of the present disclosure are human antibodies. The term “human antibody,” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. However, the human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced in vitro by random mutagenesis or site-directed mutagenesis, or in vivo by somatic mutation), for example, in the CDR, particularly in CDR3. However, the term “human antibody,” as used herein, is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, is grafted onto a human framework sequence.

[0056] The antibodies used in the methods of this disclosure may be recombinant human antibodies. The term “recombinant human antibody,” as used herein, is intended to include all human antibodies manufactured, expressed, produced, or isolated by recombinant means, e.g., antibodies expressed using recombinant expression vectors transfected into host cells (as further described below), antibodies isolated from recombinant combinatorial human antibody libraries (as further described below), antibodies isolated from animals transgenic to human immunoglobulin genes (e.g., mice) (see, e.g., Taylor et al., (1992) Nucl. Acids Res. 20:6287-6295), or antibodies manufactured, expressed, produced, or isolated by any other means involving splicing human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if transgenic animals for the human Ig sequence are used, in vivo somatic mutagenesis), and therefore the recombinant antibody V H Region and V L The amino acid sequence of the region is that of human germline VH Array and V L These are sequences that originate from and are related to other sequences, but may not naturally exist within the human antibody germline repertoire in vivo.

[0057] An “isolated antibody” refers to an antibody that has been identified and isolated and / or recovered from at least one component of its natural environment. For example, an antibody isolated or extracted from at least one component of an organism, or from a tissue or cell in which antibodies naturally exist or are 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 material and / or chemicals.

[0058] According to certain embodiments, the antibody used in the method of the present disclosure specifically binds to IL-4Rα. The term "specifically binds" means that the antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. For example, when used in connection with this disclosure, an antibody that "specifically binds" to IL-4Rα may have a K content of less than approximately 1000 nM, less than approximately 500 nM, less than approximately 300 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 90 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, less than approximately 50 nM, less than approximately 40 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 1 nM, less than approximately 0.5 nM, less than approximately 0.25 nM, less than approximately 0.1 nM, or less than approximately 0.05 nM when measured in a surface plasmon resonance assay. D Therefore, it contains antibodies that bind to IL-4Rα or a part thereof. However, isolated antibodies that specifically bind to human IL-4Rα may exhibit cross-reactivity with other antigens, such as IL-4Rα molecules from other (non-human) species.

[0059] In certain exemplary embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment, comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR), which include any of the amino acid sequences of an anti-IL-4R antibody as described in U.S. Patent No. 7,608,693. In certain exemplary embodiments, an anti-IL-4Rα antibody or its antigen-binding fragment, which can be used in connection with the methods of the present disclosure, comprises a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1, and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4Rα antibody or its antigen-binding fragment 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 SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0060] In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs. 3, 4, 5, 6, 7, and 8, respectively, and further comprises an HCVR having at least 85% sequence identity to the amino acid sequence of SEQ ID NO. 1 (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) and an LCVR having at least 85% sequence identity to the amino acid sequence of SEQ ID NO. 2 (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity). In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises an HCVR containing SEQ ID NO. 1 and an LCVR containing SEQ ID NO. 2.

[0061] In some embodiments, the anti-IL-4R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 10.

[0062] An exemplary antibody comprising 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 is the fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present disclosure involve the use of dupilumab. As used herein, “dupilumab” also includes bioequivalents of dupilumab. As used herein with respect to dupilumab, the term “bioequivalent” refers to an anti-IL-4R antibody or IL-4R-binding protein or fragment thereof that, when administered in equimolar doses, single or multiple doses, under similar experimental conditions, exhibits no significant difference in absorption rate and / or degree compared to that of dupilumab. In some embodiments, the term refers to an antigen-binding protein that binds to IL-4R and is clinically significant in terms of safety, purity, and / or potency compared to dupilumab.

[0063] Other anti-IL-4Rα antibodies that can be used in connection with the methods of this disclosure include, for example, the antibody known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788~796), or MEDI 9314, or all of the anti-IL-4Rα antibodies described in U.S. Patent Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, or 8,877,189, 10,774,141, or International Patent Publication No. WO2020 / 096381, the contents of which are incorporated herein by reference.

[0064] In some embodiments, the anti-IL-4Rα antibody or its antigen-binding fragment used in the methods of the present disclosure comprises one or more CDR, HCVR, and / or LCVR sequences listed in the accompanying sequence listing.

[0065] In some embodiments, the anti-IL-4Rα antibody is (i) 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 HCVRs containing the amino acid sequences of SEQ ID NO: -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) SEQ ID NOs: 12 (SCB-VL-39), 13 (SCB-VL-40), 14 (SCB-VL-41), 15 (SCB-VL-42), 16 (SCB-VL-43), 17 (SCB-VL-44), 18 (SCB-VL-45), 19 (SCB-VL-46), 20 (SCB-VL-47), 21 (SCB-VL-48), 22 The LCVR includes the amino acid sequence of (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 includes an HCVR containing the amino acid sequence of SEQ ID NO: 64 (SCB-VH-91) and an LCVR containing 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).

[0066] In some embodiments, the anti-IL-4Rα antibody is: SEQ ID NOs: 67 / 68 (MEDI-1-VH / MEDI-1-VL); SEQ ID NOs: 69 / 70 (MEDI-2-VH / MEDI-2-VL); SEQ ID NOs: 71 / 72 (MEDI-3-VH / MEDI-3-VL); SEQ ID NOs: 73 / 74 (MEDI-4-VH / MEDI-4-VL); SEQ ID NOs: 75 / 76 (MEDI-5-VH / MEDI-5-VL); SEQ ID NOs: 77 / 78 (MEDI-6-VH / MEDI-6 / VL); SEQ ID NOs: 79 / 80 (MEDI-7-VH / MEDI-7-VL); SEQ ID NOs: 81 / 82(MEDI-8-VH / MEDI-8-VL); Sequence ID 83 / 84(MEDI-9-VH / MEDI-9-VL); Sequence ID 85 / 86(MEDI-10-VH / MEDI-10-VL); Sequence ID 87 / 88(MEDI-11-VH / MEDI-11 / VL); Sequence ID 89 / 90(MEDI-12-VH / MEDI-12-VL); Sequence ID 91 / 92(MEDI-13-VH / MEDI-13-VL); Sequence ID 93 / 94(MEDI-14-VH / MEDI-14-VL); Sequence ID 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) ); Sequence ID 111 / 112 (MEDI-23-VH / MEDI-23-VL); Sequence ID 113 / 114 (MEDI-24-VH / MEDI-24-VL); Sequence ID 115 / 116 (MEDI-25-VH / MEDI-25-VL); Sequence ID 117 / 118 (MEDI-26-VH / MEDI-26-VL); Sequence ID 119 / 120 (MEDI-27-VH / MEDI-27-VL); Sequence ID 121 / 122 (MEDI-28-VH / MEDI-28-VL); Sequence ID 123 / 124 (MEDI-29-VH / MEDI-29-VL);Sequence ID 125 / 126 (MEDI-30-VH / MEDI-30-VL); Sequence ID 127 / 128 (MEDI-31-VH / MEDI-31-VL); Sequence ID 129 / 130 (MEDI-32-VH / MEDI-32-VL); Sequence ID 131 / 132 (MEDI-33-VH / MEDI-33-VL); Sequence ID 133 / 134 (MEDI-34-VH / MEDI-34-VL); Sequence ID 135 / 136 (MEDI-35-VH / MEDI-35-VL); Sequence ID 137 / 138 (MEDI-36-VH / MEDI-36-VL); Sequence ID 139 / 140 (MED This includes amino acid sequence pairs selected from the group consisting of I-37-VH / MEDI-37-VL); SEQ ID NOs: 141 / 142 (MEDI-38-VH / MEDI-38-VL); SEQ ID NOs: 143 / 144 (MEDI-39-VH / MEDI-39-VL); SEQ ID NOs: 145 / 146 (MEDI-40-VH / MEDI-40-VL); SEQ ID NOs: 147 / 148 (MEDI-41-VH / MEDI-41-VL); SEQ ID NOs: 149 / 150 (MEDI-42-VH / MEDI-42-VL); and SEQ ID NOs: 151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).

[0067] In some embodiments, the anti-IL-4Rα antibody is (i) 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 HCVRs containing the amino acid sequences of (i) 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) 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 (A Includes LCVR containing the amino acid sequence of JOU-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).

[0068] In some embodiments, the anti-IL-4Rα antibody is (i) 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) (ii) comprising HCVR; and (ii) comprising 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).

[0069] In some embodiments, the anti-IL-4Rα antibody used in the methods of the present disclosure may have pH-dependent binding properties. For example, the anti-IL-4Rα antibody used in the methods of the present disclosure may exhibit reduced IL-4Rα binding at acidic pH compared to neutral pH. Alternatively, the anti-IL-4Rα antibody of the present disclosure may exhibit enhanced antigen-binding at acidic pH compared to neutral pH. The term "acidic pH" includes pH values ​​less than about 6.2, such as 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, or less. As used herein, the term "neutral pH" means pH from about 7.0 to about 7.4. The term "neutral pH" includes pH values ​​of approximately 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0070] In a specific case, the "reduced IL-4Rα binding activity at acidic pH compared to neutral pH" was attributed to the K of the antibody that binds to IL-4Rα at acidic pH. D The value of the antibody K that binds to IL-4Rα at neutral pH. D It is expressed as a ratio to a value (and vice versa). For example, an antibody or its antigen-binding fragment has an acidic / neutral potassium ratio of approximately 3.0 or higher. D When a ratio is observed, the antibody or its antigen-binding fragment can be considered in this disclosure to exhibit "reduced IL-4Rα binding at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K of the antibody or antigen-binding fragment of this disclosure D The ratio can be approximately 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 higher.

[0071] Antibodies with pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for their binding to a specific antigen that is reduced (or enhanced) at acidic pH compared to neutral pH. Furthermore, modifications to the antigen-binding domain at the amino acid level can also yield antibodies with pH-dependent properties. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues, antibodies with reduced antigen-binding activity at acidic pH compared to neutral pH can be obtained.

[0072] Manufacturing of human antibodies Methods for generating human antibodies in transgenic mice are known in the art. Any of these known methods can be used in connection with this disclosure to produce human antibodies that specifically bind to human IL-4R.

[0073] When using VELOCIMMUNE® technology (see, for example, US6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, a high-affinity chimeric antibody against IL-4R having a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves generating a transgenic mouse having a genome containing human heavy chain variable regions and light chain variable regions operably ligated to an endogenous mouse constant region locus, such that the mouse produces an antibody containing the human variable region and the mouse constant region in response to antigen stimulation. The DNA encoding the variable regions of the antibody's heavy chain and light chain is isolated and operably ligated to the DNA encoding the human heavy chain constant region and light chain constant region. The DNA is then expressed in cells capable of expressing a fully human antibody.

[0074] Generally, VELOCIMMUNE® mice are loaded with the target antigen, and lymphoid cells (such as B cells) are recovered from mice that express antibodies. These lymphoid cells can be fused with myeloma cell lines to produce immortal hybridoma cell lines, which are then screened and selected to identify hybridoma cell lines that produce antibodies specific to the target antigen. DNA encoding the variable regions of the heavy and light chains may be isolated and ligated to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells such as CHO cells. Alternatively, antigen-specific chimeric antibodies or DNA encoding the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes.

[0075] First, a high-affinity chimeric antibody having a human variable region and a mouse constant region is isolated. This antibody is analyzed and selected for desirable properties, including affinity, selectivity, and epitopes, using standard procedures known to those skilled in the art. By replacing the mouse constant region with a desired human constant region, the fully human antibody of this disclosure, e.g., wild-type or modified IgG1 or IgG4, is generated. The selected constant region may vary depending on the specific application, but the high-affinity antigen-binding and target-specific properties reside in the variable region.

[0076] Generally, the antibodies that can be used in the methods of this disclosure have high affinity when measured by binding to an antigen immobilized on a solid phase or to an antigen in a solution phase, as described above. A fully human antibody of this disclosure is generated by replacing the mouse constant region with a desired human constant region. The selected constant region may vary depending on the specific application, but the high affinity antigen binding and target specificity properties reside in the variable region.

[0077] In one embodiment, a human antibody or its antigen-binding fragment 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 (LCDR1, LCDR2, and LCDR3) 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 the amino acid sequences of HCVRs and LCVRs are well known in the art and can be used to identify CDRs within the amino acid sequences of specific HCVRs and / or LCVRs disclosed herein. Exemplary rules that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Broadly speaking, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. For example, see Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J.Mol.Biol.273:927~948 (1997); and Martin et al., Proc.Natl.Acad.Sci.USA 86:9268~9272 (1989). Public databases are also available for identifying CDR sequences in antibodies.

[0078] Pharmaceutical composition In one embodiment, the Disclosure provides a method comprising administering an IL-4R inhibitor to a target, wherein the IL-4R inhibitor (e.g., an anti-IL-4R antibody) is contained in 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, intramuscular, oral, intraperitoneal, intrasacral, transdermal, topical, or subcutaneous administration.

[0079] In some embodiments, the pharmaceutical composition includes injectable formulations, such as dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, and intravenous infusions. These injectable formulations can be manufactured by known methods. For example, an injectable formulation can be manufactured, for example, by dissolving, suspending, or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injection. Examples of aqueous media for injection include physiological saline, isotonic solutions containing glucose and other adjuvants, which may be used in combination with suitable solubilizers such as alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. Examples of oily media include sesame oil and soybean oil, which may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. The injectable solutions thus manufactured can be filled into suitable ampoules.

[0080] The dose of antibody administered to a patient according to the method of this disclosure may vary depending on the patient's age and size, symptoms, condition, and route of administration. The dose is typically calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. Effective doses and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be determined empirically; for example, the patient's progress can be monitored by periodic assessments, and the dose adjusted accordingly. Furthermore, interspecies scaling of doses may be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Specific exemplary doses of anti-IL4R antibodies and administration regimens using them, which may be used in connection with this disclosure, are disclosed elsewhere in this specification.

[0081] Various delivery systems are known and can be used to administer pharmaceutical compositions, including liposome encapsulation, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, for example, Wu et al., 1987, J. Biol. Chem. 262:4429-4432). These methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through the epithelium or mucocutaneous lining (e.g., oral mucosa, rectal mucosa, and intestinal mucosa), and may be administered together with other bioactive agents. In some embodiments, the pharmaceutical compositions disclosed herein are administered intravenously. In some embodiments, the pharmaceutical compositions disclosed herein are administered subcutaneously.

[0082] In some embodiments, the pharmaceutical compositions of this disclosure are contained within a container. Thus, in other embodiments, a container containing the pharmaceutical compositions disclosed herein is provided. For example, in some embodiments, the pharmaceutical compositions are contained within a container selected from the group consisting of glass vials, syringes, pen delivery devices, and auto-injectors.

[0083] In some embodiments, the pharmaceutical compositions of the Disclosure are delivered, for example, subcutaneously or intravenously, by a standard needle and syringe. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, a pen delivery device or auto-injector is used to deliver the pharmaceutical compositions of the Disclosure (for example, for subcutaneous delivery). The pen delivery device may be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all of 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. Disposable pen delivery devices do not have replaceable cartridges. Rather, disposable pen delivery devices are provided with the pharmaceutical composition pre-filled in a reservoir within the device. Once the pharmaceutical composition is depleted from the reservoir, the entire device is discarded.

[0084] Examples of suitable pens and auto-injector delivery devices include AUTOPEN® (Owen Mumford, Inc., Woodstock, UK), DISETRONIC® pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 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®, and OPTIPEN Examples of disposable pen delivery devices applicable to the subcutaneous delivery of the pharmaceutical compositions of this disclosure include, but are not limited to, STARLET® and OPTICLIK® (Sanofi-Aventis, Frankfurt, Germany).

[0085] In some embodiments, the pharmaceutical composition is delivered using a controlled-release system. In one embodiment, a pump may be used (see Langer, cited above; Sefton, 1987, CRC Crit.Ref.Biomed.Eng.14:201). In another embodiment, a polymer material may be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida). In yet another embodiment, the controlled-release system may be positioned near the target of the composition so that only a portion of the systemic dose is required (see, for example, Goodson, 1984, Medical Applications of Controlled Release, cited above, Vol. 2, pp. 115-138). Other controlled-release systems are described in Langer's review, 1990, Science 249:1527-1533.

[0086] In some embodiments, the pharmaceutical compositions for use described herein are manufactured into unit dose dosage forms suitable for containing a dose of the active ingredient. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, and the like.

[0087] Exemplary pharmaceutical compositions containing an anti-IL-4R antibody that can be used in connection with this disclosure are disclosed, for example, in U.S. Patent No. 8,945,559.

[0088] Dosage and administration regimen Typically, the amount of IL-4R inhibitor (e.g., the anti-IL-4R antibody disclosed herein) administered to a subject according to the methods disclosed herein is a therapeutically effective dose. As used herein, the term “therapeutically effective dose” means an amount of IL-4R inhibitor that results in one or more of the following: (a) a reduction in the severity or duration of symptoms of eosinophilic esophagitis; (b) a reduction in the number of eosinophils in the esophagus; (c) an increase in esophageal distension; (d) a reduction in the episode or intensity of dysphagia; (e) a normalization of one or more EoE-related biomarkers or gene expression signatures; and / or (f) a reduction in the use or need for concurrent or rescue treatment with another agent (e.g., a reduction or elimination of the use of systemic and / or topical corticosteroids, PPIs, etc.).

[0089] For anti-IL-4R antibodies, the therapeutically effective dose is approximately 0.05 mg to 600 mg, 50 mg to 600 mg, or 50 mg to 300 mg of anti-IL-4R antibody, for example, approximately 0.05 mg, 0.1 mg, 1.0 mg, 1.5 mg, 2.0 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 2 It may be 40 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, or approximately 600 mg. In certain embodiments, the target is administered 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg of anti-IL-4R antibody.

[0090] The amount of IL-4R inhibitor (e.g., anti-IL-4R antibody) contained in each dose may be expressed in milligrams (i.e., mg / kg) of the activator (e.g., antibody) per kilogram of patient body weight. For example, an IL-4R inhibitor can be administered to a patient in doses of approximately 0.0001 to approximately 10 mg / kg based on patient body weight, for example, approximately 1 mg / kg to approximately 10 mg / kg, or approximately 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.

[0091] In some embodiments, an IL-4R inhibitor or a pharmaceutical composition containing an IL-4R inhibitor is administered to a subject approximately four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or at a less frequent dosing frequency as long as a therapeutic response is achieved. In certain embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, a once-weekly dosing dose can be used in amounts ranging from approximately 50 mg to approximately 600 mg, for example, approximately 75 mg, 150 mg, 200 mg, or 300 mg.

[0092] In some embodiments, multiple doses of an IL-4R inhibitor are administered to a subject over a defined period of time. In some embodiments, the method of the present disclosure includes sequential administration of multiple doses of an IL-4R inhibitor to a subject. As used herein, “sequential administration” means that each dose of the IL-4R inhibitor is administered to the subject at different times, for example, on different days with a predetermined interval (e.g., several hours, several days, several weeks, or several months). In some embodiments, the method of the present disclosure includes sequentially administering to a patient a single initial dose of an IL-4R inhibitor, followed by one or more secondary doses of an IL-4R inhibitor, and optionally one or more tertiary doses of an IL-4R inhibitor.

[0093] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the chronological order of IL-4R inhibitor administration. Thus, the “initial dose” is the dose administered at the start of the treatment regimen (also called the “loading dose”); the “secondary dose” is the dose administered after the initial dose; and the “tertiary dose” is the dose administered after the secondary dose. While the initial, secondary, and tertiary doses may each contain the same amount of IL-4R inhibitor, they may generally differ from one another in terms of the frequency of administration. However, in certain embodiments, the amounts of IL-4R inhibitor contained in the initial, secondary, and / or tertiary doses may differ from one another during the course of treatment (e.g., adjusted upwards or downwards as needed). In certain embodiments, one or more doses (e.g., 1, 2, 3, 4, or 5) may be administered as a “loading dose” at the start of the treatment regimen, followed by less frequent subsequent doses (e.g., “maintenance doses”). For example, an IL-4R inhibitor may be administered to a subject in a loading dose of approximately 200 mg, 400 mg, or 600 mg, followed by one or more maintenance doses of approximately 75 mg to 300 mg. In one embodiment, each of the initial dose and one or more secondary doses comprises 50 mg to 600 mg of the IL-4R inhibitor, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg of the IL-4R inhibitor. In some embodiments, each of the initial dose and one or more secondary doses comprises the same amount of the IL-4R inhibitor. In other embodiments, the initial dose comprises a first amount of the IL-4R inhibitor, and each of the one or more secondary doses comprises a second amount of the IL-4R inhibitor. For example, the first dose of the IL-4R inhibitor may be 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times, or more, the second dose of the IL-4R inhibitor. In some embodiments, the subject is administered an IL-4R inhibitor (e.g., approximately 50 mg to approximately 600 mg, for example, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, or one or more doses of approximately mg) without a loading dose.

[0094] In some embodiments, each of the secondary and / or tertiary doses is administered 1 to 14 weeks after the immediately preceding dose (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 weeks or more). The term "immediately preceding dose," as used herein, means the dose of the IL-4R inhibitor administered to the patient in a multiple-dosing sequence that has no intermediate doses and is immediately preceding the next dose in that sequence.

[0095] The methods of this disclosure may include administering any number of secondary and / or tertiary doses of an IL-4R inhibitor to a patient. For example, in one particular embodiment, only a single secondary dose is administered to the patient. In another embodiment, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in one particular embodiment, only a single tertiary dose is administered to the patient. In another embodiment, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0096] In some embodiments involving multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the previous dose. Similarly, in some embodiments involving multiple tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the previous dose. Alternatively, the frequency at which secondary and / or tertiary doses are administered to the patient may vary throughout the course of the treatment regimen. Furthermore, the frequency of administration may be adjusted by the physician during the course of treatment according to the individual patient's needs after clinical examinations.

[0097] In some embodiments, for subjects aged 12 years or older with eosinophilic esophagitis, a therapeutically effective dose of an IL-4R inhibitor (e.g., an anti-IL-4R antibody disclosed herein) comprises an initial (loading) dose followed by one or more secondary (maintenance) doses, the initial dose of the IL-4R inhibitor (e.g., an anti-IL-4R antibody) comprising 600 mg, and each secondary dose of the IL-4R inhibitor (e.g., an anti-IL-4R antibody) comprising 300 mg administered weekly (QW).

[0098] In some embodiments, for subjects aged 12 years or older with eosinophilic esophagitis, the therapeutically effective dose of an IL-4R inhibitor (e.g., anti-IL-4R antibody) comprises an initial (loading) dose followed by one or more secondary (maintenance) doses, the initial dose of the IL-4R inhibitor (e.g., anti-IL-4R antibody) comprising 600 mg, and each secondary dose of the IL-4R inhibitor (e.g., anti-IL-4R antibody) comprising 300 mg administered every two weeks (Q2W).

[0099] In some embodiments, for subjects aged 12 years or older with eosinophilic esophagitis, a therapeutically effective dose of an IL-4R inhibitor (e.g., anti-IL-4R antibody) includes a dose of 300 mg of the IL-4R inhibitor (e.g., anti-IL-4R antibody) administered weekly (QW).

[0100] In some embodiments, for subjects aged 12 years or older with eosinophilic esophagitis, a therapeutically effective dose of an IL-4R inhibitor (e.g., anti-IL-4R antibody) includes a dose of 300 mg of the IL-4R inhibitor (e.g., anti-IL-4R antibody) administered every two weeks (Q2W).

[0101] EoE-related parameters In some embodiments, the therapeutic methods disclosed herein result in 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, the following: (a) changes in the frequency and / or severity of dysphagia, measured using, for example, the Dysphagia Symptom Questionnaire (DSQ), the Straumann Dysphagia Instrument (SDI), the Patient's General Impression of Changes in Dysphagia (PGIC), or the Patient's General Impression of Severity (PGIS) (e.g., reduction); (b) changes in the eosinophil count in esophageal epithelium (e.g., reduction); (c) changes in one or more esophageal characteristics, such as the absence, presence, or severity of edema, cricoid sulcus, exudate, longitudinal grooves, and / or stenosis, measured using, for example, the EoE-EREFS; (d) changes in esophageal distensibility, such as those measured using, for example, the EndoFLIP (endoluminal functional lumen imaging) probe. (e) Changes in the severity and / or extent of histological features within the esophagus, as measured using, for example, the Eosinophilic Esophagitis Histological Scoring System (EoE-HSS); (f) Changes in the level of one or more EoE-related biomarkers or EoE gene expression signatures, as measured using, for example, normalization; or (g) Changes in the frequency and / or severity of other symptoms of EoE, as measured using, for example, the Eosinophilic Esophagitis Impact Questionnaire (EoE-IQ), the EoE Symptom Questionnaire, the Eosinophilic Esophagitis Activity Index (EEsAI), the Adult Eosinophilic Quality of Life (EoE-QQL-A), or the European Quality of Life 5-item scale (EQ-5D). Changes when measured using a 5-dimensional scale.Methods for evaluating these EoE-related parameters are described in the Examples section below and are disclosed in WO2019 / 028367, which is incorporated herein by reference.

[0102] To determine whether EoE-related parameters have “improved,” the parameters are quantified at baseline and at one or more time points after administration of the IL-4R inhibitor. For example, EoE-related parameters are quantified on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 after initial treatment with the pharmaceutical composition of this disclosure; or at the end of week 1, the end of week 2, the end of week 3, the end of week 4. Furthermore, measurements may be taken at the end of 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 later. By using the difference between the parameter value at a specific point in time after the start of treatment and the parameter value at baseline, it can be confirmed whether there has been improvement in the EoE-related parameter.

[0103] In some embodiments, treatment of a subject with an IL-4R inhibitor (e.g., an anti-IL-4R antibody) according to the methods disclosed herein results in an improvement in the symptoms of dysphagia. In some embodiments, the treatment results in a change (e.g., reduction) in the frequency and / or intensity of dysphagia in the subject. In some embodiments, the treatment results in a reduction in the frequency of dysphagia episodes per week, e.g., a reduction of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to baseline (e.g., the mean frequency of dysphagia episodes per week in the subject before the start of treatment). In some embodiments, the treatment results in an improvement in the DSQ score. The DSQ is a validated patient-reported outcome (PRO) used in clinical trials to measure the frequency and severity of dysphagia (Hudgens et al., J Patient Rep Outcomes 2017, 1(1):3, doi:10.1186 / s41687-017-0006-5). The DSQ uses a daily recall period and includes three questions regarding the presence and severity of EoE dysphagia. Typically, patients answer at least questions 1 and 2 of the DSQ and are required to have eaten solid food (question 1: "Have you eaten solid food since you woke up this morning?" with a "yes") to proceed to the next part of the questionnaire. If a patient answers "no" to question 1, the remaining items on the DSQ are not scored. Patients who answer "no" to Question 2 ("Have you experienced any difficulty swallowing or food getting stuck in your throat since waking up this morning?") are given a score of zero and do not proceed to Question 3 (their journal will record that day as completed). Those who answer "yes" to Questions 1 and 2 proceed to Question 3, which is scored on a 5-point scale that estimates the severity of dysphagia based on the patient's actions to alleviate symptoms, from taking no action to seeking medical attention. Thus, the DSQ scoring algorithm is constructed from the answers to Questions 2 and 3 to ensure that the final score is determined by the frequency and severity of dysphagia.To calculate the DSQ score, at least eight diary entries are required for each 14-day period to derive a standardized total score based on the cumulative score over 14 days. In some embodiments, the DSQ is a modified DSQ, and for patients who answered "no" to question 1 ("Have you eaten any solid food since you woke up this morning?"), follow-up questions are used to determine whether the patient avoided solid food due to swallowing difficulties. The DSQ score can theoretically range from 0 to 84, with lower scores indicating less frequent or severe dysphagia. In some embodiments, treatment with an IL-4R inhibitor results in a decrease in the DSQ score compared to baseline (e.g., the subject's DSQ score before the start of treatment). In some embodiments, treatment with an IL-4R inhibitor results in a decrease of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more points in the DSQ score compared to baseline. In some embodiments, treatment with an IL-4R inhibitor results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the DSQ score compared to baseline. In some embodiments, the change in the DSQ score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or thereafter after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor. In some embodiments, treatment with an IL-4R inhibitor reduces the symptoms of dysphagia in the subject (measured, for example, by the change in absolute DSQ score compared to baseline or the percentage decrease in DSQ score) within approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks from the start of treatment with the IL-4R inhibitor.

[0104] Changes in dysphagia symptoms can also be assessed using the Patient's Global Impression of Change in Dysphagia (PGIC). The PGIC is a one-item questionnaire that asks patients to provide a comprehensive self-assessment of changes in their difficulty swallowing food on a 7-point scale (significantly improved; moderately improved; slightly improved; no change; slightly worsened; moderately worsened; or significantly worsened). In some embodiments, treatment with an IL-4R inhibitor results in a decrease in the PGIC score compared to baseline (e.g., the subject's PGIC score before the start of treatment). In some embodiments, treatment with an IL-4R inhibitor results in a decrease of at least 1, 2, 3, or more points in the PGIC score compared to baseline. In some embodiments, treatment with an IL-4R inhibitor results in a PGIC assessment of "significantly improved" or "moderately improved." In some embodiments, treatment with an IL-4R inhibitor reduces the symptoms of dysphagia in subjects (measured, for example, by improvement in the PGIC score compared to the baseline value for that subject) within approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks from the start of treatment with the IL-4R inhibitor.

[0105] In some embodiments, the procedure results in an improvement in the SDI score. SDI is an unproven patient-reported outcome (PRO) used in clinical trials to determine the frequency and severity of dysphagia (Straumann 2010). There is a one-week recall period for SDI. The frequency of dysphagia events is graded on a 5-point scale: 0 = none, 1 = once a week, 2 = several times a week, 3 = once a day, and 4 = several times a day. The severity of dysphagia events is graded on a 6-point scale: 0 = no difficulty swallowing, 1 = slight resistance, 2 = slight nausea with delayed passage, 3 = short-term obstruction requiring intervention (e.g., beverage intake, breathing), 4 = longer-term obstruction that can only be relieved by vomiting, and 5 = long-term complete obstruction requiring endoscopic intervention. The total SDI score ranges from 0 to 9. In some embodiments, treatment with an IL-4R inhibitor results in a reduction of 1, 2, 3, 4, 5, 6, or more points in the SDI score compared to baseline (e.g., the subject's SDI score before the start of treatment). In some embodiments, treatment with an IL-4R inhibitor results in a reduction of at least 3 points in the SDI score compared to baseline. In some embodiments, treatment with an IL-4R inhibitor results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the SDI score compared to baseline. In some embodiments, the change in the SDI score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or thereafter after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor.

[0106] In some embodiments, treatment of a subject with an IL-4R inhibitor (e.g., an anti-IL-4R antibody) results in an improvement (e.g., reduction) of the peak esophageal intraepithelial eosinophil count. “Peak esophageal intraepithelial eosinophil count” refers to the number of eosinophils contained in a single high-magnification field (hpf). In some embodiments, treatment with an IL-4R inhibitor results in a decrease in the peak esophageal intraepithelial eosinophil count compared to baseline (e.g., the subject's peak count before the start of treatment). In some embodiments, treatment with an IL-4R inhibitor results in a decrease of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the peak esophageal intraepithelial eosinophil count compared to baseline. In some embodiments, treatment with an IL-4R inhibitor results in a decrease of 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 inhibitor results in a reduction of the peak esophageal intraepithelial eosinophil count to ≤6 eos / hpf, ≤5 eos / hpf, ≤4 eos / hpf, ≤3 eos / hpf, ≤2 eos / hpf, or ≤1 eos / hpf. In some embodiments, the change in peak esophageal intraepithelial eosinophil count is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or thereafter after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor.

[0107] In some embodiments, treatment with an IL-4R inhibitor (e.g., anti-IL-4R antibody) results in improvement of one or more endoscopic features of EoE. In some embodiments, treatment with an IL-4R inhibitor (e.g., anti-IL-4R antibody) results in improvement of the EoE-EREFS score. EoE-EREFS [(edema, rings, exudates, furrows, strictures)] is a validated scoring system for the inflammatory and remodeling features of disease, used to measure the inflammatory and remodeling features of EoE esophageal mucosa identified endoscopically (Hirano). 2014). This measurement method includes a total of 17 items related to the presence and severity of esophageal features. Specific esophageal features include: annular grooves (concentric annular grooves surrounding the esophagus - absent, mild, moderate, severe, not applicable); stricture (narrowing of the esophagus - present, absent, not applicable); diameter of stricture (if applicable); exudate (referring to white patches - absent, mild, severe); longitudinal grooves (longitudinal lines running through the esophagus - absent, present); edema (loss of vascular shadows in the mucosa - absent, present); crepe-like esophagus (absent, present); and a comprehensive overall appearance integrating all EoE findings identified endoscopically (i.e., fixed annular grooves, stricture, whitish exudate, longitudinal groove formation, edema, and crepe-like mucosa). Furthermore, mucosal changes associated with gastroesophageal reflux disease are considered in relation to erosion. The results are recorded using the Angeles classification system (no erosion, or LA classification A, B, C, D). In some embodiments, treatment with an IL-4R inhibitor results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the EoE-EREFS score compared to baseline (e.g., the subject's EoE-EREFS score before the start of treatment). In some embodiments, the change in the EoE-EREFS score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or thereafter after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor.

[0108] In some embodiments, targeted treatment with an IL-4R inhibitor (e.g., anti-IL-4R antibody) results in improvement of one or more histological features of EoE. In some embodiments, targeted treatment with an IL-4R inhibitor (e.g., anti-IL-4R antibody) results in improvement of the EoE-HSS score. EoE-HSS is a validated measurement method that generates distinct severity (grade) and extent (stage) disease scores. This score is used to measure eight histological features (parameters) of EoE in three different regions of the esophagus (proximal, middle, and distal) (Collins et al., 2017). The eight parameters include: eosinophil density, basal hyperplasia, eosinophil abscess, eosinophil surface laminarization, intercellular space dilation, surface epithelial changes, abnormal keratinocytes, and lamina propria fibrosis. A scale of 0 to 3 is used for each parameter in both grade and stage (0 being the mildest and normal inflammation). In some embodiments, treatment with an IL-4R inhibitor results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the EoE-HSS score compared to baseline (e.g., the subject's EoE-HSS score before the start of treatment). In some embodiments, treatment with an IL-4R inhibitor results in a reduction 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 days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or thereafter after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor.

[0109] In some embodiments, treatment with an IL-4R inhibitor (e.g., an anti-IL-4R antibody) results in improved esophageal distensibility. In some embodiments, esophageal distensibility is assessed using an intraluminal functional lumen imaging probe (EndoFLIP, Medtronic, USA) to measure the diameter and pressure of the esophageal lumen. The EndoFLIP device is a catheter-based technique that records intraluminal pressure during esophageal volume expansion while simultaneously measuring cross-sectional area at multiple locations along the esophagus. Analysis of the relationship between esophageal cross-sectional area and pressure allows for the determination of esophageal compliance and distensibility plateau (DP). DP has been shown to be significantly reduced in EoE patients compared to healthy controls (Kwiatek 2011). In some embodiments, treatment with an IL-4R inhibitor results in an increase of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in esophageal distension (as measured by DP) compared to baseline (e.g., the subject's esophageal distension or DP before the start of treatment). In some embodiments, treatment with an IL-4R inhibitor results in an increase of at least 0.5 mm, 1 mm, 1.5 mm, or more in DP. In some embodiments, the change in esophageal distension is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or thereafter after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor.

[0110] In some embodiments, targeted treatment with an IL-4R inhibitor (e.g., an anti-IL-4R antibody) according to the methods disclosed herein results in an improvement in health-related quality of life. In some embodiments, the treatment results in an improvement in the EoE-IQ score. The EoE-IQ assesses the impact of EoE on a scale of 1 to 5; a higher score indicates a greater deterioration in health-related QoL. In some embodiments, treatment with an IL-4R inhibitor results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the EoE-IQ score compared to baseline. In some embodiments, changes in the EoE-IQ score are measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or thereafter after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor. In some embodiments, treatment with the IL-4R inhibitor improves the health-related quality of life in subjects (measured, for example, by the change in absolute EoE-IQ score compared to the baseline value for that subject, or by the percentage decrease in the EoE-IQ score) within approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks from the start of treatment with the IL-4R inhibitor.

[0111] In some embodiments, targeted treatment with an IL-4R inhibitor (e.g., an anti-IL-4R antibody) according to the methods disclosed herein results in improvement of symptoms other than dysphagia. In some embodiments, the treatment results in improvement of the EoE-SQ frequency score. The EoE-SQ frequency scale evaluates symptoms other than dysphagia on a scale of 5 to 25; a higher score indicates a higher symptom load. In some embodiments, treatment with an IL-4R inhibitor results in a decrease of at least 1, 2, 3, 4, 5, 6, or more points in the EoE-SQ frequency score compared to baseline. In some embodiments, treatment with an IL-4R inhibitor results in a decrease of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the EoE-SQ frequency score compared to baseline. In some embodiments, changes in the EoE-SQ frequency score are measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or thereafter after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor. In some embodiments, treatment with the IL-4R inhibitor improves symptoms other than dysphagia in the subject (measured, for example, by the change in the absolute EoE-SQ frequency score compared to the baseline value for that subject, or by the percentage decrease in the EoE-SQ frequency score) within approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks from the start of treatment with the IL-4R inhibitor.

[0112] In some embodiments, treatment of a target with an IL-4R inhibitor (e.g., an anti-IL-4R antibody) results in the normalization of the Normalized Enrichment Score (NES) calculated for one or more EoE-related biomarkers, EoE gene signatures, type 2 inflammatory gene signatures, and / or sets of EoE-related genes. In some embodiments, treatment of a target with an IL-4R inhibitor suppresses the NES calculated for EoE gene signatures, type 2 inflammatory gene signatures, and / or sets of EoE-related genes 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 in or detectable in EoE patients at a level or amount different (e.g., higher or lower) than that of a marker present in or detectable in non-EoE patients. In some embodiments, EoE-related biomarkers are genes 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 IgE and allergen-specific IgE), serum IgG (total IgG and allergen-specific IgG), arachidonic acid 15-lipoxygenase (ALOX15), IL-13, IL-5, serum thymic and activating regulatory chemokines (TARC; CCL17), thymic interstitial lymphocyte neogenesis factor (TSLP), serum eosinophil cation proteins (ECP), and collagen genes (e.g., COL4A3, COL4A4, COL4A6, C). Examples of genes that may be included are, but are not limited to, OL8A2, COL14A1, and COL21A1), calpain 14, desmoglein-1 (DSG1), filaggrin (FLG), signaling and transcriptional activator 6 (STAT6), Kazal-type serine peptidase inhibitor 5 (SPINK5), SPINK7, SPINK8, interleukin-4 receptor (IL-4R), eosinophil-related genes (e.g., CLC and SIGLEC8), anoctamin-1 (ANO1), cathepsin C (CTSC), CC chemokine receptor 3 (CCR3), and eosinophil-derived neurotoxins (EDN). The term “EoE gene signature” refers to the differential gene expression profile of esophageal biopsies from EoE patients compared to healthy controls, and is also called the “EoE disease transcriptome” (Sherrill, 2014). In some embodiments, the EoE gene signature is a smaller set of genes from the publicly available EoE disease transcriptome, such as the EoE diagnostic panel (EDP, clinically available as EoGenuis®, Inform Diagnostics, USA). The “type 2 inflammation gene signature” refers to the transcriptome of a set of genes associated with type 2 inflammation. Exemplary type 2 inflammation-associated genes include, but are not limited to, CCL26, ALOX15, CCR3, and IL1RL1. A list of exemplary genes in the type 2 inflammation gene signature is shown in Figure 3.The normalized enrichment score (NES) reflects the extent to which the activity levels of a transcript set are over-presented at both ends (upper or lower) of the ranked list of transcripts in the sample, normalized by taking into account the number of transcripts in the set (Subramanian, 2005) (Barbie, 2009).

[0113] In some embodiments, EoE-related biomarkers, EoE gene signatures, type 2 inflammatory gene signatures, and / or NES are determined using tissue samples from the subject (e.g., esophageal pinch biopsy samples from the proximal, middle, and / or distal regions). In some embodiments, treatment of the subject with an IL-4R inhibitor results in the normalization of one or more EoE-related biomarkers, EoE gene signatures, type 2 inflammatory gene signatures, and / or NES compared to baseline (e.g., the expression level of the subject's EoE-related biomarkers, EoE gene signature, or NES before the start of treatment) when measured, for example, on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or later after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor. In some embodiments, treatment of a subject with an IL-4R inhibitor suppresses NES for one or more EoE-related biomarkers, EoE gene signatures, or type 2 inflammatory gene signatures compared to baseline (e.g., NES of the subject before the start of treatment), when measured, for example, on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or thereafter after administration of the IL-4R inhibitor, or 24 weeks after treatment with the IL-4R inhibitor.

[0114] In some embodiments, treatment of the target with an IL-4R inhibitor (e.g., an anti-IL-4R antibody) results in normalization of the type 2 inflammatory gene signature, or normalization of a subset of genes in the type 2 inflammatory gene signature. In some embodiments, the gene signature is the one shown in Figure 3, which includes, for example, the genes IL13RA1, FCER1A, CCL17, ARG1, IL4R, STAT6, CCR4, TSLP, DPP4, SIGLEC8, GATA1, PTGDR2, CCR3, CLC, HRH1, CCL24, ALOX15, CCL26, IL1RL1, HDC, TPSAB1, CMA1, IL25, IL4, GATA3, IL13, IL5, POSTN, CCL13, CCL18, IL33, CCL11, MUC5B, MUC5AC, PTGDS, and FCER2. In some embodiments, treatment with an IL-4R inhibitor results in the normalization of at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the type 2 inflammatory gene signature, for example, the type 2 inflammatory gene signature shown in Figure 3. In some embodiments, normalization of the gene signature or a subset of the gene signature is measured, for example, on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or later after administration of an IL-4R inhibitor, or 24 weeks after treatment with an IL-4R inhibitor, compared to baseline (e.g., the target gene signature before the start of treatment (e.g., gene expression level)).

[0115] In some embodiments, treatment of the target with an IL-4R inhibitor (e.g., an anti-IL-4R antibody) results in the normalization of the gene signature shown in Figure 6, or the normalization of a subset of genes in the gene signature of Figure 6, including, for example, the genes TNFAIP6, LRRC31, SLC26A4-AS1, ALOX15, CCL26, TGM6, NRXN1, PMCH, SLC26A4, CXCL1, CCR3, TREML2, POSTN, LURAP1L, CXCL6, CRTAC1, BC107108, SFTA2, C2orf16, KRTAP3-2, PLNIPRP3, CIDEA, SLC8A1-AS1, SPINK8, DPCR1, MUC22, CRISP2, DSG1, GYS2, and CRISP3. In some embodiments, treatment of the target with an IL-4R inhibitor (e.g., an anti-IL-4R antibody) reduces, suppresses, or normalizes the expression of TARC (e.g., serum TARC), eotaxin-3 (e.g., plasma eotaxin-3), and / or IgE (e.g., total serum IgE).

[0116] Combination therapy In some embodiments, the methods of the present disclosure include administering one or more additional therapeutic agents to a subject in combination with an IL-4R inhibitor. As used herein, the expression “in combination with” means that the additional therapeutic agent is administered before, after, or concurrently with the pharmaceutical composition comprising the IL-4R antagonist. The term “in combination with” also includes sequential or concurrent administration of the IL-4R antagonist and the second therapeutic agent or therapy. In some embodiments, the second therapeutic agent or therapy is an IL-1β inhibitor, an IL-5 inhibitor or an IL-5R inhibitor (e.g., an anti-IL-5 antibody 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., omalizumab). These include anti-IgE antibodies, TSLP inhibitors (e.g., anti-TSLP antibodies such as tezeperumab), CRTH2 inhibitors, Siglec-8 inhibitors, prostaglandin D2 inhibitors, integrin inhibitors (e.g., integrin α4β7 inhibitors such as vedolizumab), eotaxin inhibitors, immunosuppressants, topical corticosteroids, oral corticosteroids, systemic corticosteroids, inhaled corticosteroids, glucocorticoids, PPIs, decongestants, antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs), esophageal dilation, allergen removal, or dietary management. In some embodiments, IL-4R inhibitors are used in combination with dietary management. In some embodiments, IL-4R inhibitors are used in combination with corticosteroids (e.g., swallowing topical corticosteroids).

[0117] In some embodiments, IL-4R inhibitors are used in combination with PPIs, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole. In some embodiments, IL-4R inhibitors are used in combination with high-dose PPI regimens. For example, in some embodiments, IL-4R inhibitors are used in combination with omeprazole in doses of 40 mg QD or 20 mg BID, esomeprazole in doses of 40 mg QD or 20 mg BID, lansoprazole in doses of 60 mg QD or 30 mg BID, dexlansoprazole in doses of 60 mg QD, rabeprazole in doses of 40 mg QD or 20 mg BID, or pantoprazole in doses of 80 mg QD or 40 mg BID.

[0118] In some embodiments, administration of an IL-4R inhibitor reduces dependence on or need for concurrent therapy (e.g., PPIs, corticosteroids, or glucocorticoids). In some embodiments, administration of an IL-4R inhibitor in combination with a second therapy (e.g., PPIs, corticosteroids, or glucocorticoids) reduces the amount of the second therapy (e.g., PPIs, corticosteroids, or glucocorticoids) 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 before treatment with the IL-4R inhibitor. [Examples]

[0119] The following examples are provided to give a complete disclosure and explanation of how the methods and compositions of this disclosure are prepared and used, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantity, temperature, etc.), but some experimental error and deviation should be taken into consideration. Unless otherwise stated, parts are parts by weight, molecular weight is average molecular weight, temperature is Celsius temperature, and pressure is atmospheric pressure or near atmospheric pressure. [Examples]

[0120] Clinical trial to investigate the efficacy and safety of dupilumab in adult and adolescent patients with eosinophilic esophagitis. Study design and objectives This example describes a three-part, phase 3, randomized clinical trial (NCT03633617) to investigate the efficacy and safety of dupilumab in adult and adolescent patients with eosinophilic esophagitis (EoE). Parts A and B of the clinical trial are 24-week treatment, randomized, double-blind, placebo-controlled trial phases, and Part C is a 28-week extended active treatment phase enrolling patients from Parts A and B. Dupilumab is a fully human anti-IL-4R antibody containing a heavy chain with the amino acid sequence of SEQ ID NO: 9 and a light chain with the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair with SEQ ID NO: 1 / 2; and heavy and light chain CDR sequences with SEQ ID NOs: 3-8.

[0121] The primary objective of Part A of the trial is to determine the efficacy of dupilumab treatment compared to placebo in adult and adolescent EoE patients after 24 weeks of treatment, as assessed by histological and clinical scales, and to obtain / confirm information for determining the final sample size for Part B. The primary objective of Part B is to demonstrate the efficacy of dupilumab treatment compared to placebo in adult and adolescent EoE patients after 24 weeks of treatment, as assessed by histological and clinical scales. The primary objective of Part C is to evaluate the safety and efficacy of dupilumab treatment in adult and adolescent EoE patients after up to 52 weeks of treatment, as assessed by histological and clinical scales. The secondary objectives of the study include: evaluating the safety, tolerability, and immunogenicity of dupilumab treatment in adult and adolescent EoE patients; exploring the relationship between dupilumab concentration and response in adult and adolescent EoE patients using descriptive analysis; and evaluating the effects of dupilumab on transcriptome signatures associated with EoE and type 2 inflammation.

[0122] Part A consists of the screening period, randomization period, and treatment period, as follows: • Screening period (maximum 12 weeks): After obtaining informed consent, the patient's eligibility for the study will be assessed at the first visit. Study participants must have a confirmed diagnosis of EoE, which may be confirmed by a history of previous biopsies or by a biopsy performed during the screening period. All patients who meet the clinical and laboratory eligibility criteria will undergo an endoscopy with biopsy at the second visit to establish a baseline reference. For patients without a history of previous biopsies, the biopsy at the second visit will serve both to confirm the EoE diagnosis and establish the baseline reference. • Randomization: Patients who still meet the eligibility criteria at baseline visit (third visit) will enter a 24-week placebo-controlled, double-blind treatment period and will be randomly assigned in a 1:1 ratio to receive either dupilumab 300 mg once weekly (QW) or placebo subcutaneously (SC). • Placebo-controlled, double-blind treatment period (24 weeks): Co-primary endpoints will be evaluated at week 24, one week after the last administration of the study drug during the double-blind treatment period, to obtain / confirm information for determining the final sample size for Part B. At the end of the double-blind treatment visit (week 24), eligible patients from Part A may enter a 28-week extended active treatment period (Part C). Patients not participating in Part C will enter a 12-week follow-up period. Patients enrolled in Part A will not be eligible to participate in Part B. • Follow-up period (12 weeks): After completing Part C, or immediately after Part A or B if the patient is ineligible for Part C, all patients will be followed up for an additional 12 weeks.

[0123] Enrollment for Part B will be scheduled to begin immediately after the last patient is enrolled in Part A. The screening procedure for Part B is the same as that described above for Part A. For randomization, patients who still meet the eligibility criteria at baseline visit (third visit) will enter a 24-week double-blind treatment period and be randomly assigned in a 1:1:1 ratio to receive dupilumab 300 mg quarterly (QW), dupilumab 300 mg every two weeks (Q2W), or placebo in a single dose (SC). The procedure for the placebo-controlled double-blind treatment period (24 weeks) is the same as for Part A. At the end of the double-blind treatment visit (week 24), eligible patients in Part B may enter a 28-week extended active treatment period (Part C). Patients who do not participate in Part C will enter a 12-week follow-up period.

[0124] In the 28-week extended active treatment period of Part C, eligible patients from Parts A and B may enter the 28-week extended active treatment period at the end of the double-blind treatment visit (week 24), during which all patients will receive active treatment with dupilumab, except for Part B patients, who will be blinded to their treatment regimen in Part C. Part A patients who were randomly assigned to placebo during the double-blind treatment period will receive dupilumab 300 mg QW in Part C. Part A patients who were randomly assigned to dupilumab 300 mg QW during the double-blind treatment period will continue to receive dupilumab 300 mg QW in Part C. Part B patients who were randomly assigned to placebo during the double-blind treatment period will be re-randomized in a 1:1 ratio to either dupilumab 300 mg QW or dupilumab 300 mg Q2W. Patients randomly assigned to dupilumab 300 mg Q2W will also receive a matched placebo Q2W dose alternately with dupilumab to match the injection frequency with other groups for the purpose of regimen blinding. All other patients will maintain the same dupilumab regimen they were randomly assigned to during the double-blind treatment period. All patients will be followed up for an additional 12 weeks after completing Part C, or immediately after Part A or B if they are ineligible for Part C.

[0125] This trial was conducted in accordance with the provisions of the Declaration of Helsinki, the Clinical Trial Guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, and 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 all adult patients. For adolescent patients, written informed consent or informed assent was obtained from the patient, and written informed consent was obtained from the patient's parent or legal guardian.

[0126] Patient group This trial will enroll adult men and women aged 18 or older at the time of trial participation, as well as adolescent men and women aged 12 to under 18, who have EoE.

[0127] Inclusion Criteria: To be eligible for inclusion in the study, patients must meet the following criteria: (1) be male or female 12 years of age or older; (2) have a record of a diagnosis of EoE by endoscopic biopsy, indicated by intraepithelial eosinophil infiltration (peak cell count ≥ 15 eos / hpf) in at least one esophageal region, performed prior to screening, following treatment with a high-dose PPI regimen for at least 8 weeks. If a patient discontinues PPI therapy, the biopsy must be performed within 2 weeks of the discontinuation date. If a previous (past) endoscopic biopsy meeting these criteria is not available (or there are no available previous biopsies), patients meeting other clinical and laboratory eligibility criteria will receive treatment with a high-dose PPI regimen for at least 8 weeks prior to baseline endoscopy / biopsy. Note: If a patient is already using an acceptable high-dose PPI regimen at the time of screening, baseline endoscopy may be scheduled at any point during the screening period after the 8 weeks of treatment have been recorded. (3) Intraepithelial eosinophil infiltration (peak cell count ≥ 15 eos / hpf) demonstrated by central interpretation of baseline endoscopic biopsy in at least two of the three biopsied esophageal regions (proximal, mid, or distal); (4) A history of at least two episodes of dysphagia (regarding solid intake) per week on average during the four weeks prior to screening (as reported by the patient); (5) At least four episodes of dysphagia recorded by eDiary during the two weeks prior to baseline, at least two of which required liquid, cough or dry vomiting, vomiting, or medical intervention to alleviate the symptoms; (6) At least 11 days of DSQ in 14 days during the two weeks prior to baseline visit (third visit). (7) Completion of eDiary data entry; (8) Baseline DSQ score of 10 or higher; (9) Ability to understand and complete questionnaires related to the study; (10) Willingness to comply with and be able to perform clinic visits and procedures related to the study; (11) Provision of informed consent signed by the study patient or a legally authorized representative.For adolescents, a signed informed consent form from a parent or legal guardian must be provided (the patient must also provide a separate informed consent form to enroll in the trial).

[0128] Exclusion Criteria: The exclusion criteria for Parts A and B of the study were as follows: (1) Body weight ≤ 40 kg; (2) Previous participation in a clinical trial of dupilumab, or past or present treatment with dupilumab; (3) Initiation or modification of an elimination diet regime, or reintroduction of a previously eliminated food group, within the 6 weeks prior to screening. Patients on an elimination diet must maintain the same diet throughout the study period. (4) Other causes of esophageal eosinophilia or the following conditions: Eosinophilic syndrome and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Note: Patients with eosinophilic gastroenteritis are eligible, subject to meeting other eligibility criteria. (5) Active Helicobacter pylori infection; (6) History of achalasia, Crohn's disease, ulcerative colitis, celiac disease, and / or esophageal surgery; (7) Any esophageal stricture that is inaccessible by a standard 9-10 mm upper endoscope, or any significant esophageal stricture requiring dilation, at the time of screening; (8) History of bleeding disorders or esophageal varices that, in the opinion of the principal investigator, would expose the patient to an excessive risk of serious complications from the endoscopic procedure; (9) Treatment with topical corticosteroids via swallowing within 8 weeks prior to baseline; (10) Initiation, discontinuation, or modification of the following medication dosage regimens within 8 weeks prior to baseline endoscopy: proton pump inhibitors (except for patients requiring a PPI trial before baseline endoscopy), leukotriene inhibitors, or intranasal and / or inhaled corticosteroids. Patients who have received a certain dose of these medications for at least 8 weeks prior to baseline endoscopy may be enrolled in the study, but the dose should not be changed during the study. (11) Starting, stopping, or changing the dosage regimen of SC immunotherapy (SCIT). Patients who have received a certain dose of these medications for at least one year prior to their first visit may be included in the study, but their dose must not be changed during the study.(12) Having received sublingual immunotherapy (SLIT); (13) Having received oral immunotherapy (OIT) within 6 months prior to the first visit; (14) Having received any of the following within 3 months prior to screening, or having any condition that the principal investigator believes is likely to require such treatment during the study: systemic immunosuppressants / immunomodulators, including but not limited to systemic corticosteroids, omalizumab, cyclosporine, mycophenolate mofetil, interferon-gamma [IFN-γ], Janus kinase inhibitors, azathioprine, and methotrexate (Note: One use of corticosteroids as part of anesthesia preparation during each endoscopic procedure is permitted); (15) Having received treatment with the investigational drug within 2 months prior to the first visit or within 5 half-lives (if known), whichever is longer; (16) Having planned or anticipated use of any prohibited drugs or procedures during the study; (17) Having planned or anticipated major surgery during the study; (18) Baseline (19) Having received treatment with a live (attenuated) vaccine within four weeks prior to the visit; having an active parasitic infection or suspected parasitic infection unless the possibility of active infection has been ruled out by clinical and (if necessary) laboratory evaluation prior to randomization; (20) Having had a chronic or acute infection requiring treatment with systemic antibiotics, antiviral drugs, or antifungal drugs within two weeks prior to the baseline visit; (21) Having had an invasive opportunistic infection (e.g., tuberculosis [TB], non-tuberculous mycobacterial infection) regardless of resolution of the infection. (22) Having a known or suspected immunodeficiency disorder, including a history of infectious diseases (histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis), or, in the judgment of the principal investigator, having an unusually high frequency of recurrent infections or a long-term infection suggestive of an immunocompromised state; (23) Having a confirmed diagnosis of hepatitis B virus infection at the time of screening, or being positive for hepatitis B surface antigen (HBsAg) at the time of screening.Patients who have acquired immunity against hepatitis B virus infection after vaccination (patients who are negative for HBsAg, positive for hepatitis B surface antibody [HBsAb], and negative for hepatitis B core antibody [HBcAb]) are eligible for the study. Patients with positive HBcAb are eligible for the study only if the hepatitis B virus DNA level is undetectable. (24) Diagnosis of hepatitis C virus (HCV) infection is confirmed at the time of screening. Patients with positive hepatitis C antibody (Ab) are eligible for the study only if HCV RNA is negative; (25) Currently undergoing treatment for liver diseases including, but not limited to, acute or chronic hepatitis, cirrhosis, or liver failure, or having evidence of liver disease indicated by persistent (confirmed by repeated tests taken more than two weeks apart) elevation of transaminases (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) above three times the upper limit of normal [ULN] during the screening period; (26) Having any of the following abnormal test values at the time of screening: platelets < 100 × 10. 3 / μL, neutrophils < 1.5 × 10 3 / μL, or estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m 2(27) The presence of a severe comorbidity that the Principal Investigator considers to be adverse to the patient's participation in the study. Examples include, but are not limited to, a short life expectancy, uncontrolled diabetes, cardiovascular conditions (e.g., NYHA class III or IV heart failure), severe renal conditions (e.g., severe nephrotic syndrome), hepatobiliary conditions (e.g., Child-Pugh class B or C), neurological conditions (e.g., demyelinating disease), active major autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrine disorders, gastrointestinal disorders, metabolic disorders, lung diseases, or lymphatic disorders. (28) Having a history of malignancy other than fully treated cervical intraepithelial neoplasia and fully treated non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin within the five years prior to screening; (29) Having a history of alcohol or drug abuse within the six months prior to screening; (30) Having any other medical or psychological condition, including relevant laboratory abnormalities, at the time of screening, in the opinion of the principal investigator, that suggests a new disease and / or a poorly understood disease, could unduely risk the patient as a result of the patient's participation in the clinical trial, could undermine the reliability of patient participation, or could interfere with the evaluation of the trial; (31) The patient or a close relative of the patient is a member of the clinical trial team; (32) A woman who is pregnant or lactating, or a woman who plans to become pregnant or lactate during the trial; (33) A woman of childbearing potential who does not intend to practice highly effective contraception before the start of the initial dose / first treatment, during the trial, and for at least 12 weeks after the last dose. A postmenopausal woman must have been amenorrhea for at least 12 months to be considered childbearing. Pregnancy testing and contraception are not required for women with a history of hysterectomy or tubal ligation. (34) A history of systemic hypersensitivity to dupilumab or its excipients.

[0129] Test treatment In this study, the dupilumab formulation was supplied at a concentration of 150 mg / mL, and 300 mg of the test drug (2.0 mL of 150 mg / mL solution) was delivered in single-use, pre-filled glass syringes with 2.0 mL snap-off caps. A placebo matching dupilumab was prepared using the same method, but without the addition of protein (i.e., the active substance, the anti-IL-4Rα monoclonal antibody).

[0130] In the double-blind, placebo-controlled Parts A and B, and Part C, all patients will receive weekly (QW) subcutaneous (SC) injections. In Part A, all patients will receive either dupilumab 300 mg or placebo on QW. Patients in Part B will receive either dupilumab 300 mg QW, dupilumab 300 mg Q2W, or placebo QW. For the dupilumab 300 mg SC Q2W group, to maintain blinding, placebo SC injections will be administered between dupilumab administrations to match the injection frequency with the other two groups (dupilumab QW and placebo). In the extended active treatment Part C, patients will receive dupilumab injections at the frequency assigned to their treatment (QW, or Q2W with placebo alternating with dupilumab administration to ensure identical injection frequency in both groups for regimen blinding purposes). The subcutaneous injection sites for the study drug should be alternated between four sections of the abdomen (avoiding the navel and lower back), the upper thigh, and the upper arm, so that injections are not administered to the same site twice in a row.

[0131] Background Treatment: Patients undergoing a trial of high-dose PPI therapy initiated before screening or during the Part A or Part B screening period must maintain the dosage regimen listed below for a 52-week treatment period. High-dose PPI regimens are defined as follows: Omeprazole 40 mg once daily (QD) or 20 mg twice daily (BID) • Esomeprazole 40mg QD or 20mg BID Lansoprazole 60mg QD or 30mg BID • Dexlansoprazole 60mg QD • Rabeprazole 40mg QD or 20mg BID • Pantoprazole 80mg QD or 40mg BID

[0132] Patients who indicate they are currently using a PPI at their initial screening visit must also maintain the same or a similar approved dosage regimen for the entire 52-week treatment period. Patients may switch to a different approved PPI during the trial. PPI therapy is prohibited for all other patients.

[0133] Rescue treatment: Rescue medication (systemic and / or topical corticosteroids for swallowing) or emergency esophageal dilation is permitted for study patients if medically necessary (e.g., for the treatment of unacceptable EoE symptoms). Endoscopy with biopsy will be performed prior to the initiation of rescue therapy. Patients undergoing endoscopy with biopsy to initiate rescue therapy will not undergo endoscopy / biopsy at the scheduled end-of-treatment visit. Patients receiving rescue treatment during the double-blind period of the study will be ineligible for the extended active treatment period unless endoscopy with biopsy is performed before the initiation of the rescue treatment. However, if endoscopy with biopsy is not possible, the rescue treatment should not be delayed, and these patients will be eligible for Part C. Part C treatment will be initiated only at clinic visits as scheduled for the events. Patients receiving rescue therapy may continue to receive the study medication. These patients will remain blinded and will be required to revisit the clinic for all remaining study visits throughout the double-blind treatment period and follow-up period, in accordance with the designated event schedule, and to participate in all evaluations at these visits. For the purpose of efficacy analysis, patients who receive rescue treatment during the trial will be considered to have failed treatment.

[0134] Evaluated outcomes The coprimary endpoints in both Parts A and B of the study were: the proportion of patients achieving a peak esophageal intraepithelial eosinophil count of ≤6 eos / hpf at week 24; and the absolute change in DSQ score from baseline to week 24.

[0135] The primary secondary endpoints in both Parts A and B of the study were: absolute change in EoE-EREFS from baseline to week 24; percentage change in peak esophageal intraepithelial eosinophil count (eos / hpf) from baseline to week 24; absolute change in EoE grade score by the EoE Histological Scoring System (EoEHSS) from baseline to week 24; and absolute change in EoE stage score by the EoEHSS from baseline to week 24.

[0136] Other secondary endpoints include: the proportion of patients achieving a peak esophageal intraepithelial eosinophil count of less than 15 eos / hpf at week 24; the proportion of patients achieving a peak esophageal intraepithelial eosinophil count of less than 1 eos / hpf at week 24; the percentage change in DSQ from baseline to week 24; the normalized enrichment score (NES) for the relative change from baseline to week 24 in the EoE diagnostic panel (EDP) transcriptome signature; the NES for the relative change from baseline to week 24 in the type 2 inflammatory transcriptome signature; the absolute change from baseline to week 24 in the severity and / or frequency of EoE symptoms other than dysphagia; the proportion of patients receiving rescue medication or procedures during the 24-week placebo-controlled treatment period; and the absolute change from baseline in the esophageal distensibility plateau at week 24, as measured by functional lumen imaging, if collected.

[0137] The procedure for evaluating efficacy is described below and also in WO2019 / 028367, which is incorporated herein by reference.

[0138] EoE-EREFS: EoE esophageal characteristics are analyzed based on EoE-EREFS, a validated scoring system for the inflammatory and remodeling features of the disease, using both an overall score and scores for each individual characteristic (Hirano, 2013). The proximal and distal esophageal regions are scored separately; the score for each region ranges from 0 to 9, and the overall score ranges from 0 to 18. Major esophageal features include: edema (absent, present); cricoid sulcus (absent, mild, moderate, severe); exudate (absent, mild, severe); longitudinal grooves (absent, mild, severe); and stenosis (absent, present). In addition to these major features, data on the following minor features are also obtained by the physician performing the endoscopic procedure: crepe-like esophagus (mucosal fragility or tearing during the passage of the diagnostic endoscope): absent, present; narrow esophagus (reduction in the lumen diameter of most of the tubular esophagus): absent, present; and diameter of stricture. Mucosal changes associated with gastroesophageal reflux disease are also recorded using the Los Angeles classification system for erosion (no erosion, or grade A, B, C, or D).

[0139] Biopsy: Biopsies will be taken via endoscopy at the second screening visit (second visit, day 21 ± 7), at the visits at weeks 24 and 52, and immediately before the initiation of rescue medication or procedures during the double-blind treatment period. A total of nine mucosal pinch biopsies will be collected from three esophageal regions at each time point: three proximal, three middle, and three distal. Two samples from each region will be used for histological examination (required for study inclusion criteria and endpoint evaluation) and other histological analyses (may include, but are not limited to, immunohistochemistry [IHC], RNA scopy (in situ hybridization), and RNA sequencing). A third sample from each region will be processed for RNA analysis. In addition, to rule out the possibility of other etiologies of esophageal eosinophilia, gastric and / or duodenal biopsy samples will be taken from all patients under 18 years of age at the second visit. In adults, targeted gastric and / or duodenal biopsies should only be taken if there are abnormal endoscopic findings (other than typical EoE findings) or if another etiology is clinically suspected. Gastric biopsy samples should include two samples from the pyloric sac and two samples from the body. Duodenal biopsy samples should include two bulbar samples and two from other parts of the duodenum. Biopsy samples should be evaluated for peak eos per hpf and assigned an EoE grade score and stage score. The EoE grade score and stage score assess the following eight features: eosinophil density, basal hyperplasia, eosinophil abscess, eosinophil surface laminarization, intercellular space dilation, surface epithelial changes, abnormal keratotic epithelial cells, and lamina propria fibrosis (absence / presence).

[0140] EndoFLIP: The EndoFLIP device is a catheter-based technique that records intraluminal pressure during esophageal volume expansion while simultaneously measuring cross-sectional area at multiple points along the esophagus. Analysis of the relationship between esophageal cross-sectional area and pressure allows for the determination of esophageal compliance and distension plateau. Distension plateau has been shown to be significantly reduced in EoE patients compared to healthy controls (Kwiatek, 2011). Furthermore, esophageal distension is associated with both food impaction and the need for esophageal dilation outcomes (Nicodeme, 2013).

[0141] The Dysphagia Questionnaire (DSQ) is a validated PRO used in clinical trials to measure the frequency and severity of dysphagia (Hudgens et al., J Patient Rep Outcomes 2017, 1(1):3, doi:10.1186 / s41687-017-0006-5). For patients who answered "No" to Question 1 ("Have you eaten any solid food since waking up this morning?"), the DSQ was modified by including follow-up questions to determine whether the patient avoided solid food due to swallowing difficulties. This modified DSQ was completed daily by the patient using an eDiary from screening until the end of the trial or ET visit. The DSQ uses a daily recall period and includes three questions regarding the presence and severity of EoE dysphagia. All patients must answer questions 1 and 2, and must have eaten solid food (answer "yes" to question 1: "Have you eaten solid food since waking up this morning?") in order to proceed to the next part of the questionnaire. If a patient answers "no" to question 1, the remaining items on the DSQ are not scored. Patients who answer "no" to question 2 ("Have you experienced any difficulty swallowing food since waking up this morning?") are given a score of zero and do not proceed to answer question 3 (the log is recorded as completed for the day). Those who answer "yes" to questions 1 and 2 proceed to question 3, which is scored on a 5-point scale that estimates the severity of dysphagia based on the patient's actions to alleviate symptoms, from inaction to seeking medical attention. Therefore, the DSQ scoring algorithm is constructed from the answers to questions 2 and 3 to ensure that the final score is determined by the frequency and severity of dysphagia. To calculate the DSQ score, at least eight diary entries are required for each 14-day period to derive a standardized total score based on the cumulative score over 14 days. The DSQ score can theoretically range from 0 to 84, with lower scores indicating less frequent or severe dysphagia.

[0142] EoE Impact Questionnaire (EoE-IQ): The EoE-IQ is a disease-specific measure of health-related quality of life for patients with EoE, developed by the sponsor. The EoE-IQ measures the impact of EoE on a patient's emotional, social, work and academic, and sleep patterns on a scale of 1 to 5; a higher score indicates a greater symptom burden. Concepts measured in the EoE-IQ (with a 5-point response range from "strongly disagree" to "strongly agree") may include: "In the last 7 days, have you experienced any of the following: been troubled by symptoms of EoE; worried about dysphagia; worried about choking; felt embarrassed; worried about dysphagia while in public; had difficulty participating in social activities involving eating; had EoE affect your relationships with family; had EoE affect your relationships with friends; had difficulty keeping up with things at work or school; missed work or school; had sleep disturbances?" The EoE-IQ is completed by the patient using an electronic questionnaire at a specifically defined time during the trial.

[0143] EoE Symptom Questionnaire (EoE-SQ): The EoE Symptom Questionnaire is a questionnaire that measures the frequency and severity of symptoms other than dysphagia and dysphagia on a scale of 5 to 25; a higher score indicates a higher symptom burden. It is developed by the sponsor. Concepts measured in EoE-SQ frequency (with a 5-point response range from "never" to "more than twice a day") may include: "How often have you experienced the following in the last 7 days?: chest pain; stomach pain; chest burning (heartburn); reflux of food or liquid into the throat; vomiting." The EoE Symptom Questionnaire is completed by the patient using an electronic questionnaire at a specifically defined time during the trial.

[0144] Patient's Overall Impression of Changes in Swallowing Difficulty (PGIC): The PGIC is a one-item questionnaire that asks patients to provide an overall self-assessment of changes in their difficulty swallowing food on a 7-point scale (significantly improved; moderately improved; slightly improved; no change; slightly worsened; moderately worsened; or significantly worsened). The PGIC is completed by the patient using an electronic questionnaire at a specifically defined time during the study.

[0145] The Total Nasal Symptom Score (TNSS), measured on a 0-9 scale, is a composite assessment of symptoms of nasal congestion, itching / sneezing, and runny nose (each graded on a 0-3 scale, with 3 being the most severe). The TNSS is administered only to patients with a history of allergic rhinitis who are fluent in the language in which the questionnaire is presented (based on the availability of translations in the participating countries). The TNSS is completed by patients using an electronic questionnaire at a specifically defined time during the study.

[0146] The Standardized Rhinoconjunctivitis Quality of Life Questionnaire for ages 12+ (RQLQ(S)+12) is a self-administered questionnaire that measures health-related quality of life for individuals aged 12 and older as a result of perennial or seasonal allergic rhinitis. The RQLQ(S) consists of 28 items divided into seven domains: activity limitations, sleep disturbances, nasal symptoms, ocular symptoms, non-nasal / non-ocular symptoms, reality problems, and emotional functioning. Responses to the RQLQ(S)+12 are based on a 7-point Likert scale, ranging from 0 (no difficulty) to 6 (very difficult). The overall RQLQ(S)+12 score is the average of the responses to all 28 items, while individual domain scores are the average of the items in the relevant domain. A higher score indicates a greater deterioration in health-related quality of life (a lower score is considered better). A change of 0.5 points or more in the total score is considered clinically significant. The RQLQ(S)+12 is completed by patients using an electronic questionnaire at a specifically defined time during the study.

[0147] The Juniper Asthma Control Questionnaire (ACQ): The five-question Juniper ACQ (ACQ-5) is a validated questionnaire for assessing asthma control. The ACQ-5 score is the average of the scores for the five items, ranging from 0 (fully controlled) to 6 (severely uncontrolled). A score of less than 1.0 reflects good asthma control, while a score of 1.0 or higher reflects poor asthma control. A higher score indicates lower asthma control. A recommended change of 0.50 is a reasonable threshold for defining a meaningful individual-level change. The ACQ-5 is administered only to patients with a history of asthma who are fluent in the language in which the questionnaire is presented (based on the availability of validated translations in participating countries). The ACQ-5 is completed by patients using an electronic questionnaire at a specifically defined time during the trial.

[0148] Patient-Oriented Eczema Measure (POEM): The POEM is a seven-item, validated questionnaire used in clinical practice and clinical trials to assess disease symptoms in children and adults with Alzheimer's disease (AD) (Charman, 2004). The format consists of seven items (dryness, itchiness, scaling, cracking, sleep disturbance, bleeding, and exudation) answered using a five-point scale based on the frequency of occurrence over the past week. The possible scores for each question were as follows: a composite scoring system from 0 to 28, with 0 (none), 1 (1-2 days), 2 (3-4 days), 3 (5-6 days), and 4 (daily); higher scores indicate more severe AD. The following POEM banding scores have been established: 0-2 = clear or nearly clear; 3-7 = mild eczema; 8-16 = moderate eczema; 17-24 = severe eczema; and 25-28 = very severe eczema. The POEM will only be administered to patients with a history of Alzheimer's disease (AD) who are fluent in the language in which the questionnaire is presented (based on the availability of valid translations in participating countries). The POEM will be completed by the patient using an electronic questionnaire at a specifically defined time during the trial.

[0149] The European Quality of Life 5-Item Scale (EQ-5D): The European Quality of Life 5-Item Scale (EQ-5D) is a standardized questionnaire used to assess health status (Rabin, 2014). It consists of a descriptive system and an EQ Visual Analog Scale (EQ VAS). The EQ-5D-3L (3-level) descriptive system consists of the following five items: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. For each item, the patient selects one of three levels: no problem, somewhat problematic, and very problematic. The EQ VAS is a vertical visual analog scale with endpoints labeled "best possible health condition" and "worst possible health condition," in which the patient records their self-assessed health status. The EQ-5D-3L is completed by the patient using an electronic questionnaire at a specifically defined time during the test.

[0150] Pharmacodynamic and exploratory biomarker methods This study will evaluate eoeE, how dupilumab may alter the underlying disease processes of eoeE, type 2 inflammation, and predictors of dupilumab safety and efficacy. Samples for eotaxin-3 (heparinized plasma), serum TARC, total IgE, and allergen-specific IgE and IgG4 will be collected at specified time points. The biomarkers under study are thought to be relevant to the pathophysiology of eoeE, response to treatment (i.e., assessment of type 2 inflammation), and baseline predictors of response and dupilumab mechanism of action.

[0151] EoE diagnostic panel and type 2 inflammatory transcriptomics The differential gene expression profiles of esophageal biopsies from EoE patients compared to healthy controls constitute the EoE disease transcriptome (Sherrill et al., Genes Immun 2014, 15(6):361-369). This disease gene expression signature has been further refined to smaller gene sets for use as an EoE diagnostic panel (EDP) (Dellon et al., Clin Transl Gastroenterol 2017, 8(2):e74).

[0152] The normalized enrichment score (NES) is normalized by taking into account the number of transcripts in a set, reflecting the extent to which the activity levels of a transcript set are over-presented at both ends (upper or lower) of a ranked list of transcripts in the sample (Subramanian, 2005; Barbie, 2009). The NES score is calculated for each transcriptome signature in each sample by each individual patient, calculating the difference between baseline and week 24 in expression levels (TPM, transcripts per million) for all genes in the transcriptome, determining where a pre-selected set of transcripts is located in the distribution, and calculating the enrichment score (the extent to which the difference in expression levels is located at both ends of the distribution). For statistical comparison, once the NES has been calculated for each individual, the Wilcoxon signed-rank test is used to determine whether there is a significant difference between the placebo group and the dupilumab group.

[0153] Results for Part A of the clinical trial Baseline characteristics The baseline demographic and disease characteristics of patients enrolled in Part A of the study are summarized in Tables 1 and 2 below.

[0154] [Table 1]

[0155] [Table 2]

[0156] Baseline demographic and disease characteristics were similar across treatment groups, as shown in Tables 1 and 2. The mean DSQ of the population was approximately 34, indicating a significant degree of baseline symptoms. As shown in Table 2, a high percentage of subjects had a history of prior use of topical swallowing steroids and esophageal dilation. Baseline peak eosinophil counts were elevated. In addition, the majority of subjects had at least one concomitant allergic condition (excluding EoE), as shown in Table 3.

[0157] [Table 3]

[0158] efficacy Treatment with dupilumab resulted in statistically significant improvements in the coprimary endpoint (the proportion of patients achieving a peak esophageal intraepithelial eosinophil count of ≤6 eos / hpf at week 24, and the absolute change in DSQ score from baseline to week 24), as shown in Table 7 below. The majority of patients (59.5%) who received dupilumab at a dose of 300 mg QW achieved a peak esophageal intraepithelial eosinophil count of ≤6 eos / hpf at week 24, compared to 5.1% in the placebo group, which was consistent with histological disease remission. Patients who received dupilumab achieved a mean reduction in absolute DSQ score of 21.92, compared to a reduction of 9.60 in the placebo group. The absolute change in total DSQ score over time from baseline is shown in Figure 1. Dupilumab significantly and rapidly reduced the severity of dysphagia in patients with edema (EoE). Compared to placebo-treated patients, dupilumab-treated patients showed a greater improvement in DSQ scores, reaching statistical significance from week 4 onward.

[0159] Dupilumab treatment resulted in statistically significant improvements in the primary and other secondary endpoints, as shown in Table 7. Patients treated with dupilumab showed a -71.24% change from baseline in peak esophageal intraepithelial eosinophil count (eos / hpf), compared to a -2.98% change in the placebo group. The majority of patients treated with dupilumab (64.3%) achieved a peak esophageal intraepithelial eosinophil count of less than 15 eos / hpf, compared to only 7.7% in the placebo group. A significant proportion of patients treated with dupilumab achieved a peak esophageal intraepithelial eosinophil count of less than 1 eos / hpf (21%, compared to 0 in the placebo group). Dupilumab also significantly improved EoE histological scores at week 24; patients treated with dupilumab showed reduced absolute change from baseline in mean grade and mean stage scores on the EOEHSS (mean grade score: -0.761 with dupilumab vs. -0.001 with placebo; mean stage score: -0.753 with dupilumab vs. -0.012 with placebo).

[0160] Dupilumab reduced the endoscopic features of EoE at week 24, as measured by the EoE-EREFS scale, which measures the severity of endoscopic findings; a higher score indicates greater severity. EREFS was assessed at screening and at week 24 by endoscopy of the proximal and distal esophagus. The features assessed were edema (score range 0–1), cricoid sulcus (0–3), exudate (0–2), longitudinal sulcus (0–2), and stricture (0–1), with a higher score indicating greater severity. The total score represents the sum of all features in both regions (0–18). Changes from baseline in the total score, inflammation subscore (sum of edema, exudate, and longitudinal sulcus), remodeling subscore (sum of cricoid sulcus and stricture), and individual feature scores were analyzed at week 24.

[0161] At baseline, mean [SD] total EREFS scores were similar in patients assigned to dupilumab and those assigned to placebo (6.5 [3.20] vs. 6.0 [2.38]) (Table 4). At week 24, patients assigned to dupilumab and those assigned to placebo showed significantly greater changes (improvements) in total EREFS scores and inflammation subscores (both P<0.0001), and there was a trend toward improvement in remodeling subscores. At week 24, statistically nominal or numerical improvements were observed in proximal and distal edema (least squares mean difference for dupilumab over placebo: -0.3 and -0.1, respectively), annular sulcus (-0.2 and -0.2), exudate (-0.4 and -0.5), and longitudinal sulcus (-0.5 and -0.6), but not in stenosis (0 and 0) (Figure 2B).

[0162] [Table 4]

[0163] As shown in Tables 4 and 7 and Figure 2A, dupilumab-treated patients showed an absolute change of -3.2 from baseline in the EoE-EREFS total score, compared to -0.3 in the placebo group. Figure 2B also shows the decrease from baseline in EREFS component scores in dupilumab-treated patients compared to placebo.

[0164] During the study, patients completed the DSQ daily using an electronic diary. The DSQ score (range 0–84) was based on patients' responses to questions regarding "food passing slowly or getting stuck" and actions taken to "pass food or get relief." The dysphagia-related pain score (range 0–56) was based on follow-up questions regarding "pain during swallowing." Higher scores indicated greater severity. The proportion of patients achieving a 30% or greater reduction in DSQ and a 50% or greater reduction (generally assessed PRO respondent analysis thresholds) at week 24 was analyzed using the Cochrane-Mantel-Henzel test. The least squares (LS) mean change in dysphagia-related pain score from baseline to week 24 was evaluated using an analysis of covariance model. 76.2% of dupilumab-treated patients achieved a reduction of 30% or more in their DSQ score, compared to 41.0% of placebo-treated patients (P<0.01). 71.4% of dupilumab-treated patients achieved a reduction of 50% or more, compared to 30.8% of placebo-treated patients (P<0.001) (Table 5). A greater reduction in dysphagia-related pain scores was observed with dupilumab compared to placebo from week 2 (mean LS difference: -2.3; 95% CI -4.4 to -0.1; P<0.05), and continued to decrease until week 24 (mean LS difference: -5.7; 95% CI -8.7 to -2.7; P<0.001). The change in DSQ from baseline for dupilumab-treated patients was -69.17%, compared to -31.68% for placebo-treated patients.

[0165] [Table 5]

[0166] The EoSinophilic Esophagitis Histological Scoring System (EoE-HSS) assesses the severity (grade) and extent (stage) of histological features correlated with clinical symptoms in EoE esophageal biopsies. Biopsies were taken from proximal, middle, and distal esophageal regions, and the severity and extent of abnormalities of eight features (basal hyperplasia [BZH], eosinophilic inflammation [EI], eosinophilic abscess [EA], eosinophilic surface laminatinization [ESL], intercellular dilation [DIS], surface epithelial changes [SEA], abnormal keratotic epithelial cells [DEC], and lamina propria fibrosis [LPF]) were scored by a central pathologist (0 normal to 3 maximum change). The mean EoE-HSS grade score or stage score was calculated by summing the assigned scores and dividing by the maximum possible score in each esophageal region; the three scores from each region were added together to obtain the total score. For grades and stages, we analyzed the absolute change from baseline to week 24 in total score and individual feature scores.

[0167] Baseline characteristics, including mean EoE-HSS grade (1.26 vs. 1.32) and stage (1.30 vs. 1.38) total scores, were similar in the dupilumab and placebo groups. At week 24, the dupilumab group showed improvement in both mean EoE-HSS total grade and stage scores compared to the placebo group (both P<0.001); significant improvements were observed in most histological features, including grade scores for BZH, EI, EA, ESL, DIS, and SEA, and stage scores for BZH, EI, EA, ESL, and SEA; all P<0.05 (Table 6). For DEC and LPF grade and stage scores, improvements were seen in the dupilumab group compared to the placebo group. Sample size was reduced because LPF was often not detected in biopsies. These data document the beneficial effects of dupilumab on the non-eosinophilic component of esophageal epithelium, including benzodiazepines (BZH) and dermatologic septic (DIS).

[0168] [Table 6-1] [Table 6-2] [Table 6-3]

[0169] A total of five placebo patients received the following rescue therapies: topical steroids for swallowing (3), systemic steroids (1), or a steroid smear (1). None of the dupilumab-treated patients utilized rescue therapy.

[0170] [Table 7]

[0171] safety Safety data from the study are shown in Table 8 below. No new or unexpected adverse events were observed during the study, and no related SAEs were observed. Dupilumab was well-tolerated, and the severity of AEs was mild in the majority of cases.

[0172] [Table 8]

[0173] Gene expression profiles The effect of dupilumab treatment on differential gene expression profiles was evaluated by RNA sequencing using tissues obtained via esophageal biopsies from patients in this study, compared to pre-treatment baseline tissue profiles. The dysregulated gene expression during disease (EoE disease transcriptome) is known to include not only genes associated with eosinophils and type 2 inflammation, but also those related to epithelial proliferation, barrier function, remodeling, and fibrosis. Using scores derived from transcriptome signatures provides a mechanism for quantifying the overall dysregulation of disease and target inflammatory pathways. Furthermore, the transcriptome yields a quantitative molecular phenotype of the disease, including parameters related not only to inflammation but also to epithelial barrier, remodeling, and fibrosis, which are not readily measurable by other methodologies.

[0174] In Part A, dupilumab treatment suppressed both type 2 inflammation and the normalized enrichment score (NES) of the EoE diagnostic panel (EDP), whereas placebo did not. See Figures 3 and 4. The type 2 inflammation transcriptome is a list of genes selected by Regeneron for genes associated with type 2 inflammation, as shown in Figure 3. The EDP is a publicly available panel of 96 genes differentially expressed in esophageal pinch biopsies of EoE patients and controls (Wen et al., Gastroenterology 2013;145(6):1289~1299). As shown in Table 9 below, dupilumab reduced the EoE disease signature in esophageal biopsies by -2.66 (compared to -0.160 with placebo), resulting in a phenotype more similar to normal esophageal tissue, and reduced the type 2 inflammation signature by -1.97 from baseline (compared to -0.32 with placebo).

[0175] [Table 9]

[0176] Other endpoints HRQoL was assessed using an 11-item EoE Impact Questionnaire (EoE-IQ) measuring the impact of EoE on emotions, socialization, productivity, and sleep (score range: 1-5). Symptom burden was assessed using a 5-item EoE Symptom Questionnaire (EoE-SQ-Frequency) measuring the frequency of EoE symptoms other than dysphagia / dysphagia, including chest pain, stomach pain, heartburn, reflux, and vomiting (score range: 5-25). Higher EoE-IQ / EoE-SQ-Frequency scores indicate a greater impact on HRQoL / symptom burden. The proportion of patients reporting improvement in dysphagia in the Patient's General Perception of Change (PGIC) was assessed. In the PGIC, patients rated the overall change in difficulty swallowing food since starting the test treatment on a 7-point scale from "significantly improved" to "significantly worsened."

[0177] result At baseline, the mean EoE-IQ was 2.0 / 2.4 and the mean EoE-SQ-frequency was 10.1 / 11.5 in the dupilumab and placebo groups, respectively. At week 24, the mean LS difference of change from baseline for dupilumab compared to placebo was -0.4 (95% CI: -0.6, -0.1; nominal P=0.008) for EoE-IQ and -1.7 (-2.9, -0.5; nominal P=0.005) for EoE-SQ-frequency. At week 24, 40.5% of dupilumab patients versus 7.7% of placebo patients (nominal P<0.001) reported "significant improvement" in dysphagia compared to baseline at PGIC; 26.2% versus 10.3% (nominal P=0.074) reported "moderate improvement."

[0178] Biomarker analysis The effects of dupilumab on circulating biomarkers of type 2 inflammation over a 24-week treatment period were analyzed. Median serum thymus and activated modulated chemokines (TARCs), plasma eotaxin-3, and serum total immunoglobulin E (IgE), as well as the median changes from baseline, were assessed at weeks 4, 12, and 24.

[0179] Baseline levels of TARC, eotaxin-3, and total IgE were similar between treatment groups (dupilumab vs. placebo, median [Q1-Q3] were: TARC: 322.0 pg / mL [232.0-430.0] vs. 293.0 pg / mL [226.0-418.0]; eotaxin-3: 217.5 pg / mL [139.0-330.0] vs. 217.0 pg / mL [163.0-448.0]; total IgE: 110.0 kU / L [51.1-463.0] vs. 100.0 kU / L [46.7-294.0]). In dupilumab-treated patients compared to placebo-treated patients, TARC and eotaxin-3 decreased rapidly from baseline, and the effect persisted for 24 weeks, although total IgE decreased more progressively (Figures 7A-7C). At week 24, the median values ​​(Q1-Q3) for dupilumab versus placebo were 196.5 pg / mL (134.0-277.0) versus 319.0 pg / mL (191.0-381.0) for TARC, 110.0 pg / mL (82.3-133.0) versus 203.0 pg / mL (164.0-358.0) for eotaxin-3, and 59.8 kU / L (21.7-161.0) versus 106.0 kU / L (42.7-228.0) for total IgE (dupilumab showed P<0.0001 compared to placebo for all median changes from baseline). The median changes from baseline for dupilumab versus placebo at weeks 4, 12, and 24 were as follows: TARC, -109.0 pg / mL vs. -1.5 pg / mL, -109.0 pg / mL vs. -9.0 pg / mL, -115.5 pg / mL vs. -35.0 pg / mL; Eotaxin-3, -109.1 pg / mL vs. -4.0 pg / mL, -118.4 pg / mL vs. -14.5 pg / mL, -88.6 pg / mL vs. -9.0 pg / mL; Total IgE, -13.6 kU / L vs. -0.7 kU / L, -32.1 kU / L vs. -1.8 kU / L, -45.7 kU / L vs. -8.6 kU / L (all P<0.0001).

[0180] In summary, over a 24-week treatment period, dupilumab treatment resulted in rapid and sustained suppression of serum TARC and plasma eotaxin-3, as well as gradual suppression of serum total IgE, in adolescents and adults with EoE. These results demonstrate IL-4 / IL-13-dependent regulation of type 2 inflammation, consistent with previous findings in EoE and other type 2 inflammatory diseases.

[0181] conclusion Data from Part A of this Phase 3 clinical trial demonstrate that weekly administration of dupilumab is effective in improving histological and endoscopic measures for the management of dysphagia and eosinophilia (EoE). The trial met both of its coprimary endpoints (absolute change in DSQ and the percentage of patients achieving a peak esophageal intraepithelial eosinophil count of ≤6 eos / hpf at week 24), as well as all major secondary endpoints. Notably, this is the first Phase 3 trial with a biopharmaceutical to report improvement in patients' food swallowing ability, as reported by efficacy-confirmed DSQ. Compared to 5% of placebo-treated patients, 60% of dupilumab-treated patients showed a reduction in esophageal eosinophil count to within the normal range. Dupilumab also reduced abnormal endoscopic findings, as measured by EREFS, compared to placebo. Furthermore, transcriptional profiling revealed that dupilumab normalized the expression of EoE-related genes, including those associated with eosinophils and type 2 inflammation, epithelial proliferation, barrier function, remodeling, and fibrosis, demonstrating a molecular reversal of the disease beyond a reduction in eosinophilic inflammation. [Examples]

[0182] Transcriptome analysis of eosinophilic esophagitis patients treated with dupilumab This example describes the results of transcriptome analysis of adult patients (18-65 years old) enrolled in a Phase 2 clinical trial (NCT02379052). Transcriptome results were available for 19 of the 24 enrolled patients receiving placebo (79%) and 22 of the 23 enrolled patients receiving dupilumab (96%); six patients were excluded from the analysis due to the unavailability of biopsy samples.

[0183] method After patients completed a 35-day screening period, they were randomly assigned in a 1:1 ratio to receive either dupilumab 300 mg once weekly (QW) for 12 weeks (with a loading dose of 600 mg on day 1) or a matched placebo via subcutaneous injection, followed by a 16-week follow-up period. Pinch biopsies for RNA analysis were collected from the proximal, mid, and distal esophagus during screening and endoscopic procedures at week 12 and frozen in RNALater. Following RNA extraction, strand-specific RNA-seq libraries were prepared using the KAPA stranded mRNA-Seq Kit (KAPA Biosystems, Roche Sequencing and Life Sciences, MA, USA). After amplification, sequencing was performed using Illumina HiSeq® 2000 (Illumina Inc., CA, USA) with multiplex single-read runs (80 bp, 40 M reads). Using Array Studio software (OmicSoft, NC, USA), reads were mapped to the human genome (GRCh37 from the National Center for Biotechnology Information). Differentially expressed genes were identified using the DESeq2 package.

[0184] Using a gene set enrichment analysis tool (www.mathworks.com / matlabcentral / fileexchange / 33599-gsea2) that takes into account both positive and negative gene sets, normalized enrichment scores (NES) were generated using the top 50 most upregulated and top 50 most downregulated genes in EoE. Gene expression profiles were first converted to z-scores, and the NES for a single sample was calculated using the ranked z-scores for each sample, representing the overall disease signature score for the sample, denoted as EoE-NES.

[0185] Gene set enrichment analysis (GSEA) was performed using gene ontology (GO) biological process gene sets from the molecular signature database (MSigDB, c5.bp.v7.0) to perform an unbiased global transcriptome analysis. Gene sets exceeding 100 in size were pre-filtered to ensure biological process specificity, and higher GO terms were selected if the FDR was less than 0.05 in both the EoE vs. healthy comparison and the dupilumab-treated vs. baseline comparison.

[0186] Differential expression analysis was performed using DESeq2 version 1.26.0. In two arms (placebo and dupilumab 300 mg QW), week 12 was compared to baseline. Genes were considered significantly adjusted by treatment (dupilumab or placebo) if the relative log change from baseline ≥ 2 and the q-value ≤ 0.05 threshold, reflecting correction for multiple testing, were reached. Pearson correlations were calculated between (i) publicly available gene changes at EoE (disease vs. health) and (ii) gene changes after dupilumab treatment (post-treatment vs. pre-treatment).

[0187] result When comparing week 12 to baseline, no differentially expressed genes (relative logarithmic change from baseline ≥ 2, q ≤ 0.05) were found in the placebo arm. At week 12, treatment with dupilumab 300 mg QW adjusted the expression of 1,302 genes, DpxOme-EoE™, compared to baseline (relative logarithmic change from baseline ≥ 2, q ≤ 0.05), of which 513 were downregulated and 789 were upregulated (Figure 5). Post-treatment results were highly similar in all three esophageal regions sampled; therefore, the mean values ​​for all samples are presented. The top 50 genes most upregulated and the top 50 genes most downregulated in EoE were used to generate a normalized enrichment score (EoE-NES). For all genes, dupilumab treatment showed significantly lower EoE-NES (Wilcoxon rank-sum test, P < 5.0 × 10⁻⁶). -8 No significant changes were observed in the placebo group. The 30 genes showing the highest expression changes with dupilumab included those related to type 2 inflammation, tissue remodeling / fibrosis, barrier function, and proliferation / differentiation (Figure 6). Genes upregulated in the EoE transcriptome that were downregulated by dupilumab included ALOX15, CCL26, POSTN, NRXN1, and CCR3; genes downregulated at disease and upregulated by dupilumab included SPINK8 and DSG1.

[0188] Compared to a published EoE transcriptome against a healthy transcriptome, dupilumab treatment (week 12 vs. baseline) normalized the transcriptome at week 12. A strong negative correlation was observed between the published EoE transcriptome (vs. healthy) and DpxOme-EoE® (week 12 vs. baseline) (Pearson correlation coefficient: ρ = -0.872, P < 1 × 10⁻¹⁰). -6). A trend toward normalization was observed for genes that did not meet the significance threshold, and dupilumab significantly adjusted for several genes that were not included in the publicly available EoE transcriptome. Furthermore, many of the genes that did not overlap between the EoE and dupilumab signatures were unmeasurable in either dataset. The main genes altered in EoE and modified by dupilumab treatment included the following gene ontology (GO) groups: immune function / inflammation (e.g., interleukin-12 production, B cell-mediated immunity, response to type 1 interferon), eosinophil migration remodeling (e.g., degradation of the extracellular matrix), mast cell activation, and epithelial differentiation (e.g., keratinization and keratinization).

[0189] At week 12, dupilumab modulated type 2 inflammatory genes, eosinophil-related genes, and genes associated with mast cell activation. These modulated genes included CCL26, MUC5B, CLC, IL1RL1, HDC, IL13, FCER1G, GATA2, and KIT. Dupilumab treatment reduced eosinophilic tissue infiltration at week 12, with similar effects across all three sampled regions. The changes observed in eosinophil-related gene expression were consistent with the decrease in eosinophil density observed in esophageal biopsies after dupilumab treatment.

[0190] At week 12, dupilumab treatment also modulated genes associated with fibrosis, stromal remodeling, and TGFβ and integrin signaling, such as collagen family genes and barrier-related genes including DSG1, SPINK5, SPINK7, and SPINK8. Further changes in expression were observed in type 1 inflammatory genes, publicly available anti-IL-13 genes, and genes not modulated by the anti-IL-13 antibody QAX576.

[0191] Correlation analyses were performed using individual gene results and NES to evaluate the relationship between gene expression profiles and total EoE-HSS grade scores, eosinophil counts, and mucosal inflammatory and remodeling characteristics (EoE-EREFS). The DpxOme-EoE® NES score was strongly correlated with histological severity (ρ=0.832, P<0.001), demonstrating a biological relationship between molecular signatures and clinical measures. Furthermore, the expression of several individual genes was also highly correlated. The single gene most highly correlated with total EoE-HSS was CTSC, a protease involved in the activation of other pro-inflammatory proteinases (cathepsin C; ρ=0.826, P<0.001). This gene was also found to be highly correlated with eosinophil count, along with other genes including CCL26, CCR3, ANO1, and SPINK8 (ρ=0.783, P<0.001). Other correlations in the range of ρ = 0.585 to 0.623 were observed for EoE-EREFS.

[0192] The present invention is not limited in scope by the specific embodiments described herein. In fact, various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are intended to be included in the appended claims. All disclosures of patents and non-patent documents cited herein are expressly incorporated by reference in their entirety.

[0193] [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] Table 10-6 Table 10-7 Table 10-8 Table 10-9 Table 10-10 Table 10-11 Table 10-12 Table 10-13

Claims

1. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) inhibitor for use in a method of treating, preventing, or relieving at least one symptom of eosinophilic esophagitis (EoE) in subjects aged 12 years or older, The aforementioned subjects had a Swallowing Disorder Symptoms Questionnaire (DSQ) score of 10 or more prior to the start of treatment. The IL-4R inhibitor is an antibody that binds to IL-4Rα and comprises a heavy chain complementarity-determining region (HCDR) 1 containing the amino acid sequence of SEQ ID NO: 3, an HCDR 2 containing the amino acid sequence of SEQ ID NO: 4, an HCDR 3 containing the amino acid sequence of SEQ ID NO: 5, a light chain complementarity-determining region (LCDR) 1 containing the amino acid sequence of SEQ ID NO: 6, an LCDR 2 containing the amino acid sequence of SEQ ID NO: 7, and an LCDR 3 containing the amino acid sequence of SEQ ID NO:

8. The IL-4R inhibitor is administered subcutaneously once a week at a dose of 300 mg. The treatment with the IL-4R inhibitor is performed for at least 24 weeks. The DSQ score of the subject will decrease by at least 30% compared to baseline after 24 weeks of treatment; and / or, The DSQ score of the subject decreases by at least 10 points compared to the baseline after 24 weeks of treatment. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the subject is an adult.

3. The pharmaceutical composition according to claim 1, wherein the subject is a young person aged 12 or older but under 18 years of age.

4. The subject is a pharmaceutical product according to any one of claims 1 to 3, wherein, before the commencement of the procedure, at least two of the proximal, middle, and distal esophageal regions have an intraepithelial eosinophil infiltration peak cell count of 15 eos / hpf or more as measured by endoscopic biopsy. composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the subject has a history of having at least two episodes of dysphagia per week on average over a period of at least four weeks.

6. The subject is unresponsive to or inadequately responds to treatment with local corticosteroids and / or proton pump inhibitors (PPIs) in swallowing, according to any one of claims 1 to 5.

7. The subject has a DSQ score of 30 or more before the start of treatment, as described in any one of Claims 1 to 6.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the IL-4R inhibitor comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the IL-4R inhibitor comprises 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.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the IL-4R inhibitor is dupilumab.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the IL-4R inhibitor is administered in combination with a second therapeutic agent or therapy.

12. The pharmaceutical composition according to claim 11, wherein the second therapeutic agent or therapy 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 immunosuppressant, a topical corticosteroid, an oral corticosteroid, a systemic corticosteroid, an inhaled corticosteroid, a glucocorticoid, a PPI, a decongestant, an antihistamine, a nonsteroidal anti-inflammatory drug (NSAID), an esophageal dilator, an allergen removal, or dietary management.

13. The pharmaceutical composition according to claim 12, wherein the IL-4R inhibitor is administered in combination with a PPI.

14. The pharmaceutical composition according to claim 13, wherein the PPI is administered as a high-dose regimen selected from the group consisting of omeprazole in a dose of 40 mg QD or 20 mg BID, esomeprazole in a dose of 40 mg QD or 20 mg BID, lansoprazole in a dose of 60 mg QD or 30 mg BID, dexlansoprazole in a dose of 60 mg QD, rabeprazole in a dose of 40 mg QD or 20 mg BID, and pantoprazole in a dose of 80 mg QD or 40 mg BID.

15. The treatment with the aforementioned IL-4R inhibitor is The peak esophageal eosinophil count of the subject is reduced by at least 50% compared to baseline after 24 weeks of treatment; and / or, The pharmaceutical composition according to claim 4, which reduces the target peak esophageal intraepithelial eosinophil count to 6 eos / hpf or less after 24 weeks of treatment.

16. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) inhibitor for use in a method to improve the food swallowing ability of a subject with eosinophilic esophagitis (EoE), The aforementioned subjects had a Swallowing Disorder Symptoms Questionnaire (DSQ) score of 10 or more prior to the start of treatment. The IL-4R inhibitor is an antibody that binds to IL-4Rα and comprises a heavy chain complementarity-determining region (HCDR) 1 containing the amino acid sequence of SEQ ID NO: 3, an HCDR 2 containing the amino acid sequence of SEQ ID NO: 4, an HCDR 3 containing the amino acid sequence of SEQ ID NO: 5, a light chain complementarity-determining region (LCDR) 1 containing the amino acid sequence of SEQ ID NO: 6, an LCDR 2 containing the amino acid sequence of SEQ ID NO: 7, and an LCDR 3 containing the amino acid sequence of SEQ ID NO:

8. The IL-4R inhibitor is administered subcutaneously once a week at a dose of 300 mg. The treatment with the IL-4R inhibitor is performed for at least 24 weeks. The DSQ score of the subject will decrease by at least 30% compared to baseline after 24 weeks of treatment; and / or, The DSQ score decreases by at least 10 points compared to baseline after 24 weeks of treatment. The aforementioned pharmaceutical composition.

17. The pharmaceutical composition according to claim 16, wherein the subject is 12 years of age or older.

18. The pharmaceutical composition according to claim 17, wherein the subject is an adult.

19. The pharmaceutical composition according to claim 17, wherein the subject is a young person aged 12 or older but under 18 years of age.

20. The subject has a DSQ score of 30 or more before the start of treatment, and is a pharmaceutical composition according to any one of claims 16 to 19.

21. The pharmaceutical composition according to any one of claims 16 to 20, wherein the subject has a history of at least two episodes of dysphagia per week on average over a period of at least four weeks.

22. The subject is unresponsive to or poorly responds to treatment with local corticosteroids and / or proton pump inhibitors (PPIs) in swallowing, according to any one of claims 16 to 21.

23. The pharmaceutical composition according to any one of claims 16 to 22, wherein the IL-4R inhibitor comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

24. The pharmaceutical composition according to any one of claims 16 to 23, wherein the IL-4R inhibitor comprises 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.

25. The pharmaceutical composition according to any one of claims 16 to 24, wherein the IL-4R inhibitor is dupilumab.

26. The pharmaceutical composition according to any one of claims 16 to 25, wherein the IL-4R inhibitor is administered in combination with a second therapeutic agent or therapy.

27. The second therapeutic agent or therapy is an IL-1β inhibitor, IL-5 inhibitor, IL-9 inhibitor, IL-13 inhibitor, IL-17 inhibitor, IL-25 inhibitor, TNFα inhibitor, eotaxin-3 inhibitor, IgE inhibitor, prostaglandin D2 inhibitor, immunosuppressant, topical corticosteroid, oral corticosteroid, systemic corticosteroid, inhaled corticosteroid. The pharmaceutical composition according to claim 26, comprising a steroid, glucocorticoid, PPI, decongestant, antihistamine, nonsteroidal anti-inflammatory drug (NSAID), esophageal dilator, allergen removal, or dietary management.

28. The pharmaceutical composition according to claim 27, wherein the IL-4R inhibitor is administered in combination with a PPI.

29. The pharmaceutical composition according to claim 28, wherein the PPI is administered as a high-dose regimen selected from the group consisting of omeprazole in a dose of 40 mg QD or 20 mg BID, esomeprazole in a dose of 40 mg QD or 20 mg BID, lansoprazole in a dose of 60 mg QD or 30 mg BID, dexlansoprazole in a dose of 60 mg QD, rabeprazole in a dose of 40 mg QD or 20 mg BID, and pantoprazole in a dose of 80 mg QD or 40 mg BID.

30. The pharmaceutical composition according to any one of claims 16 to 29, wherein treatment with the IL-4R inhibitor improves the patient's overall impression (PGIC) score regarding changes in swallowing difficulties.

31. The pharmaceutical composition according to any one of claims 1 to 30, wherein the IL-4R inhibitor is contained in a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an auto-injector.

32. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) inhibitor for use in the treatment of EoE in subjects aged 12 years or older, The aforementioned subjects had a Swallowing Disorder Symptoms Questionnaire (DSQ) score of 10 or more prior to the start of treatment. The aforementioned IL-4R inhibitor is dupilumab. The IL-4R inhibitor is administered subcutaneously at a dose of 300 mg once a week or once every two weeks for at least 24 weeks. The DSQ score of the subject will decrease by at least 30% compared to baseline after 24 weeks of treatment; and / or, The DSQ score decreases by at least 10 points compared to baseline after 24 weeks of treatment. The aforementioned pharmaceutical composition.

33. The pharmaceutical composition according to claim 32, wherein the subject is an adult.

34. The pharmaceutical composition according to claim 32, wherein the target is a young person aged 12 or older but under 18 years of age.

35. The pharmaceutical composition according to claim 34, wherein the subject is a young person aged 12 to under 18 years who has a weight of more than 40 kg before the start of treatment.

36. The pharmaceutical composition according to claim 32, wherein the subject is unresponsive to or poorly responds to treatment with a local corticosteroid and / or proton pump inhibitor (PPI) for swallowing.

37. The pharmaceutical composition according to claim 32, wherein the subject has a DSQ score of 30 or more before the start of treatment.

38. The IL-4R inhibitor is administered subcutaneously once a week at a dose of 300 mg, claim 3 The pharmaceutical composition described in 2.

39. The pharmaceutical composition according to claim 32, wherein the IL-4R inhibitor is administered subcutaneously once every two weeks at a dose of 300 mg.

40. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) inhibitor for use in a method to improve the food swallowing ability of a subject having eosinophilic esophagitis (EoE), The aforementioned subjects had a Swallowing Disorder Symptoms Questionnaire (DSQ) score of 10 or more prior to the start of treatment. The aforementioned IL-4R inhibitor is dupilumab. The IL-4R inhibitor is administered subcutaneously at a dose of 300 mg once a week or once every two weeks for at least 24 weeks. The DSQ score of the subject will decrease by at least 30% compared to baseline after 24 weeks of treatment; and / or, The DSQ score decreases by at least 10 points compared to baseline after 24 weeks of treatment. The aforementioned pharmaceutical composition.

41. The pharmaceutical composition according to claim 40, wherein the subject has a DSQ score of 30 or more before the start of treatment.

42. The pharmaceutical composition according to claim 40, wherein the subject is an adult.

43. The pharmaceutical composition according to claim 40, wherein the target is a young person aged 12 or older but under 18 years of age.

44. The pharmaceutical composition according to claim 43, wherein the subject is a young person aged 12 to under 18 years old who has a weight of more than 40 kg before the start of treatment.

45. The pharmaceutical composition according to claim 40, wherein the subject is unresponsive to or poorly responds to treatment with a local corticosteroid and / or proton pump inhibitor (PPI) for swallowing.

46. The pharmaceutical composition according to claim 40, wherein the IL-4R inhibitor is administered subcutaneously once a week at a dose of 300 mg.

47. The pharmaceutical composition according to claim 40, wherein the IL-4R inhibitor is administered subcutaneously once every two weeks at a dose of 300 mg.

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