RU2776651C2 - Methods for treatment of active eosinophilic esophagitis - Google Patents

Abstract

FIELD: biochemistry.

SUBSTANCE: invention relates to the field of biochemistry, in particular to a method for increasing extensibility of the esophagus in a patient with eosinophilic esophagitis (hereinafter – EoE).

EFFECT: invention allows for effectively increasing extensibility of the esophagus in a patient with EoE, using therapeutically effective amount of a pharmaceutical composition containing a path inhibitor of interleukin-2/interleukin-13 (IL-4/IL-13).

22 cl, 6 tbl, 12 dwg, 1 ex

Description

[0001] This application was filed Aug. 3, 2018 as a PCT International Patent Application and claims priority under U.S. Provisional Application 62/541,242 filed Aug. 4, 2017; 62/561593, 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 TECHNOLOGY TO WHICH THE INVENTION RELATES

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

Prior Art

[0003] Esophageal stricture (narrowing of the esophagus) results from damage to the esophageal mucosa and results in, inter alia, difficulty in swallowing (dysphagia), food or fluid regurgitation, 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 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 (Liacourasetal 2011, The Journal of AllergyandClinicalImmunology. 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 a 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, food or fluid regurgitation, and weight loss. Emergency endoscopy for long-term eating disorders is associated with the risk of serious damage to the esophagus. EoE has been found to be associated with food allergies in many patients. Some patients may also have comorbid 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 social, emotional, financial, work and school, and sleep impacts, is also important and relevant in the EoE population and, if alleviated, could reflect benefit of treatment for patients with EoE.

[0005] Current therapeutic approaches include full-time diet (including food allergen withdrawal), ingested topical corticosteroids (not approved for the treatment of EoE in the US), and esophageal dilatation. Although ingested topical corticosteroids have been reported to cause partial clinical responses and histological remission, they are not equally effective and may be associated with fungal infections as well as relapse after discontinuation. There are currently no approved drugs for EoE. Thus, there is an unmet need in the art for effective therapeutic approaches without adverse events that prevent or treat eosinophilic esophagitis. Esophageal stricture can be treated with proton pump inhibitors, which inhibit the secretion of stomach acid. Esophageal dilatation by endoscopy is currently used to treat esophageal stricture and increase esophageal distensibility. However, it is a surgical procedure that is invasive and can lead to complications such as perforation and bleeding. Accordingly, there is an unmet need for safe and effective therapies that increase esophageal distensibility and treat esophageal stricture (eg, in eosinophilic esophagitis).

SUMMARY OF THE INVENTION

[0006] According to one aspect of the present invention, methods are provided for increasing the distensibility of the esophagus. Methods in accordance with this aspect include: (a) selecting a patient with moderate or severe eosinophilic esophagitis (EoE), in which the patient in need of it has a symptom or is selected based on a criterion selected from the group consisting of: (i) the patient has ≥15 eosinophils per field of view (p/p) in the esophagus before or during treatment (“baseline”); (ii) the patient has at least one episode of dysphagia per week; and (iii) the patient has a Strauman Dysphagia Rating Scale (SDI) score of ≥ 2; and (b) administering a therapeutically effective amount of a pharmaceutical composition comprising an inhibitor of the interleukin-4/interleukin-13 (IL-4/IL-13) pathway to a patient in need thereof, thereby increasing esophageal compliance as measured by a functional lumen imaging probe. (EndoFLIP®, Crospon, Ireland). In one embodiment, the patient has an active EoE. In one embodiment, the patient is ≥18 years old. In one embodiment, the patient has previously been treated with proton pump inhibitors (PPIs). In one embodiment, the patient has had at least one previous dilatation of the esophagus. In one embodiment, the patient has a characteristic selected from the group consisting of: (1) prior treatment with at least one of PPIs, esophageal dilatation, corticosteroids, allergen withdrawal, and/or diet modification; (2) the patient is non-responsive or resistant to prior treatment with PPI or esophageal dilatation; (3) the patient has an eosinophilic esophagitis severity and activity score (EEsAI) ≥30, ≥40, or ≥50; (4) the patient has been suffering from EoE for at least 3 years; (5) the patient prior to or at the time of 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; and (6) the patient has elevated levels of a biomarker selected from the group consisting of eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum thymus-regulated and activated chemokine (TARC) , thymic stromal lymphopoietin (TSLP), serum eosinophilic 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 connection "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 for increasing esophageal compliance, wherein the patient has at least one characteristic selected from the group consisting of:

(1) prior treatment with at least one of PPIs, esophageal dilatation, corticosteroids, allergen withdrawal, and/or diet modification;

(2) the patient is unresponsive or unresponsive to pre-treatment for PPI or esophageal dilatation;

(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 elevated levels of at least one biomarker selected from the group consisting of eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, thymus-regulated serum chemokine and activation (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophilic 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 can also, based on this formulation, 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 feature (1), feature (2), feature (3), feature (4), feature (5), and feature (6).

[0008] According to another aspect of the present invention, methods are provided for treating, preventing, or alleviating at least one symptom or sign of active eosinophilic esophagitis (EoE) in a patient. Methods in accordance with this aspect of the invention include selecting a patient with moderate to severe EoE and administering a therapeutically effective amount of a pharmaceutical composition containing an inhibitor of the interleukin-4/interleukin-13 (IL-4/IL-13) pathway to a patient in need thereof. . In some embodiments, a patient in need of this is selected based on an attribute or criterion selected from the group consisting of: (1) the patient has ≥15 eosinophils per field of view (p/sp) in the esophagus before or during treatment ("baseline level"); (2) prior treatment with at least one of high dose proton pump inhibitors (PPIs), esophageal dilatation, corticosteroids, allergen withdrawal, and/or diet modification; (3) the patient exhibits at least one episode of dysphagia per week; (4) the patient does not respond or is resistant to previous treatment with high doses of PPI or dilatation of the esophagus; (5) the patient has a Strauman Dysphagia Rating Scale (SDI) score of ≥5; (6) the patient has an eosinophilic esophagitis severity and activity score (EEsAI) ≥30, ≥40, or ≥50; (7) the patient has been suffering from EoE for at least 3 years; (8) the patient prior to or during administration of the IL-4/IL-13 pathway inhibitor was or 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 elevated levels of a biomarker selected from the group consisting of eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum thymus-regulated and activated chemokine (TARC) , thymic stromal lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP), and eosinophil-derived neurotoxin (EDN).

[0009] In accordance with another aspect of the present invention, methods for reducing dysphagia are provided, comprising selecting a patient with moderate to severe EoE, where the patient (i) has ≥1 episode of dysphagia per week; (ii) previously treated with high doses of proton pump inhibitors (PPIs); and/or (iii) had at least one previous dilatation of the esophagus; and (b) administering a therapeutically effective amount of a pharmaceutical composition containing 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 inhibitor of the IL-4/IL-13 pathway, wherein administration results in an improvement in a parameter selected from the group consisting of: (a) a reduction of at least 40% from baseline in the frequency and severity of dysphagia measured by the Strauman Dysphagia Rating Scale (SDI); (b) a reduction of 3 points from baseline SDI; (c) a greater than 85% reduction from baseline in the peak number of intraepithelial eosinophils in the proximal, middle, and/or distal esophagus; (d) an increase of at least 10% from baseline in esophageal compliance as measured by impedance planimetry; (e) a reduction of greater than 50% from baseline in disease severity and extent as measured by the EoE-Specific Histological Score (HSS) scoring scale; and (f) greater than 30% reduction from baseline in dysphagia as measured by the Eosinophilic Esophagitis Severity and Activity Rating Scale (EEsAI).

[0011] According to another aspect of the present invention, methods are provided for reducing eosinophilic infiltration of the esophagus in a patient in need thereof. In some embodiments, methods for reducing inflammation in the esophagus are provided. The methods include administering a therapeutically effective amount of a pharmaceutical composition containing an IL-4/IL-13 pathway inhibitor. In some embodiments, the eosinophilic infiltration of the esophagus is greater than or equal to about 15 eosinophils per field of view in the esophagus of a patient in need thereof. In some embodiments, the implementation of the number of eosinophils decreases ≥85% after administration of an inhibitor of the IL-4/IL-13 pathway. In some embodiments, inflammation (eg, mucosal inflammation) is identified by endoscopy and features such as esophageal edema, rings, exudates, sulci, and strictures (EREFS). In some embodiments, administration of an IL-4/IL-13 pathway inhibitor results in a decrease 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 in this specification).

[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 chemokine, thymus-regulated and activated (TARC; CCL17), thymic stromal lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP), and eosinophil-derived neurotoxin (EDN). The methods include administering a therapeutically effective amount of a pharmaceutical composition containing 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 comorbid 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 inhibitors of the IL-4/IL-13 pathway that can be used in the context of the methods of the present invention include, without limitation, anti-IL-4 antibody, anti-IL-13 antibody, anti-IL-4/IL- bispecific antibody 13 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] Exemplary 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 to IL-4R or its ligands. In some embodiments, an IL-4R inhibitor is an antibody or antigen-binding protein that binds the IL-4Rα chain and blocks IL-4, IL-13, or both IL-4 and IL-13 signaling. 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 CDR ( LCVR) containing 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 the treatment or inhibition or prevention of active eosinophilic esophagitis in a patient, including a human.

[0018] In some embodiments, the 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 the treatment or inhibition or prevention of 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 to increase esophageal compliance in a patient, including a human. In one embodiment, the patient has an active EoE. In one embodiment, the patient has moderate to severe EoE.

[0020] In some embodiments, the invention relates to the use of an antibody or antigen-binding fragment thereof that binds to IL-4R in the manufacture of a medicament to increase esophageal compliance in a patient, including a human. In one embodiment, the patient has an 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 components including weekly eosinophilic esophagitis severity and activity index (EEsAI) scores.

[0023] Figure 2 shows the mean change from baseline in the Strauman Dysphagia Rating Scale (SDI) score over a 12-week treatment period in patients treated with a once-a-weekly (qw) dose of 300 mg of dupilumab versus placebo.

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

[0025] Figure 4 shows the mean percent change from baseline in EEsAI scores over a 12-week treatment period in patients treated with a once-weekly (qw) dose of 300 mg of dupilumab versus placebo.

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

[0027] Figure 6 shows the mean change from baseline in the EoE-Specific Histological Score (HSS) total score for the severity (severity) subcomponents at week 12 in patients administered once a week (qw) 300 mg dupilumab versus placebo.

[0028] Figure 7 shows the mean change from baseline in the total EoEHSS score for the stage (grade) subcomponents at week 12 in patients treated with dupilumab 300 mg once a week (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 stratification; 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 proximal, middle, and distal esophageal eosinophil abscess samples taken at week 12 from patients treated with dupilumab 300 mg once weekly (qw) compared with 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 EoEHSS scoring 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 the eosinophilic superficial layer in the proximal, middle, and distal esophagus sampled at week 12 in patients treated with dupilumab 300 mg once a week (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 superficial change, and Figure 10C shows the mean change from baseline in the EoEHSS score for samples of apoptotic epithelial cells in the proximal, middle, and distal esophagus sampled at 12 week, in patients who received once-weekly (qw) 300 mg dupilumab versus 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 superficial change, and Figure 11C shows the mean change from baseline in the EoEHSS stage score for samples of apoptotic epithelial cells in the proximal, middle, and distal esophagus collected at week 12 in patients who received once-weekly (qw) 300 mg dupilumab versus placebo.

[0033] Figure 12 shows the percent change from baseline in the compliance plateau at week 12 in patients treated with dupilumab 300 mg 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 specific embodiments only and is not intended to be limiting, as the scope of the present invention will only be limited by the appended claims.

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

[0036] While any methods and materials similar or equivalent to those described herein may be used in the practice of the present invention, preferred methods and materials will now be described. All publications cited in this document are incorporated herein by reference for description in their entirety.

Methods for treating, preventing, or alleviating eosinophilic esophagitis

[0037] The present invention includes methods for treating, preventing, or alleviating at least one symptom or sign of active eosinophilic esophagitis (EoE) in a patient. Methods according to this aspect of the invention include administering a therapeutically effective amount of a pharmaceutical composition containing an inhibitor of the IL-4/IL-13 pathway to a patient in need thereof. As used herein, the term "treat", "treatment", or the like, means to alleviate symptoms, eliminate the causes of symptoms either temporarily or permanently, or to 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, without limitation, eosinophilic infiltration of the esophagus, thickening of the esophageal wall, inflammation in the esophagus, tracheal rings or protrusions in the esophagus, chest pain, and stomach, 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. The primary symptoms of EoE include, without limitation, 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 either allergic or non-allergic depending on the condition of the patient. 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 whose patient has ≥15 eosinophils per field of view (p/sp) 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, eg 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 (eg, ≥15 eosinophils/p/sp in the esophageal mucosa) and frequent episodes of dysphagia, have an SDI score ≥ 2 and/or an EEsAI score ≥ 30, have an EoE duration of at least 2 years and/or are unresponsive or resistant to prior therapy (including PPI or esophageal dilatation).

[0040] As used herein, "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 exhibit) one or more EoE features, such as, for example, overexpression in the esophagus of pro-inflammatory mediators such as mast cells, eosinophilic infiltration esophagus, thickening of the esophageal wall, dysphagia, food retention and chest and abdominal pain and/or an elevated EoE-associated biomarker. The term specifically includes patients who show ≥15 eosinophils per high power field in the esophagus. In some embodiments, the term also includes patients with elevated peripheral eosinophils (eg, ≥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 the pathology and symptoms seen in patients with chronic esophagitis, including gastroesophageal reflux disease (GERD). In some embodiments, the term "patient in need thereof" includes patients who are non-responsive 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" may include a subset of the population that is more susceptible to EoE or may exhibit elevated levels 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, prior to or at the time of 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. Such a patient population may show elevated levels of an EoE-associated biomarker such as, for example, IgE, eotaxin-3, periostin, IL-5, or IL-13.

[0043] In some embodiments, "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) prone to allergic reactions or reactions when exposed to one or more allergens; (b) has previously shown 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 that is 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 can be found in or derived from foods such as, for example, dairy products (eg cow's milk), eggs, wheat, soy, corn, rye, fish, seafood, peanuts and tree nuts. Alternatively, the allergen may be contained in or derived from non-food products such as, for example, dust (eg containing dust mites), pollen, insect venom (eg venom from bees, wasps, mosquitoes, etc.), mold , animal dander, latex, medicines, drugs, ambrosia, grass and birch.

[0045] In some embodiments, the term "patient in need thereof" includes a subset of the population that exhibits an allergic reaction to a food allergen. For example, "a patient in need" 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, peanut, forest nuts, beef, chicken, oats, barley, pork, green beans, and fruits like apple and pineapple.

[0046] In some embodiments, the term includes a patient allergic to a non-food allergen, such as allergens derived from dust, mold, insects, plants, including pollen, and pets such as cats and dogs. Examples of non-food allergens (also known as environmental or airborne allergens) include, but are not limited to, house dust mite allergens, pollen allergens, animal dander allergens, insect venom, grass allergens, and latex.

[0047] As used herein, the expressions "allergic response", "allergic reaction", "allergic symptom", and the like 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 exhalation (PEF), gastrointestinal upset, flushing, swollen lips, swollen tongue, low blood pressure, anaphylaxis, and organ dysfunction/failure. "Allergic response", "allergic reaction", "allergic symptom", etc. also include immunological responses and reactions such as, for example, increased production of IgE, increased production of allergen-specific immunoglobulin and/or eosinophilia.

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

[0049] The present invention also includes methods for increasing the distensibility of the esophagus. Methods according to this aspect of the invention include administering to a patient in need thereof one or more doses of a pharmaceutical composition containing an inhibitor of the IL-4/IL-13 pathway, thereby increasing the distensibility of the patient's esophagus.

[0050] The present invention also includes methods for reducing eosinophilic infiltration. Methods according to this aspect of the invention include administering to a patient in need thereof one or more doses of a pharmaceutical composition containing an inhibitor of the IL-4/IL-13 pathway to reduce or eliminate the number of eosinophils, for example, in the mucosa of the esophagus.

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 the gastrointestinal tract, including, without limitation, the esophagus and stomach. Eosinophilic infiltration is analyzed, for example, in a tissue biopsy of the esophagus of a subject suffering from EoE. In specific embodiments, "eosinophilic infiltration" refers to the presence of ≥15 eosinophils per field of view in the esophagus. The term "high magnification field of view" refers to a standard total magnification of 400 times with a microscope used to view eosinophils in tissue, such as from a patient's esophagus. In some embodiments, "eosinophilic infiltration" includes tissue infiltration with leukocytes, such as lymphocytes, neutrophils, and mast cells. Leukocyte infiltration into, for example, esophageal tissue can be detected using cell surface markers such as eosinophil-specific markers (eg, CD11cLow/Neg, SiglecF+, F4/80+, EMR1+, Siglec8+, and MBP2+), macrophage-specific markers (eg. , CD11b+, F4/80+, CD14+, EMR1+, and CD68+), neutrophil-specific markers (eg, CD11b+, Ly6G+, Ly6C+, CD11b+, and CD66b+) and T cell-specific markers (eg, CD3+ CD4+ CD8+).

[0052] As used herein, a decrease in esophageal eosinophils means that the number of eosinophils and other leukocytes measured in the esophagus of a patient with EoE and treated with an IL-4/IL-13 pathway inhibitor is at least 5%, 10% lower , 20%, 50%, 70%, 80%, or 90% than esophageal eosinophils measured in the same or equivalent patient who was not treated with an IL-4/IL-13 pathway inhibitor. In some embodiments, the reduction in eosinophilic infiltration means finding less than 15 eosinophils per 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 field. vision on biopsy of the esophageal mucosa. In some embodiments, a decrease in esophageal eosinophils means that no eosinophils are found in the patient's esophageal mucosa.

[0053] The present invention includes methods of 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 particular therapeutic dosing regimen. For example, a therapeutic dosing regimen may include administering multiple doses of a pharmaceutical composition to a patient 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 a month, once every two months, once every three months, once every four months or less.

[0054] The methods of the present invention, in accordance with some embodiments, include administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising an inhibitor of the IL-4/IL-13 pathway 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-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, eotaxin-3 inhibitor, IgE inhibitor, prostaglandin D2 inhibitor, immunosuppressant, topical corticosteroid, oral corticosteroid (eg, budesonide), systemic corticosteroid, inhaled corticosteroid, glucocorticoid, proton pump inhibitor, decongestant, antihistamine, and non-steroidal anti-inflammatory drug (NSAID) . In some embodiments, the IL-4/IL-13 pathway inhibitor of the invention may be administered in combination with therapy including esophageal dilatation, allergen removal, and diet control. Used in the present description, the expression "in combination with" means that a pharmaceutical composition containing an inhibitor of the IL-4/IL-13 pathway is administered to the patient simultaneously, immediately before or immediately after the introduction of the second therapeutic agent. In some embodiments, the second therapeutic agent is co-formulated with an inhibitor of the IL-4/IL-13 pathway. In a related embodiment, the present invention includes methods comprising administering a therapeutically effective amount of a pharmaceutical composition containing an inhibitor of the IL-4/IL-13 pathway to a patient on an anti-allergic therapeutic regimen. The background antiallergic therapeutic regimen may include a course of administration of, for example, steroids, antihistamines, decongestants, anti-IgE agents, etc. An IL-4/IL-13 pathway inhibitor (eg, an anti-IL-4R antibody) may be added over a background anti-allergic therapeutic regimen. In some embodiments, an IL-4/IL-13 pathway inhibitor is added as part of a "background taper" regimen in which background antiallergic therapy is phased out in a patient over time (e.g., in stages), while the IL-4/ IL-13 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 including 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 detectable in an EoE patient at a level or amount which is different from (eg, more or less than) the level or amount of the marker present or detectable in a patient without EoE. Exemplary EoE-associated biomarkers include, but are not limited to, for example, esophageal eosinophils, eotaxin-3 (CCL26), periostin, serum IgE (total and allergen-specific), serum IgG (total and allergen-specific), IL-13, IL -5, thymus-regulated serum chemokine and activation (TARC; CCL17), thymic stromal lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP), calpain 14, filaggrin (FLG), signal transducer and transcriptional activator 6 (STAT6), receptor interleukin 4 (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 (Blanchardetal. 2006, J. Clin. Invest. 116: 536-547). Alternatively, an "EoE-associated biomarker" also includes genes that are negatively regulated due to EoE, such as terminal differentiation proteins (eg, filaggrin) (Blanchardetal 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 inhibitor of the IL-4/IL-13 pathway. Methods for detecting and/or quantifying such EoE-associated biomarkers are known in the art; kits for measuring these EoE-associated biomarkers are available from various commercial sources; and various commercial diagnostic laboratories offer services that also provide measurements of such biomarkers.

[0056] In accordance with some aspects of the invention, methods for treating EoE are provided, which include: (a) selecting a patient that demonstrates 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 containing a therapeutically effective amount of an inhibitor of the IL-4/IL-13 pathway. In some embodiments of this aspect of the invention, the patient is selected based on an elevated level of IgE or eotaxin-3.

[0057] In accordance with 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 inhibitor of the IL-4/IL-13 pathway, wherein administering the pharmaceutical composition to the patient results in a reduction in at least one EoE-associated biomarker (eg, esophageal eosinophils, eotaxin-3, IgE, etc.) during post-administration of the pharmaceutical composition compared to the level of the biomarker in the patient prior to 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 specific point in time following administration of a pharmaceutical composition containing an inhibitor of the IL-4/IL pathway -13 with (ii) the level of the biomarker measured in the patient prior to administration of a pharmaceutical composition containing an inhibitor of the IL-4/IL-13 pathway (i.e., baseline measurement). The specific point in time 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 a pharmaceutical composition containing an IL pathway inhibitor -4/IL-13.

[0059] In accordance with 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 containing an inhibitor of the IL-4/IL-13 pathway (for example, an antibody against IL -4R). For example, around 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 the first, a second, third, or fourth dose of a pharmaceutical composition containing about 75 to about 600 mg of an anti-IL-4R antibody (e.g., dupilumab), a patient of 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 of baseline (where "baseline" is defined as the patient's eotaxin-3 level just before the first injection). Similarly, on approximately 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 the first, second, third, or fourth dose of a pharmaceutical composition containing about 75 to about 600 mg of an anti-IL-4R antibody (e.g., dupilumab), a patient of the present invention may experience 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 of baseline (where "baseline" is defined as the IgE level in the patient immediately before the first injection).

[0060] The present invention also includes methods for determining whether a patient is a suitable patient for whom administration of a pharmaceutical composition comprising an IL-4/IL-13 pathway antagonist would be beneficial. For example, if an individual, prior to receiving a pharmaceutical composition containing an IL-4/IL-13 pathway antagonist, detects 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 a pharmaceutical composition of the invention (composition containing an anti-IL-4R antibody). In related embodiments, the present invention includes methods of treating eligible patients, where the eligible patient may be more susceptible to EoE, for example due to food allergy or atopic disease. For example, the present invention includes methods comprising administering an IL-4/IL-13 pathway antagonist to patients who have 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 who have inherited Mendelian connective tissue disorders, such as Marfan syndrome, Lois-Dietz syndrome, Ehlers-Danlos hypermobility syndrome (EDS), or joint hypermobility syndrome. (JHS). Such patient populations may have elevated levels of the 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 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, more than about 300 pg/ml, more than about 350 pg/ml, more than about 400 pg/ml, more than about 450 pg/ml, or more than about 500 pg/ml; or (ii) a serum IgE level 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. more than about 2000 kU/l, more than about 2500 kU/l, more than about 3000 kU/l, more than about 3500 kU/l, more than about 4000 kU/l, more than about 4500 kU/l, or more than about 5000 kU/l; or (iii) ≥ 15 eosinophils per field of view in the patient's esophagus. Additional criteria such as other clinical indicators of EoE (eg, dysphagia, esophageal wall thickening, and food allergy indicative of EoE) may be used in conjunction with any of the above EoE-associated biomarkers to identify an individual as a suitable candidate for anti-IL-antibody therapy. 4/IL-13, as described elsewhere in this document.

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, the methods comprising administering a pharmaceutical composition comprising an inhibitor of the IL-4/IL-13 pathway to the patient.

[0063] Examples of "EoE related parameters" include: (a) the Straumann Dysphagia Rating Scale (SDI); (b) eosinophilic esophagitis activity index (EEsAI); c) signs of eosinophilic esophagitis such as edema, rings, exudates, furrows and strictures (EoE-EREFS); (d) EoE-specific histological scoring scale (EoE-HSS); (e) intraepithelial eosinophils of the esophagus; and (e) distensibility of the esophagus. "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 compliance means an increase from baseline. Used in this document, the term "baseline" in relation to the parameter related to EoE, means the numerical value of the parameter related to EoE for the patient before or during the administration of the pharmaceutical composition of the present invention.

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

[0065] The Straumann Dysphagia Rating Scale (SDI). SDI is a non-validated outcome based on patient outcome assessment (PRO) that has been used in clinical trials to determine the frequency and intensity of dysphagia (Straumann 2010). SDI has a 1 week evaluation period. The incidence of dysphagia 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 is rated on a 6- scoring scale: 0=swallowing without restriction, 1=slight sense of resistance, 2=mild vomiting with breath holding, 3=short period of obstruction requiring intervention (e.g. drinking, breathing), 4=long period of obstruction relieved by vomiting alone, 5= prolonged complete obstruction requiring endoscopic intervention. The overall SDI score ranges from 0 to 9. In accordance with some embodiments of the present invention, administration of an IL-4/IL-13 pathway inhibitor to a patient results in a 3-point decrease in SDI score from baseline. For example, the present invention includes therapeutic methods that result in a decrease from baseline in the SDI score, a decrease of 1, 2, 3, 4, 5, 6 or more points from baseline in the SDI. 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 per 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 (eg, after approximately 300 mg subcutaneously antibodies against IL-4R or antigen-binding fragment). 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 SDI of at least 40%.

[0066] Eosinophilic Esophagitis Activity Index (EEsAI). EEsAI is an unvalidated multi-module index under development at the University Hospital Inselspital (Bern, Switzerland) (Schoepfer 2014), part of the international research group EEsAI. 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 overall EEsAIPRO score ranges from 0 to 100 (Figure 1), where higher scores indicate worse symptoms. The score consists of 5 parts: frequency of swallowing problems, duration of swallowing problems, swallowing pain, visual dysphagia question and avoidance, modification, and slow feeding (AMS). In accordance with some embodiments of the present invention, administration of an IL-4/IL-13 pathway inhibitor to a patient results in a decrease in EEsAI. For example, the present invention includes therapeutic methods that result in a reduction from baseline in EEsAI of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or more per day. 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or later after administration of an inhibitor of the IL-4/IL-13 pathway (e.g., after subcutaneous administration of approximately 300 mg of anti-IL antibody -4R or an 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 EEsAI of at least 30% following administration.

[0067] Signs associated with eosinophilic esophagitis such as edema, rings, exudates, furrows and strictures (EoE-EREFS). EoE-EREFS (edema, rings, exudates, furrows, strictures) is used to measure endoscopically identified signs of inflammation and remodeling of the EoE esophageal mucosa. This tool includes 17 items related to the presence and severity of esophageal features. Specific features of the esophagus include: rings (concentric rings around the esophagus - none, light, medium, heavy, not applicable); strictures (narrowing of the esophagus - yes, no, not applicable); stricture diameter (if applicable); exudates (see white plaques - absent, light, heavy), furrows (vertical lines down the esophagus - absent, present); edema (loss of vascular marks on the mucous membrane - absent, present); esophagus resembling corrugated paper (absent, present); general appearance including all endoscopically identified EoE findings (i.e., fixed rings, strictures, whitish exudate, groove, edema, and crepe paper-like mucosa). In addition, mucosal changes associated with gastroesophageal reflux disease are recorded using the Los Angeles erosion 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 disease features, using both total scores and scores for each individual feature (Hirano 2014). In accordance with some embodiments of the present invention, administration of an IL-4/IL-13 pathway inhibitor to a patient results in a reduction in EoE-EREFS. For example, the present invention includes therapeutic methods that result in an EREFS reduction from 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 an inhibitor of the IL-4/IL-13 pathway (for example, after subcutaneous administration of approximately 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof).

[0068] Eosinophilic Esophagitis EoE-Specific Histological Score Scale (EoE-HSS). The EoE-HSS generates separate scores for the severity (grade) and extent (stage) of the disease. The score is used to measure 8 histological signs (parameters) of EoE from 3 different sections (proximal, middle and distal) of the esophagus (Collinsetal 2017). Eight parameters include: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophilic superficial layers, dilated intercellular spaces, superficial epithelial changes, non-keratized cells, and lamina propria fibrosis. For each parameter, a scale from 0 to 3 is used, both grade and stage (0 - least inflamed, normal). In accordance with some embodiments of the present invention, administration of an IL-4/IL-13 pathway inhibitor to a patient results in a decrease in EoE-HSS. For example, the present invention includes therapeutic methods that result in a reduction in EoE-HSS from 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 an IL-4/IL-13 pathway inhibitor (eg, following 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 EoE-HSS of at least 50%.

[0069] Esophageal intraepithelial eosinophils. This refers to ≥15 eosinophils per field of view (f/f) on esophageal biopsy. Peak intraepithelial eosinophils refers to ≥15 eosinophils per field of view in at least 2 of the 3 areas of the esophagus that were sampled. In accordance with some embodiments of the present invention, administration of an inhibitor of the IL-4/IL-13 pathway to a patient results in a reduction in the peak of intraepithelial eosinophils. For example, the present invention includes therapeutic methods that result in a reduction from baseline in intraepithelial eosinophils of 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 following administration of an IL-4/IL-13 pathway inhibitor (eg, following subcutaneous administration of approximately 300 mg of 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 intraepithelial eosinophils of at least 85%.

[0070] Distensibility of the esophagus. Esophageal distensibility is assessed using an 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 cross-sectional area at multiple locations along the esophagus while recording intraluminal pressure during esophageal volumetric distension. Analysis of the cross-sectional area as a function of pressure of the esophagus allows you to determine the plasticity of the esophagus, as well as the distensibility plateau (DP). DP has been shown to be significantly reduced in EoE patients compared to healthy controls (Kwiatek 2011). In accordance with some embodiments of the present invention, administration of an IL-4/IL-13 pathway inhibitor to a patient results in an increase in esophageal distensibility. For example, the present invention includes therapeutic methods that result in an increase from baseline in esophageal compliance of at least about 5%, 10%, 15%, 20%, 25% or more at the end of weeks 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, or later following administration of an IL-4/IL-13 pathway inhibitor (eg, following subcutaneous administration of about 300 mg of 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 an increase from baseline in esophageal compliance of at least 10%, as measured by impedanoplanimetry.

[0071] Questionnaire for determining the quality of life in eosinophilic esophagitis in adults (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 areas such as social functioning, emotional functioning, and the impact of disease on daily life. EoE-QOL-A has a 1 week evaluation period. Elements are rated on a 5-point scale: "Not at all", "A little", "Moderate", "A little" and "Extremely". In some embodiments, administration of an IL-4/IL-13 pathway inhibitor to a patient results in an improvement in the patient's quality of life.

IL-4/IL-13 pathway inhibitors

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

[0073] As used herein, 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.) .e) is any agent that inhibits or impairs at least one of: (i) the binding of IL-4 and/or IL-13 to their respective receptors; (ii) signaling and/or activity of IL-4 and/or IL-13; and/or (iii) downstream signaling/activity that results from the binding of IL-4 and/or IL-13 to their respective receptors. Exemplary inhibitors of the IL-4/IL-13 pathway include, but are not limited to, anti-IL-4 antibodies (e.g., antibodies disclosed in US Pat. No. 7,740,843 and US Patent Application Publications 20100297110, Antibodies disclosed in US patents 7501121, 7674459, 7807788, 7910708, 7915388, 7935343, 8088618, 8691233, 9605065, publications of patent applications 20060073148, 2008004420 and EP2627673B1), Bispyphyni, Bispypyn , antibodies disclosed in US Pat. No. 8,388,965, US Patent Application Publications 20110008345, 20130251718, 20160207995), and IL-4 receptor (IL-4R) inhibitors (described below).

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

[0075] Non-limiting examples of categories of IL-4R inhibitors include IL-4 muteins (e.g., pitrakynra), small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., peptibody molecules), "receptor bodies" (eg, engineered molecules containing the ligand-binding domain of a component of IL-4R) and antibodies or antigen-binding antibody fragments 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 their antigen-binding fragments

[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. As used herein, the term "antibody" includes immunoglobulin molecules containing four polypeptide chains, two heavy (H) chains, and two light (L) chains linked together by disulfide bonds, as well as their multimers (eg, IgM). In a typical antibody, each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region includes three domains, CH1, CH2 and CH3. Each light chain contains a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region contains 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 to carboxy in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FR of an anti-IL-4R antibody (or an antigen-binding portion thereof) may be identical to human germline sequences, or may 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 derived, synthetic, or 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, including the 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, antibody phage libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or by molecular biology techniques, for example, to place one or more of the variable and/or constant domains in a suitable configuration, or to introduce codons, create cysteine residues, modify, add or remove amino acids, etc. d.

[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 an antibody hypervariable region (eg, a complementarity-determining region (CDR), such as a CDR3 peptide), or a limited FR3-CDR3-FR4 peptide. Other engineered molecules such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, tribodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, divalent nanobodies, etc.) , small modular immunopharmaceuticals (SMIPs), and shark IgNAR variable domains are also included in the expression "antigen binding fragment" as used herein.

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

[0080] In some embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary variable and constant domain configurations that can be found in an 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 either be directly linked to each other, or may be linked by a complete or partial hinge or linker region. The hinge region may be at least 2 (eg, 5, 10, 15, 20, 40, 60 or more) amino acids, resulting in a flexible or semi-flexible bond between adjacent variable and/or constant domains in a single polypeptide molecule. In addition, an antigen-binding fragment of an 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 VH or VL monomeric domains (e.g. , disulfide bond(s)).

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

[0082] The antibodies used in the methods of the present invention may be human antibodies. As used herein, the term "human antibody" is intended to refer to antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies of the invention may, however, include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-directed mutagenesis or in vivo somatic mutation), e.g., in 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, generated, or isolated by recombinant methods, such as antibodies expressed using a recombinant expression vector transfected into a host cell (more details described below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., mouse) that is transgenic for human immunoglobulin genes (see, e.g., Tayloretal. (1992) Nucl. AcidsRes. 20: 6287-6295) or antibodies produced, expressed, constructed or isolated by any other method which 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 undergo in vitro mutagenesis (or, when a transgenic animal for human Ig sequences is used, somatic in vivo mutagenesis), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibody are sequences that, although and derived from and linked to human germline VH and VL sequences cannot naturally exist in the germline human antibody repertoire in vivo.

[0084] In 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 an antibody, or antigen-binding fragment thereof, forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody 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 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, an isolated antibody that specifically binds human IL-4Rα may be cross-reactive with other antigens, such as IL-4Rα molecules from other (non-human) species.

[0085] According to some exemplary embodiments of the present invention, the 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) containing any of the amino acid sequences of anti-IL-4R antibodies as described in US Pat. No. 7,608,693. In some exemplary embodiments, an anti-IL-4Rα antibody, or antigen-binding fragment thereof, useful in the context of the methods of the present invention comprises heavy chain complementarity determining regions (HCDR), heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1, and light chain complementarity determining regions (LCDR), light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, an anti-IL-4Rα antibody, or antigen-binding fragment thereof, comprises three HCDR (HCDR1, HCDR2 and HCDR3) and three LCDR (LCDR1, LCDR2 and LCDR3), where HCDR1 contains the amino acid sequence of SEQ ID NO: 3; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In still other embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2. In some embodiments, the methods of the present invention include the use of an anti-IL-4R antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. An exemplary antibody containing a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10 is a fully human anti-IL-4R antibody known as dupilumab. According to some exemplary embodiments, the methods of the present invention include the use of dupilumab or a bioequivalent thereof. The term "bioequivalent" as used herein refers to antibodies against IL-4R or IL-4R binding proteins or fragments thereof, which are pharmaceutical equivalents or pharmaceutical alternatives, the rate and/or degree of absorption of which does not show a significant difference with the corresponding values. in dupilumab when administered at the same molar dose under similar experimental conditions, single or multiple doses. In the context of the invention, the term refers to antigen-binding proteins that bind to IL-4R, which have no clinically significant differences from dupilumab in their safety, purity and/or efficacy.

[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 described in US Pat. No. 7,186,809; US Pat. No. 7,605,237; US Pat. No. 7,638,606; .

[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 increased binding to its antigen at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values less than about 6.2, for example, 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. Used in the present description, the expression "neutral pH" means a pH from about 7.0 to about 7.4. The expression "neutral pH" includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

[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 may 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 acid/neutral KD ratio of about 3 or greater. In some exemplary embodiments, the acid/neutral KD ratio for an antibody or antigen-binding fragment of the present invention may 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 increased) binding to a particular antigen at acidic pH compared to neutral pH. In addition, modifications to 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 (eg, within the CDR) with a histidine residue, an antibody with reduced antigen-binding activity at acidic pH relative to neutral pH can be obtained. Used in the present description, the expression "acidic pH" means pH 6 or less.

Pharmaceutical compositions

[0090] The present invention includes methods that include 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. Pharmaceutical compositions of the invention may be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerability, and the like. Many suitable formulations can be found in a formulation 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, lipid containing lipid (cationic or anionic) vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water emulsions, and water. -in-oil, carbovax emulsions (polyethylene glycols of various molecular weights), semi-solid gels and semi-solid mixtures containing carbovax. 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, oral mucosa, 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. In addition, with regard to subcutaneous delivery, the pen delivery device easily finds use in delivering the pharmaceutical composition of the present invention. Such a pen delivery device may be reusable or disposable. A reusable pen delivery device typically uses a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been introduced and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. There is no replaceable cartridge in the disposable pen delivery device. Rather, a disposable pen delivery device comes pre-filled with a pharmaceutical composition held in a reservoir within the device. Once the reservoir is empty 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 can 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 can be placed in the vicinity of the target of the composition so that only a fraction of the systemic dose is required (see, for example, Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are reviewed by Langer, 1990, Science 249: 1527-1533.

[0094] Formulations for injection may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc. These injections can be prepared by known methods. For example, injectable formulations can be prepared, for example, by dissolving, suspending, or emulsifying an antibody or salt thereof, as described above, in a sterile aqueous or oily medium commonly used for injection. As the aqueous injection medium, for example, physiological saline, isotonic saline containing glucose and other additional agents, etc. are used, which can be used in combination with an appropriate solubilizing agent such as an alcohol (for example, ethanol), a polyalcohol (for example, , propylene glycol, polyethylene glycol), non-ionic surfactant [eg, polysorbate 80, HCO-50 (polyoxyethylene adduct (50 mol) of hydrogenated castor oil)], etc. As the 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 thus obtained is preferably filled into a suitable ampoule.

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

[0096] Exemplary pharmaceutical compositions containing an anti-IL-4R antibody that can be used in the context of the present invention are disclosed, for example, in US Pat. No. 8,945,559.

Introduction schemes

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

[0098] In accordance with some embodiments of the present invention, multiple doses of an IL-4/IL-13 pathway inhibitor may be administered to a patient over a period of time. Methods according to this aspect of the invention include sequential administration of multiple doses of an inhibitor of the IL-4/IL-13 pathway 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 point in time, e.g., 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 one or more secondary doses of an IL-4/IL-13 pathway inhibitor and optionally one or more tertiary doses of an IL-4/IL-13 pathway inhibitor. IL-4/IL-13.

[0099] The terms "initial dose", "secondary doses" and "tertiary doses" refer to the time sequence of administration of an inhibitor of the IL-4/IL-13 pathway. Thus, the "starting dose" is the dose that is administered at the beginning of the treatment regimen (also referred to as the "initial dose"); "secondary doses" are doses that are administered after the initial dose; and "tertiary doses" are doses that are administered after secondary doses. The initial, secondary, and tertiary doses may contain the same amount of IL-4/IL-13 pathway inhibitor, but may generally differ from each other in terms of frequency of administration. In some embodiments, however, the amount of IL-4/IL-13 pathway inhibitor contained in the initial, secondary, and/or tertiary doses varies relative to each other (eg, adjusted as appropriate) during the course of treatment. In some embodiments, the initial dose contains a first amount of the antibody or antigen-binding fragment thereof, and each of the one or more secondary doses contains a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or fragment thereof (initial dose) is 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x the second amount of the antibody or antigen-binding fragment (secondary dose). one or more (eg, 1, 2, 3, 4, or 5) doses are administered at the start of the treatment regimen as "loading doses" followed by doses that are administered less frequently (eg, "maintenance doses"). For example, an inhibitor of the IL-4/IL-13 pathway 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 10 mg to 600 mg of an IL-4/IL-13 pathway inhibitor, e.g., 100 mg to 400 mg of an IL-4/IL-13 pathway inhibitor, e.g., 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg of an IL-4/IL-13 pathway inhibitor. In one embodiment, the initial dose is 2 times the secondary dose.

[00100] In one illustrative embodiment of the present invention, each secondary and/or tertiary dose is administered from 1 to 14 (for example, 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 multiple dose sequence, the dose of an inhibitor of the IL-4/IL-13 pathway that is administered to a patient prior to the next immediately following dose in the sequence without intermediate doses.

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

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

[00103] The methods of the present invention, in accordance with some embodiments, include administering a corticosteroid (CS) to a patient in combination with an inhibitor of the IL-4/IL-13 pathway (eg, an anti-IL-4R antibody). Used in the present description, the expression "in combination with" means that CS is administered before, after or simultaneously with an inhibitor of the IL-4/IL-13 pathway. The term "in combination with" also includes the sequential or concomitant administration of an inhibitor of the IL-4/IL-13 and CS pathway.

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

Dosage

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

[00106] In the case of an anti-IL-4R antibody, a therapeutically effective amount may be from about 0.05 mg to about 600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg , about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg , about 120 mg, about 130 mg about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, etc. 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 anti-IL-4R antibody. In some embodiments, 300 mg of an anti-IL-4R antibody is administered.

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

Selected Embodiments

[00108] In Embodiment 1, the present invention includes a method for 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 previous dilatation of the esophagus; and (b) administering a therapeutically effective amount of a pharmaceutical composition containing an inhibitor of the interleukin-4/interleukin-13 (IL-4/IL-13) pathway to a patient in need thereof.

[00109] In Embodiment 2, the present invention includes a method for increasing esophageal distensibility, comprising: (a) selecting a patient having at least one of the following characteristics: (i) the patient has ≥1 episode of dysphagia per week; (ii) the patient has previously been treated with high-dose PPIs; and (iii) the patient has had at least one previous dilatation of the esophagus; and (b) administering a therapeutically effective amount of a pharmaceutical composition containing 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 a pharmaceutical composition comprising an IL-4/IL-13 pathway inhibitor to a patient who needs it.

[00112] In Embodiment 5, the present invention includes a method of any 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 field of view (n /sp) in the esophagus before or during treatment ("baseline"); (2) prior treatment with at least one of the following: high dose PPIs, esophageal dilatation, corticosteroids, allergen withdrawal, and/or diet modification; (3) the patient has ≥1 episode of dysphagia per week; (4) the patient does not respond or is resistant to prior treatment with high dose PPIs or esophageal dilatation; (5) the patient has a Strauman Dysphagia Rating Scale (SDI) score ≥ 2; (6) the patient has an eosinophilic esophagitis severity and activity score (EEsAI) ≥30, ≥40, or ≥50; (7) the patient has been suffering from EoE for at least 3 years; (8) the patient prior to or at the time of 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; and (9) the patient has elevated levels of a biomarker selected from the group consisting of eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum thymus-regulated chemokine and activation (TARC) , thymic stromal lymphopoietin (TSLP), serum eosinophilic 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 administration of an IL-4/IL-13 pathway inhibitor results in an improvement in an EoE-related parameter selected from the group consisting of: reduction in the frequency and severity of dysphagia by at least 40% compared with baseline, as measured by the Strauman Dysphagia Rating Scale (SDI); (b) a reduction of 3 points from baseline in the SDI score; (c) a greater than 85% reduction from baseline in the peak number of intraepithelial eosinophils in the proximal, middle, and/or distal esophagus; (d) an increase of at least 10% from baseline in esophageal distensibility as measured by impedance planimetry; (e) a reduction of greater than 50% from baseline in disease severity and grade as measured by the histological EoE scoring scale (HSS); and (f) greater than 30% reduction from baseline in dysphagia as measured by the Eosinophilic Esophagitis Severity and Activity Score (EEsAI).

[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 the IL-4 receptor (IL -4R).

[00115] In Embodiment 8, the present invention includes a method of any 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 a method of any 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 a method of any 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, with each secondary dose administered 1-4 weeks after the immediately preceding dose.

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

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

[00120] In Embodiment 13, the present invention includes a method of any of embodiments 10-12, wherein the initial dose contains 600 mg of an inhibitor of the IL-4/IL-13 pathway and each secondary dose contains 300 mg of an inhibitor of the IL-4 pathway /IL-13.

[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 of Embodiments 4-15, wherein the symptom or sign of EoE is selected from the group consisting of eosinophilic 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, wherein the patient has an allergic reaction to a food allergen contained in a food selected from the group consisting of dairy, egg, wheat, soy, corn, fish, seafood, peanuts, nuts, beef, chicken, oats, barley, pork, green beans, apples and pineapples.

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

[00126] In Embodiment 19, the present invention includes the method of any of Embodiments 1-18, wherein administration of an inhibitor of the IL-4/IL-13 pathway results in a decrease 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 a method of any 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 group consisting of IL-1beta inhibitor, IL-5 inhibitor, IL-9 inhibitor, IL-13 inhibitor, IL-17 inhibitor, IL-25 inhibitor, TNF-alpha inhibitor, eotaxin-3 inhibitor, IgE inhibitor, prostaglandin D2 inhibitor , immunosuppressant, topical corticosteroid, oral corticosteroid, systemic corticosteroid, inhaled corticosteroid, glucocorticoid, proton pump inhibitor, NSAID, esophageal dilatation, allergen removal, and diet control.

[00129] In Embodiment 22, the present invention includes the method of any of Embodiments 1-21, wherein the IL-4/IL-13 pathway inhibitor is selected from the group consisting of anti-IL-4 antibody, anti-IL-4 antibody. 13, 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 Embodiment 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 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 interaction. -4 and/or IL-13 with type 1 or type 2 IL-4 receptor.

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

[00136] In Embodiment 29, the present invention includes the method of Embodiment 28, wherein the antibody or antigen-binding fragment thereof 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 light chain complementarity determining regions (LCDR), light chain variable region (LCVR) containing 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), where HCDR1 contains the amino acid sequence SEQ ID NO: 3; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7; and LCDR3 contains the amino acid sequence of SEQ ID NO: 8.

[00138] In Embodiment 31, the present invention includes the method of Embodiment 30 wherein HCVR comprises the amino acid sequence of SEQ ID NO: 1 and LCVR comprises the amino acid sequence of SEQ ID NO: 2.

[00139] In Embodiment 32, the present invention includes the method of any of Embodiments 29-31, 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 of Embodiments 1-31, 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 is AMG317 or MEDI9314.

EXAMPLES

[00142] The following examples are used to provide one of skill 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 authors consider their invention. Efforts have been made to ensure accuracy with respect to the numbers used (eg amounts, temperatures, etc.), but some experimental errors and deviations must 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.

Example 1 Clinical Study of Subcutaneous Dupilumab in Adult Patients with Moderate to Severe Active Eosinophilic Esophagitis (EoE)

[00143] This study is a 32-week, double-blind, randomized, placebo-controlled trial to investigate the efficacy, safety, tolerability, and immunogenicity of dupilumab in adult patients with active EoE. Dupilumab is a fully human anti-IL-4R antibody containing a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10; a pair of amino acid sequences HCVR/LCVR containing SEQ ID NO: 1/2; and heavy and light chain CDR sequences comprising SEQ ID NOs: 3-8.

Research objectives

[00144] The primary objective of the study was to evaluate the clinical efficacy of repeated subcutaneous (SC) doses of dupilumab versus placebo for symptomatic 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 dupilumab SC doses in adult patients with active, moderate, or severe EoE; (2) evaluate the effect of dupilumab on esophageal eosinophilic infiltration; and (3) evaluate the pharmacokinetics (PK) of dupilumab in adult patients with EoE.

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

Study plan

[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 during the screening visit (which should occur between day -35 and day -1). Patients who met the eligibility criteria underwent day one 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 take study drug for another 16 weeks.

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

Study group

[00150] The target group included adult (18 to 65 years old) males or females with active EoE.

[00151] Inclusion Criteria: The 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 during screening. Note: Must include demonstration of intraepithelial eosinophilic infiltration (cell peak ≥15 eosinophils/field [eos/n/sp] [400X]) from endoscopy esophageal biopsy specimens performed no more than 2 weeks after at least 8 weeks of high-dose (or twice-daily) proton pump inhibitor (PPI) treatment;

(3) History (as reported by the patient) averaged at least 2 episodes of dysphagia (with solid anti-inflammatory therapy) per week during the 4 weeks prior to screening and averaged at least 2 episodes of documented dysphagia per week during the weeks between screening and baseline; according to the patient's report, dysphagia is defined as a problem with swallowing solid food or solid food sticks;

(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 the absence of 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 or more of any of the following: allergic disease (eg, allergic asthma, allergic rhinitis, AD, or food allergy), peripheral eosinophil count ≥0.25 billion/L, serum total 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 research-related questionnaires; provide signed informed consent; and

(8) Endoscopy with screening photographs demonstrating intraepithelial eosinophilic infiltration (peak cell count ≥15 eos/p/sp) 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 not eligible to participate in this study: (1) prior participation in a dupilumab (anti-IL-4R antibody) clinical trial; (2) Other causes of esophageal eosinophilia or the following: 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 prior to screening; (4) Any esophageal stricture that cannot be seen with a standard adult diagnostic endoscope (9 to 10 mm) or any critical esophageal stricture that requires dilatation at screening; (5) a history of bleeding or esophageal varices; (6) Continuous use of aspirin, non-steroidal drugs, or anticoagulants within 2 weeks prior to screening. Patients do not have to stop taking these drugs solely to be eligible for this study; (7) Treatment with investigational drug for 2 months or 5 half-lives (if known), whichever is longer, prior to screening; (8) Use of systemic corticosteroids within 3 months or topical corticosteroids by ingestion within 6 weeks prior to screening; (9) Use of inhaled or nasal corticosteroids within 3 months prior to screening and during the study, except for a stable dose for at least 3 months prior to biopsy screening, which cannot be changed during the study; (10) Treatment with oral immunotherapy (OIT) within 6 months prior to screening; (11) Allergen immunotherapy (sublingual immunotherapy [SLIT] and/or subcutaneous immunotherapy [SCIT] unless a stable dose was taken for at least 1 year prior to screening; (12) The following treatments within 3 months prior to screening attendance or any other condition that, in the opinion of the investigator, is likely to require such treatment(s) within 3 months of investigational treatment: systemic immunosuppressants/immunomodulators (eg, omalizumab, cyclosporine, mycophenolate mofetil, interferon-gamma [IFN-γ], Janus kinase inhibitors, azathioprine, methotrexate, leukotriene inhibitors [other than stable dose for at least 3 months prior to screening], etc.) (13) with diagnosed active parasitic infection, suspected parasitic infection if no clinical and ( if necessary) laboratory evaluation ruled out active infection prior to randomization; (14) chronic or acute infection requiring treatment with systemic antibiotics, antiviral drugs aratami or antifungal drugs within 1 month before screening; (15) use of oral antibiotics/anti-infectives within 2 weeks prior to screening; (16) Known or suspected immunosuppression, including a history of opportunistic invasive infections (eg, tuberculosis, non-tuberculous mycobacterial infections, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis), despite elimination of the infection, or other recurrent infections of abnormal frequency, prolonged or prolonged infections suggesting a weakened immune state, according to the researcher; (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]) more than 3 times upper limit of normal (> 3x upper limit of normal [ULN]) at screening; (20) history of malignancy within 5 years prior to screening, excluding completely healed in situ cervical carcinoma and completely healed and eliminated non-metastatic squamous or basal cell carcinoma of the skin; (21) patients' history of reporting that they had abused alcohol or drugs in the 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, suggests a new and/or poorly understood disease, may pose an unreasonable risk to the patient under investigation, as a result of which his/her participation in this clinical study may make patient participation unreliable or may interfere with study evaluation. The specific rationale for patients excluded by this criterion will be noted in the study documents (chart notes, case report form [CRF], etc.); (23) severe comorbid condition(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 next of kin are members of the study group; (27) pregnant or lactating women or women planning to become pregnant or breastfeeding during the study; (28) Women unwilling to use adequate birth control if they are of reproductive potential* and sexually active.

Investigational treatment

[00153] Investigational drug: dupilumab SC, loading dose of 600 mg 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, an anti-IL-4R monoclonal antibody) SC, volume corresponding to the loading dose of dupilumab on day 1, followed by weekly doses corresponding to the volume of the weekly dose of dupilumab with 1st to 11th week.

[00155] Patients received SC dupilumab 300 mg or matching placebo qw during a 12-week double-blind treatment phase. Patients received 2 injections (initial dose of 300 mg followed by a loading dose of 300 mg) on Day 1 followed by weekly injections.

Approved (Concomitant) Medicines

[00156] Treatment with concomitant medications was allowed during the study. This included contraceptive treatment, a stable dose of proton pump inhibitors (PPIs) (patients who used PPIs at screening did not stop or change their dosing regimen until the end of treatment [EOT]); stable dose (at least 3 months prior to screening) of systemic leukotriene inhibitors, topical, nasal, and/or inhaled corticosteroids; oral antihistamines for any period; and oral antibiotics for up to 2 weeks.

Medicines and procedures with limited use

[00157] Drugs with limited use during the study period included: (1) Drugs used to treat EoE (these were considered emergency drugs): topical corticosteroids for ingestion, systemic corticosteroids, initiation or dose change of systemic leukotriene inhibitors, topical, nasal and/or inhaled corticosteroids and systemic treatment of EoE with 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 was stable for 1 year or more; however, OIT was prohibited); (3) Patients who had not used a PPI in the 8 weeks prior to screening were prohibited from starting PPI therapy prior to the EOT visit; (4) Treatment with live (attenuated) vaccine against (Chickenpox (chickenpox), FluMist-Influenza, Intranasal influenza, Measles (rubeola), combined measles-mumps-rubella, combined measles-mumps-rubella-varicella, mumps, oral polio (Sabin), oral typhoid, rubella, smallpox (vaccinia), yellow fever, tuberculosis vaccine (Bacille Calmette-Guerin), varicella (shingles), rotavirus); and (5) treatment with an investigational medicinal product (other than dupilumab)

[00158] The following concomitant procedures were prohibited during study treatment (up to week 12): (1) Major elective surgical procedures; (2) dilatation of the esophagus (considered an emergency procedure); and (3) dietary modification (patients were required to remain on a stable diet for at least 6 weeks prior to screening and throughout the study; 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's Dysphagia Assessment (SDI) score from Patient Reports (PRO) from baseline to week 10.

[00160] Secondary endpoints were: percent change in weekly PRO score of eosinophilic esophagitis activity score (EEsAI) from baseline to week 10; 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 quality of life score for adult eosinophilic esophagitis (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 from baseline; Percentage of patients who achieved improvement in EEsAI score ≥ 40% from baseline by week 10; Percentage change in total peak intraepithelial eos/n/sp (400X) of the esophagus from baseline to week 12; Change in Endoscopic Eosinophilic Esophagitis Reference Score (EoEEREFs) (endoscopic visual anatomical assessment) from baseline to week 12; Percentage of patients using lifesaving drugs or procedures (eg, esophageal dilatation) before week 12; and the incidence of adverse events occurring during treatment (TEAE).

[00161] The efficacy endpoints of the study were: change in the mean number of intraepithelial eosinophils in the esophagus (eos/n/sp) [calculated using peak values for each esophageal site] from baseline to week 12; Proportion of patients who achieve intraepithelial eosinophils of the esophagus <1 eos/p/sp at week 12; Change in Collins histological score from baseline to week 12; and change in esophageal compliance plateau as measured by functional lumen imaging from baseline to week 12.

Procedures and assessments

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

[00163] Efficiency Procedures. Efficacy was assessed during the study at selected clinic visits using a patient outcome assessment (PRO) including the Strauman Dysphagia Rating Scale (SDI), Eosinophilic Esophagitis Activity Score (EEsAI), and Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QOL-A). ), as well as a biopsy of the esophagus and photographs (an endoscopy procedure). The measurement of inflammatory and remodeling features of the esophagus based on scoring signs of eosinophilic esophagitis such as edema, rings, exudates, furrows and strictures (EoE-EREFS) was included as part of the endoscopy procedure. An endolumenal functional luminal imaging (EndoFLIP) procedure to measure esophageal compliance was performed during endoscopy procedures. EoE Histological Score Scale (HSS) was used to measure 8 histological features of EoE.

Strauman Dysphagia Scale - Patient Assessment of Outcome

[00164] SDI is a non-validated PRO that has been used in clinical studies to determine the frequency and intensity of dysphagia (Straumann 2010). SDI has a 1 week evaluation period. The incidence of dysphagia 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 is rated on a 6- scoring scale: 0=swallowing without restriction, 1=slight sense of resistance, 2=mild vomiting 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. In the Straumann study, clinical response (improvement) was defined as a decrease in SDI score of at least 3 points from baseline.

[00165] This assessment was conducted by the patient weekly electronically in a questionnaire from the start of screening until the end of the study or early termination. The elements used to quantify the SDI have been included in the EEsAI/SDI.

Eosinophilic esophagitis activity index - evaluation of the result by the patient

[00166] EEsAI is a non-validated multi-module index under development at the University Hospital Inselspital (Bern, Switzerland) (Schoepfer 2014), part of the international EEsAI research group. The EEsAI PRO module (questionnaire) used in this study includes items related to the intensity and frequency of dysphagia, the effect of certain food groups on dysphagia symptoms, and other symptoms independent of food or drink (e.g., heartburn, acid regurgitation, and chest pain). cell). The overall EEsAI PRO score ranges from 0 to 100 (Figure 1), where higher scores indicate worse symptoms. The score consists of 5 parts: frequency of swallowing problems, duration of swallowing problems, swallowing pain, visual dysphagia question, and avoidance, change, and slow eating (AMS). EEsAI PRO uses 24 hour and 1 week evaluation periods.

[00167] This assessment was performed electronically by the patient daily and weekly on a questionnaire from the start of screening until the end of the study or early termination.

Questionnaire for assessing the quality of life in eosinophilic esophagitis in adults Assessment of the result by the patient

[00168] The EoE-QOL-A questionnaire is a validated indicator of health-related quality of life in patients with EoE (Taft 2011). The instrument used in this study, EoE-QOL-A v.3.0, includes 30 items related to established areas such as social functioning, emotional functioning, and the impact of disease on daily life. EoE-QOL-A has a 1 week evaluation period. Elements are rated on a 5-point scale: "Not at all", "A little", "Moderate", "A little" and "Extremely".

[00169] This score was recorded by the patient in a questionnaire at the beginning of the study, and then monthly until the end of the study or early termination.

Endoscopy with biopsy of the esophagus and photographs

[00170] Biopsies of the esophagus were obtained by endoscopy at screening and week 12 visits. Screening endoscopy was performed during the screening period to allow results to be available before day -1 to assess eligibility for inclusion. At each time point, 9 mucosal biopsies were taken from 3 sections of the esophagus: 3 proximal, 3 middle and 3 distal. Two samples from each department were used for histology (required for inclusion criteria and also for the secondary endpoint). To participate in the study, patients had to have a peak intraepithelial eosinophil count ≥ 15 eos/p/sp (400X) in at least 2 of the 3 selected esophagus regions. Eoz peak change. esophagus/n/sp (400X) from baseline to week 12 was the secondary endpoint; this was determined by counting the eosinophils in the most inflamed areas of each esophagus sampled at each time point and calculating the change in the number of peaks at each site obtained at baseline compared to the number obtained at week 12. As a research objective, the change in the mean value of all three peak values, i.e. the peak amount in each of the 3 esophageal compartments for each patient at each time point (screening and 12th week), was calculated. 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 and remodeling of the esophageal mucosa. This tool includes 17 items related to the presence and severity of signs of the esophagus. Specific features of the esophagus include: rings (concentric rings around the esophagus - none, light, medium, heavy, not applicable); strictures (narrowing of the esophagus - yes, no, not applicable); stricture diameter (if applicable); exudates (see white plaques - absent, light, heavy), furrows (vertical lines down the esophagus - absent, present); edema (loss of vascular marks on the mucous membrane - absent, present); esophagus type "corrugated paper" (absent, present); final general appearance including all endoscopically identified EoE findings (i.e., fixed rings, strictures, whitish exudate, sulci, edema, and crepe paper mucosa). In addition, mucosal changes associated with gastroesophageal reflux disease were also recorded using the Los Angeles erosion classification system (no erosions or LA classification A, B, C, D). Characteristics of esophageal EoE were analyzed based on the EoE-EREFS, a validated scoring scale for inflammatory and remodeling disease features, 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 more deterioration. Each score included: Edema: 0-1; Rings: 0-3; Exudates: 0-2; Furrows: 0-1; and Strictures: 0-1, giving an overall possible score of 8.

[00172] Evaluation of esophageal distensibility using an endolumenal functional lumen imaging probe (EndoFLIP, Crospon, Ireland) was also performed to measure lumen diameter and pressure in the esophagus (e.g., esophageal stiffness) as part of the screening endoscopy procedure. and at 12 weeks. The EndoFLIP device is a catheter-based procedure that measures cross-sectional area at multiple locations along the esophagus while recording intraluminal pressure during esophageal volumetric distension. Analysis of the cross-sectional area as a function of the pressure of the esophagus allows you to determine the plasticity of the esophagus, as well as the distensibility plateau (DP). DP has been shown to be significantly reduced in EoE patients compared to healthy controls (Kwiatek 2011). In addition, esophageal distensibility has been associated with the consequences of both obstructed passage of food through the esophagus and the need for esophageal dilatation (Nicodème 2013).

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

[00174] Photographs were taken in sections as part of the endoscopic procedure and biopsy taking.

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

[00176] A serious adverse event (SAE) is any adverse medical event that, at any dose, results in death, is life-threatening, requires inpatient hospitalization, results in permanent or significant disability/disability, is a congenital anomaly/birth defect, and/or is an important 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 studies, vital signs, electrocardiograms (ECGs), clinical laboratory tests, and clinical assessments. Patients were asked to monitor all AEs observed from 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 analyses.

results

[00179] Baseline characteristics: Patients were randomized in a 1:1 ratio to receive a subcutaneous (SC) loading dose of 600 mg dupilumab or placebo SC followed by weekly administration of SC 300 mg of dupilumab or placebo SC during a 12-week double-blind treatment phase. Randomization was stratified by the baseline Strauman Dysphagia Rating Scale (SDI) PRO (≥5 and ≤7 vs. >7). Baseline demographic and disease characteristics were generally balanced between the two groups (Tables 1-2), except for mean total IgE (dupilumab 217.8 kU/L; placebo 468.2 kU/L).

Table 1: Baseline demographic summary

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 0 0 Male sex, n (%) 10 (41.7%) 13 (56.5%) Race: white, n (%) 21 (87.5%) 23 (100%) BMI (average value kg/m2) thirty 27.7

Table 2: Summary of baseline disease characteristics

Placebo (N=24) 300 mg dupilumab qw
(N=23) Age at the time of EoE manifestation, 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 EoE years 5.0 3.6 Blood eosinophils (SD) billion/l 0.43 (0.3) 0.31 (0.2) Average 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) Weekly EEsAI score (0-100) 62.2 62.0 Mean total peak eosinophils/n/sp (SD) 101.1 (57.1) 102.1 (53.5) Rating scale for EoE-specific histological features (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 Previous treatment with high dose PPI, n (%) 24 (100%) 23 (100%) Previous use of topical corticosteroids, n (%) 20 (83.3) 18 (78.3) Prior dilatation, n (%) 10 (41.7) 11 (47.8) Number of previous esophageal dilatations (SD) 3.9 (3.3) 5.7 (8.0) Any concomitant disease, n (%) 19 (79.2) 20 (87.0)

[00180] Both groups showed a high level of atopic disease (Table 3).

Table 3: Summary of personal history of EoE/allergic disease

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 (drugs, 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] Performance Results: Table 4 summarizes the primary and secondary endpoint results. Dupilumab significantly improved subjective EoE measures of dysphagia, as well as objective histological and endoscopic disease measures in EoE, compared with placebo. During the 12-week double-blind treatment period, no patient received emergency medications/procedures.

Table 4: Outcomes - Primary and Secondary Endpoints*

end point Placebo1 (N=24) 300 mg dupilumab qw1
(N=23) Mean Difference LS versus 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 EoE-QOL-A PRO change 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 a decrease of at least 3 SDI points 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 intraepithelial esophageal eosinophils/per visual field (eos/p/sp) (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 of both baseline and subsequent values

* For continuous variables, multiple missing data substitution/ANCOVA was used, LS (SE) was introduced; for binary variables, patients with missing data were considered non-responders and Fisher's exact test was used for comparison, and the number and % of responders were reported.

** For secondary endpoints, all p-values were nominal

[00182] Dupilumab improved the Strauman Dysphagia Rating Scale (SDI) score compared to placebo (-3 vs -1.3, P=0.0304; 45.05% vs 18.59%, P=0.0312) by week 10 (Table 4, Figure 2). 39% of patients treated with dupilumab achieved ≥3 reductions in SDI compared to 12.5% in the placebo group at week 10. At both weeks 10 and 12, dupilumab improved both the incidence and severity of dysphagia on the SDI scale (Figure 3).

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

[00184] Dupilumab significantly reduced peak eosinophils (eos/n/sp) from baseline to week 12 compared with placebo [-94.1 (-91.8%) vs -7.4 (+15.1%) , P<0.0001] (Tables 4 and 6). A decrease in tissue infiltration by eosinophils was observed in all patients in the dupilumab group (Table 5). The effect of dupilumab was similar for the proximal, middle, and distal esophagus.

Table 5: Responder Analysis

Peak Eoz (eos/p/sp) at week 12 Proportion of patients responding at week 12, n (%) 300mg 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 (mean change in LS p=0.0006, mean change in LS p=0.0004) (Table 4). Dupilumab significantly reduced the overall EREFS score as well as the exudate and sulcus subcomponents, with trends observed for the edema subcomponents, rings, and strictures (Figure 5).

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

[00187] Dupilumab significantly improved esophageal compliance at week 12 compared to placebo (Table 6). An increase (improvement) in the compliance plateau was observed in more patients treated with dupilumab compared to placebo (Figure 12).

[00188] Table 6 summarizes the effect of dupilumab on subjective patient outcomes, on dysphagia, and on objective measures assessed by clinicians.

Table 6: Efficacy of dupilumab on subjective and objective EoE measures

PBO
(N=24) Dupilumab 300 mg qw
(N=23) least squares mean difference vs. PBO (95% CI) SDI scoring baseline score, mean (± SD) 6.4 (1.01) 6.4 (1.04) Week 10 n=14 n=17 Change in RMS 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 % RMS change from baseline (± SE) -11.3 (9.9) -34.6 (9.1) -23.2 (-49.7, 3.2)# Peak number of intraepithelial eosinophils (eos/p/sp) baseline score, mean (± SD) 101.1 (57.1) 102.1 (53.5) Week 12 n=22 n=22 Change in RMS values from baseline (± SE) -7.4 (9.61) -94.1 (9.52) % RMS change from baseline (± SE) 15.1 ( 12.5) -91.8 ( 12.3) -106.9 (-141.4, -72.5)*** Patients with response <6 eos/n/sp, n (%) 0.0 14 (60.9) Patients with response <15 eos/n/sp, n (%) 0.0 18 (78.3) EoE-EREFS scoring baseline score, mean (± SD) 4.3 (1.46) 3.9 (1.87) Week 12 n=22 n=23 Change in RMS 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, % RMS change from baseline (± SE) 2.7 (5.3) -57.0 (5.3) -59.7 (-74.3, -45.1)*** Mean, % change in RMS from baseline (± SE) -8.1 (7.0) -70.8 (6.8) -62.7 (-81.7, -43.7)*** Proximal, % change in RMS 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, % RMS change from baseline (± SE) 5.1 (6.3) -50.6 (6.3) -55.6 (-73.2, -38.1)*** Mean, % change in RMS from baseline (± SE) -18.4 (5.7) -62.0 (5.5) -43.5 (-59.1, -28.0)*** Proximal, % change in RMS values from baseline (± SE) 43.1 (21.6) -46.9 (19.2) -90.0 (-146.5, -33.5)*** Tensile Plateau (mm) Baseline, mean (± SD) 17.60 (2.879) 18.66 (3.799) Week 12 n=12 n=12 % change in RMS 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. SDI is a 9-item measure of dysphagia; score range 0-9 with higher scores indicating worse symptoms. EEsAI is a 5-item measure of dysphagia; score range 0-100 with higher scores indicating worse symptoms. The EoE-Specific Histological Features Scoring Scale (EoEHSS) measures eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophilic surface stratification, superficial epithelial changes, non-keratized epithelial cells, and dilated intercellular spaces. The intrinsic plate was excluded from the analysis because ~50% of the captured biopsies were not deep enough to be assessed. Esophageal compliance plateau is measured with a functional esophageal sphincter imaging probe (EndoFLIP, ® Crospon), a probe using impedance planimetry. Continuous efficacy endpoints were analyzed in the full analysis set (FAS) using multiple missing data substitutions (MI) followed by covariance model analysis (ANCOVA) with treatment group as fixed effect and baseline SDI and corresponding baseline value as covariates. LS, least squares; qw, every week.

[00189] Safety results: dupilumab was well tolerated by patients with EoE. The most common treatment-emerging adverse events (TEAEs) were injection site erythema (dupilumab 34.8%, placebo 8.3%) and nasopharyngitis (dupilumab 17.4%, placebo 4.2%).

Conclusion

[00190] Compared to placebo, dupilumab demonstrated a statistically significant reduction in the primary endpoint, change from baseline on the Strauman Dysphagia Rating Scale (SDI) at week 10, mean LS difference from change from baseline at week 10 between the dupilumab and placebo groups was -1.7 (p=0.0304). There were also improvements in other subjective measures of dysphagia, including EEsAI (at week 10) and EOE-QOL (at week 12). Finally, there were statistical improvements in both histological and visual endoscopic objective measures of disease activity, including percentage change from baseline in peak eosinophils and absolute change from baseline in features of eosinophilic esophagitis such as edema, rings, exudate, sulci, and stricture (EoE-EREFS) at 12 weeks. Treatment with dupilumab was generally safe and well tolerated. The most common TEAEs were mild ISRs and viral infections of the upper respiratory tract 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 accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

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<---

Claims (25)

1. A method for increasing esophageal distensibility in a patient having eosinophilic esophagitis (EoE), comprising: (a) selecting a patient having an EoE that has a baseline level of ≥ 15 eosinophils per visual field (p/p) in the esophagus where the patient has previously been treated with proton pump inhibitors (PPIs) and has had at least one prior esophageal dilatation; and (b) administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising an inhibitor of the interleukin-4/interleukin-13 (IL-4/IL-13) pathway, wherein the IL-4/IL-13 pathway inhibitor is an antibody or an antigen-binding fragment thereof, which bind to IL-4Rα, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDR) of the heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDR) of the variable light chain region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. 2. The method according to p. 1, characterized in that the patient is ≥12 years old. 3. The method according to claim 1 or 2, characterized in that the patient is ≥18 years old. 4. The method according to any one of paragraphs. 1-3, characterized in that the patient has a concomitant disease or condition selected from the group consisting of food allergy, non-food allergy, atopic dermatitis, asthma, chronic sinusitis, urticaria, allergic rhinitis and allergic conjunctivitis. 5. The method according to any one of paragraphs. 1-4, characterized in that 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 chemokine thymus-regulated and activated (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP), and/or eosinophil-derived neurotoxin (EDN). 6. The method according to any one of paragraphs. 1-5, characterized in that the introduction of an inhibitor of the IL-4/IL-13 pathway leads to an increase of at least 10% from the initial level of distensibility of the esophagus, measured using a functional imaging probe. 7. The method according to any one of paragraphs. 1-6, characterized in that the inhibitor of the IL-4/IL-13 pathway is administered at a dose of from about 50 to about 600 mg. 8. The method according to any one of paragraphs. 1-7, characterized in that the IL-4/IL-13 pathway inhibitor is administered at a dose of about 300 mg. 9. The method according to any one of paragraphs. 1-8, characterized in that the IL-4/IL-13 pathway inhibitor is administered at an initial dose followed by one or more secondary doses, with each secondary dose administered 1-4 weeks after the immediately preceding dose. 10. The method of claim. 9, characterized in that the initial dose contains 50-600 mg of an inhibitor of the IL-4/IL-13 pathway. 11. The method according to claim 9 or 10, characterized in that each secondary dose contains 25-400 mg of an inhibitor of the IL-4/IL-13 pathway. 12. The method according to any one of paragraphs. 9-11, characterized in that the initial dose contains 600 mg of an IL-4/IL-13 pathway inhibitor and each secondary dose contains 300 mg of an IL-4/IL-13 pathway inhibitor. 13. The method of any of paragraphs. 9-12, characterized in that each secondary dose is administered one week after the immediately preceding dose. 14. The method according to any one of paragraphs. 9-12, characterized in that each secondary dose is administered 2 weeks after the immediately preceding dose. 15. The method according to any one of paragraphs. 1-14, characterized in that the patient has an allergic reaction to a food allergen contained in a food product, where the food product is selected from the group consisting of a dairy product, eggs, wheat, soy, corn, fish, seafood, peanuts, nuts, beef, chicken, oats, barley, pork, green beans, apples and/or pineapples. 16. The method according to any one of paragraphs. 1-14, characterized in that the patient has an allergic reaction to a non-food allergen derived from dust, pollen, mold, plant, cat, dog or insect. 17. The method according to any one of paragraphs. 1-16, characterized in that the inhibitor of the IL-4/IL-13 pathway is administered in combination with a second therapeutic agent or therapy, where the second therapeutic agent or therapy is selected from the group consisting of an IL-1beta inhibitor, an IL-5 inhibitor, an inhibitor IL-9, IL-13 inhibitor, IL-17 inhibitor, IL-25 inhibitor, TNF-alpha inhibitor, eotaxin-3 inhibitor, IgE inhibitor, prostaglandin D2 inhibitor, immunosuppressant, topical corticosteroid, oral corticosteroid, systemic corticosteroid, inhaled corticosteroid, glucocorticoid, proton pump inhibitor, NSAID, esophageal dilatation, allergen removal and/or diet control. 18. The method according to any one of paragraphs. 1-17, characterized in that the antibody or its antigen-binding fragment contains three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where HCDR1 contains the amino acid sequence of SEQ ID NO: 3; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7; and LCDR3 contains the amino acid sequence of SEQ ID NO: 8. 19. The method according to any one of paragraphs. 1-18, characterized in that HCVR contains the amino acid sequence of SEQ ID NO: 1, and LCVR contains the amino acid sequence of SEQ ID NO: 2. 20. The method according to any one of paragraphs. 1-19, characterized in that the antibody or its antigen-binding fragment contains a heavy chain containing the amino acid sequence of SEQ ID NO: 9, and a light chain containing the amino acid sequence of SEQ ID NO: 10. 21. The method according to any one of paragraphs. 1-20, characterized in that the inhibitor of the IL-4/IL-13 pathway is dupilumab or its bioequivalent. 22. The method according to any one of paragraphs. 1-21, characterized in that the IL-4R/IL-13 pathway inhibitor is administered subcutaneously.

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