Methods for treatment active eosinophilic esophagitis

Abstract

FIELD: biotechnology.SUBSTANCE: method is proposed for reducing dysphagia in a subject having eosinophilic esophagitis, where the subject has a score on the original Strauman Dysphagia Rating Scale≥ 5. The method comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody against IL-4Rα.EFFECT: provision of a safe and effective increase in esophageal distensibility in a patient with eosinophilic esophagitis.19 cl, 12 dwg, 6 tbl, 1 ex

Description

[0001] This application was filed on August 3, 2018, as an international patent application under the PCT and claims priority under U.S. Provisional Patent Application Nos. 62 / 541,242, filed August 4, 2017; 62 / 561,593, filed September 21, 2017; and European Application No. EP18305252.1, filed March 8, 2018, the disclosures of each of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The present invention relates to the use of interleukin-4 / interleukin-13 pathway inhibitors for the treatment or prevention of active eosinophilic esophagitis in a patient in need thereof.Background Art

[0003] Esophageal stricture (narrowing of the esophagus) occurs as a result of damage to the esophageal mucosa and leads, among other things, to difficulty swallowing (dysphagia), regurgitation of food or liquid, heartburn, and unintentional weight loss. Treatment of esophageal stricture is very important, as it reduces quality of life due to dysphagia, weight loss, and malnutrition. Esophageal stricture can be caused by chronic ulceration or chronic inflammation, as a complication of chemotherapy, radiation therapy, esophageal cancer or endoscopic surgery, gastric ulcer disease, or gastroesophageal reflux. Esophageal stricture is also caused by eosinophilic esophagitis.

[0004] Eosinophilic esophagitis (EoE) is a new, chronic, immune / antigen-mediated disease characterized by esophageal dysfunction and eosinophilic inflammation in the esophagus (Liacourase et al 2011, The Journal of Allergy and Clinical Immunology. 128: 3-20 e6; quiz 1-2; Weinbrand-Goichberg et al 2013, Immunologic Research. 56: 249-60; Zhang et al 2013, Digestive Diseases and Sciences 58: 1497-506). Adult patients with EoE have significantly impaired quality of life (QOL) due to dysphagia and possible risk of malnutrition (DeBrosse et al 2011, The Journal of Allergy and Clinical Immunology 128: 132–8; Falk et al 2014, Gastroenterology Clinics of North America 43: 231–42; Straumann 2008, Gastrointestinal Endoscopy Clinics of North America 18: 99–118; Straumann et al 2003, Gastroenterology 125: 1660–9). Patients with active disease or moderate to severe EoE suffer from esophageal stricture, leading to difficulty swallowing, regurgitation of food or fluid, and weight loss.Emergency endoscopy for long-term eating disorders carries the risk of serious esophageal injury. EoE has been found to be associated with food allergies in many patients. Some patients may also have concomitant asthma or an atopic disease, such as atopic dermatitis or allergic rhinitis. The symptomatic burden of EoE, including food avoidance, changes in eating behavior, and impact on social, emotional, financial, work, school, and sleep, is also important and relevant for the EoE population. If alleviated, this could reflect a treatment benefit for EoE patients.

[0005] Current therapeutic approaches include chronic dietary interventions (including food allergen withdrawal), oral topical corticosteroids (not approved for the treatment of EoE in the US), and esophageal dilation. Although oral topical corticosteroids have been reported to produce partial clinical responses and histological remission, they are not uniformly effective and may be associated with fungal infections and disease relapse after discontinuation. Currently, there are no approved medications for EoE. Thus, there is an unmet need in this field for effective therapeutic approaches that are free of adverse effects and that prevent or treat eosinophilic esophagitis. Esophageal stricture can be treated with proton pump inhibitors, which inhibit gastric acid secretion.Endoscopic esophageal dilation is currently used to treat esophageal strictures and increase esophageal compliance. However, this surgical procedure is invasive and can lead to complications such as perforation and bleeding. Consequently, there is an unmet need for safe and effective treatments that increase esophageal compliance and treat esophageal strictures (e.g., in eosinophilic esophagitis). SUMMARY OF THE INVENTION

[0006] According to one aspect of the present invention, methods for increasing esophageal compliance are provided. The methods according to this aspect comprise: (a) selecting a patient with moderate to severe eosinophilic esophagitis (EoE), wherein the patient in need thereof has a feature or is selected based on a criterion selected from the group consisting of: (i) the patient has ≥ 15 eosinophils per high-power field (HPF) in the esophagus before or during treatment ("baseline"); (ii) the patient exhibits at least one episode of dysphagia per week; and (iii) the patient has a Strauman Dysphagia Inventory (SDI) score ≥ 2;and (b) administering a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 / interleukin-13 (IL-4 / IL-13) pathway inhibitor to a patient in need thereof, thereby increasing esophageal distensibility 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 old. In one embodiment, the patient has been previously treated with proton pump inhibitors (PPIs). In one embodiment, the patient has at least one prior esophageal dilation. In one embodiment, the patient has a characteristic selected from the group consisting of: (1) prior treatment with at least one PPI, esophageal dilation, corticosteroids, allergen withdrawal, and / or diet modification; (2) the patient is non-responsive to or resistant to prior treatment with PPIs or esophageal dilation;(3) the patient has an eosinophilic esophagitis severity and activity score (EEsAI) of ≥30, ≥40, or ≥50; (4) the patient has suffered from EoE for at least 3 years; (5) the patient has had or was diagnosed with a disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis before or during administration of the IL-4 / IL-13 pathway inhibitor; and (6) the patient has an elevated level 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).;

[0007] In embodiments of the invention that indicate the 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 the following list indicates that the elements in the sequence are alternatives to each other, and that one (or more) of these elements is / are selected. This does not mean that each of the items is necessarily selected. For example, for a method of increasing esophageal distensibility, wherein the patient has at least one characteristic selected from the group consisting of: (1) prior treatment with at least one of a PPI, esophageal dilation, corticosteroids, allergen withdrawal, and / or diet modification; (2) the patient is non-responsive or refractory to prior treatment with a PPI or esophageal dilation; (3) the patient has an Eosinophilic Esophagitis Severity and Activity Scale (EEsAI) score of ≥30, ≥40, or ≥50;(4) the patient has suffered from EoE for at least 3 years; (5) the patient, prior to or during administration of the IL-4 / IL-13 pathway inhibitor, had or was diagnosed with a disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and / or allergic conjunctivitis;and / or(6) the patient has an elevated level 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 neurotoxin (EDN), which means that the patient has at least characteristic (1) or characteristic (2), or characteristic (3), or characteristic (4), or characteristic (5), or characteristic (6). The patient may also, based on such wording, have more than one of the six characteristics (e.g., (1) and (2), (4) and (5), (1), (2) and (6), and so on). However, this does not mean that the patient must have at least characteristic (1), characteristic (2), characteristic (3), characteristic (4), characteristic (5) and characteristic (6).;

[0008] According to another aspect of the present invention, there are provided methods for treating, preventing, or ameliorating at least one symptom or sign of active eosinophilic esophagitis (EoE) in a patient. The methods according to this aspect of the invention comprise selecting a patient with moderate to severe EoE and administering a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 / interleukin-13 (IL-4 / IL-13) pathway inhibitor to the patient in need thereof. In some embodiments, the patient in need thereof is selected based on an attribute or criterion selected from the group consisting of: (1) the patient has ≥ 15 eosinophils per high-power field (HPF) in the esophagus before or during treatment ("baseline"); (2) prior 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 to or resistant to previous treatment with high-dose PPIs or esophageal dilation; (5) the patient has a Strauman Dysphagia Rating Scale (SDI) score ≥5; (6) the patient has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) ≥30, ≥40, or ≥50; (7) the patient has had EoE for at least 3 years; (8) the patient had or was diagnosed with a disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis before or during administration of the IL-4 / IL-13 pathway inhibitor;and (9) the patient has an elevated level 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).;

[0009] According to another aspect of the present invention, methods for reducing dysphagia are provided, comprising selecting a patient with moderate to severe EoE, wherein the patient (i) experiences ≥1 episode of dysphagia per week; (ii) has been previously treated with high doses of proton pump inhibitors (PPI); and / or (iii) has had at least one previous esophageal dilation; and (b) administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor to a patient in need thereof.

[0010] According to another aspect of the present invention, methods for improving a parameter are provided, the methods comprising 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) a decrease of at least 40% from baseline in the frequency and severity of dysphagia, as measured by the Strauman Dysphagia Inventory (SDI); (b) a decrease of 3 points from baseline in the SDI; (c) a decrease of more than 85% from baseline in the peak count of intraepithelial eosinophils in the proximal, mid, and / or distal esophagus; (d) an increase of at least 10% from baseline in esophageal distensibility, as measured by impedance planimetry;(e) a greater than 50% reduction from baseline in disease severity and extent as measured by the EoE-specific histological score (HSS); and (f) a greater than 30% reduction from baseline in dysphagia as measured by the eosinophilic esophagitis severity and activity score (EEsAI).

[0011] According to another aspect of the present invention, methods for reducing eosinophilic infiltration of the esophagus in a patient in need thereof are provided. In some embodiments, methods for reducing inflammation in the esophagus are provided. The methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor. In some embodiments, eosinophilic infiltration of the esophagus is represented by greater than or equal to about 15 eosinophils per high-power field in the esophagus of a patient in need thereof. In some embodiments, the eosinophil count is reduced by ≥85% after administration of the IL-4 / IL-13 pathway inhibitor. In some embodiments, inflammation (e.g., mucosal inflammation) is identified using endoscopy and features such as esophageal edema, rings, exudates, furrows, and strictures (EREFS).In some embodiments, administration of an IL-4 / IL-13 pathway inhibitor results in a reduction in 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 (disclosed elsewhere herein).

[0012] According to another aspect of the present invention, methods are provided for reducing the level of an EoE-associated biomarker in a patient. In some embodiments, the EoE-associated biomarker is selected from the group consisting of, for example, esophageal or circulating eosinophils, eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum thymus-regulated activation chemokine (TARC; CCL17), thymic stromal lymphopoietin (TSLP), serum eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN). The methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor.

[0013] In some embodiments, the IL-4 / IL-13 pathway inhibitor is administered in combination with a second therapeutic agent or therapy.

[0014] In some embodiments, the patient in need thereof has a concomitant disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, and hereditary connective tissue diseases.

[0015] Exemplary IL-4 / IL-13 pathway inhibitors that can be used in the context of the methods of the present invention include, but are not limited to, an anti-IL-4 antibody, an anti-IL-13 antibody, an anti-IL-4 / IL-13 bispecific antibody, and an IL-4 receptor (IL-4R) inhibitor. In one embodiment, the IL-4 / IL-13 pathway inhibitor is an IL-4R inhibitor (such as an anti-IL-4R antibody).

[0016] Typical IL-4R inhibitors that can be used in the context of the methods of the present invention include, for example, small molecule chemical inhibitors of IL-4R or its ligands (IL-4 and / or IL-13) or biological agents that target IL-4R or its ligands. According to some embodiments, the IL-4R inhibitor is an antibody or antigen-binding protein that binds the IL-4Rα chain and blocks the signaling of IL-4, IL-13, or both IL-4 and IL-13. In some embodiments, the anti-IL-4R antibody or antigen-binding protein comprises a heavy chain complementarity determining region (HCDR), 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.One such type of antigen-binding protein that can be used in the context of the methods of the present invention is an anti-IL-4R antibody, such as dupilumab.

[0017] In some embodiments, the present invention relates to 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 patient, including a human.

[0018] In some embodiments, the present invention relates to the use of an antibody or antigen-binding fragment thereof that binds to IL-4R in the manufacture of a medicament for treating or inhibiting or preventing active eosinophilic esophagitis in a patient, including a human.

[0019] In some embodiments, the present invention relates to the use of an IL-4 / IL-13 pathway inhibitor in the manufacture of a medicament for increasing esophageal compliance in a patient, including a human. In one embodiment, the patient has active EoE. In one embodiment, the patient has moderate to severe EoE.

[0020] In some embodiments, the present invention relates to the 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 patient, including a human. In one embodiment, the patient has active EoE. In one embodiment, the patient has moderate to severe EoE.

[0021] Other embodiments of the present invention will become apparent from a review of the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 lists the components comprising the weekly eosinophilic esophagitis severity and activity index (EEsAI) score.

[0023] Figure 2 shows the mean change from baseline in the Strauman Dysphagia Inventory (SDI) score during the 12-week treatment period in patients administered a once-weekly (qw) dose of 300 mg dupilumab compared to placebo.

[0024] Figure 3 shows the mean percentage change from baseline in the frequency and severity of dysphagia as measured by the Strauman Dysphagia Inventory (SDI) at weeks 10 and 12 with dupilumab 300 mg once weekly (qw) compared with placebo.

[0025] Figure 4 shows the mean percentage change from baseline in EEsAI score during the 12-week treatment period in patients administered a once-weekly (qw) dose of 300 mg dupilumab compared with placebo.

[0026] Figure 5 shows the mean percentage change from baseline in the EoE Edema, Rings, Furrows, and Strictures Scale (EREFS) total score and EREFS score subcomponents at week 12 in patients administered 300 mg dupilumab once weekly (qw) compared to placebo.

[0027] Figure 6 shows the mean change from baseline in the EoE-specific histology score (HSS) total score for grade (severity) subcomponents at week 12 in patients administered 300 mg dupilumab once weekly (qw) compared with placebo.

[0028] Figure 7 shows the mean change from baseline in the EoEHSS total score for stage (grade) subcomponents at week 12 in patients administered 300 mg dupilumab once weekly (qw) compared with placebo.

[0029] Figure 8 consists of Figures 8A, 8B, 8C, and 8D. Figure 8A shows the mean change from baseline in the EoEHSS score for basal zone hyperplasia; Figure 8B shows the mean change from baseline in the EoEHSS score for superficial eosinophil layering; Figure 8C shows the mean change from baseline in the EoEHSS score for eosinophil inflammation; and Figure 8D shows the mean change from baseline in the EoEHSS score for eosinophil abscess samples in the proximal, mid, and distal esophagus collected at week 12 in patients administered 300 mg dupilumab once weekly (qw) compared to placebo.

[0030] Figure 9 consists of Figures 9A, 9B, 9C, and 9D. Figure 9A shows the mean change from baseline in the EoEHSS stage score for basal zone hyperplasia; Figure 9B shows the mean change from baseline in the EoEHSS stage score for eosinophil abscess; Figure 9C shows the mean change from baseline in the EoEHSS stage score for eosinophil inflammation; and Figure 9D shows the mean change from baseline in the EoEHSS stage score for eosinophil superficial layer in the proximal, mid, and distal esophagus, collected at week 12 in patients administered 300 mg dupilumab once weekly (qw) compared with placebo.

[0031] Figure 10 consists of Figures 10A, 10B, and 10C. Figure 10A shows the mean change from baseline in the EoEHSS score for dilated intercellular spaces; Figure 10B shows the mean change from baseline in the EoEHSS score for surface change, and Figure 10C shows the mean change from baseline in the EoEHSS score for apoptotic epithelial cell samples in the proximal, mid, and distal esophagus collected at week 12 in patients administered 300 mg of dupilumab once weekly (qw) compared to placebo.

[0032] Figure 11 consists of Figures 11A, 11B, and 11C. Figure 11A shows the mean change from baseline in the EoEHSS stage score for dilated intercellular spaces; Figure 11B shows the mean change from baseline in the EoEHSS stage score for surface change, and Figure 11C shows the mean change from baseline in the EoEHSS stage score for apoptotic epithelial cell samples in the proximal, mid, and distal esophagus collected at week 12 in patients administered 300 mg dupilumab once weekly (qw) versus placebo.

[0033] Figure 12 shows the percentage change from baseline in plateau distensibility at week 12 in patients administered 300 mg dupilumab once weekly (qw) compared to placebo.DETAILED DESCRIPTION

[0034] Before describing the present invention, it should be understood that this invention is not limited to the specific methods and experimental conditions described, as such methods and conditions may vary. It should also 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.

[0035] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. The term "about" as used in this specification, when used in relation to a specific numerical value given, means that the value may differ from the given value by no more than 1%. For example, when used in this specification, the expression "about 100" includes 99 and 101 and all values ​​​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0036] 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 now described. All publications mentioned herein are hereby incorporated by reference for the disclosure in their entirety. Methods for treating, preventing, or ameliorating eosinophilic esophagitis

[0037] The present invention includes methods for treating, preventing, or ameliorating at least one symptom or sign of active eosinophilic esophagitis (EoE) in a patient. The methods according to this aspect of the invention comprise administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor to a patient in need thereof. As used herein, the terms "treat," "treating," or the like mean to alleviate symptoms, eliminate the causes of symptoms either temporarily or permanently, or prevent or slow the onset of symptoms of eosinophilic inflammation in the esophagus.In some embodiments, the present methods 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, inflammation in the esophagus, the appearance of tracheal rings or protrusions in the esophagus, chest and abdominal pain, food refusal, vomiting, dysphagia, and malnutrition.

[0038] "Eosinophilic esophagitis" (EoE) as used herein means an inflammatory disease characterized by abnormal eosinophilic inflammation in the esophagus and esophageal dysfunction. Primary symptoms of EoE include, but are not limited to, chest and abdominal pain, dysphagia, heartburn, food refusal, vomiting, and malnutrition. The clinical pathology of EoE is characterized by the presence of ridges or tracheal 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 mucosa. EoE can be classified as allergic or non-allergic depending on the patient's condition. The present invention includes methods for treating both allergic and non-allergic forms of EoE.

[0039] As used herein, the term “active EoE” refers to EoE disease in a patient who has ≥15 eosinophils per high-power field (HPF) on esophageal biopsy even after 8 weeks of treatment with proton pump inhibitors (PPIs). The term also refers to EoE disease in patients who exhibit frequent dysphagia, for example, the patient has 2, 3, 4, 5, or more episodes of dysphagia per week. The term “active EoE” includes moderate EoE as well as moderate to severe EoE. The term “moderate to severe” refers to EoE disease in patients who, in addition to eosinophilia (e.g., ≥15 eosinophils / field in the esophageal mucosa) and frequent episodes of dysphagia, have an SDI ≥2 and / or an EEsAI ≥30, have an EoE duration of at least 2 years, and / or are unresponsive to or resistant to prior therapy (including PPIs or esophageal dilation).

[0040] As used herein, the term "patient in need thereof" means 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 "patient in need thereof" may also include, for example, patients who, prior to treatment, exhibit (or have exhibited) one or more signs of EoE, such as, for example, overexpression of proinflammatory mediators in the esophagus, such as mast cells, eosinophilic infiltration of the esophagus, esophageal wall thickening, dysphagia, food retention, and chest and abdominal pain, and / or an elevated level of an EoE-associated biomarker. The term specifically includes patients who show the presence of ≥15 eosinophils per high-power field in the esophagus.In some embodiments, the term also includes patients with elevated peripheral eosinophil counts (e.g., ≥100, ≥150, ≥200, or ≥300 cells / μL) or elevated serum IgE (>150 kU / L).

[0041] In some embodiments, the present methods can be used to treat patients who exhibit pathologies and symptoms observed in patients with chronic esophagitis, including gastroesophageal reflux disease (GERD). In some embodiments, the term "patient in need thereof" includes patients who are refractory or resistant to anti-GERD therapy. For example, the present methods can be used to treat patients resistant to proton pump inhibitors (PPIs).

[0042] In the context of the present invention, a "patient in need thereof" may include a subgroup of the population that is more susceptible to EoE or may exhibit an elevated level of an EoE-associated biomarker. For example, a "patient in need thereof" may include a patient suffering from an atopic disease or disorder, such as food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis. In some embodiments, the term "patient in need thereof" includes a patient who, before or during administration of the IL-4 / IL-13 pathway inhibitor, had or was diagnosed with a disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis. In some embodiments, the term "patient in need thereof" may include patients with inherited connective tissue disorders.This patient population may exhibit elevated levels of an EoE-associated biomarker such as IgE, eotaxin-3, periostin, IL-5, or IL-13.

[0043] In some embodiments, a "patient in need thereof" includes a patient susceptible to an allergen. For example, a "patient in need thereof" includes a patient who may exhibit one of the following characteristics: (a) is prone to allergic reactions or reactions when exposed to one or more allergens; (b) has previously exhibited an allergic response or reaction to one or more allergens; (c) has a history of allergies; and / or (d) exhibits a sign or symptom of an allergic response or anaphylaxis. In some embodiments, the patient is allergic to an allergen associated with EoE or that makes the subject susceptible and / or prone to developing EoE.

[0044] As used herein, the term "allergen" includes any substance, chemical, particle, or composition that is capable of stimulating an allergic response in a susceptible individual. Allergens may be contained in foods or food derivatives, such as, for example, dairy products (e.g., cow's milk), eggs, wheat, soy, corn, rye, fish, seafood, peanuts, and tree nuts. Alternatively, an allergen may be contained in or derived from non-food products, such as, for example, dust (e.g., containing dust mites), pollen, insect venom (e.g., bee, wasp, mosquito venom, etc.), mold, animal dander, latex, medications, drugs, ragweed, grass, and birch.

[0045] In some embodiments, the term "patient in need thereof" includes a subgroup of the population that exhibits an allergic reaction to a food allergen. For example, "patient in need thereof" may include a patient who is allergic to an allergen contained in a food product, including, but not limited to, dairy, egg, wheat, soy, corn, rye, fish, seafood, peanuts, tree nuts, beef, chicken, oats, barley, pork, green beans, and fruits such as apples and pineapples.

[0046] In some embodiments, the term includes a patient suffering from an allergy to a non-food allergen, such as allergens originating from dust, mold, insects, plants, including pollen, and pets such as cats and dogs. Examples of non-food allergens (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.

[0047] The expressions "allergic response," "allergic reaction," "allergic symptom," and the like, as used herein, include one or more signs or symptoms selected from the group consisting of urticaria (e.g., urticaria), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinus inflammation, lacrimation, wheezing, bronchospasm, decreased peak expiratory flow (PEF), gastrointestinal upset, flushing, swollen lips, swollen tongue, decreased blood pressure, anaphylaxis, and organ dysfunction / failure. "Allergic response," "allergic reaction," "allergic symptom," and the like, also include immunological responses and reactions, such as, for example, increased IgE production, increased allergen-specific immunoglobulin production, and / or eosinophilia.

[0048] In some embodiments, the methods described herein are for the treatment of adults, adolescents, or children. Adults are ≥18 years old, adolescents are ≥12 and ≤18 years old, and children are ≤12 years old. In some embodiments, the methods described herein can be used to treat EoE in children ≤3 years old. In one embodiment, an IL-4 / IL-13 pathway inhibitor is used to treat moderate to severe EoE in patients that are not adequately controlled with standard treatment (e.g., oral corticosteroids, dilation, etc.). The subject can be an adult, adolescent, or child.

[0049] The present invention also includes methods for increasing esophageal compliance. The methods according to this aspect of the invention comprise 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.

[0050] The present invention also includes methods for reducing eosinophilic infiltration. The methods according to this aspect of the invention comprise 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 the number of eosinophils, for example, in the esophageal mucosa.

[0051] As used herein, the term "eosinophilic infiltration" refers to the presence of eosinophils in an organ or tissue, including the blood, esophagus, stomach, duodenum, and ileum of a patient. In the context of the invention, the term "eosinophilic infiltration" refers to the presence of eosinophils in the mucosa of a region of the gastrointestinal tract, including, but not limited to, the esophagus and stomach. Eosinophilic infiltration is analyzed, for example, in a biopsy of esophageal tissue from a subject suffering from EoE. In certain embodiments, "eosinophilic infiltration" refers to the presence of ≥15 eosinophils per high-power field in the esophagus. The term "high power field" refers to the standard total magnification of 400x with a microscope used to view eosinophils in tissue, such as from a patient's esophagus.In some embodiments, "eosinophilic infiltration" includes infiltration of tissue by leukocytes, such as lymphocytes, neutrophils, and mast cells. Leukocyte infiltration, such as into esophageal tissue, can be detected using cell surface markers such as eosinophil-specific markers (e.g., CD11cLow / Neg, SiglecF+, F4 / 80+, EMR1+, Siglec8+, and MBP2+), macrophage-specific markers (e.g., CD11b+, F4 / 80+, CD14+, EMR1+, and CD68+), neutrophil-specific markers (e.g., CD11b+, Ly6G+, Ly6C+, CD11b+, and CD66b+), and T-cell-specific markers (e.g., CD3+ CD4+ CD8+).

[0052] As used herein, a reduction in esophageal eosinophils means that the number of eosinophils and other white blood cells measured in the esophagus of a patient with EoE and who was treated with an IL-4 / IL-13 pathway inhibitor is lower by at least 5%, 10%, 20%, 50%, 70%, 80% or 90% than the esophageal eosinophils measured in the same or an equivalent patient who was not treated with an IL-4 / IL-13 pathway inhibitor. In some embodiments, a reduction in eosinophil infiltration means detecting less than 15 eosinophils per high-power field, more preferably less than 10 eosinophils, less than 9 eosinophils, less than 8 eosinophils, less than 7 eosinophils, less than 6 eosinophils, or less than 5 eosinophils per high-power field in an esophageal mucosal biopsy. In some embodiments, a reduction in esophageal eosinophils means that no eosinophils are detected in the patient's esophageal mucosa.

[0053] The present invention includes methods for treating, preventing, or reducing the severity of eosinophilic esophagitis, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor to a patient in need thereof, wherein the pharmaceutical composition is administered to the patient in multiple doses, for example, as part of a certain therapeutic dosing regimen. For example, the therapeutic dosing regimen may comprise administering to the patient multiple doses of the pharmaceutical composition at a frequency of about once a day, 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 every month, once every two months, once every three months, once every four months, or less frequently.

[0054] The methods of the present invention, in some embodiments, comprise administering to a patient 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 an agent selected from the group consisting of, for example, an IL-1-beta inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, IL-17, 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 some embodiments, an IL-4 / IL-13 pathway inhibitor of the invention may be administered in combination with a therapy comprising esophageal dilation, allergen removal, and dietary control. As used herein, the term "in combination with" means that a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor is administered to a patient concurrently with, immediately before, or immediately after the administration of a second therapeutic agent. In some embodiments, the second therapeutic agent is co-administered with the IL-4 / IL-13 pathway inhibitor. In a related embodiment, the present invention includes methods comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor to a patient along with an anti-allergy therapeutic regimen. The background anti-allergy therapeutic regimen may include a course of administration of, for example, steroids, antihistamines, decongestants, anti-IgE agents, etc.d. An IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody) can be added on top of the background antiallergic therapy regimen. In some embodiments, the IL-4 / IL-13 pathway inhibitor is added as part of a "background tapering" regimen, in which the background antiallergic therapy is gradually withdrawn from the patient over time (e.g., in a stepwise manner), while the IL-4 / IL-13 pathway inhibitor is administered to the patient at a constant dose, or at an increasing dose, or at a decreasing dose over time. In some embodiments, the IL-4 / IL-13 pathway inhibitor is administered as monotherapy. Biomarkers associated with eosinophilic esophagitis.

[0055] The present invention also includes methods comprising 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 activity, metabolite, nucleic acid, carbohydrate, or other biomolecule that is present or detected in an EoE patient at a level or amount that differs from (e.g., greater or less than) the level or amount of the marker present or detected in a patient without EoE.Typical 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 a gene or gene probe known in the art that is differentially expressed in a patient with EoE compared to a patient without EoE.For example, genes that are significantly upregulated in a patient 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-induced protein 6 (Blanchard et al. 2006, J. Clin. Invest. 116: 536-547). Alternatively, an "EoE-associated biomarker" also includes 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 invention relate to the use of these biomarkers to monitor disease reversal upon administration of an IL-4 / IL-13 pathway inhibitor.Methods for detecting and / or quantifying such 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 offer services that also provide measurements of such biomarkers.

[0056] According to some aspects of the invention, methods of treating EoE are provided, which comprise: (a) selecting a patient that exhibits a level of at least one EoE-associated biomarker before or during treatment that is indicative of a disease state; and (b) administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an IL-4 / IL-13 pathway inhibitor. In some embodiments of this aspect of the invention, the patient is selected based on an elevated level of IgE or eotaxin-3.

[0057] According to other aspects of the invention, methods of treating EoE are provided, which comprise administering to a patient a pharmaceutical composition comprising a therapeutically effective amount of an IL-4 / IL-13 pathway inhibitor, wherein administration of the pharmaceutical composition to the patient results in a decrease in at least one EoE-associated biomarker (e.g., esophageal eosinophils, eotaxin-3, IgE, etc.) at a time after administration of the pharmaceutical composition compared to the level of the biomarker in the patient before administration.

[0058] As will be understood 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 patient at a certain 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 before administration of the pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor (i.e., a baseline measurement). The specific time point at which the biomarker is measured may 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 the pharmaceutical composition containing the IL-4 / IL-13 pathway inhibitor.

[0059] According to some embodiments of the present invention, a patient may experience a decrease in the level of one or more 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, day 4, day 8, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, or day 85 after administration of a first, second, third, or fourth dose of a pharmaceutical composition comprising from about 75 to about 600 mg of an anti-IL-4R antibody (e.g., dupilumab), a patient according to the present invention may experience a decrease in eotaxin-3 of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more from baseline (where "baseline" is defined as the patient's eotaxin-3 level immediately before the first administration).Similarly, at about day 1, day 4, day 8, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, or day 85, following administration of a first, second, third, or fourth dose of a pharmaceutical composition comprising from about 75 to about 600 mg of an anti-IL-4R antibody (e.g., dupilumab), a patient according to the present invention may exhibit a decrease in IgE of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more from baseline (where "baseline" is defined as the patient's IgE level immediately before the first administration).

[0060] The present invention also includes methods for determining whether a patient is a suitable patient who would benefit from the administration of a pharmaceutical composition comprising an IL-4 / IL-13 pathway antagonist. For example, if an individual, prior to receiving a pharmaceutical composition comprising an IL-4 / IL-13 pathway antagonist, exhibits a level of an EoE-associated biomarker that indicates a disease state, then the individual is identified as a suitable patient who would benefit from the administration of the pharmaceutical composition of the invention (a composition comprising an anti-IL-4R antibody). In related embodiments, the present invention includes methods for treating suitable patients, where the suitable patient may be more susceptible to EoE, for example, due to a food allergy or an atopic disease.For example, the present invention includes methods comprising administering an IL-4 / IL-13 pathway antagonist to patients with food allergies, atopic dermatitis, asthma, allergic rhinitis, or allergic conjunctivitis. In another example, the present invention includes methods comprising administering an IL-4 / IL-13 pathway antagonist to patients with inherited Mendelian connective tissue disorders, such as Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos hypermobility syndrome (EDS), or joint hypermobility syndrome (JHS). Such patient populations may have elevated levels of an EoE-associated biomarker.

[0061] According to some exemplary embodiments, an individual may be identified as a good candidate for anti-IL-4 / IL-13 antibody therapy if the individual exhibits one or more of the following: (i) an eotaxin-3 level of greater than about 30 μg / mL, greater than about 40 pg / mL, greater than about 50 pg / mL, greater than about 100 pg / mL, greater than about 1500 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) a serum IgE level of greater than about 114 kU / L, greater than about 150 kU / L, greater than about 500 kU / L, 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 (iii) ≥ 15 eosinophils per high-power field in the patient's esophagus. Additional criteria, such as other clinical indicators of EoE (e.g., dysphagia, esophageal wall thickening, and food allergy indicative of EoE), may be used in combination with any of the aforementioned EoE-associated biomarkers to identify an individual as a suitable candidate for anti-IL-4 / IL-13 antibody therapy, as described elsewhere herein.Parameters associated with eosinophilic esophagitis.

[0062] The present invention includes methods for improving one or more parameters associated with eosinophilic esophagitis (EoE) in a patient in need thereof, wherein the methods comprise administering a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor to the patient.

[0063] Examples of “EoE-related parameters” include: (a) Straumann Dysphagia Rating Scale (SDI); (b) Eosinophilic Esophagitis Activity Index (EEsAI); (c) Eosinophilic esophagitis features such as edema, rings, exudates, grooves, and strictures (EoE-EREFS); (d) EoE-Specific Histology Score (EoE-HSS); (e) Esophageal Intraepithelial Eosinophils; and (f) Esophageal Distensibility. “Improvement in an EoE-related parameter” means a decrease from baseline in one or more of the SDI, EEsAI, EoE-EREFS, EoE-HSS, or Esophageal Intraepithelial Eosinophils. Improvement in Esophageal Distensibility means an increase from baseline. As used herein, the term "baseline" in relation to an EoE-related parameter means the numerical value of the EoE-related parameter for a patient before or during administration of the pharmaceutical composition of the present invention.

[0064] To determine whether an EoE-related parameter has "improved," the parameter is quantified at the beginning and at one or more time points after administration of the pharmaceutical composition of the present invention. For example, the EoE-related parameter can be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85; or at the end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24 or longer after the initial treatment with the pharmaceutical composition of the present invention.The difference between the parameter value at a particular time point after the start of treatment and the parameter value at baseline is used to determine whether there has been an "improvement" (e.g., decrease) in the EoE-related parameter.

[0065] Straumann Dysphagia Inventory (SDI). SDI is a non-validated patient-reported outcome (PRO) that has been used in clinical studies to determine the frequency and intensity of dysphagia (Straumann 2010). SDI has a 1-week assessment period. The frequency of dysphagia events is rated 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, and the intensity of dysphagia events is rated on a 6-point scale: 0=swallowing without restriction, 1=mild resistance, 2=mild gagging with breath holding, 3=short period of obstruction requiring intervention (e.g., drinking, breathing), 4=long period of obstruction relieved only by vomiting, 5=long-term complete obstruction requiring endoscopic intervention. The overall SDI score ranges from 0 to 9.According to some 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 compared to baseline. For example, the present invention includes therapeutic methods that result in a 1, 2, 3, 4, 5, 6, or more point reduction in the SDI compared to baseline. In some exemplary embodiments, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a reduction of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more on day 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or later 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 some exemplary embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a reduction in SDI of at least 40% compared to baseline.

[0066] Eosinophilic Esophagitis Activity Index (EEsAI). The EEsAI is an unvalidated multimodular index under development at the University Hospital Inselspital Bern, Switzerland (Schoepfer 2014), a member of the international EEsAI research group. The EEsAIPRO module (questionnaire) used in this study includes items related to the intensity and frequency of dysphagia, the effect of certain food groups on dysphagia symptoms, and other symptoms independent of food or drink intake (e.g., heartburn, acid regurgitation, and chest pain). The EEsAIPRO total score ranges from 0 to 100 (Figure 1), with higher scores indicating worse symptoms. The assessment consists of 5 parts: frequency of swallowing problems, duration of swallowing problems, pain when swallowing, visual dysphagia question, and avoidance, modification, and slow feeding (AMS).According to some embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a reduction in the EEsAI score. For example, the present invention includes therapeutic methods that result in a reduction, compared to a baseline value, in the EEsAI score of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or more on day 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or later 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 some exemplary embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a reduction from baseline in the EEsAI score of at least 30% following administration.

[0067] Eosinophilic Esophagitis Associated Features such as Edema, Rings, Exudates, Furrows, and Strictures (EoE-EREFS) The EoE-EREFS (edema, rings, exudates, furrows, strictures) is used to measure endoscopically identified features of inflammation and mucosal remodeling in EoE esophagus. This instrument includes 17 items related to the presence and severity of esophageal features. Specific esophageal features include: 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 (seewhite plaques - absent, mild, severe), striations (vertical lines down the esophagus - absent, present); edema (loss of vascular markings on the mucosa - absent, present); crinkle-paper esophagus (absent, present); overall appearance including all endoscopically identified EoE findings (i.e., fixed rings, strictures, whitish exudate, striation, edema, and crinkle-paper mucosa). Additionally, mucosal changes associated with gastroesophageal reflux disease are recorded using the Los Angeles erosions classification system (no erosions or LA, A, B, C, D classification). Esophageal EoE characteristics are analyzed based on the EoE-EREFS, a validated scoring system for inflammatory and remodeling features of the disease, using both total scores and scores for each individual feature (Hirano 2014).According to some embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a reduction in the EoE-EREFS score. For example, the present invention includes therapeutic methods that result in a reduction from baseline in the EREFS score of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more on day 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, or later 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).

[0068] Eosinophilic Esophagitis EoE-Specific Histologic Scoring Scale (EoE-HSS). The EoE-HSS generates separate scores for disease severity (grade) and extent (stage). The score is used to measure 8 histologic features (parameters) of EoE from 3 different compartments (proximal, middle, and distal) of the esophagus (Collins et al. 2017). The eight parameters include: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophilic superficial layers, dilated intercellular spaces, superficial epithelial changes, nonkeratotic cells, and lamina propria fibrosis. A scale from 0 to 3 is used for each parameter, both grade and stage (0 = least inflamed, normal). According to some embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a reduction in EoE-HSS score.For example, the present invention includes therapeutic methods that result in a reduction in EoE-HSS compared to baseline of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more on day 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 some exemplary embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a reduction in EoE-HSS score by at least 50% compared to baseline.

[0069] Esophageal intraepithelial eosinophils. This refers to ≥15 eosinophils per high-power field (HPF) in an esophageal biopsy. A peak intraepithelial eosinophil count refers to ≥15 eosinophils per HPF in at least 2 of the 3 esophageal regions sampled. According to some embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a decrease in the peak intraepithelial eosinophil count. For example, the present invention includes therapeutic methods that result in a reduction, compared to baseline, of intraepithelial eosinophils by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or more on day 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 some exemplary embodiments of the present invention, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in a reduction in intraepithelial eosinophils by at least 85% compared to baseline.

[0070] Esophageal Distensibility. Esophageal distensibility is assessed using the Endoluminal Functional Lumen Imaging Probe (EndoFLIP, Crospon, Ireland) to measure esophageal lumen diameter and pressure. The EndoFLIP device is a catheter-based procedure that measures the cross-sectional area at multiple locations along the esophagus while simultaneously recording intraluminal pressure during volumetric esophageal distension. Analysis of the cross-sectional area versus esophageal pressure 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 some 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 present invention includes therapeutic methods that result in an increase, compared to baseline, in esophageal distensibility of at least about 5%, 10%, 15%, 20%, 25%, or more at the end of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 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 some exemplary embodiments, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in an increase, compared to baseline, in esophageal distensibility of at least 10%, as measured by impedanoplanimetry.

[0071] Quality of Life in Eosinophilic Esophagitis in Adults Questionnaire (EoE-QoL-A). The EoE-QOL-A questionnaire is a validated measure of health-related quality of life in patients with EoE (Taft 2011). The instrument used in this study, EoE-QOL-Av.3.0, includes 30 items related to established domains such as social functioning, emotional functioning, and the impact of illness on daily life. The EoE-QOL-A has a 1-week assessment period. Items are rated on a 5-point scale: “Not at all,” “A little,” “Moderately,” “Very little,” and “Extremely.” According to some embodiments, administration of an IL-4 / IL-13 pathway inhibitor to a patient results in improved quality of life scores in the patient. IL-4 / IL-13 pathway inhibitors

[0072] The methods of the present invention comprise administering to a patient in need thereof a therapeutic composition comprising an IL-4 / IL-13 pathway inhibitor.

[0073] The term "IL-4 / IL-13 pathway inhibitor" (also referred to herein as "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) the signaling and / or activity of IL-4 and / or IL-13; and / or (iii) the downstream signaling / activity that results 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., those disclosed in U.S. Patent 7,740,843 and U.S. Patent Application Publications 20100297110, 20160207995), anti-IL-13 antibodies (e.g., those disclosed in U.S. Patents 7,501,121, 7,674,459, 7,807,788, 7,910,708, 7,915,388, 7,935,343, 8,088,618, 8,691,233, 9,605,065, U.S. Patent Application Publications 2006,007,3148, 2008,004,4420, and EP2627,673B1), bispecific antibodies that bind to IL-4 and IL-13 (e.g., antibodies disclosed in U.S. Patent 8,388,965, U.S. Patent Application Publications 20110008345, 20130251718, 20160207995) and IL-4 receptor (IL-4R) inhibitors (described below).

[0074] The term "IL-4R inhibitor" (also referred to herein as "IL-4 / IL-13 pathway inhibitor," "IL-4R antagonist," "IL-4R blocker," "IL-4Rα blocker," etc.) is any agent that binds to or interacts with IL-4R or an IL-4R ligand and inhibits or attenuates the normal biological signaling function of IL-4 receptor type 1 and / or type 2. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. IL-4 receptor type 1 is a dimeric receptor containing an IL-4Rα chain and a γc chain. IL-4 receptor type 2 is a dimeric receptor containing an IL-4Rα chain and an IL-13Rα1 chain. IL-4 type 1 receptors interact with and are stimulated by IL-4, whereas IL-4 type 2 receptors interact with and are stimulated by 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 signaling, or both IL-4 and IL-13 signaling. Thus, the IL-4R inhibitors of the present invention can prevent the interaction of IL-4 and / or IL-13 with the type 1 or type 2 receptor.

[0075] 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., engineered molecules comprising the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind human IL-4Rα. As used herein, an IL-4R inhibitor also includes antigen-binding proteins that specifically bind IL-4 and / or IL-13. Anti-IL-4R antibodies and antigen-binding fragments thereof

[0076] According to some exemplary embodiments of the present invention, the IL-4 / IL-13 pathway inhibitor is an anti-IL-4R 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 linked together by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1).The VH and VL regions can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with regions that are more conserved, called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FRs of an anti-IL-4R antibody (or its antigen-binding portion) can be identical to human germline sequences or can be naturally or artificially modified. The amino acid consensus sequence can be determined based on parallel analysis of two or more CDRs.

[0077] As used herein, the term "antibody" also includes antigen-binding fragments of complete 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 produced, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody can be obtained, for example, from complete antibody molecules using any suitable standard methods, such as proteolytic cleavage or recombinant genetic engineering methods involving manipulation and expression of variable and optionally constant domains encoding DNA. Such DNA is known and / or readily available from, for example, 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, for example, to arrange one or more of the variable and / or constant domains in a suitable configuration or to introduce codons, create cysteine ​​residues, modify, add or delete amino acids, etc.

[0078] 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 molecules (scFv); (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic a hypervariable region of an antibody (e.g., a distinct complementarity determining region (CDR), such as a CDR3 peptide), or a restricted FR3-CDR3-FR4 peptide. Other engineered molecules such as domain-specific antibodies, single-domain antibodies, domain-deletion antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, divalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark IgNAR variable domains are also included in the term "antigen-binding moiety" when used herein.

[0079] An antigen-binding fragment of an antibody typically comprises at least one variable domain. The variable domain can be of any size or amino acid composition and will typically contain at least one CDR adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain linked to a VL domain, the VH and VL domains can be arranged relative to each other in any suitable arrangement. For example, the variable region can be dimeric and comprise VH-VH, VH-VL, or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody can comprise a monomeric VH or VL domain.

[0080] In some embodiments, the antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting example configurations of variable and constant domains that may be found in the antigen-binding fragment of an antibody of the present invention include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of the variable and constant domains, including any of the above exemplary configurations, the variable and constant domains may be either directly linked to each other or may be linked by all or part of a hinge or linker region.The hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, resulting in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide of the molecule. In addition, the antigen-binding fragment of the antibody of the present invention may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above, in non-covalent association with each other and / or with one or more monomeric VH or VL domains (e.g., disulfide bond(s)).

[0081] As used herein, the term "antibody" also includes multispecific (e.g., bispecific) antibodies. A multispecific antibody or antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any format of a multispecific antibody can be adapted for use in the context of an antibody or antigen-binding fragment of an antibody of the present invention using routine techniques available in the art. For example, the present invention includes methods comprising the use of bispecific antibodies in which one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or 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, for example, scFv or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knobs-in-holes, conventional light chain (e.g., conventional light chain with knobs-in-holes, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, Duotelo, IgG1 / IgG2, Fab (DAF)-IgG dual-acting, and Mab2 bispecific formats (see, for example, Kleinetal. 2012, mAbs 4: 6, 1-11, and references cited therein, for a review of the aforementioned formats).Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, for example, in which unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with defined composition, valence, and geometry. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).

[0082] The antibodies used in the methods of the present invention can be human antibodies. The term "human antibody" as used herein is intended to refer to antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention, however, may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or somatic mutation in vivo), for example, in the CDRs and, in particular, CDR3. However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of other mammalian species, such as mice, have been grafted onto human framework sequences.

[0083] The antibodies used in the methods of the present invention may be recombinant human antibodies. The term "recombinant human antibody," as used herein, is intended to include all human antibodies that are produced, expressed, created, or isolated by recombinant methods, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in more detail below), antibodies isolated from a recombinant, combinatorial library of human antibodies (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. AcidsRes. 20: 6287-6295), or antibodies produced, expressed, created, or isolated by any other method that involves splicing human immunoglobulin gene sequences with other DNA sequences.Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, to in vivo somatic mutagenesis) and, therefore, the amino acid sequences of the VH and VL regions of the recombinant antibody represent sequences that, although derived from and related to human germline VH and VL sequences, cannot naturally exist in the germline repertoire of a human antibody in vivo.

[0084] According to certain embodiments, the antibodies used in the methods of the present invention specifically bind IL-4Rα. The term "specifically binds" or the like means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody binds to a specific antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.For example, an antibody that "specifically binds" IL-4Rα, as used in the context of the present invention, includes antibodies that bind IL-4Rα or a portion thereof with a KD 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 surface plasmon resonance analysis. However, the isolated antibody that specifically binds human IL-4Rα may have cross-reactivity with other antigens, such as IL-4Rα molecules from other (non-human) species.

[0085] According to some exemplary embodiments of the present invention, an IL-4 / IL-13 pathway inhibitor is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of anti-IL-4R antibodies as disclosed in U.S. Patent No. 7,608,693. In some exemplary embodiments, an anti-IL-4Rα antibody or antigen-binding fragment thereof that may be used in the context of the methods of the present invention comprises heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence SEQ ID NO: 2.According to some 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 yet other embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2. In some embodiments, the methods of the present invention comprise using 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 a fully human anti-IL-4R antibody known as dupilumab. According to some exemplary embodiments, the methods of the present invention involve using dupilumab or a bioequivalent thereof.The term "bioequivalent" as used herein refers to anti-IL-4R antibodies or IL-4R-binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternatives, the rate and / or extent of absorption of which do not show a significant difference compared to dupilumab when administered at the same molar dose under similar experimental conditions, either in single or multiple doses. In the context of the invention, the term refers to antigen-binding proteins that bind to IL-4R that do not exhibit clinically significant differences in safety, purity, and / or efficacy compared to dupilumab.

[0086] Other anti-IL-4Rα antibodies that can be used in the context of the methods of the present invention include, for example, the antibody referred to and known in the art as AMG317 (Correnetal., 2010, Am J Respir Crit Care Med, 181 (8): 788-796) or MEDI 9314, or any of the anti-IL-4Rα antibodies disclosed in U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, or U.S. Patent No. 8,877,189.

[0087] Anti-IL-4R antibodies used in the context of the methods of the present invention may have pH-dependent binding characteristics. For example, an anti-IL-4Rα antibody for use in the methods of the present invention may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody of the invention may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The term "acidic pH" includes pH values ​​less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or less. As used herein, the term "neutral pH" means a pH from about 7.0 to about 7.4. The term "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.

[0088] In some cases, “reduced binding to IL-4Rα at acidic pH compared to neutral pH” is expressed as the ratio of the KD value of antibody binding to IL-4Rα at acidic pH to the KD value of antibody binding to IL-4Rα at neutral pH (or vice versa). For example, an antibody or antigen-binding fragment thereof can be considered to exhibit “reduced binding to IL-4Rα at acidic pH compared to neutral pH” for the purposes of the present invention if the antibody or antigen-binding fragment thereof exhibits an acidic / neutral KD ratio of about 3 or higher. In some exemplary embodiments, the acidic / neutral KD ratio for an antibody or antigen-binding fragment of the present invention 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.

[0089] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at an acidic pH compared to a neutral pH. In addition, modifications of the antigen-binding domain at the amino acid level can produce antibodies with pH-dependent characteristics. For example, by replacing one or more amino acids of the antigen-binding domain (e.g., within the CDRs) with a histidine residue, an antibody with reduced antigen-binding activity at an acidic pH relative to a neutral pH can be obtained. As used herein, the term "acidic pH" means a pH of 6 or less. Pharmaceutical compositions

[0090] The present invention includes methods that involve administering an IL-4 / IL-13 pathway inhibitor to a patient, wherein the IL-4 / IL-13 pathway inhibitor is contained in a pharmaceutical composition. The pharmaceutical compositions of the invention can be prepared with suitable carriers, excipients, and other agents that provide suitable transport, delivery, tolerability, and the like. A variety of suitable formulations can be found in the formulas known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid-containing (cationic or anionic) vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al."Compendium of excipients for parenteral formulations" PDA, 1998, J Pharm Sci Technol 52:238-311.

[0091] Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, for example, Wu et al., 1987, J. Biol. Chem. 262: 4429-4432). Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes of administration. The composition can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through the epithelial or mucous membrane (for example, the oral mucosa, the rectal and intestinal mucosa, etc.) and can be administered together with other biologically active agents.

[0092] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously using a standard needle and syringe. Furthermore, for subcutaneous delivery, a syringe pen delivery device is easily used to deliver the pharmaceutical composition of the present invention. Such a syringe pen delivery device can be reusable or disposable. A reusable syringe pen delivery device typically uses a replaceable cartridge that contains the pharmaceutical composition. After all the pharmaceutical composition inside 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 syringe pen delivery device can then be reused. A disposable syringe pen delivery device does not have a replaceable cartridge.Rather, a single-use pen delivery device comes prefilled with a pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0093] In some cases, the pharmaceutical composition may be delivered in a controlled release system. In one embodiment, a pump may be used. In another embodiment, polymeric materials may be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system may be placed near the target of the composition, thus requiring only a portion of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249: 1527-1533.

[0094] Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, drip infusions, etc. These injectable preparations can be produced by known methods. For example, the injectable preparations can be produced by, for example, dissolving, suspending, or emulsifying the antibody or its salt described above in a sterile aqueous medium or oil medium commonly used for injection. As an aqueous medium for injection, for example, physiological saline, isotonic solution containing glucose and other additional agents, etc. are used, which can be used in combination with an appropriate solubilizing agent such as alcohol (e.g. ethanol), polyalcohol (e.g. propylene glycol, polyethylene glycol), nonionic surfactant [e.g. polysorbate 80, HCO-50 (polyoxyethylene adduct (50 mol) hydrogenated castor oil)], etc.As an oil medium, for example, sesame oil, soybean oil, etc. are used, which can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection preparation thus obtained is preferably filled into an appropriate ampoule.

[0095] Preferably, the pharmaceutical compositions for oral or parenteral use described above are prepared as unit dosage forms appropriate for the dose of the active ingredient. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0096] Illustrative pharmaceutical compositions containing an anti-IL-4R antibody that can be used in the context of the present invention are disclosed, for example, in U.S. Patent 8,945,559. Administration regimens

[0097] The present invention includes methods comprising administering to a patient an IL-4 / IL-13 pathway inhibitor at a dosing frequency of about four times per week, twice per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently until a therapeutic response is achieved. In some embodiments comprising administering an IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody), a dosage of once per week is used in an amount of about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In some embodiments involving administration of an anti-IL-4R antibody, a dosage of about 25, 50, 100, 150, 200, or 300 mg is administered once every 2 weeks.

[0098] According to some embodiments of the present invention, multiple doses of an IL-4 / IL-13 pathway inhibitor can be administered to a patient over a certain period of time. The methods according to this aspect of the invention include sequentially administering multiple doses of an IL-4 / IL-13 pathway inhibitor to a patient. As used herein, the term "sequential administration" means that each dose of the IL-4 / IL-13 pathway inhibitor is administered to the patient at a different time point, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). The present invention includes methods that include sequentially administering to a patient a single initial dose of an IL-4 / IL-13 pathway inhibitor, followed by administration of one or more secondary doses of the IL-4 / IL-13 pathway inhibitor and, optionally, one or more tertiary doses of the IL-4 / IL-13 pathway inhibitor.

[0099] The terms “initial dose,” “secondary doses,” and “tertiary doses” refer to the temporal sequence of administration of the IL-4 / IL-13 pathway inhibitor. Thus, an “initial dose” is a dose that is administered at the beginning of a treatment regimen (also referred to as an “initial dose”); “secondary doses” are doses that are administered after the initial dose; and “tertiary doses” are doses that are administered after the secondary doses. The initial, secondary, and tertiary doses may contain the same amount of the IL-4 / IL-13 pathway inhibitor, but may typically differ from each other in terms of administration frequency. In some embodiments, however, the amount of the IL-4 / IL-13 pathway inhibitor contained in the initial, secondary, and / or tertiary doses varies relative to each other (e.g., adjusted depending on the situation) over the course of treatment. In some embodiments, the initial dose contains a first amount of the antibody or antigen-binding compound thereoffragment, and each of the one or more secondary doses comprises a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or antigen-binding fragment thereof (the initial dose) is 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x the second amount of the antibody or antigen-binding fragment thereof (the secondary dose). In some embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by doses that are administered less frequently (e.g., "maintenance doses"). For example, an IL-4 / IL-13 pathway inhibitor may be administered to a patient in need thereof at a dose of about 300 to about 600 mg, followed by one or more maintenance doses of about 25 to about 400 mg. In one embodiment, the initial dose and one or more secondary doses each comprise from 10 mg to 600 mg of the IL-4 / IL-13 pathway inhibitor, such as from 100 mg to 400 mg of the IL-4 / IL-13 pathway inhibitor, such as 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 initial dose is 2 times the secondary dose.

[00100] In one exemplary embodiment of the present invention, each secondary and / or tertiary dose is administered 1 to 14 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½ or more) weeks after the immediately preceding dose. The phrase "immediately preceding dose" as used herein means, in a sequence of multiple administrations, a dose of the IL-4 / IL-13 pathway inhibitor that is administered to a patient before the immediately following dose in the sequence, without intermediate doses.

[00101] The methods according to this aspect of the invention may comprise administering to the patient any number of secondary and / or tertiary doses of the IL-4 / IL-13 pathway inhibitor. For example, in some embodiments, the patient is administered onlyone secondary dose. In other embodiments, the patient is administered two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses. Similarly, in some embodiments, the patient is administered only one tertiary dose. In other embodiments, the patient is administered two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses.

[00102] In embodiments including multiple secondary doses, each secondary dose can be administered at the same frequency as the other secondary doses. For example, each secondary dose can be administered to the patient 1-6 weeks after the immediately preceding dose. Similarly, in embodiments including multiple tertiary doses, each tertiary dose can be administered at the same frequency as the other tertiary doses. For example, each tertiary dose can be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which secondary and / or tertiary doses are administered to the patient maychange during the course of treatment.

[00103] The methods of the present invention, in some embodiments, comprise administering to a patient a corticosteroid (CS) 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 concomitant administration of the IL-4 / IL-13 pathway inhibitor and the CS.

[00104] For example, when administered "before" the IL-4 / IL-13 pathway inhibitor, CS may be administered more than 72 hours before, about 72 hours before, about 60 hours before, about 48 hours before, about 36 hours before, about 24 hours before, about 12 hours before, about 10 hours before, about 8 hours before, about 6 hours before, about 4 hours before, about 2 hours before, about 1 hour before, about 30 minutes before, about 15 minutes before, or about 10 minutes before the IL-4 / IL-13 pathway inhibitor. When administered"after" the IL-4 / IL-13 pathway inhibitor, the CS may be administered within 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 IL-4 / IL-13 pathway inhibitor. Administering “concurrently” with the IL-4 / IL-13 pathway inhibitor means that the CS is administered to the patient in a separate dosage form within less than 5 minutes (before, after, or at the same time) of the administration of the IL-4 / IL-13 pathway inhibitor, or is administered to the patient as a single combination dosage composition containing both the CS and the IL-4 / IL-13 pathway inhibitor. Dosage

[00105] The amount of the IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody) administered to the patient in accordance with the methods of the present invention is typically a therapeutically effective amount. Used inAs used herein, the term "therapeutically effective amount" means an amount of an IL-4 / IL-13 pathway inhibitor that results in one or more of: (a) a decrease in the severity or duration of a symptom of eosinophilic esophagitis; (b) a decrease in the number of eosinophils in the esophagus; (c) an increase in esophageal distensibility; (d) a decrease in episodes of dysphagia; (e) the prevention or alleviation of an allergic reaction; and (f) a decrease in the use of or need for conventional allergy therapy (e.g., a decrease in or elimination of the use of antihistamines, decongestants, nasal or inhaled steroids, anti-IgE treatment, epinephrine, etc.).

[00106] In the case of an anti-IL-4R antibody, the therapeutically effective amount may be from about 0.05 to about 600 mg, such as 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, about70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg of an anti-IL-4R antibody. In some embodiments, 300 mg of an anti-IL-4R antibody is administered.IL-4R.

[00107] The amount of the IL-4 / IL-13 pathway inhibitor contained in the individual doses can be expressed as milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the IL-4 / IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody) can be administered to the patient at a dose of from about 0.0001 to about 100 mg / kg of patient body weight. Selected Embodiments

[00108] In embodiment 1, the present invention includes a method of reducing dysphagia, comprising: (a) selecting a patient having at least one of the following characteristics: (i) the patient exhibits ≥1 episode of dysphagia per week; (ii) the patient has previously been treated with high doses of proton pump inhibitors (PPIs); and (iii) the patient has had at least one prior esophageal dilation; and (b) administering a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 / interleukin-13 (IL-4 / IL-13) pathway inhibitor to a patient in need thereof.

[00109] In embodiment 2the present invention includes a method of increasing esophageal compliance, comprising: (a) selecting a patient having at least one of the following characteristics: (i) the patient exhibits ≥1 episode of dysphagia per week; (ii) the patient has been previously treated with high doses of PPIs; and (iii) the patient has had at least one prior esophageal dilation; and (b) administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4 / IL-13 pathway inhibitor to a patient in need thereof.

[00110] In embodiment 3, the present invention includes the method of embodiment 1 or 2, wherein the patient has moderate to severe EoE.

[00111] 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 a therapeutically effective amount of the pharmaceuticala composition comprising an IL-4 / IL-13 pathway inhibitor to a patient in need thereof.

[00112] In embodiment 5, the present invention includes the method of any one of embodiments 1-4, wherein the patient has one or more characteristics selected from the group consisting of: (1) the patient has ≥ 15 eosinophils per high-power field (HPF) in the esophagus before or during treatment ("baseline"); (2) prior treatment with at least one of high-dose PPI, esophageal dilation, corticosteroids, allergen withdrawal, and / or diet modification; (3) the patient has ≥ 1 episode of dysphagia per week; (4) the patient is non-responsive to or resistant to prior treatment with high-dose PPI or esophageal dilation; (5) the patient has a Strauman Dysphagia Inventory (SDI) score ≥ 2; (6) the patient has an eosinophilic esophagitis severity and activity score (EEsAI) of ≥30, ≥40, or ≥50; (7) the patient has had EoE for at least 3 years; (8) the patient has had a history of EoE before or duringadministration of an IL-4 / IL-13 pathway inhibitor, had or was diagnosed with a disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis; and (9) the patient has an elevated level 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).

[00113] In embodiment 6, the present invention includes the method of any one of embodiments 1-5, wherein the administration of the IL-4 / IL-13 pathway inhibitor results in an improvement in an EoE-related parameter selected from the group consisting of: a reduction in the frequency and severity of dysphagia by at least 40% compared to baseline, as measured byStrauman Dysphagia Inventory (SDI); (b) a 3-point decrease from baseline in the SDI score; (c) a greater than 85% decrease from baseline in peak intraepithelial eosinophil counts in the proximal, mid, and / or distal esophagus; (d) an increase from baseline of at least 10% in esophageal distensibility as measured by impedance planimetry; (e) a greater than 50% decrease from baseline in disease severity and extent as measured by the Histologic EoE Score (HSS); and (f) a greater than 30% decrease from baseline in dysphagia as measured by the Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score.

[00114] In embodiment 7, the present invention includes the method of any one of embodiments 1-6, wherein the IL-4 / IL-13 pathway inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to a receptorIL-4 (IL-4R).

[00115] In embodiment 8, the present 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.

[00116] In embodiment 9, the present 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.

[00117] In embodiment 10, the present invention includes the method of any one of embodiments 1-7, wherein the IL-4 / IL-13 pathway inhibitor is administered at an initial dose followed by one or more secondary doses, wherein each secondary dose is administered 1-4 weeks after the immediately preceding dose.

[00118] In embodiment 11, the present invention includes the method of embodiment 10, wherein the initial dose comprises 50-600 mg of an IL-4 / IL-13 pathway inhibitor.

[00119] In embodiment 12, the present invention includes the method of embodimentembodiment 10 or 11, wherein each secondary dose comprises 25-400 mg of an IL-4 / IL-13 pathway inhibitor.

[00120] In embodiment 13, the present invention includes the method of any one of embodiments 10-12, wherein the initial 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.

[00121] In embodiment 14, the present invention includes the method of embodiment 13, wherein each secondary dose is administered one week after the immediately preceding dose.

[00122] In embodiment 15, the present invention includes the method of embodiment 13, wherein each secondary dose is administered 2 weeks after the immediately preceding dose.

[00123] In embodiment 16, the present invention includes the method of any one of embodiments 4-15, wherein the symptom or sign of EoE is selected from the group consisting ofeosinophilic infiltration of the esophagus, thickening of the esophageal wall, food refusal, vomiting, abdominal pain, heartburn, regurgitation, dysphagia, and malnutrition.

[00124] In embodiment 17, the present invention includes the method of any one of embodiments 1-16, characterized in that the patient exhibits an allergic reaction to a food allergen contained in a food product selected from the group consisting of a dairy product, an egg, wheat, soy, corn, fish, seafood, peanuts, tree nuts, beef, chicken, oats, barley, pork, green beans, apples, and pineapples.

[00125] In embodiment 18, the present invention includes the method of any one of embodiments 1-17, wherein the patient exhibits an allergic reaction to a non-food allergen derived from dust, pollen, mold, a plant, a cat, a dog, or an insect.

[00126] In embodiment 19, the present invention includes the method of any one of embodiments 1-18, whereinthat administration of an IL-4 / IL-13 pathway inhibitor results in a reduction in the level of an EoE-associated biomarker in a patient.

[00127] In embodiment 20, the present 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.

[00128] In embodiment 21, the present invention includes the method of any one of embodiments 1-20, 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-1beta 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 dietary control.

[00129] In embodiment 22, the present 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-4.13 antibody, an anti-IL-4 / IL-13 bispecific antibody, an IL-4 receptor (IL-4R) inhibitor, and an anti-IL-4R antibody.

[00130] In embodiment 23, the present invention includes the method of embodiment 22, wherein the IL-4 / IL-13 pathway inhibitor is an IL-4R inhibitor.

[00131] In embodiment 24, the present invention includes the method of embodiment 22, wherein the IL-4 / IL-13 pathway inhibitor is an anti-IL-4 antibody.

[00132] In embodiment 25, the present invention includes the method of embodimentembodiment 22, wherein the IL-4 / IL-13 pathway inhibitor is an anti-IL-13 antibody.

[00133] In embodiment 26, the present 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.

[00134] In embodiment 27, the present invention includes the method of any one of embodiments 1-23, wherein the IL-4 / IL-13 pathway inhibitor is an antibody or antigen-binding fragment thereof that binds to IL-4R and prevents IL-4 and / or IL-13 from interacting with an IL-4 receptor type 1 or type 2.

[00135] In embodiment 28, the present invention includes the method of embodiment 27, wherein the antibody or antigen-binding fragment thereof prevents the interaction of IL-4 with IL-4 receptors type 1 and type 2.

[00136] In embodiment 29, the present invention includes the methodembodiment 28, wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining regions (HCDRs) of the heavy chain variable region (HCVRs) comprising the amino acid sequence of SEQ ID NO: 1 and light chain complementarity determining regions (LCDRs) of the light chain variable region (LCVRs) comprising the amino acid sequence of SEQ ID NO: 2.

[00137] 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 LCDR3comprises the amino acid sequence of SEQ ID NO: 8.

[00138] In embodiment 31, the present 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.

[00139] In embodiment 32, the present invention includes the method of any one 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.

[00140] In embodiment 33, the present invention includes the method of any one of embodiments 1 to 31, wherein the IL-4 / IL-13 pathway inhibitor is dupilumab or a bioequivalent thereof.

[00141] In embodiment 34, the present invention includes the method of embodiment 23, wherein the IL-4R inhibitor isAMG317 or MEDI9314. EXAMPLES

[00142] The following examples are used to provide one skilled in the art with a complete disclosure and description of how to make or use the methods and compositions of the invention and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and variations should be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. Example 1: Clinical Study of Subcutaneously Administered Dupilumab in Adult Patients With Moderate to Severe Active Eosinophilic Esophagitis (EoE)

[00143] This study is a 32-week, double-blind, randomizedA placebo-controlled study 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 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; the 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. Study Objectives

[00144] The primary objective of the study was to evaluate the clinical efficacy of repeated subcutaneous (SC) doses of dupilumab compared to placebo for symptom relief in adult patients with active, moderate, or severe EoE.

[00145] The secondary objectives of the study were: (1) to evaluate the safety, tolerability, and immunogenicity of SC doses of dupilumab in adult patients with active, moderate, or severe EoE; (2) to evaluate the effect of dupilumab oneosinophilic infiltration of the esophagus; and (3) to evaluate the pharmacokinetics (PK) of dupilumab in adult patients with EoE.

[00146] The exploratory objective of the study was to evaluate the effect of dupilumab on other pathological features of esophageal biopsy associated with EoE.Study Design

[00147] 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.

[00148] After providing informed consent, patient eligibility was assessed at the screening visit (which must occur between day -35 and day -1). Patients who met the eligibility criteria underwent day 1 baseline assessments. Patients were randomized 1:1 to receive dupilumab or placebo during a 12-week double-blind treatment phase. After the 12-week double-blind treatment phase, patients did not receive study medication.drug for an additional 16 weeks.

[00149] Patients received concomitant medications (except prohibited drugs [see below]) as needed while continuing treatment during the study. Efficacy, safety, and laboratory assessments were performed, and samples were collected at specific time points to determine dupilumab concentrations and potential anti-drug antibody (ADA) response to dupilumab, as well as study samples.Study Population

[00150] The target population included adult (18 to 65 years) men or women with active EoE.

[00151] Inclusion Criteria: A patient had to meet the following criteria to be eligible for inclusion in the study:(1) Male or female, 18 to 65 years of age;(2) Documented diagnosis of EoE by endoscopy before or at screening. Note: Should include demonstration of intraepithelial eosinophilic infiltration (peak cell count ≥15 eosinophils / power field [400X]) from specimensesophageal biopsy from endoscopy performed no more than 2 weeks after at least 8 weeks of treatment with high-dose (or twice daily) proton pump inhibitors (PPIs);(3) Patient-reported history of an average of at least 2 episodes of dysphagia (with solid anti-inflammatory therapy) per week in the 4 weeks prior to screening and an average of at least 2 episodes of documented dysphagia per week in the weeks between screening and baseline; patient-reported dysphagia defined as difficulty swallowing solid foods or sticks of solid food;(4) Must remain on a stabilized diet for at least 6 weeks prior to screening and during the course of the study; a stable diet is defined as no initiation of a single or multiple elimination diet or reintroduction of previously excluded food groups;(5) SDI PRO score ≥5 at screening and baseline;(6) Documented history or presence of 1 ormore than any of the following: allergic disease (e.g., allergic asthma, allergic rhinitis, AD, or food allergy), peripheral eosinophil count ≥0.25 billion / L, total serum immunoglobulin E (IgE) ≥100 kU / L;(7) Willingness and ability to comply with all clinic visits and study-related procedures; be able to understand and complete study-related questionnaires; provide signed informed consent; and(8) Endoscopy with photographs taken at screening demonstrating intraepithelial eosinophilic infiltrate (peak cell count ≥15 eosinophils / field of view) in at least 2 of 3 esophageal biopsies (proximal, middle, or distal).

[00152] Exclusion criteria: A patient who met any of the following criteria was ineligible to participate in this study: (1) Prior participation in a clinical trial of dupilumab (anti-IL-4R antibody); (2) Other causes of esophageal eosinophilia or the followingdiseases: hypereosinophilic syndromes, 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) any esophageal stricture that cannot be passed with a standard adult diagnostic endoscope (9 to 10 mm) or any critical esophageal stricture that requires dilation at screening; (5) history of bleeding or esophageal varices; (6) current use of aspirin, nonsteroidal drugs, or anticoagulants within 2 weeks prior to screening. Patients should not stop taking these medications solely to become eligible for this study; (7) Treatment with the investigational medicinal product for 2 months or 5 half-lives (if known), whichever is longer, prior to screening; (8) Usesystemic corticosteroids within 3 months or topical corticosteroids for oral administration within 6 weeks prior to screening; (9) Use of inhaled or nasal corticosteroids within 3 months prior to screening and during the study, except a stable dose for at least 3 months prior to biopsy screening that 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 a stable dose for at least 1 year prior to screening; (12) The following treatments within 3 months prior to the screening visit, or any other condition that, in the opinion of the investigator, is likely to require such treatment(s) within 3 months of study treatment: systemic immunosuppressants / immunomodulators (e.g., omalizumab, cyclosporine, mycophenolate mofetil, interferon-gamma[IFN-γ], Janus kinase inhibitors, azathioprine, methotrexate, leukotriene inhibitors [except at a stable dose for at least 3 months before screening], etc.) (13) with diagnosed active parasitic infection, suspected parasitic infection if no clinical and (if necessary) laboratory assessment excluded active infection before randomization; (14) chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 1 month before screening; (15) use of oral antibiotics / anti-infectives within 2 weeks before screening; (16) Known or suspected immunosuppression, including a history of opportunistic invasive infections (e.g., tuberculosis, non-tuberculous mycobacterial infections, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite resolution of the infection, or other recurrent infections with abnormal frequency, prolongedor prolonged infections suggesting a weakened immune state, in the opinion of the investigator; (17) history of known human immunodeficiency virus (HIV) infection; (18) positive or indeterminate hepatitis B surface antigen (HBsAg) or hepatitis C antibody at screening; (19) elevated transaminase (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) greater than 3 times the upper limit of normal (> 3x the upper limit of normal [ULN]) at screening; (20) history of malignancy within 5 years prior to screening, with the exception of completely healed in situ carcinoma of the cervix and completely healed and eliminated non-metastatic squamous cell or basal cell carcinoma of the skin; (21) Patients' history of alcohol or drug abuse within 6 months prior to screening; (22) Any other medical or psychological condition, including relevant laboratory abnormalities at screening,which, in the opinion of the investigator, involve a new and / or poorly understood disease, may pose an unreasonable risk to the study patient such that his / her participation in this clinical trial may render the patient's participation unreliable or may interfere with the evaluation of the study. The specific justification for patients excluded by this criterion will be noted in the study documents (chart notes, case report form [CRF], etc.); (23) severe concomitant disease(s) that, in the opinion of the investigator, would adversely affect 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 a live (attenuated) vaccine within 3 months prior to screening; (26) the patient or his / her immediate family members are members of the study cohort; (27) women who are pregnant or lactating, or women planning to become pregnant orbreastfeeding during the study; (28) Women unwilling to use adequate birth control if they are of reproductive potential* and sexually active. Study Treatment

[00153] Study Drug: Dupilumab SC, 600 mg loading dose on day 1 followed by weekly doses of 300 mg from week 1 to week 11.

[00154] Placebo: Placebo (same formulation as dupilumab without the active substance, anti-IL-4R monoclonal antibody) SC, volume matching the dupilumab loading dose on day 1, followed by weekly doses matching the weekly dupilumab dose volume from weeks 1 to 11.

[00155] Patients received dupilumab SC 300 mg or matching placebo qw during the 12-week double-blind treatment phase. Patients received 2 injections (initial dose 300 mg, then loading dose 300 mg) on ​​day 1, followed by weekly injections. Approved (concomitant) medicinal products

[00156] During the study,Concomitant medications were allowed. This included contraceptive use, a stable dose of proton pump inhibitors (PPIs) (patients who were using PPIs at screening were not stopped or changed in their dosing regimen until the end of treatment [EOT]); a stable dose (at least 3 months prior to screening) of systemic leukotriene inhibitors, topical, nasal and / or inhaled corticosteroids; oral antihistamines for any duration; and oral antibiotics for up to 2 weeks. Drugs and procedures with restricted use

[00157] Drugs with restricted use during the study period included: (1) Drugs used to treat EoE (these were considered rescue medications): topical corticosteroids for oral administration, systemic corticosteroids, initiation or dose change of systemic leukotriene inhibitors, topical, nasal and / or inhaled corticosteroids, and systemic treatment of EoE withwith an immunosuppressive / immunomodulatory agent (including, but not limited to, omalizumab, cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, IFN-γ, or other biologics); (2) Allergen immunotherapy (SCIT and SLIT were allowed if the dose had been stable for 1 year or more; however, OIT was prohibited); (3) Patients who had not used a PPI within 8 weeks prior to screening were prohibited from starting PPI therapy until the EOT visit; (4) Treatment with live (attenuated) vaccines (Varicella (chickenpox), FluMist-Flu, Intranasal influenza, Measles (rubeola), combined measles-mumps-rubella, combined measles-mumps-rubella-varicella, mumps, oral polio (Sabin), oral typhoid, rubella, smallpox (cowpox), yellow fever, tuberculosis vaccine (Bacille Calmette-Guerin), chickenpox (shingles), rotavirus); and (5) treatmentstudy medicinal product (except dupilumab)

[00158] The following concomitant procedures were prohibited during study treatment (through week 12): (1) Major elective surgical procedures; (2) esophageal dilation (considered an emergency procedure); and (3) dietary change (patients were required to remain on a stable diet for at least 6 weeks prior to screening and during the study; a stable diet was defined as no initiation of a single or multiple elimination diet or reintroduction of previously excluded food groups). Study Endpoints

[00159] The primary efficacy endpoint was: Change in Strauman Dysphagia Inventory (SDI) score as measured by patient reports (PROs) from baseline to week 10.

[00160] Secondary endpoints were: percentage change in weekly eosinophilic esophagitis activity score (EEsAI) PRO score from baseline to 10weeks; Change in weekly EEsAI PRO score from baseline to week 10; Percent change in weekly EEsAI PRO score from baseline to week 12; 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; Change in SDI PRO score from baseline to week 12; Change in Adult Eosinophilic Esophagitis Quality of Life (EoE-QOL-A) (questionnaire) from baseline to week 12; Percentage of patients with SDI PRO response at week 10; where response is defined as a decrease of at least 3 points on the SDI compared to baseline; Percentage of patients who achieved an improvement in EEsAI score ≥40% from baseline to week 10; Percentage change in total peak intraepithelial eosinophils / p / zr (400X) of the esophagus from baseline to week 12; Change in EndoscopicEosinophilic Esophagitis Reference Evaluation (EoEEREFs) (an endoscopic visual anatomical assessment) from baseline to week 12; Percentage of patients using salvage medications or procedures (eg, esophageal dilation) by week 12; and incidence of treatment-emergent adverse events (TEAEs).

[00161] The study efficacy endpoints were: change in mean esophageal intraepithelial eosinophil count (e / pf) [calculated using peak values ​​for each esophageal site] from baseline to week 12; Proportion of patients achieving esophageal intraepithelial eosinophils <1 e / pf at week 12; Change in Collins histology score from baseline to week 12; and change in esophageal distensibility plateau measured by functional luminal imaging from baseline to week 12.Procedures and Assessments

[00162] Screening / Baseline Procedures: The following procedures were performedonly at screening and / or baseline visit for the sole purpose of determining study eligibility or baseline cohort characteristics: serum FSH (to confirm menopausal status), total serum IgE, HBsAg, and hepatitis C antibodies.

[00163] Efficacy procedures. Efficacy was assessed during the study at specific clinic visits using patient-reported outcomes (PROs), including the Straumann Dysphagia Assessment Scale (SDI), the Eosinophilic Esophagitis Activity Score (EEsAI), and the Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QOL-A), as well as esophageal biopsy and photographs (endoscopy procedure). Measurement of inflammatory and remodeling features of the esophagus based on the Eosinophilic Esophagitis Erosion Rating Scale (EoE-EREFS) was included as part of the endoscopy procedure. The Endolumenal Functional Lumen Imaging (EndoFLIP) procedure forEsophageal distensibility measurements were performed during endoscopy procedures. The EoE Histologic Score (HSS) was used to measure 8 histologic features of EoE. The Straumann Dysphagia Scale - Patient-Rated Outcome

[00164] is an unvalidated PRO that has been used in clinical trials to determine the frequency and severity of dysphagia (Straumann 2010). The SDI has a 1-week assessment period. The frequency of dysphagia episodes is assessed 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, and the intensity of dysphagia episodes is assessed on a 6-point scale: 0=swallowing without limitation, 1=mild resistance, 2=mild gagging with breath holding, 3=short period of obstruction requiring intervention (e.g., drinking, breathing), 4=long period of obstruction, relieved only by vomiting, 5=long-term complete obstruction requiring endoscopic intervention. The overall SDI scoreranges from 0 to 9. In the Straumann study, clinical response (improvement) was defined as a decrease in the SDI score of at least 3 points from baseline.

[00165] This assessment was completed by the patient weekly electronically in a questionnaire from the beginning of screening until the end of the study or early termination. The items used to quantify the SDI were included in the EEsAI / SDI.Eosinophilic Esophagitis Activity Index - Patient-Assessed Outcome

[00166] The EEsAI is an unvalidated multimodular index under development at the University Hospital Inselspital Bern, Switzerland (Schoepfer 2014), a member of the international EEsAI study group. The EEsAI PRO module (questionnaire) used in this study includes items related to the intensity and frequency of dysphagia, the effect of specific food groups on dysphagia symptoms, and other symptoms independent of food or drink intake (e.g., heartburn, acid regurgitation, and chest pain).cell). The EEsAI PRO total score ranges from 0 to 100 (Figure 1), with higher scores indicating worse symptoms. The assessment consists of 5 parts: frequency of swallowing problems, duration of swallowing problems, pain on swallowing, a visual dysphagia question, and avoidance, modification, and slow feeding (AMS). The EEsAI PRO uses 24-hour and 1-week assessment periods.

[00167] This assessment was completed by the patient electronically on a daily and weekly questionnaire from the beginning of screening until the end of the study or early termination.Eosinophilic Esophagitis Quality of Life Questionnaire in Adults Patient-Assessed Outcome

[00168] The EoE-QOL-A questionnaire is a validated measure of health-related quality of life in patients with EoE (Taft 2011). The instrument used in this study, the EoE-QOL-A v.3.0, includes 30 items related to established domains such as social functioning, emotional functioning, and the impact of illness ondaily life. The EoE-QOL-A has a 1-week assessment period. Items are rated on a 5-point scale: “Not at all,” “A little,” “Moderately,” “Very little,” and “Extremely.”

[00169] This rating was recorded by the patient on a questionnaire at baseline and then monthly until the end of the study or early termination. Endoscopy with Esophageal Biopsy and Photographs

[00170] Esophageal biopsies were obtained by endoscopy at screening and week 12 visits. Screening endoscopy was performed during the screening period to allow results to be obtained by day -1 to assess eligibility. At each time point, 9 mucosal biopsies were collected from 3 sections of the esophagus: 3 proximal, 3 middle, and 3 distal. Two samples from each section were used for histology (required for study inclusion criteria, as well as for a secondary endpoint). To participate in the study, patients had to have a peakIntraepithelial eosinophil count ≥15 eos / field of view (400X) in at least 2 of the 3 selected esophageal regions. Change in peak eos. esophageal / field of view (400X) from baseline to week 12 was a secondary endpoint; this was determined by counting eosinophils in the most inflamed areas of each esophageal region sampled at each time point and calculating the change in the peak count at each site obtained at baseline compared with the count at week 12. The exploratory endpoint was the change in the mean of all three peak counts, i.e., the peak count in each of the 3 esophageal regions for each patient at each time point (screening and week 12). Tissue blocks remaining after histological evaluation were donated for research purposes.

[00171] EoE-EREFS (edema, rings, exudates, furrows, strictures) was used to measure endoscopically identified EoE signs of inflammation andEsophageal mucosal remodeling. This instrument includes 17 items related to the presence and severity of esophageal features. Specific esophageal features include: 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 plaques - absent, mild, severe), striations (vertical lines down the esophagus - absent, present); edema (loss of vascular markings on the mucosa - absent, present); "cirrel-paper" esophagus (absent, present); final gross appearance including all endoscopically identified EoE findings (i.e., fixed rings, strictures, whitish exudate, striations, edema, and "cirrel-paper" mucosa). In addition, mucosal changes associated with gastroesophageal reflux disease have also been reported withusing the Los Angeles erosions classification system (no erosions or LA classification A, B, C, D). Esophageal EoE characteristics were analyzed based on the EoE-EREFS, a validated rating scale for inflammatory and remodeling features of the disease, using both total scores and scores for each individual feature (Hirano 2014). The modified EREFS score in this study was based on an overall score range of 0-8; where higher scores indicate greater deterioration. Each score included: Edema: 0-1; Rings: 0-3; Exudates: 0-2; Furrows: 0-1; and Strictures: 0-1, yielding a total possible score of 8.

[00172] Esophageal distensibility assessment using an endoluminal functional imaging probe (EndoFLIP, Crospon, Ireland) was also performed to measure luminal diameter and esophageal pressure (e.g., esophageal rigidity), with measurements taken as part of the endoscopy procedure performed at screening and at 12week. The EndoFLIP device is a catheter-based procedure that measures the cross-sectional area at multiple locations along the esophagus while simultaneously recording intraluminal pressure during volumetric esophageal distension. Analysis of the cross-sectional area versus esophageal pressure 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). Furthermore, esophageal compliance has been associated with the consequences of both esophageal transit obstruction and the need for esophageal dilation (Nicodème 2013).

[00173] The EoE-HSS generated separate scores for disease severity (class) and extent (stage). The assessment was used to measure 8 histological features (parameters) of EoE from 3 different sections (proximal, mid, and distal) of the esophagus (Collins, et al. 2017). The eight parameters include: eosinophil density,Basal zone hyperplasia, eosinophil abscesses, eosinophilic superficial layers, dilated intercellular spaces, superficial epithelial changes, nonkeratized cells, and lamina propria fibrosis. A scale of 0 to 3 was used for each parameter, both class and stage (0 = least inflamed, normal). The total score range for each compartment in this study was 0-21 (excluding the lamina propria parameter). Lamina propria assessment was excluded given that 50% of biopsy specimens would not be deep enough to assess the lamina propria. The total score per patient was calculated as (0-21 score x 3 compartments = total possible score of 63 per time point). Two scores were obtained for each patient at each time point, one each for class (severity) and stage (grade).

[00174] Photographs were taken at the sites as part of the endoscopic procedure and biopsy collection.

[00175] Safety procedures: AE is any unwanted eventa medical event in a patient administered an investigational medicinal product that may or may not have a causal relationship with the investigational medicinal product. Therefore, an AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or illness that is temporally associated with the use of an investigational medicinal product, whether or not it is considered related to the investigational medicinal product. An AE also includes any worsening (i.e., any clinically significant change in the frequency and / or intensity) of a pre-existing condition that is temporally associated with the use of an investigational medicinal product.

[00176] A serious adverse event (SAE) is any untoward medical event that, at any dose, results in death, is life-threatening, requires inpatient hospitalization, results in permanent or significant disability / incapacity, is congenitalabnormality / congenital defect and / or is a major medical event (such as one that may pose a threat to the patient or may require intervention to prevent 1 of the other serious outcomes listed above).

[00177] Safety and tolerability were assessed using physical examinations, vital signs, electrocardiograms (ECG), clinical laboratory tests, and clinical assessments. Patients were asked to monitor all AEs that occurred from the time of informed consent until their last study visit.

[00178] Pharmacokinetic and Antibody Procedures: Serum samples were collected for dupilumab level analysis, and PK parameters were calculated using dupilumab concentration data. Serum samples were collected for ADA analysis and study assays. Results

[00179] Baseline Characteristics: Patients were randomized 1:1 to receive a subcutaneous (SC) loading dose of 600 mgdupilumab or placebo SC followed by weekly SC administration of 300 mg dupilumab or placebo SC during a 12-week double-blind treatment phase. Randomization was stratified by baseline Strauman Dysphagia Inventory (SDI) PRO score (≥5 and ≤7 vs. >7). Baseline demographic and disease characteristics were generally balanced between the two groups (Tables 1–2), with the exception of mean total IgE (dupilumab 217.8 kU / L; placebo 468.2 kU / L). Table 1: Summary of baseline demographic characteristics Placebo (N=24) 300 mg dupilumab qw (N=23) Age, mean (SD), years 36,1 (12,75) 33,1 (8,70) Age group, n (%) ≥18 - <40 years 15 (62,5%) 16 (69,6%) ≥40 - <65 years 9 (37,5%) 7 (30,4%) ≥65 years old 0 0 Male gender, n (%) 10 (41,7%) 13 (56,5%) Race: White, n (%) 21 (87,5%) 23 (100%) BMI (average value kg / m2) 30 27,7 Table 2: Summary of baseline disease characteristics Placebo (N=24) 300 mg dupilumab qw (N=23) Age at onset of EoE, n (%) 0-18 years old 4 (16,7%) 7 (13,0%) 19-24 years old 5 (20,8%) 10 (21,7%) 25-50 years old 13 (54,2%) 28 (65,2%) >50 years 2 (8,3%) 0 Duration of EoE years 5,0 3,6 Blood eosinophils (SD) billion / l 0,43 (0,3) 0,31 (0,2) Mean total IgE (SD) kU / L 486,2 (900,7) 217,8 (288,8) SDI mean score (SD), (0-9) 6,4 (1,0) 6,4 (1,0) EEsAI Weekly Score (0-100) 62,2 62,0 Mean total peak eosinophil count / field of view (SD) 101,1 (57,1) 102,1 (53,5) EoE-specific histological features grading scale (0-63) 27,4 27,9 # dysphagia / week between screening and baseline 12,4 13,7 EREF endoscopy score (0-9) 4,3 3,9 Prior treatment with high-dose PPI, n (%) 24 (100%) 23 (100%) Previous use of topical corticosteroids, n (%) 20 (83,3) 18 (78,3) Previous dilation, n (%) 10 (41,7) 11 (47,8) Number of previous esophageal dilations (SD) 3,9 (3,3) 5,7 (8,0) Any concomitant disease, n (%) 19 (79,2) 20 (87,0)

[00180] Both groups showed high levels of atopic disease (Table 3).Table 3: Summary of personal history of EoE / allergic diseases Placebo (N=24) 300 mg dupilumab qw (N=23) Patients with a history of at least one condition 24 (100%) 23 (100%) Food allergy 17 (70,8%) 14 (60,9%) Allergic rhinitis 15 (62,5%) 16 (69,6%) Other allergies (medicines, animals, plants, mold, dust mites, etc.) 12 (50,0%) 14 (60,9%) Asthma 9 (37,5%) 11 (47,8%) Chronic sinusitis 8 (33,3%) 2 (8,7%) Urticaria 6 (25,0%) 7 (30,4%) Atopic dermatitis 5 (20,8%) 3 (13,0%) Allergic conjunctivitis 3 (12,5%) 3 (13,0%)

[00181] Efficacy Results: Table 4 summarizes the primary and secondary endpoint outcomes. Dupilumab significantly improved subjective EoE measures reflected by dysphagia, as well as objective histologic and endoscopic disease measures in EoE, compared with placebo. No patients received rescue medications / procedures during the 12-week double-blind treatment period. Table 4: Results - Primary and Secondary Endpoints* The end point Placebo1 (N=24) 300 mg dupilumab qw1 (N=23) Difference in mean values ​​determined by the LS method compared with placebo (95% CI) P-value** Primary efficacy endpoint Change in SDI score from baseline to week 10 (range 0-9) N=14 N=17 -1,3 (0,6) -3,0 (0,5) -1,7 (-3,22, -0,16) 0,0304 Secondary efficacy endpoint % Change in weekly EEsAI score from baseline to week 10 (range 0-100) N=13 n-17 -11,3 (9,9) -34,6 (9,1) -23,2 (-49,68, 3,21) 0,0850 Change in weekly EEsAI score from baseline to week 10 (range 0-100) N=13 N=17 -9,0 (5,6) -22,9 (5,0) -13,9 (-28,54, 0,78) 0,0635 % Change in weekly EEsAI score from baseline to week 12 (range 0-100) N=8 N=15 -3,3 (12,7) -37,0 (11,2) -33,6 (-68,83, 1,54) 0,0608 Change in weekly EEsAI score from baseline to week 12 (range 0-100) N=8 N=15 -5,0 (7,1) -26,1 (5,9) -21,1 (-40,42, -1,86) 0,0318 % Change in SDI score from baseline to week 10 (range 0-9) N=14 N=17 -18,6 (9,0) -45,0 98,4) -26,5 (-50,52, -2,39) 0,0312 Change in SDI score from baseline to week 12 (range 0-9) N=9 N=16 -2,2 (0,7) -2,9 (0,6) -0,8 (-2,48, 0,96) 0,3830 % Change in SDI score from baseline to week 12 (range 0-9) N=9 N=16 -31,8 (10,7) -42,8 (8,6) -11,0 (-37,46, 15,47) 0,4147 Change in EoE-QOL-A PRO cumulative from baseline to week 12 (range 1-5) N=21 N=23 0,47 (0,14) 0,80 (0,14) 0,33 (-0,05, 0,72) 0,0910 Proportion of patients with at least a 3-point reduction in SDI score from baseline to week 10 N=14 N=17 3 (12,5%) 9 (39,1%) 26,6 (-3,04, 51,05) 0,049 Proportion of patients who achieved ≥40% improvement in EEsAI PRO from baseline to week 10 N=13 N=17 2 (8,3%) 6 (26,1%) 17,8 (-11,54, 43,55) 0,1365 % Change in total peak of esophageal intraepithelial eosinophils / per field of view (EO / p / zr) (400X) from baseline to week 12 N=22 N=22 15,1 (12,5) -91,8 (12,3) -107 (-141,4, -72,46) <0,0001 1n represents the number of patients with actual observed values ​​for both baseline and follow-up values*For continuous variables, multiple imputation of missing data / ANCOVA was used, LS (SE) was presented; for binary variables, patients with missing data were considered as non-responders and Fisher's exact test was used for comparison, the number and % of responders are presented.**For secondary endpoints, all p values ​​were nominal

[00182] Dupilumab improved the Strauman Dysphagia Inventory (SDI) score compared with placebo (-3 vs -1.3, P=0.0304; 45.05% vs 18.59%, P=0.0312) at week 10 (Table 4, Figure 2). Thirty-nine percent of patients receiving dupilumab achieved a ≥3 reduction in SDI compared with 12.5% ​​in the placebo group at week 10. At both weeks 10 and 12, dupilumab improved both the frequency and severity of dysphagia as measured by the SDI (Figure 3).

[00183] Dupilumab numerically reduced EEsAI (-34.6% vs -11.3%, P=0.085) compared with placebo through week 10 (Table 4, Figure 4).

[00184] Dupilumab significantly reduced peak eosinophil counts (EOs / P / E) from baseline to week 12 compared with placebo [-94.1 (-91.8%) vs -7.4 (+15.1%), P<0.0001] (Tables 4 and 6). Reductions in tissue eosinophil infiltration were observed in all patients in the dupilumab group (Table 5). The effect of dupilumab was similar for the proximal, mid, and distal esophagus. Table 5: Responder analysis. Peak number of eosinophils (eosin / p / zr) at week 12 Proportion of patients with response at week 12, n (%) 300 mg dupilumab Placebo P value <1 3 (13) 0 (0) 0,1092 <6 14 (60,9) 0 (0) <0,0001 <15 18 (78,3) 0 (0) <0,0001

[00185] Dupilumab significantly reduced EREFS relative to placebo at week 12 (LS mean change p=0.0006, LS mean change p=0.0004) (Table 4). Dupilumab significantly reduced the total EREFS score as well as the exudates and sulci subcomponents, with trends observed for the edema, rings, and stricture subcomponents (Figure 5).

[00186] Dupilumab significantly reduced both the total EoE-HSS class and stage scores from baseline to week 12 compared with placebo (P < 0.001 compared with placebo) (Table 6; Figures 6 and 7). Dupilumab significantly reduced both grade (severity) and stage (extent) scores for basal layer hyperplasia (BZH), eosinophilic inflammation (EI), eosinophilic superficial layer (SL), and eosinophilic abscess (EA) in the proximal, mid, and distal regions (Figures 8 and 9).In addition, dupilumab reduced grade and stage scores for dilated intracellular spaces and surface changes in all compartments and in distal apoptotic epithelial cells (Figures 10 and 11).

[00187] Dupilumab significantly improved esophageal distensibility at week 12 compared with placebo (Table 6). More patients receiving dupilumab experienced an increase (improvement) in the distensibility plateau compared with placebo (Figure 12).

[00188] Table 6 summarizes the effects of dupilumab on patient-reported outcomes, dysphagia, and clinician-assessed objective measures.Table 6: Efficacy of dupilumab on subjective and objective EoE measures. PBO (N=24) Dupilumab 300 mg qw (N=23) Difference in means determined by the least squares method versus PBO (95% CI) SDI score baseline score, mean (± SD) 6,4 (1,01) 6,4 (1,04) Week 10 n=14 n=17 Change in mean square values ​​from baseline (± SE) −1,3 (0,6) −3,0 (0,5) −1,7 (−3,2, −0,2)* EEsAI score baseline score, mean (± SD) 62,2 (16,45) 62,0 (18,36) Week 10 n=13 n=17 % change in mean square values ​​from baseline (± SE) -11,3 (9,9) -34,6 (9,1) -23,2 (-49,7, 3,2)# Peak intraepithelial eosinophil count (EOC / pf) baseline score, mean (± SD) 101,1 (57,1) 102,1 (53,5) Week 12 n=22 n=22 Change in mean square values ​​from baseline (± SE ) -7,4 (9,61) -94,1 (9,52) % change in mean square values ​​from baseline (± SE) 15,1 ( 12,5) −91,8 ( 12,3) −106,9 (−141,4, −72,5)*** Patients with a response of <6 eos / field of vision, n (%) 0,0 14 (60,9) Patients with a response of <15 eosin / field of view, n (%) 0,0 18 (78,3) EoE-EREFS score baseline score, mean (± SD) 4,3 (1,46) 3,9 (1,87) Week 12 n=22 n=23 Change in mean square values ​​from baseline (± SE) −0,3 (0,3) −1, 9 (0,3) −1,6 (−2,5, −0,7)*** EoE-HSS baseline score, mean (± SD) 27,4 (6,46) 27,9 (6,05) Total score - class (severity) Week 12 n=20 n=21 All departments, % change in mean square values ​​from baseline (± SE) 3,9 (6,6) −64,2 (6,4) −68,1 (−85,8, −50,3)*** Distal, % change in mean square values ​​from baseline (± SE) 2,7 (5,3) −57,0 (5,3) −59,7 (−74,3, −45,1)*** Mean, % change in standard deviations from baseline (± SE) −8,1 (7,0) −70,8 (6,8) −62,7 (−81,7, −43,7)*** Proximal, % change in mean square values ​​from baseline (± SE) 66,1 (27,4) −50,2 (24,5) −116,3 (−188,0, −44,5)*** Total score - stage (degree) Week 12 n=20 n=21 All departments, % change in mean square values ​​from baseline (± SE) −3,5 (5,0) −58,1 (4,7) −54,6 (−68,1, −41,0)*** Distal, % change in mean square values ​​from baseline (± SE) 5,1 (6,3) −50,6 (6,3) −55,6 (−73,2, −38,1)*** Mean, % change in standard deviations from baseline (± SE) −18,4 (5,7) −62,0 (5,5) −43,5 (−59,1, −28,0)*** Proximal, % change in mean square values ​​from baseline (± SE) 43,1 (21,6) −46,9 (19,2) −90,0 (−146,5, −33,5)*** Plateau of tensile strength (mm) Baseline, mean (±SD) 17,60 (2,879) 18,66 (3,799) Week 12 n=12 n=12 % change in mean square values ​​from baseline (± SE) −6,2 (2,7) 11,8 (2,7) 18,0 (10,9, 25,2)*** * P < 0.05, *** P < 0.001, # = P=0.085 vs. PBO. The SDI is a 9-item measure of dysphagia; score range is 0-9 with higher scores indicating worse symptoms. The EEsAI is a 5-item measure of dysphagia; score range is 0-100 with higher scores indicating worse symptoms. The EoE-specific histologic features grading scale (EoEHSS) measures eosinophil density, basal zone hyperplasia, eosinophil abscesses, surface eosinophilic stratification, superficial epithelial changes, nonkeratizing epithelial cells, and dilated interstitial spaces. The lamina propria was excluded from analysis as ~50% of captured biopsies were not deep enough for assessment. Esophageal distensibility plateau was measured using a functional esophageal sphincter imaging probe (EndoFLIP, ® Crospon), a probe using impedance planimetry. Continuous efficacy endpoints were analyzed in the full analysis set (FAS) withusing multiple imputation of missing data (MI) followed by analysis of covariance (ANCOVA) with treatment group as a fixed effect and baseline SDI and corresponding baseline value as covariates. LS, ordinary least squares; qw, weekly.

[00189] 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%). Conclusion

[00190] Compared with placebo, dupilumab demonstrated a statistically significant reduction in the primary endpoint, change from baseline in the Strauman Dysphagia Inventory (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 subjectivedysphagia measures, including EEsAI (at week 10) and EOE-QOL (at week 12). Finally, statistical improvements were noted in both histologic and visual endoscopic objective assessments of disease activity, including the percentage change from baseline in peak eosinophils and the absolute change from baseline in eosinophilic esophagitis features such as edema, rings, exudate, furrows, and stricture (EoE-EREFS) at week 12. Dupilumab treatment was generally safe and well tolerated. The most common TEAEs were mild ISR and viral upper respiratory tract infections and nasopharyngitis.

[00191] The present invention should not be limited in scope to the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures.It is intended that such modifications fall within the scope of the appended claims. --->SEQUENCE LISTING <110> Regeneron Pharmaceuticals, Inc.Sanofi Biotechnology <120> Treatment options for active eosinophilic esophagitis <130> 10375WO01 <160> 11 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 124 <212> Protein <213> Artificial sequence <220> <223> HCVR <400> 1Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr20 25 30Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40 45Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys85 90 95Ala Lys 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<220> <223> HCDR3 <400> 5Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu1 5 10 15Asp Val <210> 6 <211> 11 <212> Protein <213> Artificialsubsequence <220> <223> LCDR1 <400> 6Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr1 5 10 <210> 7 <211> 3 <212> Protein <213> Artificial sequence <220> <223> LCDR2 <400> 7Leu Gly Ser1 <210> 8 <211> 9 <212> Protein <213> Artificial sequence <220> <223> LCDR3 <400> 8Met Gln Ala Leu Gln Thr Pro Tyr Thr1 5 <210> 9 <211> 451 <212> Protein <213> Artificial sequence <220> <223> HC <400> 9Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr20 25 30Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40 45Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys85 90 95Ala Lys Asp Arg Leu Ser Ile Thr Ile 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310 315 320Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser325 330 335Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln ProArg Glu Pro Gln340 345 350Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val355 360 365Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val370 375 380Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro385 390 395 400Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr405 410 415Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val420 425 430Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu435 440 445Ser Leu Gly450<210> 10<211> 219<212> Белок<213> Искусственная последовательность<220><223> LC<400> 10Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser20 25 30Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro50 55 60Asp Arg 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Claims

1. A method for reducing dysphagia in a subject having eosinophilic esophagitis (EoE), comprising: administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 / interleukin-13 (IL-4 / IL-13) pathway inhibitor, wherein the IL-4 / IL-13 pathway inhibitor is an antibody that binds to IL-4Rα, wherein the antibody comprises a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 2; where the subject has a baseline Strauman Dysphagia Inventory (SDI) score ≥5.

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

3. The method according to paragraph 1 or 2, characterized in that the subject is ≥18 years old.

4. The method according to any one of paragraphs 1-3, characterized in that the subject has previously been treated with a proton pump inhibitor (PPI).

5. The method according to any one of paragraphs 1-4, characterized in that the subject had at least one previous dilation of the esophagus.

6. The method according to any one of paragraphs 1-5, characterized in that the subject has had EoE for at least 3 years.

7. The method according to any one of paragraphs 1-6, characterized in that the subject being treated: (1) has a baseline SDI score ≥7; and / or (2) has a score on the eosinophilic esophagitis severity and activity index (EEsAI) scale ≥50.

8. The method according to any one of paragraphs 1-7, characterized in that the administration of the IL-4 / IL-13 pathway inhibitor results in an improvement in at least one parameter selected from the group consisting of: (a) a reduction in the frequency and severity of dysphagia by at least 40% from the baseline SDI score; (b) a decrease of ≥3 points from baseline in the SDI score; and (c) a decrease of more than 30% from baseline in the Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score.

9. The method according to any one of claims 1-8, characterized in that the IL-4 / IL-13 pathway inhibitor is administered at a dose of from about 50 to about 600 mg.

10. The method according to any one of claims 1-9, characterized in that the IL-4 / IL-13 pathway inhibitor is administered at a dose of about 300 mg.

11. The method according to any one of claims 1-8, characterized in that the IL-4 / IL-13 pathway inhibitor is administered in an initial dose, followed by one or more secondary doses, wherein each secondary dose is administered 1-4 weeks after the immediately preceding dose.

12. The method according to claim 11, characterized in that the initial dose contains 50-600 mg of an IL-4 / IL-13 pathway inhibitor.

13. The method according to claim 11 or 12, characterized in that each secondary dose contains 25-400 mg of an IL-4 / IL-13 pathway inhibitor.

14. The method according to any one of claims 11-13, characterized in that the initial dose contains 600 mg of the IL-4 / IL-13 pathway inhibitor, and each secondary dose contains 300 mg of the IL-4 / IL-13 pathway inhibitor.

15. The method according to claim 14, characterized in that each secondary dose is administered one week after the immediately preceding dose.

16. The method according to claim 14, characterized in that each secondary dose is administered 2 weeks after the immediately preceding dose.

17. The method according to any one of claims 1-16, characterized in that the IL-4 / IL-13 pathway inhibitor is administered subcutaneously.

18. The method according to any one of claims 1-17, characterized in that 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.

19. The method according to any one of claims 1-18, characterized in that the IL-4 / IL-13 pathway inhibitor is dupilumab.

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