How to Treat Active Eosinophilic Esophagitis

Abstract

To provide methods for treating, preventing or reducing the severity of active eosinophilic esophagitis, and methods for increasing esophageal distensibility.SOLUTION: The methods of the present invention comprise administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 / interleukin-13 (IL-4 / IL-13) pathway inhibitor such as an anti-IL-4R antibody.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 541242, filed August 4, 2017, U.S. Provisional Patent Application No. 62 / 561593, filed September 21, 2017, and European Application No. 18305252.1, filed March 8, 2018, which were filed as PCT International Patent Applications on August 3, 2018, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] The present invention relates to the use of an interleukin-4 / interleukin-13 pathway inhibitor for treating or preventing active eosinophilic esophagitis in a subject in need thereof. [Background technology]

[0003] Esophageal strictures (narrowing of the esophagus) result from damage to the lining of the esophagus and can result in, among other things, difficulty swallowing (dysphagia), regurgitation of food or liquids, heartburn, and unintended weight loss. Treatment of esophageal strictures is crucial because of the reduced quality of life caused by dysphagia, weight loss, and nutritional imbalances. Esophageal strictures can be caused by chronic ulcers or chronic inflammation as a complication of chemotherapy, radiation therapy, esophageal cancer, endoscopic surgery, peptic ulcers, or gastroesophageal reflux. Esophageal strictures can also be caused by eosinophilic esophagitis.

[0004] Eosinophilic esophagitis (EoE) is a novel chronic immune / antigen-mediated disease characterized by esophageal dysfunction and eosinophilic inflammation of the esophagus (Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3). Adult patients with EoE experience significant impairment of quality of life (QOL) due to dysphagia and the potential risk of food impaction (Non-Patent Document 4; Non-Patent Document 5; Non-Patent Document 6; Non-Patent Document 7). Patients with active disease or moderate to severe EoE suffer from esophageal strictures leading to dysphagia, food or liquid regurgitation, and weight loss. Urgent endoscopy for prolonged food impaction is associated with the risk of severe esophageal damage. EoE has been found to be associated with food allergies in many patients. Some patients may also have concurrent asthma or atopic disorders such as atopic dermatitis or allergic rhinitis. The symptomatic burden of EoE, such as food avoidance, dietary modification behaviors, and social, emotional, economic, work and school, and sleep impacts, are also important to the EoE population and, if relevant and improved, may reflect treatment outcomes in EoE patients. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Liacouras et al., 2011, The Journal of Allergy and Clinical Immunology. Vol. 128:3-20 e6; quiz 1-2 [Non-patent document 2] Weinbrand-Goichberg et al., 2013, Immunologic Research. 56:249-60 [Non-patent document 3] Zhang et al., 2013, Digestive Diseases and Sciences 58:1497-506 [Non-patent document 4] DeBrosse et al., 2011, The Journal of Allergy and Clinical Immunology 128:132-8 [Non-Patent Document 5] Falk et al., 2014, Gastroenterology Clinics of North America 43:231-42; [Non-patent document 6] Straumann 2008, Gastrointestinal Endoscopy Clinics of North America 18:99-118 [Non-Patent Document 7] Straumann et al., 2003, Gastroenterology 125:1660-9 Summary of the Invention [Problem to be solved by the invention]

[0006] Current therapeutic approaches include chronic dietary elimination (including food allergen withdrawal), swallowed topical corticosteroids (not approved for the treatment of EoE in the United States), and esophageal dilation. While swallowed topical corticosteroids have been reported in clinical trials to induce partial clinical responses and histological remission, they are not uniformly effective and are associated with fungal infections and disease recurrence after discontinuation. Currently, there are no approved pharmacological therapies for EoE. Thus, there is an unmet need in the art for effective therapeutic approaches to prevent or treat eosinophilic esophagitis without adverse side effects. Esophageal strictures are treated with proton pump inhibitors, which inhibit gastric acid secretion. Endoscopic esophageal dilation is currently used to treat esophageal strictures and increase esophageal distensibility. However, it is an invasive surgical procedure and can lead to complications such as perforation and bleeding. Therefore, there is an unmet need for safe and effective therapies to increase esophageal distensibility and treat esophageal strictures (e.g., in eosinophilic esophagitis). [Means for solving the problem]

[0007] According to one aspect of the present invention, there is provided a method for increasing esophageal compliance, the method comprising the steps of: (a) selecting a patient with moderate to severe eosinophilic esophagitis (EoE), the patient having an attribute or being selected based on criteria selected from the group consisting of: (i) the patient having 15 or more eosinophils per high-power field (hpf) in the esophagus before or at the time of treatment ("baseline"); (ii) the patient exhibiting at least one episode of dysphagia per week; and (iii) the patient having a Straumann Dysphagia Instrument (SDI) score of 2 or greater; and (b) administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 / interleukin-13 (IL-4 / IL-13) pathway inhibitor, thereby increasing esophageal compliance as measured by a functional luminal imaging probe (EndoFLIP®, Crospon, Ireland). In one embodiment, the patient has active EoE. In one embodiment, the patient is 18 years of age or older. In one embodiment, the patient has been previously treated with a proton pump inhibitor (PPI). In one embodiment, the patient has undergone at least one prior esophageal dilation.In one embodiment, the patient has (1) previous treatment with at least one of PPI, esophageal dilation, corticosteroids, allergen withdrawal, and / or dietary modification; (2) the patient is unresponsive or resistant to previous treatment with PPI or esophageal dilation; (3) the patient has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score of 30 or greater, 40 or greater, or 50 or greater; (4) the patient has suffered from EoE for at least 3 years; (5) the patient has a history of food allergy, atopy, or other conditions prior to or at the time of administration of the IL-4 / IL-13 pathway inhibitor. (6) the patient has or has been diagnosed with a disease or disorder selected from the group consisting of allergic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis; and (7) the patient has a characteristic selected from the group consisting of elevated levels of a biomarker selected from the group consisting of eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum thymus- and activation-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN).

[0008] In embodiments of the invention specifying a selection of "at least one selected from the group consisting of" or simply "selected from the group consisting of," the use of the conjunction "and / or" between the last two items of a list following such language or the like indicates that the items in that order are alternatives to each other, and that one (or more) of those items are selected. It does not mean that each item is necessarily selected. For example, for a method of increasing esophageal compliance, a patient may receive one of the following: (1) previous treatment with at least one of the following: PPI, esophageal dilation, corticosteroids, allergen withdrawal, and / or dietary modification; (2) the patient is unresponsive or refractory to previous treatment with PPIs or esophageal dilation; (3) patients have an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score of ≥30, ≥40, or ≥50; (4) the patient had EoE for at least 3 years; (5) the patient has or has been diagnosed with a disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and / or allergic conjunctivitis prior to or at the time of administration of the IL-4 / IL-13 pathway inhibitor; and / or (6) the patient has at least one characteristic selected from the group consisting of elevated levels of at least one biomarker selected from the group consisting of eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum thymus- and activation-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophil cationic protein (ECP), and / or eosinophil-derived neurotoxin (EDN); It means that the patient has at least characteristic (1), or characteristic (2), or characteristic (3), or characteristic (4), or characteristic (5), or characteristic (6). A patient can also have one or more of the six characteristics based on these terms (e.g., (1) and (2), or (4) and (5), or (1), (2) and (6), etc.). However, it does not mean that a patient must have at least characteristic (1), characteristic (2), characteristic (3), characteristic (4), characteristic (5), and characteristic (6).

[0009] According to another aspect of the present invention, there is provided a method for treating, preventing, or ameliorating at least one symptom or sign of active eosinophilic esophagitis (EoE) in a subject. The method according to this aspect of the present invention includes the steps of selecting a patient having moderate to severe EoE and administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 / interleukin-13 (IL-4 / IL-13) pathway inhibitor. In certain embodiments, a patient in need thereof is identified as having: (1) the patient has 15 or more eosinophils per high-power field (hpf) in the esophagus before or at the time of treatment ("baseline"); (2) previous treatment with at least one of high-dose proton pump inhibitors (PPIs), esophageal dilation, corticosteroids, allergen withdrawal, and / or dietary modification; (3) the patient exhibits at least one episode of dysphagia per week; (4) the patient is unresponsive or resistant to previous treatment with high-dose PPIs or esophageal dilation; (5) the patient has a Straumann Dysphagia Scale (SDI) of 5 or greater. (6) the patient has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score of 30 or greater, 40 or greater, or 50 or greater; (7) the patient has had EoE for at least three years; (8) the patient has or has been diagnosed with a disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis prior to or at the time of administration of the IL-4 / IL-13 pathway inhibitor; and (9) the patient has levels of eotaxin-3, periostin, serum IgE (total and allergen-specific), IgE, and IgA. The patients are selected based on an attribute or criteria selected from the group consisting of elevated levels of a biomarker selected from the group consisting of L-13, IL-5, serum thymus and activation-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN).

[0010] According to another aspect of the present invention, there is provided a method of alleviating dysphagia, the method comprising the steps of selecting a patient with moderate to severe EoE, the patient (i) exhibiting one or more episodes of dysphagia per week; (ii) having been previously treated with a high-dose proton pump inhibitor (PPI); and / or (iii) having undergone at least one previous esophageal dilation; and (b) administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor.

[0011] According to another aspect of the present invention, there is provided a method for improving a parameter, the method comprising the steps of selecting a patient with moderate to severe EoE and administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor, wherein the administration results in an improvement in a parameter selected from the group consisting of: (a) at least a 40% reduction from baseline in the frequency and severity of dysphagia, as measured by the Straumann Dysphagia Measure (SDI) score; (b) a 3-point reduction from baseline in the SDI score; (c) a greater than 85% reduction from baseline in peak intraepithelial eosinophil count in the proximal, middle, and / or distal regions of the esophagus; (d) at least a 10% increase from baseline in esophageal distensibility, as measured by impedance planimetry; (e) a greater than 50% reduction from baseline in the severity and extent of disease, as measured by the EoE Histological Scoring System (HSS) score; and (f) a greater than 30% reduction from baseline in dysphagia, as measured by the Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score.

[0012] According to another aspect of the present invention, a method for reducing esophageal eosinophil infiltration in a patient in need thereof is provided. In certain embodiments, a method for reducing inflammation in the esophagus is provided. The method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor. In certain embodiments, esophageal eosinophil infiltration is represented by greater than or equal to about 15 eosinophils per high-power field in the esophagus of a subject in need thereof. In certain embodiments, the number of eosinophils is reduced by 85% or more after administration of an IL-4 / IL-13 pathway inhibitor. In certain embodiments, inflammation (e.g., mucosal inflammation) is identified by endoscopic examination and features such as esophageal edema, rings, exudates, grooves, and strictures (EREFS). In certain embodiments, administration of an IL-4 / IL-13 pathway inhibitor reduces the EREFS score to less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, or less than 2 (as disclosed elsewhere herein).

[0013] According to another aspect of the present invention, there is provided a method for reducing the level of an EoE-associated biomarker in a subject. In certain embodiments, the EoE-associated biomarker is selected from the group consisting of, for example, circulating or esophageal eosinophils, eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum thymus and activation-regulated chemokine (TARC; CCL17), thymic stromal lymphopoietin (TSLP), serum eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN). The method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor.

[0014] In certain embodiments, the IL-4 / IL-13 pathway inhibitor is administered in combination with a second therapeutic agent or therapy.

[0015] In certain embodiments, the subject in need thereof is a patient suffering from a food allergy, atopic dermatitis, have a co-occurring disease or disorder selected from the group consisting of allergic rhinitis, asthma, allergic conjunctivitis, and inherited connective tissue disorders.

[0016] Exemplary IL-4 / IL-13 pathway inhibitors that can be used in connection with the methods of the present invention include, but are not limited to, anti-IL-4 antibodies, anti-IL-13 antibodies, bispecific anti-IL-4 / IL-13 antibodies, and IL-4 receptor (IL-4R) inhibitors. In one embodiment, the IL-4 / IL-13 pathway inhibitor is an IL-4R inhibitor (e.g., an anti-IL-4R antibody).

[0017] Exemplary IL-4R inhibitors that can be used in connection with the methods of the present invention include, for example, small molecule chemical inhibitors of IL-4R or its ligands, or biological agents that target IL-4R or its ligands (IL-4 and / or IL-13). According to certain embodiments, the IL-4R inhibitor is an antibody or antigen-binding protein that binds to the IL-4Rα chain and blocks signaling by IL-4, IL-13, or both IL-4 and IL-13. In certain embodiments, the anti-IL-4R antibody or antigen-binding protein comprises a heavy chain complementarity-determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain CDR of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. One such type of antigen-binding protein that can be used in connection with the methods of the present invention is an anti-IL-4Rα antibody, such as dupilumab.

[0018] In certain embodiments, the present invention provides the use of an IL-4 / IL-13 pathway inhibitor in the manufacture of a medicament for treating or inhibiting or preventing active eosinophilic esophagitis in a subject, including a human.

[0019] In certain embodiments, the present invention provides use of an antibody or antigen-binding antibody fragment thereof that binds to IL-4R in the manufacture of a medicament for treating, inhibiting, or preventing active eosinophilic esophagitis in a subject, including a human.

[0020] In certain embodiments, the present invention provides use of an IL-4 / IL-13 pathway inhibitor in the manufacture of a medicament for increasing esophageal compliance in a subject, including a human. In one embodiment, the subject has active EoE. In one embodiment, the subject has moderate to severe EoE.

[0021] In certain embodiments, the present invention provides use of an antibody or antigen-binding fragment thereof that binds to IL-4R in the manufacture of a medicament for increasing esophageal compliance in a subject, including a human. In one embodiment, the subject has active EoE. In one embodiment, the subject has moderate to severe EoE.

[0022] Other embodiments of the present invention will become apparent from consideration of the following detailed description. [Brief explanation of the drawings]

[0023] [Figure 1] FIG. 1 lists the components comprising the weekly Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score. [Figure 2] FIG. 1 shows the mean change from baseline in Straumann Dysphagia Measure (SDI) scores during the 12-week treatment period in patients receiving 300 mg dupilumab once weekly (qw) versus placebo. [Figure 3] FIG. 1 shows the mean percent change from baseline in the dysphagia frequency and severity components of the Straumann Dysphagia Measure (SDI) score at weeks 10 and 12 upon administration of 300 mg dupilumab once weekly (qw) versus placebo. [Figure 4] FIG. 1 shows the mean percent change from baseline in EEsAI scores during the 12-week treatment period in patients receiving 300 mg dupilumab once weekly (qw) versus placebo. [Figure 5]FIG. 1 shows the mean percent change from baseline in the total EoE edema, ring, exudate, groove and stenosis (EREFS) score and subcomponents of the EREFS score at week 12 in patients receiving 300 mg dupilumab once weekly (qw) versus placebo. [Figure 6] FIG. 1 shows the mean change from baseline in the total EoE Histology Scoring System (HSS) score of grade (severity) subcomponents at week 12 in patients receiving 300 mg dupilumab once weekly (qw) versus placebo. [Figure 7] FIG. 7 illustrates the mean change from baseline in stage (range) subcomponent total EoE HSS score at week 12 in patients receiving 300 mg dupilumab once weekly (qw) versus placebo. [Figure 8] Figure 8 is composed of Figures 8A, 8B, 8C, and 8D. Figure 8A shows the mean change from baseline in EoE HSS grade scores for basal hyperplasia. Figure 8B shows the mean change from baseline in EoE HSS grade scores for surface layering of eosinophils. Figure 8C shows the mean change from baseline in EoE HSS grade scores for eosinophilic inflammation. Figure 8D shows the mean change from baseline in EoE HSS grade scores for eosinophilic abscesses in the proximal, middle, and distal regions of the esophagus sampled at week 12 from patients receiving 300 mg dupilumab once weekly (qw) versus placebo. [Figure 9] Figure 9 is composed of Figures 9A, 9B, 9C, and 9D. Figure 9A shows the mean change from baseline in EoE HSS stage scores for basal hyperplasia. Figure 9B shows the mean change from baseline in EoE HSS stage scores for eosinophilic abscess. Figure 9C shows the mean change from baseline in EoE HSS stage scores for eosinophilic inflammation. Figure 9D shows the mean change from baseline in EoE HSS stage scores for the eosinophilic surface layer of the proximal, middle, and distal regions of the esophagus sampled at week 12 from patients receiving 300 mg dupilumab once weekly (qw) versus placebo. [Figure 10]Figure 10 is composed of Figures 10A, 10B, and 10C. Figure 10A shows the mean change from baseline in EoE HSS grade scores for dilated intercellular spaces. Figure 10B shows the mean change from baseline in EoE HSS grade scores for surface changes, and Figure 10C shows the mean change from baseline in EoE HSS grade scores for apoptotic epithelial cells in the proximal, middle, and distal regions of the esophagus sampled at week 12 from patients receiving 300 mg dupilumab once weekly (qw) versus placebo. [Figure 11] Figure 11 is composed of Figures 11A, 11B, and 11C. Figure 11A shows the mean change from baseline in EoE HSS stage scores for dilated intercellular spaces. Figure 11B shows the mean change from baseline in EoE HSS stage scores for surface changes, and Figure 11C shows the mean change from baseline in EoE HSS stage scores for apoptotic epithelial cells in the proximal, middle, and distal regions of the esophagus sampled at week 12 from patients receiving dupilumab 300 mg once weekly (qw) versus placebo. [Figure 12] FIG. 1 shows the percent change from baseline in distensible plateau at week 12 in patients receiving 300 mg dupilumab once weekly (qw) versus placebo. DETAILED DESCRIPTION OF THE INVENTION

[0024] Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0025] Unless otherwise defined, all technical and scientific terms used herein refer to the The term "about" has the same meaning as that generally understood by those skilled in the art to which it pertains.As used herein, when used in relation to a specific numerical value listed, the term "about" means that the numerical value can vary by less than 1% from the listed value.For example, as used herein, the expression "about 100" includes 99 and 101, and all values ​​therebetween (for example, 99.1, 99.2, 99.3, 99.4, etc.).

[0026] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are described herein. All publications mentioned herein are incorporated by reference as if set forth in their entireties.

[0027] Methods for treating, preventing, or ameliorating eosinophilic esophagitis The present invention includes methods for treating, preventing, or ameliorating at least one symptom or sign of active eosinophilic esophagitis (EoE) in a subject. The method according to this aspect of the present invention comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor. As used herein, the terms "treat," "treating," and the like mean alleviating symptoms, eliminating the cause of symptoms, either temporarily or permanently, or preventing or delaying the onset of symptoms of eosinophilic inflammation in the esophagus. In certain embodiments, the methods of the present invention are useful for treating or ameliorating at least one symptom or sign of EoE, including, but not limited to, eosinophilic infiltration of the esophagus, thickening of the esophageal wall, esophageal inflammation, the appearance of trachea-like rings or protrusions in the esophagus, chest and abdominal pain, anorexia, vomiting, dysphagia, and food impaction.

[0028] "Eosinophilic esophagitis" (EoE), as used herein, refers to an inflammatory disease characterized by abnormal eosinophilic inflammation in the esophagus and esophageal dysfunction. Cardinal symptoms of EoE include, but are not limited to, chest and abdominal pain, dysphagia, heartburn, anorexia, vomiting, and food impaction. The clinical pathology of EoE is characterized by the presence of protrusions or trachea-like rings in the esophageal wall and eosinophilic infiltration in the esophageal mucosa. EoE is diagnosed by esophageal endoscopy followed by microscopic and biochemical analysis of the esophageal mucosal lining. EoE can be classified as allergic or non-allergic, depending on the subject's condition. The present invention includes methods for treating both allergic and non-allergic forms of EoE.

[0029] As used herein, the term "active EoE" refers to EoE disease in patients with 15 or more eosinophils per high-power field (hpf) in esophageal biopsies, even after 8 weeks of proton pump inhibitor (PPI) treatment. This term also refers to EoE disease in patients with frequent dysphagia, for example, patients experiencing 2, 3, 4, 5, or more episodes of dysphagia per week. The term "active EoE" includes mild EoE as well as moderate to severe EoE. The term "moderate to severe" refers to EoE disease in patients with eosinophilia (e.g., 15 or more eosinophils per hpf in the esophageal mucosa) and frequent episodes of dysphagia, an SDI score of 2 or more, and / or an EEsAI score of 30 or more, a duration of EoE of at least 2 years, and / or unresponsive or resistant to previous treatments (including PPIs or esophageal dilation).

[0030] As used herein, the phrase "subject in need thereof" refers to a human or non-human mammal that exhibits one or more symptoms or signs of eosinophilic esophagitis and / or has been diagnosed with eosinophilic esophagitis (EoE). Throughout this disclosure, the term "subject" is used interchangeably with the term "patient." The term "subject in need thereof" also refers to a human or non-human mammal that exhibits one or more symptoms or 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, and / or dysphagia, prior to treatment. The term includes patients who present (or have presented) with hemiplegic indentation, chest and abdominal pain, and / or elevated levels of EoE-associated biomarkers. The term specifically includes subjects who present with 15 or more eosinophils per high-power field in the esophagus. In certain embodiments, the 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).

[0031] In certain embodiments, this method can be used to treat patients who show pathology and symptoms observed in subjects with chronic esophagitis, including gastroesophageal reflux disease (GERD).In certain embodiments, the term "subject in need thereof" includes subjects who are unresponsive or resistant to anti-GERD therapy.For example, this method can be used to treat subjects who are resistant to proton pump inhibitors (PPIs).

[0032] In the context of the present invention, a "subject in need thereof" may include a portion of a population that is more susceptible to EoE or that may exhibit elevated levels of EoE-associated biomarkers. For example, a "subject in need thereof" may include subjects suffering from an atopic disease or disorder, such as food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis. In certain embodiments, the term "subject in need thereof" includes patients who have or have been diagnosed with a disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis before or at the time of administration of an IL-4 / IL-13 pathway inhibitor. In certain embodiments, the term "subject in need thereof" may include patients with a genetic connective tissue disorder. Such a subject population may exhibit elevated levels of EoE-associated biomarkers, such as IgE, eotaxin-3, periostin, IL-5, or IL-13.

[0033] In certain embodiments, a "subject in need thereof" includes a patient who is sensitive to an allergen. For example, a "subject in need thereof" includes a patient who may exhibit one of the following characteristics: (a) prone to an allergic reaction or response when exposed to one or more allergens; (b) previously exhibited an allergic reaction or reaction to one or more allergens; (c) have a history of allergy; and / or (d) exhibit signs or symptoms of an allergic response or anaphylaxis. In certain embodiments, the patient is allergic to an allergen associated with EoE or an allergen that renders the subject susceptible to and / or prone to developing EoE.

[0034] The term "allergen" as used herein includes any substance, chemical substance, particle or composition that can stimulate an allergic response in susceptible individuals.Allergens can be contained in or derived from foods, such as dairy products (e.g., milk), eggs, wheat, soybeans, corn, rye, fish, shellfish, peanuts and tree nuts.Alternatively, allergens can be contained in or derived from non-foods, such as dust (e.g., dust mites), pollen, insect venom (e.g., bee, wasp, mosquito venom), mold, animal dander, latex, medicine, drug, ragweed, grass and birch.

[0035] In certain embodiments, the term "subject in need thereof" includes a portion of the population that exhibits an allergic reaction to a food allergen. For example, a "subject in need thereof" includes, but is not limited to, a subject who has an allergy to allergens found in foods including dairy products, eggs, wheat, soybeans, corn, rye, fish, shellfish, peanuts, tree nuts, beef, chicken, oats, barley, pork, green beans, and fruits, such as apples and pineapples.

[0036] In certain embodiments, the term includes subjects who are allergic to non-food allergens, such as allergens from dust, mold, insects, plants including pollen, and pets, e.g., cats and dogs. Examples of non-food allergies (also known as environmental allergens or aeroallergens) include, but are not limited to, house dust mite allergens, pollen allergens, animal dander allergens, insect venom, grass allergens, and latex.

[0037] As used herein, the phrases "allergic response," "allergic reaction," "allergic symptoms," and the like include one or more signs or symptoms selected from the group consisting of urticaria (e.g., hives), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinus inflammation, watery eyes, wheezing, bronchospasm, decreased peak expiratory flow (PEF), gastrointestinal distress, flushing, swollen lips, swollen tongue, decreased blood pressure, anaphylaxis, and organ dysfunction / failure. "Allergic response," "allergic reaction," "allergic symptoms," and the like also include immunological responses and reactions, such as increased IgE production, increased allergen-specific immunoglobulin production, and / or eosinophilia.

[0038] In some embodiments, the methods herein are for the treatment of adults, adolescents, or children. Adults are 18 years of age or older, adolescents are 12 years of age or older but not older than 18 years, and children are 12 years of age or younger. In some embodiments, the methods herein can be used to treat EoE in children 3 years of age or younger. In one embodiment, an inhibitor of the IL-4 / IL-13 pathway is used to treat moderate to severe EoE in subjects not adequately controlled with standard therapeutic treatments (e.g., oral corticosteroids, dilation, etc.). The subject is an adult, adolescent, or child.

[0039] The present invention also includes a method of increasing esophageal compliance, the method according to this aspect of the invention comprising administering to a patient in need thereof one or more doses of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor, thereby increasing esophageal compliance in the patient.

[0040] The present invention also includes a method for reducing eosinophil infiltration. The method according to this aspect of the invention comprises administering to a patient in need thereof one or more doses of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor to reduce or eliminate eosinophil numbers, for example, in the esophageal mucosa.

[0041] As used herein, "eosinophil infiltration" refers to the presence of eosinophils in organs or tissues of a subject, including the blood, esophagus, stomach, duodenum, and ileum. In the context of the present invention, the term "eosinophil infiltration" refers to the presence of eosinophils in the mucosal lining of regions of the gastrointestinal tract, including, but not limited to, the esophagus and stomach. Eosinophil infiltration is analyzed, for example, in an esophageal tissue biopsy of a subject suffering from EoE. According to certain embodiments, "eosinophil infiltration" refers to the presence of 15 or more eosinophils per high-power field in the esophagus. The term "high-power field" refers to a standard total magnification of 400x under a microscope used to observe eosinophils in tissue, for example, in tissue from the esophagus of a subject. In certain embodiments, "eosinophil infiltration" includes infiltration of tissue by leukocytes, such as lymphocytes, neutrophils, and mast cells. For example, leukocyte infiltration into esophageal tissue can be detected by the expression of eosinophil-specific markers (e.g., CD11c). Low / Neg , SiglecF + , 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 + ) as well as T cell specific markers (e.g., CD3 + CD4 + CD8 + ) can be detected by cell surface markers such as

[0042] As used herein, a reduction in esophageal eosinophils means that the number of eosinophils and other leukocytes measured in the esophagus of a subject with EoE and treated with an IL-4 / IL-13 pathway inhibitor is at least 5%, 10%, 20%, 50%, 70%, 80%, or 90% lower than the number of esophageal eosinophils measured in the same or similar subject not treated with an IL-4 / IL-13 pathway inhibitor. In certain embodiments, a reduction in eosinophil infiltration means detecting fewer than 15 eosinophils per high-power field, more preferably fewer than 10 eosinophils, fewer than 9 eosinophils, fewer than 8 eosinophils, fewer than 7 eosinophils, fewer than 6 eosinophils, or fewer than 5 eosinophils per high-power field, in a biopsy of the esophageal mucosa. In certain embodiments, a reduction in esophageal eosinophils means that eosinophils are not detected in the esophageal mucosa of the subject.

[0043] The present invention includes methods for treating, preventing, or reducing the severity of eosinophilic esophagitis, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor, wherein the pharmaceutical composition is administered to the subject in multiple doses, e.g., as part of a particular therapeutic dosing regimen. For example, the therapeutic dosing regimen may comprise administering multiple doses of the pharmaceutical composition to the subject about once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, or less frequently.

[0044] According to certain embodiments, the methods of the present invention include administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor in combination with a second therapeutic agent. The second therapeutic agent may be, for example, an IL-1 beta inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNF alpha inhibitor, an eotaxin-3 inhibitor, an IgE inhibitor, a prostaglandin D2 inhibitor, an immunosuppressant, a topical corticosteroid, an oral corticosteroid (e.g., budesonide), a systemic corticosteroid, an inhaled corticosteroid, a glucocorticoid, a proton pump inhibitor, a decongestant, an antihistamine, and a nonsteroidal anti-inflammatory drug (NSAID). In certain embodiments, the IL-4 / IL-13 pathway inhibitor of the present invention may be administered in combination with a therapy including esophageal dilation, allergen removal, and dietary management. As used herein, the phrase "in combination" means that a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor is administered to a subject simultaneously with, immediately before, or immediately after the administration of a second therapeutic agent. In certain embodiments, the second therapeutic agent is administered as a co-formulation with an IL-4 / IL-13 pathway inhibitor. In related embodiments, the present invention includes a method comprising administering to a subject undergoing a background anti-allergy treatment regimen a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor. The background anti-allergy treatment regimen may include, for example, administration routes of steroids, antihistamines, decongestants, anti-IgE agents, and the like. The IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody) can be added in addition to the background anti-allergy treatment regimen. In some embodiments, the IL-4 / IL-13 pathway inhibitor is added as part of a "background step-down" scheme, where the background anti-allergy therapy is gradually withdrawn from the subject over time (e.g., in a phased manner), while the IL-4 / IL-13 pathway inhibitor is administered to the subject at a constant dose or in increasing or decreasing doses over time. In certain embodiments, the IL-4 / IL-13 pathway inhibitor is administered as monotherapy.

[0045] Eosinophilic esophagitis-related biomarkers The present invention also includes methods involving the use, quantification, and analysis of EoE-associated biomarkers. As used herein, the term "EoE-associated biomarker" means any biological response, cell type, parameter, protein, polypeptide, enzyme, enzymatic activity, metabolite, nucleic acid, carbohydrate, or other biomolecule that is present or detectable in EoE patients at a level or amount that differs (e.g., greater or lesser) than the level or amount of the marker that is present or detectable in non-EoE patients. Exemplary EoE-associated biomarkers include, but are not limited to, esophageal eosinophils, eotaxin-3 (CCL26), periostin, serum IgE (total and allergen-specific), serum IgG (total and allergen-specific), IL-13, IL-5, serum thymus- and activation-regulated chemokine (TARC; CCL17), thymic stromal lymphopoietin (TSLP), serum eosinophil cationic protein (ECP), calpain 14, filaggrin (FLG), signal transducer and activator of transcription 6 (STAT6), interleukin-4 receptor (IL-4R), and eosinophil-derived neurotoxin (EDN). The term "EoE-associated biomarker" also includes genes or gene probes known in the art that are differentially expressed in subjects with EoE compared to subjects without EoE. For example, genes that are significantly upregulated in subjects with EoE include, but are not limited to, T helper 2 (Th2)-associated chemokines, such as CCL8, CCL23, and CCL26, periostin, cadherin-like 26, and TNFα-inducible protein 6 (Blanchard et al., 2006, J. Clin. Invest. 116:536-547). Alternatively, "EoE-associated biomarkers" also include genes that are downregulated due to EoE, such as terminal differentiation proteins (e.g., filaggrin) (Blanchard et al., 2006, J. Clin. Invest. 116:536-547). Certain embodiments of the present invention relate to the use of these biomarkers to monitor disease reversal by administration of IL-4 / IL-13 pathway inhibitors.Methods for detecting and / or quantifying EoE-associated biomarkers are known in the art; kits for measuring such EoE-associated biomarkers are available from various commercial sources; and various commercial diagnostic laboratories similarly offer services that provide measurement of such biomarkers.

[0046] According to certain aspects of the present invention, there are provided methods for treating EoE, comprising: (a) selecting a subject exhibiting a pre-treatment or treatment level of at least one EoE-associated biomarker indicative of a disease state; and (b) administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor. In certain embodiments of this aspect of the invention, the subject is selected based on elevated levels of IgE or eotaxin-3.

[0047] According to another aspect of the present invention, there is provided a method for treating EoE, comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4 / IL-13 pathway inhibitor, wherein administration of the pharmaceutical composition to a subject results in a decrease in at least one EoE-associated biomarker (e.g., esophageal eosinophils, eotaxin-3, IgE, etc.) at a time point after administration of the pharmaceutical composition compared to the level of the EoE-associated biomarker in the subject before administration.

[0048] As will be appreciated by one of skill in the art, an increase or decrease in an EoE-associated biomarker can be determined by comparing (i) the level of the biomarker measured in a subject at a predetermined time point after administration of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor with (ii) the level of the biomarker measured in the patient prior to administration of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor (i.e., a "baseline measurement"). The predetermined time point at which the biomarker is measured can be, for example, about 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, 35 days, 40 days, 50 days, 55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, or more after administration of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor.

[0049] According to certain embodiments of the present invention, a subject may exhibit a decrease in one or more levels of IgE and / or eotaxin-3 after administration of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody). For example, on about day 1, 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, or 85 after administration of a first, second, third, or fourth dose of a pharmaceutical composition comprising about 75 mg to about 600 mg of an anti-IL-4R antibody (e.g., dupilumab), a subject, according to the present invention, can exhibit about a 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or greater decrease in eotaxin-3 from baseline ("baseline" is defined as the level of eotaxin-3 in the subject immediately prior to the first administration). Similarly, on about day 1, 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, or 85 after administration of a first, second, third, or fourth dose of a pharmaceutical composition comprising about 75 mg to about 600 mg of an anti-IL-4R antibody (e.g., dupilumab), a subject, according to the present invention, can exhibit about a 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or greater decrease in IgE from baseline ("baseline" is defined as the level of IgE in the subject immediately prior to the first administration).

[0050] The present invention also includes methods for determining whether a subject is a suitable subject for whom administration of a pharmaceutical composition comprising an IL-4 / IL-13 pathway antagonist would be beneficial. For example, if an individual exhibits a level of an EoE-associated biomarker indicative of a disease state before receiving a pharmaceutical composition comprising an IL-4 / IL-13 pathway antagonist, the individual is therefore identified as a suitable patient for whom administration of a pharmaceutical composition of the present invention (a composition comprising an anti-IL-4R antibody) would be beneficial. In related embodiments, the present invention includes methods for treating a suitable subject, which may be more susceptible to EoE due to, for example, a food allergy or atopic disease. For example, the present invention includes methods comprising administering an IL-4 / IL-13 pathway antagonist to a subject with a food allergy, atopic dermatitis, asthma, allergic rhinitis, or allergic conjunctivitis. In another example, the invention includes a method comprising administering an IL-4 / IL-13 pathway antagonist to a subject with a Mendelian connective tissue disorder, e.g., Marfan syndrome, Loeys-Dietz syndrome, migratory Ehlers-Danlos syndrome (EDS), or joint hypermobility syndrome (JHS), which may have elevated levels of EoE-associated biomarkers.

[0051] According to certain exemplary embodiments, the individual has: (i) an eotaxin-3 level greater than about 30 pg / ml, greater than about 40 pg / ml, greater than about 50 pg / ml, greater than about 100 pg / ml, greater than about 150 pg / ml, greater than about 200 pg / ml, greater than about 250 pg / ml, greater than about 300 pg / ml, greater than about 350 pg / ml, greater than about 400 pg / ml, greater than about 450 pg / ml, or greater than about 500 pg / ml; or (ii) an eotaxin-3 level greater than about 114 kU / L, greater than about 150 kU / L, or greater than about 114 kU / L. or (iii) a serum IgE level greater than about 1000 kU / L, greater than about 1500 kU / L, greater than about 2000 kU / L, greater than about 2500 kU / L, greater than about 3000 kU / L, greater than about 3500 kU / L, greater than about 4000 kU / L, greater than about 4500 kU / L, or greater than about 5000 kU / L; or (iv) 15 or more eosinophils per high-power field in the subject's esophagus. Additional criteria, for example, other clinical indicators of EoE (e.g., dysphagia, esophageal wall thickening, and food allergies indicative of EoE), can be identified as good candidates for anti-IL-4 / IL-13 therapy as described elsewhere herein. Any of the aforementioned EoE-associated biomarkers can be used in combination to identify individuals as suitable candidates for anti-IL-4 / IL-13 therapy as described elsewhere herein.

[0052] Eosinophilic esophagitis-related parameters The present invention includes a method for improving one or more eosinophilic esophagitis (EoE)-associated parameters in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor.

[0053] Examples of "EoE-related parameters" include (a) Straumann Dysphagia Measure (SDI); (b) Eosinophilic Esophagitis Activity Index (EEsAI); (c) Eosinophilic Esophagitis Edema, Ring, Exudate, Groove, and Stricture (EoE-EREFS); (d) Eosinophilic Esophagitis Histologic Scoring System (EoE-HSS); (e) Esophageal Intraepithelial Eosinophils; and (f) Esophageal Distensibility. "Improvement of EoE-related parameters" refers to a decrease from baseline in one or more of the SDI, EEsAI, EoE-EREFS, EoE-HSS, or esophageal intraepithelial eosinophils. Improvement of esophageal distensibility refers to an increase from baseline. As used herein, the term "baseline" with respect to an EoE-related parameter refers to the value of the EoE-related parameter in a subject before or at the time of administration of the pharmaceutical composition of the present invention.

[0054] To determine whether an EoE-related parameter is "improved," the parameter is quantified at baseline and at one or more time points after administration of a pharmaceutical composition of the present invention. For example, the EoE-related parameter is measured 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, or at the end of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or longer after initial treatment with a pharmaceutical composition of the present invention. The difference between the value of a parameter at a particular time point after treatment initiation and the value of the parameter at baseline is used to determine whether there has been an "improvement" (eg, a decrease) in the EoE-related parameter.

[0055] Straumann Dysphagia Scale (SDI). The SDI is a non-validated patient-reported outcome (PRO) used in clinical studies to determine the frequency and intensity of dysphagia (Straumann 2010). The SDI has a one-week recall period. 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 intensity of dysphagia events is graded on a 6-point scale: 0 = unrestricted swallowing, 1 = slight resistance, 2 = slight retching with delayed passage, 3 = short-term obstruction requiring intervention (e.g., drinking, breathing), 4 = prolonged persistent obstruction relieved only by vomiting, and 5 = prolonged complete obstruction requiring endoscopic intervention. The total SDI score ranges from 0 to 9. According to certain embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a 3-point reduction in the SDI score from baseline. For example, the present invention includes methods of treatment that result in a reduction in SDI score from baseline of 1, 2, 3, 4, 5, 6, or more reductions from baseline in SDI. In certain exemplary embodiments, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more reduction on or after 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 days after administration of the IL-4 / IL-13 pathway inhibitor (e.g., after subcutaneous administration of about 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a subject results in at least a 40% reduction in SDI from baseline.

[0056] Eosinophilic Esophagitis Activity Index (EEsAI). The EEsAI is a non-validated multimodular index currently under development at the University Hospital Inselspital (Berne, Switzerland), part of the international EEsAI research group (Schoepfer 2014). The EEsAI PRO module (questionnaire) used in this study includes items related to the intensity and frequency of dysphagia, the impact of specific food groups on dysphagia symptoms, and other symptoms unrelated to eating and drinking (i.e., heartburn, acid regurgitation, and chest pain). The total EEsAI PRO score ranges from 0 to 100 (Figure 1), with higher scores indicating worse symptoms. The score consists of five components: frequency of dysphagia, duration of dysphagia, pain during swallowing, visual dysphagia question, avoidance, modification, and delayed eating (AMS). According to certain embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to patients results in a decrease in the EEsAI score. For example, the invention includes methods of treatment that result in a reduction in EEsAI score from baseline of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or more on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or later following administration of an IL-4 / IL-13 pathway inhibitor (e.g., following subcutaneous administration of about 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the invention, administration of an IL-4 / IL-13 pathway inhibitor to a subject results in a reduction in EEsAI score from baseline of at least 30% following administration.

[0057] Eosinophilic Esophagitis (EoE-EREFS): Edema, Ring, Exudate, Groove, and Stricture. The EoE-EREFS (edema, ring, exudate, groove, and stricture) was used to measure endoscopically identified features of esophageal mucosal inflammation and remodeling. This instrument includes a total of 17 items related to the presence and severity of esophageal function. Specific esophageal features included: rings (concentric rings around the esophagus—absent, mild, moderate, severe, not applicable); strictures (narrowing of the esophagus—yes, no, not applicable); stricture diameter (if applicable); exudates (see white spots—absent, mild, severe); grooves (vertical lines in the esophagus—absent, present); edema (loss of vascular markings in the mucosa—absent, present); crepe-paper esophagus (absent, present); and overall appearance incorporating all endoscopically identified EoE findings (i.e., fixed rings, strictures, whitish exudates, grooves, edema, and crepe-paper mucosa). Additionally, mucosal changes associated with gastroesophageal reflux disease were also scored using the Los Angeles Classification System for erosions (no erosion or LA classification A, B, C, D). EoE esophageal characteristics are analyzed based on the EoE-EREFS, a validated scoring system of inflammatory and remodeling features of the disease using both an overall score and individualized scores (Hirano 2014). According to certain embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a decrease in the EoE-EREFS score. For example, the invention includes methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more reduction in EREFS score from baseline on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or thereafter following administration of an IL-4 / IL-13 pathway inhibitor (e.g., following subcutaneous administration of about 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof).

[0058] Eosinophilic Esophagitis Histological Scoring System (EoE-HSS). The EoE-HSS produced distinct severity (grade) and extent (stage) disease scores. The score was used to measure eight histological features (parameters) of EoE from three different regions of the esophagus (proximal, middle, and distal) (Collins et al., 2017). The eight parameters included eosinophil density, basal hyperplasia, eosinophil abscesses, eosinophil surface stratification, intercellular space expansion, surface epithelial changes, dyskeratinized cells, and lamina propria fibrosis. For both grade and stage, a scale of 0 to 3 was used for each parameter (0 being minimal inflammation, normal). The present invention According to certain embodiments, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a decrease in EoE-HSS score. For example, the present invention includes treatment methods that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in EoE-HSS from baseline on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or later after administration of an IL-4 / IL-13 pathway inhibitor (e.g., after subcutaneous administration of about 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a subject results in at least a 50% decrease in EoE-HSS score from baseline.

[0059] Esophageal intraepithelial eosinophils refer to 15 or more eosinophils per high-power field (hpf) in an esophageal biopsy. Peak intraepithelial eosinophils refer to 15 or more eosinophils per high-power field in at least two of three esophageal regions sampled. According to certain embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a decrease in peak intraepithelial eosinophils. For example, the invention includes methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or more reduction in intraepithelial eosinophils from baseline on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or later after administration of an IL-4 / IL-13 pathway inhibitor (e.g., after subcutaneous administration of about 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the invention, administration of an IL-4 / IL-13 pathway inhibitor to a subject results in at least an 85% reduction in intraepithelial eosinophils from baseline.

[0060] Esophageal compliance. Esophageal compliance is assessed using an intraluminal functional luminal imaging probe (EndoFLIP, Crospon, Ireland) to measure esophageal lumen diameter and pressure. The EndoFLIP device is a catheter-based procedure that measures cross-sectional area at multiple sites along the esophagus while simultaneously recording intraluminal pressure during esophageal volumetric distention. Analysis of the esophageal cross-sectional area versus pressure relationship allows for the determination of esophageal compliance as well as the distensibility plateau (DP). DP has been shown to be significantly reduced in patients with EoE compared to healthy controls (Kwiatek 2011). According to certain embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in increased esophageal distensibility. For example, the invention includes methods of treatment that result in an increase in esophageal distensibility from baseline of at least about 5%, 10%, 15%, 20%, 25% or more at the end of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or thereafter following administration of an IL-4 / IL-13 pathway inhibitor (e.g., following subcutaneous administration of about 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the invention, administration of an IL-4 / IL-13 pathway inhibitor to a subject results in an increase in esophageal distensibility from baseline of at least 10%, as measured by impedance planimetry.

[0061] Eosinophilic Esophagitis Quality of Life in Adults (EoE-QoL-A) Questionnaire. The EoE-QoL-A questionnaire is a validated, disease-specific measure of health-related quality of life in patients with EoE (Taft, 2011). The instrument used in this study, EoE-QoL-A v.3.0, includes 30 items related to established domains such as social functioning, emotional functioning, and the impact of illness on daily life experiences. The EoE-QoL-A has a one-week recall period. Items are rated on a 5-point scale: "not at all," "slightly," "moderately," "quite a bit," and "extremely." According to certain embodiments, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in an increase in the patient's quality of life parameters.

[0062] IL-4 / IL-13 pathway inhibitors The method of the present invention involves administering a therapeutic composition comprising an IL-4 / IL-13 pathway inhibitor to a patient in need thereof. The method includes administering to a subject

[0063] As used herein, an "IL-4 / IL-13 pathway inhibitor" (also referred to herein as an "IL-4 / IL-13 pathway antagonist," "IL-4 / IL-13 pathway blocker," etc.) is any agent that inhibits or attenuates at least one of: (i) the binding of IL-4 and / or IL-13 to their respective receptors; (ii) IL-4 and / or IL-13 signaling and / or activity; and / or (iii) downstream signaling / activity resulting from the binding of IL-4 and / or IL-13 to their respective receptors. Exemplary IL-4 / IL-13 pathway inhibitors include, but are not limited to, anti-IL-4 antibodies (e.g., antibodies disclosed in U.S. Pat. No. 7,740,843 and U.S. Patent Application Publication Nos. 2010 / 0297110, 2016 / 0207995), anti-IL-13 antibodies (e.g., antibodies disclosed in U.S. Pat. Nos. 7,501,121, 7,674,459, 7,807,788, 7,910,708, 7,915,388, 7,935,343, 8,088,618, 8,691,233, 96 05065, U.S. Patent Application Publication Nos. 2006 / 0073148, 2008 / 0044420, and EP 2627673B1), bispecific antibodies that bind IL-4 and IL-13 (e.g., antibodies disclosed in U.S. Patent Application Publication Nos. 8,388,965, U.S. Patent Application Publication Nos. 2011 / 0008345, 2013 / 0251718, and 2016 / 0207995), and IL-4 receptor (IL-4R) inhibitors (described below).

[0064] As used herein, an "IL-4R inhibitor" (also referred to herein as an "IL-4 / IL-13 pathway inhibitor," "IL-4Rα antagonist," "IL-4R blocker," "IL-4Rα blocker," etc.) is any drug that binds to or interacts with IL-4Rα or an IL-4R ligand and inhibits or attenuates the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4R has the amino acid sequence of SEQ ID NO: 11. Type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and a γc chain. Type 2 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptor interacts with and is stimulated by IL-4, while type 2 IL-4 receptor is stimulated by both IL-4 and IL-13. Thus, IL-4R inhibitors that can be used in the methods of the present invention can function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4 and IL-13-mediated signaling. In this manner, IL-4R inhibitors of the present invention can interfere with the interaction of IL-4 and / or IL-13 with type 1 or type 2 receptors.

[0065] Non-limiting examples of categories of IL-4R inhibitors include IL-4 muteins (e.g., pitrakinra), small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor bodies" (e.g., genetically engineered molecules containing the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R inhibitors also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0066] Anti-IL-4Rα antibodies and antigen-binding fragments thereof According to certain exemplary embodiments of the present invention, the IL-4 / IL-13 pathway inhibitor is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. The term "antibody," as used herein, includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (HCVR or VVR) and a VV ... H The heavy chain constant region contains three domains. The main C H 1. C H 2 and C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) V H and V L The regions can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the present invention, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence can be defined based on a comparative analysis of two or more CDRs.

[0067] The term "antibody," as used herein, also includes antigen-binding fragments of intact antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically derived, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen and forms a complex. Antigen-binding fragments of antibodies can be derived from intact antibody molecules using any suitable standard technique, such as, for example, proteolysis or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or using molecular biology techniques to, for example, place one or more variable and / or constant regions in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids.

[0068] Non-limiting examples of antigen-binding fragments include (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are encompassed by the term "antigen-binding fragment" as used herein.

[0069] Antigen-binding fragments of antibodies typically contain at least one variable domain, which can 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 associated with the domain H In an antigen-binding fragment having a domain, V H and V L The domains can be arranged relative to each other in any suitable configuration. For example, the variable region may be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may contain a dimer of monomeric V H or V L It may include a domain.

[0070] In certain embodiments, an antigen-binding fragment of an antibody comprises at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in an antigen-binding fragment of an antibody of the invention include: (i) a V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)V L -C H 2;(x)VL -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L In any configuration of variable and constant domains, including any of the exemplary configurations above, the variable and constant domains can be directly attached to each other or can be connected by a full or partial hinge or linker region. The hinge region can be composed of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present invention can be non-covalently linked to each other and / or to one or more monomeric V H or V L The domains may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above, non-covalently associated (e.g., via disulfide bond(s)).

[0071] The term "antibody," as used herein, also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies typically contain at least two different variable domains, each capable of specifically binding to a different antigen or a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in conjunction with the antibodies or antigen-binding fragments of antibodies of the present invention using routine techniques available in the art. For example, the present invention includes methods involving the use of bispecific antibodies, where one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present invention include, but are not limited to, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knob-into-hole, common light chain (e.g., common light chain with knob-into-hole), CrossMab, CrossFab, (SEED) body, leucine zipper, duobody, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab. 2 Bispecific formats include those described in Klein et al., 2012, mAbs 4:6, pp. 1-11, and the references cited therein, for a review of such formats. Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, for example, using unnatural amino acids with orthogonal chemical reactivity to generate site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with predetermined composition, valency, and geometry (see, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: December 4, 2012]).

[0072] The antibody used in the methods of the present invention may be a human antibody. The term "human antibody," as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present invention may nevertheless contain amino acid residues (e.g., mutations induced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo) not encoded by human germline immunoglobulin sequences, for example, in the CDRs, particularly CDR3. However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0073] The antibodies used in the methods of the present invention may be recombinant human antibodies. "Human antibody," as used herein, is intended to include all human antibodies prepared, expressed, generated, or isolated by recombinant means, e.g., antibodies expressed using recombinant expression vectors transfected into host cells (described in more detail below), antibodies isolated from recombinant, combinatorial human antibodies (described in more detail below), antibodies isolated from animals (e.g., mice) transgenic for human immunoglobulin genes (e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, generated, or isolated by any other means involving splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, if animals transgenic for human Ig sequences are used), so that the amino acid sequences of the VH and VL regions of the recombinant antibodies are consistent with those of human antibody germline VH and VL regions. H and V LThese are sequences that, while derived from and related to sequences, may not naturally occur within the human antibody germline repertoire in vivo.

[0074] According to certain embodiments, the antibody used in the methods of the present invention specifically binds to IL-4Rα. The term "specifically binds" and the like means that the antibody or its antigen-binding fragment forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art, and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-4Rα, in the context of the present invention, has a K of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM, as measured in a surface plasmin resonance assay. D However, an isolated antibody that specifically binds to human IL-4Rα may have cross-reactivity to other antigens, such as IL-4Rα molecules from other (non-human) species.

[0075] According to certain exemplary embodiments of the present invention, the IL-4 / IL-13 pathway inhibitor is an anti-IL-4Rα antibody or an antigen-binding fragment thereof comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) comprising any of the amino acid sequences of an anti-IL-4R antibody described in U.S. Patent No. 7,608,693. In certain exemplary embodiments, an anti-IL-4Rα antibody or antigen-binding fragment thereof that can be used in connection with the methods of the present invention comprises a heavy chain complementarity-determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain complementarity-determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2. According to certain embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof 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. In still other embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO: 1 and a LCVR comprising SEQ ID NO: 2. In certain embodiments, the methods of the invention comprise the use of an anti-IL-4R antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 is the fully human anti-IL-4R antibody known as dupilumab. Specific illustrative According to embodiments, the methods of the present invention involve the use of dupilumab or a bioequivalent thereof. The term "bioequivalent" as used herein refers to an anti-IL-4R antibody or IL-4R binding protein, or fragment thereof, that is a pharmaceutical equivalent or pharmaceutical substitute that exhibits no significant difference in the rate and / or extent of absorption compared to dupilumab when administered at the same molar dose in either a single or multiple doses under similar experimental conditions. In the context of the present invention, this term refers to an antigen-binding protein that binds to IL-4R that has no clinically meaningful differences in safety, purity, and / or potency compared to dupilumab.

[0076] Other anti-IL-4Rα antibodies that can be used in connection with the methods of the present invention include, for example, the antibody designated and known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796) or MEDI 9314 or any of the anti-IL-4Rα antibodies described in U.S. Pat. Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, or 8,877,189.

[0077] Anti-IL-4Rα antibodies used in connection with the methods of the present invention can have pH-dependent binding properties. For example, anti-IL-4Rα antibodies for use in the methods of the present invention can exhibit decreased binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, anti-IL-4Rα antibodies of the present invention can exhibit enhanced binding to their antigen at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values ​​less than about 6.2, e.g., 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 expression "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

[0078] In certain instances, "decreased binding to IL-4Rα at acidic pH compared to neutral pH" refers to the K D K values ​​of antibodies binding to IL-4Rα at acidic pH D For example, an antibody or its antigen-binding antibody may have an acidic / neutral K of about 3.0 or greater. D When a ratio is shown, the antibody or antigen-binding fragment thereof may be considered, for purposes of the present invention, to exhibit "decreased binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K ratio for an antibody or antigen-binding fragment of the present invention is D The ratio can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or more.

[0079] Antibodies with pH-dependent binding properties can be obtained, for example, by screening antibody populations for decreased (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. In addition, modification of the antigen-binding domain at the amino acid level can result in 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 decreased antigen binding at acidic pH compared to neutral pH can be obtained. As used herein, the expression "acidic pH" refers to a pH of 6.0 or less.

[0080] Pharmaceutical Composition The present invention includes methods comprising administering to a subject an IL-4 / IL-13 pathway inhibitor, wherein the IL-4 / IL-13 pathway inhibitor is contained within a pharmaceutical composition. The pharmaceutical compositions of the present invention can be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, etc. Many suitable formulations can be found in formularies known to pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipids (cationic or anionic) including vesicles (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsions of carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures including carbowax. See also Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci Technol 52:238-311.

[0081] Various delivery systems are known and can be used to administer the pharmaceutical compositions of the present invention, including liposomes, microparticles, microcapsules, encapsulation in recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Administration methods 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, or by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa), and can be administered together with other biologically active agents.

[0082] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. Furthermore, for subcutaneous delivery, a pen delivery device can be easily used to deliver the pharmaceutical composition of the present invention. Such a pen delivery device can 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 be reused. Disposable pen delivery devices do not have a replaceable cartridge. Rather, disposable pen delivery devices are pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is empty of the pharmaceutical composition, the entire device is discarded.

[0083] In certain circumstances, pharmaceutical compositions can be delivered in controlled-release systems. In one embodiment, a pump can be used. In another embodiment, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Press, Boca Raton, Florida. In yet another embodiment, the controlled-release system can be placed in proximity to the target of the composition, thus requiring only a fraction of the systemic dosage (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled-release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0084] Injectable preparations may include intravenous, subcutaneous, intradermal and intramuscular injections, infusions, and the like. These injection preparations can be prepared by known methods. For example, injection preparations can be prepared by dissolving, suspending, or emulsifying the above-mentioned antibody or its salt in a sterile aqueous medium or an oily medium commonly used for injections. Aqueous vehicles for injection include, for example, isotonic solutions containing saline, glucose, and other adjuvants, which can be used in combination with appropriate 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)]. Oily vehicles include, for example, sesame oil and soybean oil, which can be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. The injection preparations prepared in this manner are preferably filled into appropriate ampoules.

[0085] Advantageously, the above-mentioned oral or parenteral pharmaceutical compositions are prepared in a dosage form of a unit dose suitable for the dosage of the active ingredient, such as tablets, pills, capsules, injections (ampoules), and suppositories.

[0086] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present invention are disclosed, for example, in US Pat. No. 8,945,559.

[0087] Dosing regimen The present invention includes methods comprising administering to a subject an IL-4 / IL-13 pathway inhibitor about 4 times per week, twice per week, once per week, once per 2 weeks, once per 3 weeks, once per 4 weeks, once per 5 weeks, once per 6 weeks, once per 8 weeks, once per 12 weeks, or less frequently as long as a therapeutic response is achieved. In certain embodiments involving administration of an IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody), weekly dosing is employed in an amount of about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In certain embodiments involving administration of an anti-IL-4R antibody, biweekly dosing is employed in an amount of about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 300 mg.

[0088] According to certain embodiments of the invention, multiple doses of an IL-4 / IL-13 pathway inhibitor are administered to a subject over a predetermined time course. The method according to this aspect of the invention comprises sequentially administering multiple doses of an IL-4 / IL-13 pathway inhibitor to a subject. As used herein, "sequentially administering" means that each dose of an IL-4 / IL-13 pathway inhibitor is administered to a subject at different time points, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). The invention includes methods comprising sequentially administering to a patient a single primary dose of an IL-4 / IL-13 pathway inhibitor, followed by one or more secondary doses of an IL-4 / IL-13 pathway inhibitor, and optionally thereafter one or more tertiary doses of an IL-4 / IL-13 pathway inhibitor.

[0089] The terms "primary dose," "secondary dose," and "tertiary dose" refer to the temporal order of administration of an IL-4 / IL-13 pathway inhibitor. Thus, a "primary dose" is a dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); a "secondary dose" is a dose administered after the primary dose; and a "tertiary dose" is a dose administered after the secondary dose. The primary, secondary, and tertiary doses may all contain the same amount of IL-4 / IL-13 pathway inhibitor, but generally can differ from one another in terms of frequency of administration. However, in certain embodiments, the amount of IL-4 / IL-13 pathway inhibitor contained in the primary, secondary, and / or tertiary doses varies from one another (e.g., adjusted up or down as needed) over the course of treatment. In certain embodiments, the primary dose contains a first amount of an antibody or antigen-binding fragment thereof, and one or more secondary doses each contain a first amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or antigen-binding fragment thereof (primary dose) is 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x the second amount of the antibody or antigen-binding fragment thereof (secondary dose). In certain embodiments, one or more doses (e.g., 1, 2, 3, 4, or 5) are administered as a "loading dose" at the beginning of the treatment regimen, followed by subsequent doses (e.g., "maintenance doses") administered on a less frequent basis. For example, an IL-4 / IL-13 pathway inhibitor is administered to a patient in need thereof at a loading dose of about 300 mg to about 600 mg, followed by one or more maintenance doses of about 25 mg to about 400 mg. In one embodiment, the primary dose and one or more secondary doses each contain between 10 mg and 600 mg of an IL-4 / IL-13 pathway inhibitor, e.g., between 100 mg and 400 mg of an IL-4 / IL-13 pathway inhibitor, e.g., 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg of an IL-4 / IL-13 pathway inhibitor. In one embodiment, the primary dose is 2× the secondary dose.

[0090] In an exemplary embodiment of the invention, each secondary and / or tertiary dose is administered 1 to 14 (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2, or more) weeks after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" refers to a dose of an IL-4 / IL-13 pathway inhibitor administered to a patient prior to the administration of the immediately subsequent dose in a multiple administration series, in a sequential order with no intervening doses.

[0091] The method according to this aspect of the invention may include administering any number of secondary and / or tertiary doses of an IL-4 / IL-13 pathway inhibitor to the patient. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0092] In embodiments involving multiple secondary doses, each secondary dose is administered with the same frequency as the other secondary doses. For example, each secondary dose is administered to the patient 1 to 6 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose is administered with the same frequency as the other tertiary doses. For example, each tertiary dose is administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to the patient can vary over the course of the regimen.

[0093] According to certain embodiments, the methods of the present invention include administering a corticosteroid (CS) to a subject in combination with an IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody). As used herein, the term "in combination with" means that the CS is administered before, after, or simultaneously with the IL-4 / IL-13 pathway inhibitor. The term "in combination with" also includes sequential or simultaneous administration of the IL-4 / IL-13 pathway inhibitor and the CS.

[0094] For example, when administered "before" an IL-4 / IL-13 pathway inhibitor, the CS is administered more than 72 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the IL-4 / IL-13 pathway inhibitor. When administered "after" an IL-4 / IL-13 pathway inhibitor, the CS is administered more than 72 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the IL-4 / IL-13 pathway inhibitor. The CS is administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after administration of the agent. "Concurrent administration" with an IL-4 / IL-13 pathway inhibitor means that the CS is administered to the subject in a separate dosage form less than 5 minutes after (before, after, or simultaneously with) administration of the IL-4 / IL-13 pathway inhibitor, or is administered to the subject as a single combined dosage formulation including both the CS and the IL-4 / IL-13 pathway inhibitor.

[0095] dose The amount of an IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4Rα antibody) administered to a subject according to the methods of the present invention is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to an amount of an IL-4 / IL-13 pathway 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 esophageal eosinophils; (c) an increase in esophageal compliance; (d) a reduction in the occurrence of dysphagia; (e) prevention or alleviation of allergic reactions; and (f) a reduction in the use of or need for conventional allergy treatments (e.g., a reduction or elimination of the use of antihistamines, decongestants, nasal or inhaled steroids, anti-IgE treatments, epinephrine, etc.).

[0096] In the case of an anti-IL-4Rα antibody, a therapeutically effective amount is from about 0.05 mg to about 600 mg of an anti-IL-4R antibody, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg The dose may be about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. In a specific embodiment, 300 mg of anti-IL-4R antibody is administered.

[0097] The amount of IL-4 / IL-13 pathway inhibitor contained in an individual dose is expressed in milligrams of antibody per kg of patient body weight (i.e., mg / kg). For example, an IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4Rα antibody) can be administered to a patient at a dose of about 0.0001 to about 100 mg / kg of the patient's body weight.

[0098] Selected Embodiments In embodiment 1, the present invention includes a method of alleviating dysphagia, comprising: (a) selecting a patient having at least one of the following characteristics: (i) the patient exhibits one or more episodes of dysphagia per week; (ii) the patient has previously been treated with a high-dose proton pump inhibitor (PPI); and (iii) the patient has previously undergone esophageal dilation on at least one occasion; and (b) administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 / interleukin-13 (IL-4 / IL-13) pathway inhibitor.

[0099] In embodiment 2, the invention includes a method of increasing esophageal compliance, comprising: (a) administering to a patient the following characteristics: (i) the patient exhibits one or more episodes of dysphagia per week; (ii) the patient has previously been treated with a high-dose PPI; and (iii) the patient has previously received at least one and (b) selecting a patient having at least one of the following: esophageal dilatation; and (b) administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor.

[0100] In embodiment 3, the invention includes the method of embodiment 1 or 2, wherein the patient has moderate to severe EoE.

[0101] In embodiment 4, the present invention includes a method of treating, preventing, or ameliorating at least one symptom or sign of active eosinophilic esophagitis (EoE), comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor.

[0102] In embodiment 5, the present invention provides a method for treating EoE in a patient having: (1) the patient has 15 or more eosinophils per high-power field (hpf) in the esophagus before or at the time of treatment ("baseline"); (2) previous treatment with at least one of high-dose PPI, esophageal dilation, corticosteroids, allergen withdrawal, and / or dietary modification; (3) the patient exhibits 1 or more episodes of dysphagia per week; (4) the patient is unresponsive or resistant to previous treatment with high-dose PPI or esophageal dilation; (5) the patient has a Straumann Dysphagia Measure (SDI) score of 2 or greater; (6) the patient has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score of 30 or greater, 40 or greater, or 50 or greater; (7) the patient has suffered from EoE for at least 3 years. (8) the patient has or has been diagnosed with a disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis prior to or at the time of administration of the IL-4 / IL-13 pathway inhibitor; and (9) the patient has elevated levels of a biomarker selected from the group consisting of eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum thymus- and activation-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN).

[0103] In embodiment 6, the invention includes the method of any one of embodiments 1-5, wherein administration of the IL-4 / IL-13 pathway inhibitor results in: (a) at least a 40% reduction from baseline in the frequency and severity of dysphagia, as measured by the Straumann Dysphagia Measure (SDI) score; (b) a 3-point reduction from baseline in the SDI score; (c) a greater than 85% reduction from baseline in peak intraepithelial eosinophil count in the proximal, middle, and / or distal regions of the esophagus; (d) at least a 10% increase from baseline in esophageal distensibility, as measured by impedance planimetry; (e) a greater than 50% reduction from baseline in the severity and extent of disease, as measured by the EoE Histological Scoring System (HSS) score; and (f) a greater than 30% reduction from baseline in dysphagia, as measured by the Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score. and (iii) improving an EoE-related parameter selected from the group consisting of:

[0104] In embodiment 7, the invention includes the method of any one of embodiments 1 to 6, wherein the IL-4 / IL-13 pathway inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to IL-4 receptor (IL-4R).

[0105] In embodiment 8, the invention includes the method of any one of embodiments 1-7, wherein the IL-4 / IL-13 pathway inhibitor is administered at a dose of about 50-600 mg.

[0106] In embodiment 9, the invention includes the method of any one of embodiments 1-8, wherein the IL-4 / IL-13 pathway inhibitor is administered at a dose of about 300 mg.

[0107] In embodiment 10, the invention includes the method of any one of embodiments 1-7, wherein the IL-4 / IL-13 pathway inhibitor is administered in a primary dose, followed by one or more secondary doses, each secondary dose being administered 1 to 4 weeks after the immediately preceding dose.

[0108] In embodiment 11, the invention includes the method of embodiment 10, wherein the primary dose comprises 50 to 600 mg of an IL-4 / IL-13 pathway inhibitor.

[0109] In embodiment 12, the invention includes the method of embodiment 10 or 11, wherein each secondary dose comprises 25 to 400 mg of the IL-4 / IL-13 pathway inhibitor.

[0110] In embodiment 13, the invention includes the method of any one of embodiments 10-12, wherein the primary dose comprises 600 mg of an IL-4 / IL-13 pathway inhibitor and each secondary dose comprises 300 mg of an IL-4 / IL-13 pathway inhibitor.

[0111] In embodiment 14, the invention includes the method of embodiment 13, wherein each secondary dose is administered one week after the immediately preceding dose.

[0112] In embodiment 15, the invention includes the method of embodiment 13, wherein each secondary dose is administered two weeks after the immediately preceding dose.

[0113] In embodiment 16, the present invention relates to a method for treating EoE, wherein the symptoms or signs of EoE are: 16. The method of any one of embodiments 4 to 15, wherein the symptom is selected from the group consisting of esophageal eosinophil infiltration, esophageal wall thickening, anorexia, vomiting, abdominal pain, heartburn, regurgitation, dysphagia, and food impaction.

[0114] In embodiment 17, the invention includes the method of any one of embodiments 1-16, wherein the patient has an allergic reaction to a food allergen found in foods selected from the group consisting of dairy, eggs, wheat, soy, corn, fish, shellfish, peanuts, tree nuts, beef, chicken, oats, barley, pork, green beans, apples, and pineapple.

[0115] In embodiment 18, the invention includes the method of any one of embodiments 1-17, wherein the patient has an allergic reaction to a non-food allergen derived from one of dust, pollen, mold, plants, cats, dogs, or insects.

[0116] In embodiment 19, the invention includes the method of any one of embodiments 1-18, wherein administration of the IL-4 / IL-13 pathway inhibitor results in a decrease in the level of an EoE-associated biomarker in the subject.

[0117] In embodiment 20, the invention includes the method of embodiment 19, wherein the EoE-associated biomarker is selected from the group consisting of eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum TARC, TSLP, serum ECP, and EDN.

[0118] In embodiment 21, the present invention relates to a method for treating a rheumatoid arthritis, wherein the IL-4 / IL-13 pathway inhibitor is administered in combination with a second therapeutic agent or therapy, wherein the second therapeutic agent or therapy is selected from the group consisting of an IL-1 beta inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNF alpha 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 proton pump inhibitor, an NSAID, an esophageal dilation, allergen removal, and dietary management. , including the method of any one of embodiments 1 to 20.

[0119] In embodiment 22, the invention includes the method of any one of embodiments 1-21, wherein the IL-4 / IL-13 pathway inhibitor is selected from the group consisting of an anti-IL-4 antibody, an anti-IL-13 antibody, an anti-IL-4 / IL-13 bispecific antibody, an IL-4 receptor (IL-4R) inhibitor, and an anti-IL-4R antibody.

[0120] In embodiment 23, the invention includes the method of embodiment 22, wherein the IL-4 / IL-13 pathway inhibitor is an IL-4R inhibitor.

[0121] In embodiment 24, the invention includes the method of embodiment 22, wherein the IL-4 / IL-13 pathway inhibitor is an anti-IL-4 antibody.

[0122] In embodiment 25, the invention includes the method of embodiment 22, wherein the IL-4 / IL-13 pathway inhibitor is an anti-IL-13 antibody.

[0123] In embodiment 26, the invention includes the method of embodiment 22, wherein the IL-4 / IL-13 pathway inhibitor is a bispecific antibody that specifically binds to IL-4 and IL-13.

[0124] In embodiment 27, the invention includes the methods of any one of embodiments 1 to 23, wherein the IL-4 / IL-13 pathway inhibitor is an antibody or antigen-binding fragment thereof that binds to IL-4Rα and prevents the interaction of IL-4 and / or IL-13 with type 1 or type 2 IL-4 receptors.

[0125] In embodiment 28, the invention includes the method of embodiment 27, wherein the antibody or antigen-binding fragment thereof interferes with the interaction of IL-4 with both type 1 and type 2 IL-4 receptors.

[0126] In embodiment 29, the invention includes the method of embodiment 28, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity-determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain complementarity-determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2.

[0127] In embodiment 30, the present invention includes the method of embodiment 28, wherein the antibody or antigen-binding fragment thereof 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.

[0128] In embodiment 31, the invention includes the method of embodiment 30, wherein the HCVR comprises the amino acid sequence of SEQ ID NO:1 and the LCVR comprises the amino acid sequence of SEQ ID NO:2.

[0129] In embodiment 32, the present invention includes any one of the methods of embodiments 29 to 31, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0130] In embodiment 33, the invention includes the method of any one of embodiments 1 to 31, wherein the IL-4 / IL-13 pathway inhibitor is dupilumab or a biological equivalent thereof.

[0131] In embodiment 34, the invention includes the method of embodiment 23, wherein the IL-4R inhibitor is AMG317 or MEDI9314. [Example]

[0132] The following examples are provided so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy of numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise specified, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. [Example]

[0133] A clinical trial of subcutaneously administered dupilumab in adult patients with active moderate to severe eosinophilic esophagitis (EoE) This study was a 32-week, double-blind, randomized, placebo-controlled trial to investigate the efficacy, safety, tolerability, and immunogenicity of dupilumab in adult patients with active EoE. Dupilumab is a fully human anti-IL-4R antibody containing a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NOs:1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NOs:3-8.

[0134] Research objectives The primary objective of this study was to evaluate the clinical efficacy of repeated subcutaneous (SC) administration of dupilumab compared with placebo for symptom relief in adult patients with active, moderate-to-severe EoE.

[0135] The secondary objectives of this study were (1) to evaluate the safety, tolerability, and immunogenicity of SC doses of dupilumab in adult patients with active, moderate-to-severe EoE; (2) to evaluate the effect of dupilumab on esophageal eosinophil infiltration; and (3) to evaluate the pharmacokinetics (PK) of dupilumab in adult patients with EoE.

[0136] The exploratory aim of the study was to evaluate the effect of dupilumab on other esophageal biopsy pathological features associated with EoE.

[0137] research design This was a multicenter, double-blind, randomized, placebo-controlled study investigating the efficacy, safety, tolerability, PK, and immunogenicity of dupilumab in adult patients with EoE.

[0138] After providing informed consent, patients were assessed for eligibility at the screening visit (occurring between Day -35 and Day -1). Patients who met the eligibility criteria underwent a baseline assessment on Day 1. Patients were randomized 1:1 to receive dupilumab or placebo during the 12-week double-blind treatment phase. After the 12-week double-blind treatment phase, patients were discontinued from the study drug for an additional 16 weeks.

[0139] Patients continued study treatment while receiving concomitant medications (excluding prohibited medications [see below]) as needed. Efficacy, safety, and laboratory assessments, samples for dupilumab concentrations and potential anti-drug antibody (ADA) responses to dupilumab, and study samples were performed or collected at specific time points throughout the study.

[0140] Study population The target population included adult (18–65 years) male or female patients with active EoE.

[0141] Inclusion Criteria: Patients had to meet the following criteria to be eligible for inclusion in the study: (1) Male or female, 18–65 years old; (2) Documented diagnosis of EoE by endoscopy before or at the time of screening. Note: This must include demonstration of intraepithelial eosinophilic infiltration (peak cell count ≥ 15 eosinophils / high-power field [eos / hpf] [400×]) from an esophageal biopsy specimen by endoscopy performed within 2 weeks after at least 8 weeks of treatment with a high-dose (or twice-daily) proton pump inhibitor (PPI); (3) (patient-reported) history of an average of at least two episodes of dysphagia per week (when ingesting solid foods from anti-inflammatory therapy) in the 4 weeks prior to screening, and an average of at least two documented episodes of dysphagia per week in the week between screening and baseline; dysphagia is defined as patient-reported difficulty swallowing solid foods or ingesting solid food sticks; (4) Must maintain a stable diet for at least 6 weeks prior to screening and throughout the course of the study; a stable diet is defined as no initiation of single or multiple elimination diets or reintroduction of previously eliminated food groups; (5) SDI PRO score ≥ 5 at screening and baseline; (6) history or presence of one or more of the following: allergic disease (e.g., allergic asthma, allergic rhinitis, AD, or food allergy), peripheral eosinophil count ≥ 0.25 GI / L, serum total immunoglobulin E (IgE) ≥ 100 kU / L; (7) Willing and able to comply with all visits and study-related procedures; understand and complete study-related questionnaires; provide signed informed consent; and (8) photographic endoscopy performed at screening with demonstration of intraepithelial eosinophilic infiltrates (peak cell count ≥ 15 eos / hpf) in at least two of three biopsied esophageal regions (proximal, middle, or distal).

[0142] Exclusion Criteria: Patients who met any of the following criteria were ineligible to participate in this study: (1) previous participation in a dupilumab (anti-IL-4R) clinical trial; (2) esophageal eosinophilia or other causes of the following diseases: hypereosinophilic syndrome, Churg-Strauss vasculitis, and eosinophilic gastroenteritis; (3) history of achalasia, active Helicobacter pylori infection, Crohn's disease, ulcerative colitis, celiac disease, and previous esophageal surgery before screening; (4) esophageal stricture that cannot be passed with a standard diagnostic adult (9–10 mm) upper endoscopy, or any significant esophageal stricture requiring dilation at the time of screening; (5) history of bleeding disorder or esophageal varices; (6) chronic aspirin, nonsteroidal drugs, or anticoagulant use within 2 weeks prior to screening. Patients should not have stopped these medications solely to qualify for participation in this study; (7) treatment with an investigational drug within 2 months or 5 half-lives (if known), whichever is longer, prior to screening; (8) use of systemic corticosteroids within 3 months prior to screening or swallowed topical corticosteroids within 6 weeks; (9) use of inhaled or nasal corticosteroids within 3 months prior to screening and during the study, except for stable medication for at least 3 months prior to the screening biopsy, which cannot be changed during the study; (10) treatment with oral immunotherapy (OIT) within 6 months prior to screening; (11) allergen immunotherapy (sublingual immunotherapy [SLIT] and / or subcutaneous immunotherapy [SCIT], unless on stable medication for at least 1 year prior to screening); (12) treatment with the following within 3 months prior to the screening visit, or conditions that, in the investigator's opinion, are likely to require such treatment during the 3 months of study treatment: systemic immunosuppressive / immunomodulatory drugs (e.g., omalizumab, cyclosporine, mycophenolate mofetil, interferon, etc.) (13) diagnosed with active parasitic infection; clinical and (if necessary) non-laboratory evaluation of suspected parasitic infection excluded active infection before randomization; (14) chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 1 month prior to screening; (15) use of oral antibiotics / anti-infectives within 2 weeks prior to screening; (16) known or suspected immunosuppression. (17) a history of invasive opportunistic infection despite resolution, as determined by the investigator (e.g., tuberculosis, nontuberculous mycobacterial infection, histoplasmosis, listeriosis, coccidioidomycosis, pulmonary bullous disease, aspergillosis), or other recurrent infections with unusual frequency or prolonged infection suggestive of an immunocompromised state; (18) a history of human immunodeficiency virus (HIV) infection; (19) positive or indeterminate hepatitis B surface antigen (HBsAg) or hepatitis C antibody at screening; (20) elevated transaminases (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) at screening >3 times the upper limit of normal (>3 × upper limit of normal [ULN]); (21) a history of malignancy within 5 years prior to screening. (21) a patient-reported history of alcohol or drug abuse within 6 months prior to screening; (22) any other medical or psychological condition, including relevant laboratory abnormalities at the time of screening, that, in the opinion of the investigator, suggests a new and / or poorly understood disease, may pose an unreasonable risk to the study patient as a result of the study patient's participation in this clinical trial, may decrease the reliability of the patient's participation, or may interfere with study evaluation.Specific justification for patients excluded under this criterion will be documented in study documentation (chart notes, case report forms [CRFs], etc.); (23) serious concomitant illness that, in the investigator's judgment, adversely affects the patient's participation in the study; (24) planned or anticipated use of any prohibited drugs and procedures (see below) during study treatment; (25) treatment with live (attenuated) vaccines within 3 months prior to screening; (26) the patient or their family member is a member of the investigational team; (27) pregnant or lactating women, or women planning to become pregnant or lactating during the study; (28) fertility. * Women who have and are unwilling to use adequate contraception if they are sexually active.

[0143] research treatment Study medication: dupilumab SC, 600 mg loading dose on day 1, then 300 mg weekly doses from weeks 1 to 11.

[0144] Placebo: Placebo (same formulation as dupilumab without the active substance, an anti-IL-4R monoclonal antibody) SC, in a volume matching the dupilumab loading dose on day 1, then weekly doses matching the volume of the weekly doses of dupilumab from weeks 1 to 11.

[0145] Patients received SC dupilumab 300 mg or matching placebo qw during the 12-week double-blind treatment phase. Patients received two injections (a 300 mg primary dose followed by a 300 mg loading dose) on day 1, followed by weekly injections.

[0146] Permitted (concomitant) medications Concomitant medications were permitted during the study, including contraceptives, stable-dose proton pump inhibitors (PPIs) (patients using PPIs at screening did not discontinue or change their medication regimen before the end-of-treatment [EOT] visit), stable-dose systemic leukotriene inhibitors, topical, nasal, and / or inhaled corticosteroids (at least 3 months before screening), oral antihistamines of any duration, and oral antibiotic treatment for up to 2 weeks.

[0147] Restricted Drugs and Procedures Medications that were restricted during the study period included the following: (1) medications used to treat EoE (these were considered rescue medications): swallowed topical corticosteroids, systemic corticosteroids, initiation or dose modification of systemic leukotriene inhibitors, topical, nasal, and / or inhaled corticosteroids, and systemic treatment of EoE with immunosuppressants / immunomodulators (including, but not limited to, omalizumab, cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, IFN-γ, or other biologics); (2) allergen immunotherapy (SCIT and IFN-γ if the dose was stable for more than 1 year); and SLIT were allowed, but OIT was prohibited; (3) patients who had not used a PPI in the 8 weeks prior to screening were prohibited from initiating PPI therapy before the EOT visit; (4) treatment with live (attenuated) vaccines (chickenpox (varicella), FluMist-influenza, intranasal influenza, measles (rubella), measles-mumps-rubella combination, measles-mumps-rubella-varicella combination, mumps, oral polio (Sabin), oral typhoid, rubella, smallpox (vaccinia), yellow fever, Bacille Calmette-Guerin, varicella zoster (shingles), rotavirus); and (5) treatment with investigational drugs (other than dupilumab).

[0148] The following concomitant procedures were prohibited during study treatment (up to week 12): (1) major elective surgical procedures; (2) esophageal dilation (considering rescue procedures); and (3) dietary changes (patients were to maintain a stable diet for at least 6 weeks before screening and throughout the course of the study; a stable diet did not include the initiation of one or more elimination diets or the reintroduction of previously eliminated food groups).

[0149] Study endpoints The primary efficacy endpoint was the change in Straumann Dysphagia Measure (SDI) patient-reported outcome (PRO) score from baseline to week 10.

[0150] Secondary endpoints were: percent change in weekly Eosinophilic Esophagitis Activity Index (EEsAI) PRO score from baseline to week 10; percent change in weekly EEsAI PRO score from baseline to week 10; percent change in weekly EEsAI PRO score from baseline to week 12; percent change in weekly EEsAI PRO score from baseline to week 12; percent change in SDI PRO score from baseline to week 10; percent change in SDI PRO score from baseline to week 12; percent change in SDI PRO score from baseline to week 12; percent change in SDI PRO score from baseline to week 12; percent change in Eosinophilic Esophagitis in Adults Quality of Life (EoE-QOL-A) (questionnaire) PRO score from baseline to week 12; percent change in SDI at week 10. Proportion of patients with PRO response; response defined as at least a 3-point reduction in SDI compared to baseline; proportion of patients achieving 40% or greater improvement in EEsAI score from baseline to week 10; percent change in overall peak esophageal intraepithelial eos / hpf (400X) from baseline to week 12; change in Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-EREF) (Endoscopic Visual Anatomical Score) from baseline to week 12; proportion of patients using rescue medication or procedures (e.g., esophageal dilation) by week 12; and incidence of treatment-emergent adverse events (TEAEs).

[0151] Exploratory efficacy endpoints were: change in mean esophageal intraepithelial eosinophil count (eos / hpf) from baseline to week 12 [calculated using peak counts at each esophageal site]; proportion of patients achieving an esophageal intraepithelial eosinophil count <1 eos / hpf at week 12; change in Collins histology score from baseline to week 12; and change in mean esophageal intraepithelial eosinophil count <1 eos / hpf at week 12. Changes in esophageal distensibility plateau as measured by functional luminal imaging in .

[0152] Procedures and Evaluation Screening / Baseline Procedures: The following procedures were performed only at the screening and / or baseline visit for the sole purpose of determining study eligibility or characterizing the baseline population: serum FSH (to confirm menopausal status), serum total IgE, HBsAg, and hepatitis C antibody.

[0153] Efficacy Procedures: Efficacy was assessed during the study at specific visits using patient-reported outcomes (PROs), including the Straumann Dysphagia Index (SDI), Eosinophilic Esophagitis Activity Index (EEsAI), and the Eosinophilic Esophagitis Quality of Life (EoE)-QOL-A questionnaire, as well as esophageal biopsies and photographs (endoscopy procedure). Measurement of inflammatory and remodeling esophageal features based on the Eosinophilic Esophagitis Edema, Ring, Exudate, Groove, and Stricture (EoE-EREFS) score was included as part of the endoscopy procedure. An endoscopic functional luminal imaging probe (EndoFLIP) procedure to measure esophageal distensibility was performed during the endoscopy procedure. The EoE Histological Scoring System (HSS) was used to measure eight histologic features of EoE.

[0154] Straumann Dysphagia Scale - Patient-Reported Results The SDI is a non-validated PRO used in clinical studies to determine the frequency and intensity of dysphagia (Straumann 2010). The SDI has a 1-week recall period. 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 intensity of dysphagia events is graded on a 6-point scale: 0 = unrestricted swallowing, 1 = slight resistance, 2 = slight retching with delayed passage, 3 = short-term obstruction requiring intervention (e.g., drinking, breathing), 4 = prolonged persistent obstruction relievable only by vomiting, and 5 = prolonged complete obstruction requiring endoscopic intervention. The total SDI score ranges from 0 to 9. In the Straumann study, clinical response (improvement) was defined as a reduction in the SDI score of at least 3 points from baseline.

[0155] This assessment was completed electronically by patients weekly in a questionnaire from the start of screening until the end of the study or early termination. Items used to quantify SDI were included in the EEsAI / SDI.

[0156] Activity index of eosinophilic esophagitis - patient-reported outcomes The EEsAI is a non-validated multimodular index under development at the University Hospital Inselspital (Berne, Switzerland) (Schoepfer 2014), part of the international EEsAI research group. The EEsAI PRO module (questionnaire) used in this study includes items related to the intensity and frequency of dysphagia, the influence of specific food groups on dysphagia symptoms, and other symptoms not dependent on eating or drinking (i.e., heartburn, acid regurgitation, and chest pain). The total EEsAI PRO score ranges from 0 to 100 (Figure 1), with higher scores indicating worse symptoms. The score consists of five parts: frequency of dysphagia, duration of dysphagia, pain on swallowing, visual dysphagia questions, avoidance, modification, and delayed eating (AMS). The EEsAI PRO utilizes 24-hour and 1-week recall periods.

[0157] This assessment was completed electronically by patients daily and weekly in a questionnaire from the start of screening until the end or early termination of the study.

[0158] Quality of Life Questionnaire for Adult Eosinophilic Esophagitis - Patient-Reported Outcomes The EoE-QOL-A questionnaire is a validated, disease-specific measure of health-related quality of life in patients with EoE (Taft 2011). The instrument used in this study, EoE-QOL-A v.3.0, includes 30 items related to established domains such as social functioning, emotional functioning, and the impact of illness on daily life experiences. The EoE-QOL-A has a 1-week recall period. Items are rated on a 5-point scale: "not at all," "slightly," "moderately," "quite a bit," and "extremely."

[0159] This assessment was recorded by the patient via questionnaire at baseline and monthly thereafter until the end of the study or early termination.

[0160] Esophageal biopsy and endoscopy with photography Esophageal biopsies were obtained by endoscopy at screening and the week 12 visit. Screening endoscopy was performed during the screening period, with results available for eligibility assessment on day -1. A total of nine mucosal pinch biopsies were collected at each time point from three esophageal regions: three proximal, three middle, and three distal. Two samples from each region were used for histology (study inclusion criteria and required for secondary endpoints). To participate in this study, patients had to demonstrate a peak intraepithelial eosinophil count of 15 eos / hpf (400X) or greater in at least two of the three esophageal regions sampled. The change in peak esophageal eos / hpf (400X) from baseline to week 12 was a secondary endpoint; this was determined by counting eosinophils in the most inflamed region of each esophageal region sampled at each time point and calculating the change in peak count for each site obtained at baseline compared to the count obtained at week 12. As an exploratory objective, the mean of all three peak counts was calculated, i.e., the mean change in peak counts in each of the three esophageal regions for each patient at each time point (screening and week 12). Tissue blocks remaining after histological evaluation were kept for exploratory studies.

[0161] The EoE-EREFS (edema, ring, exudate, groove, stricture) was used to measure endoscopically identified features of esophageal mucosal inflammation and remodeling in EoE. This instrument includes a total of 17 items related to the presence and severity of esophageal function. Specific esophageal features included: rings (concentric rings around the esophagus—absent, mild, moderate, severe, not applicable); stricture (narrowing of the esophagus—yes, no, not applicable); stricture diameter (if applicable); exudates (see white spots—absent, mild, severe); grooves (vertical lines in the esophagus—absent, present); edema (loss of vascular markings in the mucosa—absent, present); crepe-paper esophagus (absent, present); and overall appearance incorporating all endoscopically identified EoE findings (i.e., fixed rings, strictures, whitish exudates, grooves, edema, and crepe-paper mucosa). Additionally, mucosal changes associated with gastroesophageal reflux disease were also recorded using the Los Angeles Classification System for erosions (no erosion or LA classification A, B, C, D). EoE esophageal characteristics were analyzed based on the EoE-EREFS, a validated scoring system for inflammatory and remodeling features of the disease, using both an overall score and individual scores (Hirano 2014). The modified EREFS score for this study was based on a total score range of 0 to 8. Higher scores indicate greater impairment. Each score included edema (0–1); ring (0–3); exudate (0–2); groove (0–1); and stricture (0–1), giving a total of 8 possible scores.

[0162] Assessment of esophageal compliance was also performed using an endoscopic functional luminal imaging probe (EndoFLIP, Crospon, Ireland) to measure esophageal luminal diameter and pressure (e.g., esophageal stiffness). Measurements were taken as part of endoscopy performed at screening and at week 12. The EndoFLIP device is a catheter-based procedure that measures cross-sectional area at multiple sites along the esophagus while simultaneously recording intraluminal pressure during esophageal volumetric distension. Analysis of the relationship between esophageal cross-sectional area and pressure allowed for the assessment of esophageal compliance, This allows for the assessment of esophageal compliance as well as the distensible plateau (DP), which has been shown to be significantly reduced in patients with EoE compared to healthy controls (Kwiatek 2011). Furthermore, esophageal compliance has been associated with the outcome of both food impaction and the need for esophageal dilation (Nicodeme 2013).

[0163] The EoE-HSS produced distinct severity (grade) and extent (stage) disease scores. The scores were used to measure eight histological features (parameters) of EoE from three different regions of the esophagus (proximal, middle, and distal) (Collins et al., 2017). The eight parameters included eosinophil density, basal hyperplasia, eosinophil abscesses, eosinophil surface stratification, intercellular space dilation, surface epithelial alterations, dyskeratinized cells, and lamina propria fibrosis. For both grade and stage, a scale of 0–3 was used for each parameter (0 being minimal inflammation, normal). The total score range for each region in this study was 0–21 (except for the lamina propria parameter). Because 50% of pinch biopsies were not deep enough for evaluation of the lamina propria, evaluation of the lamina propria was excluded. The total score per patient was calculated as follows: (0–21 score × 3 regions = 63 total possible scores per time point). Two scores were generated per patient at each time point. One each for grade (severity) and stage (degree).

[0164] Photographs were taken at the site as part of the endoscopic procedure and biopsy collection.

[0165] Safety Procedures: An AE is an untoward medical occurrence in a patient receiving an investigational product, which may or may not have a causal relationship to the investigational product. Thus, an AE is any unfavorable, unintended sign (including abnormal laboratory findings), symptom, or disease transiently associated with the use of an investigational product, whether or not considered related to the investigational product. AE also includes any worsening (i.e., clinically significant change in frequency and / or intensity) of a pre-existing condition transiently associated with the use of the investigational product.

[0166] A serious adverse event (SAE) is an adverse medical occurrence at any dose that results in death, is life-threatening, requires patient hospitalization, results in permanent or significant disability / incapacity, is a congenital anomaly / birth defect, and / or is a serious medical occurrence (e.g., such an occurrence may endanger the patient or require intervention to prevent one of the other serious outcomes listed above).

[0167] Safety and tolerability were assessed by physical examination, vital signs, electrocardiogram (ECG), clinical laboratory tests, and clinical evaluation. Patients were asked to monitor any AEs they experienced from the time of informed consent until their final study visit.

[0168] Pharmacokinetic and Antibody Procedures: Serum samples were collected for assay of dupilumab levels, and dupilumab concentration data were used to calculate PK parameters. Serum samples were collected for assay of ADA and exploratory analyses.

[0169] result Baseline Characteristics: Patients were randomized 1:1 to receive a subcutaneous (SC) 600 mg dupilumab or SC placebo loading dose, followed by weekly SC 300 mg dupilumab or SC placebo during the 12-week double-blind treatment period. Randomization was stratified by baseline Straumann Dysphagia Measure (SDI) PRO score (≥5 and ≤7 vs. >7). Baseline demographic and disease characteristics were generally balanced between the two groups, except for mean total IgE (dupilumab 217.8 kU / L, placebo 468.2 kU / L) (Tables 1-2).

[0170] [Table 1]

[0171] [Table 2]

[0172] Both groups showed high levels of atopic disease (Table 3).

[0173] [Table 3]

[0174] Efficacy Results: Table 4 summarizes the results of the primary and secondary endpoints. Compared with placebo, dupilumab significantly improved subjective measures of EoE as reflected by dysphagia, as well as objective histologic and endoscopic measures of EoE disease. No patients received rescue medications / procedures during the 12-week double-blind treatment period.

[0175] [Table 4] [Table 5]

[0176] Dupilumab improved Straumann Dysphagia Measure (SDI) scores compared with placebo at week 10 (-3 vs. -1.3, P = 0.0304; 45.05% vs. 18.59%, P = 0.0312) (Table 4, Figure 2). Thirty-nine percent of patients treated with dupilumab achieved a reduction of 3 or more in the SDI at week 10 compared with 12.5% ​​in the placebo group. At both weeks 10 and 12, dupilumab improved both the frequency and severity of dysphagia components of the SDI score (Figure 3).

[0177] Dupilumab numerically reduced EEsAI scores versus placebo through 10 weeks (-34.6% vs. -11.3%, P = 0.085) (Table 4, Figure 4).

[0178] Dupilumab significantly reduced peak eosinophil counts (eos / hpf) from baseline compared with placebo by week 12 [-94.1 (-91.8%) vs. -7.4 (+15.1%), P < 0.0001] (Tables 4 and 6). Reductions in eosinophil tissue infiltration were observed in all patients in the dupilumab group (Table 5). Dupilumab effects were similar in the proximal, middle, and distal esophagus.

[0179] [Table 6]

[0180] Dupilumab significantly reduced EREFS compared with placebo at week 12 (LS mean change p = 0.0006, LS mean percent change p = 0.0004) (Table 4). Dupilumab significantly reduced the total EREFS score, as well as the effusion and groove subcomponents, with trends observed for the edema, ring, and stenosis subcomponents (Figure 4). 5).

[0181] Dupilumab significantly reduced both the total grade and stage score of the EoE-HSS by week 12 compared with placebo (P<0.001 vs. placebo) (Table 6; Figures 6 and 7). Dupilumab significantly reduced both the grade (severity) and stage (extent) scores of basal hyperplasia (BZH), eosinophilic inflammation (EI), eosinophil surface layering (SL), and eosinophil abscess (EA) in the proximal, intermediate, and distal regions (Figures 8 and 9). Dupilumab also reduced the grade and stage scores of dilated intracellular spaces and surface changes in apoptotic epithelial cells in all regions and distal regions (Figures 10 and 11).

[0182] Dupilumab significantly improved esophageal compliance compared with placebo at week 12 (Table 6). Increased distensibility plateau (improvement) was observed in more patients treated with dupilumab than with placebo (Figure 12).

[0183] Table 6 summarizes the effects of dupilumab on subjective patient-reported outcomes of dysphagia and objective clinician-assessed measures.

[0184] [Table 7] [Table 8]

[0185] Safety Results: Dupilumab was well tolerated in patients with EoE. The most common treatment-emergent adverse events (TEAEs) were injection site erythema (dupilumab 34.8%, placebo 8.3%) and nasopharyngitis (dupilumab 17.4%, placebo 4.2%).

[0186] conclusion Compared with placebo, dupilumab demonstrated a statistically significant reduction in the primary endpoint, the change from baseline in the Straumann Dysphagia Scale (SDI) at week 10. The LS mean difference in change from baseline at week 10 between the dupilumab and placebo groups was -1.7 (p=0.0304). Improvements in other subjective dysphagia measures, including the EEsAI (week 10) and the EOE-QOL (week 12), were also observed. Finally, there were significant statistical improvements in both histologic and visual endoscopic objective assessments of disease activity. This included the percent change from baseline at peak eosinophil counts and the absolute change from baseline in the Eosinophilic Esophagitis Edema, Rings, Exudates, Grooves, and Strictures (EoE-EREFS) score at week 12. Dupilumab treatment was generally safe and well tolerated. The most common TEAEs were mild ISRs, as well as viral upper respiratory tract infections and nasopharyngitis.

[0187] The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to be included within the scope of the appended claims.

Claims

1. a medicament for alleviating dysphagia in a patient, said medicament comprising an interleukin-4 / interleukin-13 (IL-4 / IL-13) pathway inhibitor; the IL-4 / IL-13 pathway inhibitor is an antibody that binds to IL-4Rα, the antibody comprising a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; The said medicament, wherein the patient to be treated has eosinophilic esophagitis (EoE), and further wherein the patient has a Straumann Dysphagia Instrument (SDI) score of 5 or greater.

2. The method of claim 1, wherein the patient exhibits at least two episodes of dysphagia per week for at least four weeks.

3. The method of claim 1, wherein the patient has been suffering from EoE for at least three years.

4. The method of claim 1, wherein the patient has been previously treated with a high-dose proton pump inhibitor (PPI).

5. The pharmaceutical composition of claim 1, wherein the patient has undergone at least one previous esophageal dilation.

6. The pharmaceutical composition of claim 1, wherein the patient to be treated is 18 years of age or older.

7. The patient to be treated: (1) selected from the group consisting of food allergies, allergic rhinitis, non-food allergies, asthma, chronic sinusitis, urticaria, atopic dermatitis, and allergic conjunctivitis; have a history of at least one other disease or condition; (2) had an SDI score of 7 or greater at baseline; and / or (3) Eosinophilic Esophagitis Severity and Activity Index (EEsAI) of 50 or more at baseline; The pharmaceutical composition according to claim 1.

8. The administration of the IL-4 / IL-13 pathway inhibitor comprises: (a) at least a 40% reduction from baseline in SDI score; (b) a 3-point or greater reduction from baseline in SDI score; and (c) a 30% or greater reduction from baseline in EEsAI score; resulting in at least one parameter selected from the group consisting of: The pharmaceutical composition according to claim 1.

9. (a) the IL-4 / IL-13 pathway inhibitor is administered at a dose of about 50 to about 600 mg; or (b) the IL-4 / IL-13 pathway inhibitor is administered at a dose of about 300 mg; The pharmaceutical composition according to any one of claims 1 to 8, wherein each dose is administered one week or two weeks after the immediately preceding dose.

10. the IL-4 / IL-13 pathway inhibitor is administered in a primary dose followed by one or more secondary doses; The method of any one of claims 1 to 8, wherein each secondary dose is administered 1 to 4 weeks after the immediately preceding dose.

11. 11. The method of claim 10, wherein the primary dose comprises 50 to 600 mg of the IL-4 / IL-13 pathway inhibitor and each secondary dose comprises 25 to 400 mg of the IL-4 / IL-13 pathway inhibitor.

12. the primary dose comprises 600 mg of an IL-4 / IL-13 pathway inhibitor and each secondary dose comprises 300 mg of an IL-4 / IL-13 pathway inhibitor; 12. The method of claim 11, wherein each secondary dose is administered one week after the immediately preceding dose, or each secondary dose is administered two weeks after the immediately preceding dose.

13. the IL-4 / IL-13 pathway inhibitor is administered in combination with a second therapeutic agent or therapy, wherein the second therapeutic agent or therapy is selected from the group consisting of an IL-1 beta inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNF alpha 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 proton pump inhibitor, an NSAID, esophageal dilation, allergen removal, and / or dietary management; The pharmaceutical composition according to any one of claims 1 to 12.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the IL-4 / IL-13 pathway inhibitor is administered subcutaneously.

15. The pharmaceutical according to any one of claims 1 to 14, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

16. The pharmaceutical composition of claim 15, wherein the IL-4 / IL-13 pathway inhibitor is dupilumab.

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