JP7417515B2 - How to treat active eosinophilic esophagitis - Google Patents

Description

This application is filed as PCT International Patent Application No. 62, filed on August 3, 2018, and U.S. Provisional Patent Application No. /541242, claims priority benefit to U.S. Provisional Patent Application No. 62/561593, filed September 21, 2017, and European Application No. 18305252.1, filed March 8, 2018. .

The present invention relates to the use of interleukin-4/interleukin-13 pathway inhibitors to treat or prevent active eosinophilic esophagitis in a subject in need thereof.

Esophageal stricture (narrowing) results from damage to the lining of the esophagus, resulting in difficulty swallowing (dysphagia), regurgitation of food or liquids, heartburn, and unintended weight loss, among other things. Treatment of esophageal stricture is very important as it reduces quality of life due to dysphagia, weight loss, and nutritional imbalance. Esophageal strictures are caused by chronic ulcers or chronic inflammation, as a complication of chemotherapy, radiation therapy, esophageal cancer or endoscopic surgery, peptic ulcers or gastroesophageal reflux. Esophageal stricture is also caused by eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an emerging chronic immune/antigen-mediated disease characterized by esophageal dysfunction and eosinophilic inflammation of the esophagus. Patent Document 3). Adult patients with EoE have a significantly impaired quality of life (QOL) due to dysphagia and the possible risk of food fragment intrusion. Reference 7). Patients with active disease or moderate to severe EoE suffer from esophageal strictures that lead to difficulty swallowing, regurgitation of food or liquids, and weight loss. Urgent endoscopy for long-term food pellet injection is associated with the risk of severe esophageal injury. EoE has been found to be associated with food allergies in a large number of patients. Some patients may also have concurrent asthma or atopic diseases, such as atopic dermatitis, or allergic rhinitis. The symptomatic burden of EoE, such as food avoidance, dietary modification behaviors, and social, emotional, economic, work and school, and sleep impacts are also important and relevant in the EoE population. If improved, it may reflect the effectiveness of treatment for EoE patients.

Liacouras et al., 2011, The Journal of Allergy and Clinical Immunology. Volume 128: 3-20 e6; quiz 1-2 Weinbrand-Goichberg et al., 2013, Immunologic Research. Volume 56: pages 249-60 Zhang et al., 2013, Digestive Diseases and Sciences 58: 1497-506 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.

Current therapeutic approaches include chronic dietary elimination (including food allergen withdrawal), swallowed topical corticosteroids (not approved for the treatment of EoE in the United States), and esophageal dilatation. Swallowed topical corticosteroids have been reported in clinical trials to induce partial clinical responses and histological remissions, but they are not uniformly effective and reduce fungal infections, as well as disease recurrence after discontinuation. associated with. There are currently no approved drug treatments for EoE. Therefore, there is an unmet need in the art for an effective therapeutic approach without harmful side effects to prevent or treat eosinophilic esophagitis. Esophageal strictures are treated with proton pump inhibitors, which inhibit gastric acid secretion. Endoscopic esophageal dilation is currently used to treat esophageal strictures and increase esophageal distensibility. However, it is an invasive surgical procedure and can lead to complications such as perforation and bleeding. Therefore, there is an unmet need for safe and effective treatments to increase esophageal distensibility and treat esophageal strictures (eg, in eosinophilic esophagitis).

According to one aspect of the invention, a method of increasing esophageal distensibility is provided. According to this aspect, the method includes the steps of: (a) selecting a patient with moderate to severe eosinophilic esophagitis (EoE), the patient in need thereof comprising: (i) the patient have at least 15 eosinophils per high power field (hpf) in the esophagus before or at the time of treatment (“baseline”); (ii) patient has at least one episode of dysphagia per week; and (iii) the patient has an attribute or is selected based on criteria selected from the group consisting of having a Straumann Dysphagia Instrument (SDI) score of 2 or more; and (b) administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibitor, thereby , including increasing esophageal distensibility as measured by a functional luminal imaging probe (EndoFLIP®, Crospon, Ireland). In one embodiment, the patient has active EoE. In one embodiment, the patient is 18 years of age or older. In one embodiment, the patient has been previously treated with a proton pump inhibitor (PPI). In one embodiment, the patient has previously undergone esophageal dilatation at least once. In one embodiment, the patient has previously received treatment with at least one of: (1) a PPI, esophageal dilatation, corticosteroids, allergen withdrawal, and/or dietary modification; (3) the patient has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score of 30 or higher, 40 or higher, or 50 or higher. (4) the patient has had EoE for at least 3 years; (5) the patient has had food allergies, atopic dermatitis, (6) the patient has or has been diagnosed with a disease or disorder selected from the group consisting of asthma, allergic rhinitis, and allergic conjunctivitis; IL-13, IL-5, serum thymic and activation-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP), and eosinophil-derived neurotoxin (EDN).

In embodiments of the invention specifying the selection of "at least one selected from the group consisting of" or simply "selected from the group consisting of", between the last two items of the list following such words, etc. The use of the conjunction "and/or" indicates that the items in that order are alternatives to each other and that one (or more) of these items is selected. This does not mean that each item is necessarily selected. For example, for methods of increasing esophageal distensibility, patients should:
(1) Previous treatment with at least one of PPI, esophageal dilatation, corticosteroids, allergen withdrawal, and/or dietary modification;
(2) the patient is unresponsive or resistant to previous treatment with PPIs or esophageal dilatation;
(3) the patient has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score of 30 or higher, 40 or higher, or 50 or higher;
(4) the patient has had EoE for at least 3 years;
(5) The patient is selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and/or allergic conjunctivitis before or at the time of administration of the IL-4/IL-13 pathway inhibitor. having or being diagnosed with a disease or disorder; and/or (6) the patient has an active at least one selected from the group consisting of stimulant-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP), and/or eosinophil-derived neurotoxin (EDN). having at least one characteristic selected from the group consisting of elevated levels of a biomarker;
What is meant is that the patient has at least characteristic (1) or characteristic (2) or characteristic (3) or characteristic (4) or characteristic (5) or characteristic (6). Based on these words, patients can also identify six characteristics (e.g., (1) and (2), or (4) and (5), or (1), (2), and (6), etc.). can have one or more of these. However, this does not mean that the patient must have at least characteristic (1) and characteristic (2) and characteristic (3) and characteristic (4) and characteristic (5) and characteristic (6).

According to another aspect of the invention, a method of treating, preventing or ameliorating at least one symptom or sign of active eosinophilic esophagitis (EoE) in a subject is provided. The method according to this aspect of the invention comprises the steps of selecting a patient with moderate to severe EoE, and comprising a therapeutically effective amount of an interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibitor. the pharmaceutical composition to a patient in need thereof. In certain embodiments, a patient in need thereof provides that: (1) the patient has 15 or more eosinophils per high power field (hpf) in the esophagus before or at the time of treatment ("baseline"); (2) prior treatment with at least one of high-dose proton pump inhibitors (PPIs), esophageal dilatation, corticosteroids, allergen withdrawal, and/or dietary modification; (3) patient (4) the patient is unresponsive or refractory to previous treatment with high-dose PPIs or esophageal dilatation; (5) the patient has a Schraumann dysphagia of 5 or more. (6) the patient has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score of 30 or higher, 40 or higher, or 50 or higher; (7) the patient (8) the patient has had food allergy, atopic dermatitis, asthma, allergic rhinitis before or at the time of administration of the IL-4/IL-13 pathway inhibitor; and (9) the patient has or has been diagnosed with a disease or disorder selected from the group consisting of: 13, consisting of IL-5, serum thymic and activation-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP), and eosinophil-derived neurotoxin (EDN) The selection is based on an attribute or criterion selected from the group consisting of: elevated levels of a biomarker selected from the group.

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

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

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

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

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

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

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

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

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

In certain embodiments, the invention provides antibodies that bind to IL-4R or antigen-binding antibody fragments thereof in the manufacture of a medicament for treating or inhibiting or preventing active eosinophilic esophagitis in a subject, including a human. provide the use of

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

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

Other embodiments of the invention will become apparent from consideration of the following detailed description.

FIG. 4 lists components including weekly Eosinophilic Esophagitis Severity and Activity Index (EEsAI) scores. FIG. 3 shows the mean change from baseline in Straumann Dysphagia Instrument (SDI) scores during the 12-week treatment period in patients receiving 300 mg dupilumab once weekly (qw) vs. placebo. Figure 2 shows the mean percent change from baseline in the dysphagia frequency and severity components of the Straumann Dysphagia Instrument (SDI) score at Weeks 10 and 12 during administration of once-weekly (qw) 300 mg dupilumab versus placebo. It is a diagram. FIG. 3 shows the mean percent change from baseline in EEsAI scores during the 12-week treatment period in patients receiving 300 mg dupilumab once weekly (qw) versus placebo. Changes from baseline in total EoE edema, rings, effusions, grooves and strictures (EREFS) scores and subcomponents of EREFS scores at week 12 in patients receiving 300 mg dupilumab once weekly (qw) vs. placebo It is a figure which shows the average of a percentage. Figure 2 shows the mean change from baseline in total EoE Histology Scoring System (HSS) score for the grade (severity) subcomponent at week 12 in patients receiving 300 mg dupilumab once weekly (qw) vs. placebo. It is. FIG. 7 shows the mean change from baseline in stage (range) subcomponent total EoE HSS score at Week 12 in patients receiving 300 mg dupilumab once weekly (qw) vs. placebo. FIG. 8 is comprised of FIGS. 8A, 8B, 8C, and 8D. FIG. 8A shows the mean change from baseline in EoE HSS grade score for basal hyperplasia. FIG. 8B shows the mean change from baseline in EoE HSS grade score of eosinophil surface stratification. FIG. 8C shows the mean change from baseline in EoE HSS grade score of eosinophilic inflammation. Figure 8D shows EoE HSS grading scores for eosinophilic abscesses in the proximal, middle, and distal regions of the esophagus sampled at week 12 from patients receiving 300 mg dupilumab once weekly (qw) versus placebo. Mean change from baseline is shown. FIG. 9 is comprised of FIGS. 9A, 9B, 9C, and 9D. Figure 9A shows the mean change from baseline in EoE HSS stage score of basal hyperplasia. Figure 9B shows the mean change from baseline in EoE HSS stage scores for eosinophilic abscesses. Figure 9C shows the mean change from baseline in EoE HSS stage score of eosinophilic inflammation. Figure 9D shows EoE HSS stage scores of the eosinophil surface layer of the proximal, middle, and distal regions of the esophagus sampled at week 12 from patients receiving 300 mg dupilumab once weekly (qw) vs. placebo. Mean change from baseline is shown. FIG. 10 is comprised of FIGS. 10A, 10B, and 10C. FIG. 10A shows the mean change from baseline in EoE HSS grade score of dilated intercellular spaces. Figure 10B shows the mean change from baseline in EoE HSS grade scores for surface changes, and Figure 10C shows the mean change from baseline in EoE HSS grade scores for surface changes, and Figure 10C shows the mean changes from baseline in EoE HSS grade scores for esophageal changes sampled at week 12 from patients receiving 300 mg dupilumab once weekly (qw) versus placebo. Shown is the mean change from baseline in EoE HSS grade scores for apoptotic epithelial cells in the proximal, intermediate, and distal regions. FIG. 11 is comprised of FIGS. 11A, 11B, and 11C. FIG. 11A shows the mean change from baseline in EoE HSS stage score of dilated intercellular spaces. Figure 11B shows the mean change from baseline in EoE HSS stage scores for surface changes, and Figure 11C shows the mean change from baseline in EoE HSS stage scores for surface changes, and Figure 11C shows the mean changes from baseline in EoE HSS stage scores for esophageal changes sampled at week 12 from patients receiving 300 mg dupilumab once weekly (qw) versus placebo. Mean change from baseline in EoE HSS stage scores for apoptotic epithelial cells in the proximal, intermediate, and distal regions is shown. FIG. 4 shows the percent change from baseline in extensibility plateau at week 12 in patients receiving 300 mg dupilumab once weekly (qw) vs. placebo.

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

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about" when used in reference to a particular recited numerical value means that the numerical value may vary by less than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101, and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.). It will be done.

Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference to be described in their entirety.

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

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

As used herein, the term "active EoE" means that a patient exhibits eosinophil/high power fields (hpf) in esophageal biopsies even after 8 weeks of treatment with proton pump inhibitors (PPIs). refers to EoE disease in patients with a score of 15 or more. The term also refers to EoE disease in patients who exhibit frequent dysphagia, eg, a patient has 2, 3, 4, 5, or more episodes of dysphagia per week. The term "active EoE" includes mild EoE, as well as moderate to severe EoE. The term "moderate to severe" refers to frequent episodes of eosinophilia (e.g., eosinophils/hpf in the esophageal mucosa >15) and dysphagia, as well as SDI scores >2 and/or EEsAI. Refers to EoE disease in patients who have a score of 30 or higher, have a duration of EoE of at least 2 years, and/or are unresponsive or resistant to previous treatments (including PPIs or esophageal dilatation).

As used herein, the expression "a subject in need thereof" refers to a subject exhibiting one or more symptoms or signs of eosinophilic esophagitis and/or eosinophilic esophagitis (EoE). means a human or non-human mammal diagnosed with Throughout this disclosure, the term "subject" is used interchangeably with the term "patient." The term "subject in need thereof" also includes, for example, one or more symptoms of EoE, e.g. overexpression of pro-inflammatory mediators such as mast cells in the esophagus, eosinophilia in the esophagus, etc. Patients who exhibit (or have had) bulbar infiltrates, esophageal wall thickening, dysphagia, food fragment intrusion, and chest and abdominal pain, and/or elevated levels of EoE-related biomarkers are included. The term specifically includes subjects who exhibit the presence of 15 or more eosinophils per high power field in the esophagus. In certain embodiments, the term includes elevated peripheral eosinophil counts (e.g., ≧100, ≧150, ≧200, or ≧300 cells/μl) or elevated serum IgE (>150 kU/L). Subjects are also included.

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

In the context of the present invention, a "subject in need thereof" may include a portion of the population that is more susceptible to EoE or can exhibit elevated levels of EoE-related biomarkers. For example, a "subject in need thereof" can include a subject suffering from an atopic disease or disorder, such as food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis. In certain embodiments, the term "subject in need thereof" includes food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic Includes patients who have or have been diagnosed with a disease or disorder selected from the group consisting of conjunctivitis. In certain embodiments, the term "subject in need thereof" can include patients with inherited connective tissue disorders. Such a subject population may exhibit elevated levels of EoE-related biomarkers, such as, for example, IgE, eotaxin-3, periostin, IL-5 or IL-13.

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

The term "allergen" as used herein includes any substance, chemical, particle or composition that is capable of stimulating an allergic response in a susceptible individual. Allergens can be contained in or derived from foods such as, for example, dairy products (eg, milk), eggs, wheat, soybeans, corn, rye, fish, shellfish, peanuts, and tree nuts. Alternatively, allergens include, for example, dust (including e.g. dust mites), pollen, insect toxins (e.g. bee, wasp, mosquito toxins, etc.), molds, animal dander, latex, pharmaceuticals, drugs, ragweed, grass and birch. can be contained within or derived from non-foods, such as;

In certain embodiments, the term "subject in need thereof" includes a portion of the population that exhibits an allergic reaction to a food allergen. For example, "subjects that require it" include, but are not limited to, dairy products, eggs, wheat, soybeans, corn, rye, fish, shellfish, peanuts, tree nuts, beef, chicken, oats, barley, pork, green beans, etc. and subjects with allergies to allergens contained in foods containing fruits, such as apples and pineapples.

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

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

In some embodiments, the methods herein are for the treatment of adults, adolescents, or children. Adults are 18 years or older, youth are 12 to 18 years old, and children are 12 years old or younger. In some embodiments, the methods herein can be used to treat EoE in children 3 years of age or younger. In one embodiment, inhibitors of the IL-4/IL-13 pathway are used to treat moderate to severe EoE in subjects that are not adequately controlled with standard therapeutic treatments (e.g., oral corticosteroids, dilation, etc.) do. The subjects are adults, adolescents or children.

The invention also includes a method of increasing esophageal distensibility. The method according to this aspect of the invention comprises administering one or more doses of a pharmaceutical composition comprising an IL-4/IL-13 pathway inhibitor to a patient in need thereof, thereby reducing the esophageal including increasing extensibility.

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

As used herein, "eosinophil infiltration" refers to the presence of eosinophils in an organ or tissue, including the blood, esophagus, stomach, duodenum, and ileum of a subject. In the context of the present invention, the term "eosinophilic infiltration" means the presence of eosinophils in the mucosal lining of regions of the gastrointestinal tract, including, but not limited to, the esophagus and stomach. Eosinophil infiltration is analyzed, for example, in esophageal tissue biopsies of subjects suffering from EoE. According to certain embodiments, "eosinophil infiltration" refers to the presence of 15 or more eosinophils per high power field in the esophagus. The term "high power field" refers to the standard total magnification of 400x on a microscope used to observe eosinophils in tissue, eg, tissue from a subject's esophagus. In certain embodiments, "eosinophil infiltration" includes infiltration of a tissue by leukocytes, such as lymphocytes, neutrophils, and mast cells. For example, leukocyte infiltration into esophageal tissue is associated with eosinophil-specific markers (e.g., CD11c ^Low/Neg , SiglecF ⁺ , F4/80 ⁺ , EMR1 ⁺ , Siglec 8 ⁺ and MBP2 ⁺ ), macrophage-specific markers (e.g., CD11b ⁺ , F4/80 ⁺ , CD14 ⁺ , EMR1 ⁺ and CD68 ⁺ ), neutrophil-specific markers (e.g. CD11b ⁺ , Ly6G ⁺ , Ly6C ⁺ , CD11b ⁺ and CD66b ⁺ ) and T cell-specific markers (e.g. , CD3 ⁺ CD4 ⁺ CD8 ⁺ ).

As used herein, esophageal eosinophil depletion refers to eosinophils and other leukocytes measured in the esophagus of subjects who have EoE and are treated with IL-4/IL-13 pathway inhibitors. the number of eosinophils is at least 5%, 10%, 20%, 50%, 70% greater than the number of esophageal eosinophils measured in the same or similar subject not treated with an IL-4/IL-13 pathway inhibitor; It means 80% or 90% lower. In certain embodiments, a reduction in eosinophil infiltration is less than 15 eosinophils per high power field, more preferably less than 10 eosinophils per high power field, in a biopsy of the esophageal mucosa. means detecting less than 2 eosinophils, less than 8 eosinophils, less than 7 eosinophils, less than 6 eosinophils or less than 5 eosinophils. In certain embodiments, a decrease in esophageal eosinophils means that eosinophils are not detected in the esophageal mucosa of the subject.

The present invention provides a method for treating, preventing or reducing the severity of eosinophilic esophagitis, comprising a therapeutically effective amount of a pharmaceutical composition comprising an IL-4/IL-13 pathway inhibitor. administering the pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in multiple doses, eg, as part of a particular therapeutic dosing regimen. For example, therapeutic dosing regimens may include approximately once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 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 It can include administering multiple doses of the pharmaceutical composition to the subject once or less frequently.

The methods of the invention, in certain embodiments, include administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an IL-4/IL-13 pathway inhibitor in combination with a second therapeutic agent. include. The second therapeutic agent can be, for example, an IL-1 beta inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNF alpha inhibitor. , eotaxin-3 inhibitors, IgE inhibitors, prostaglandin D2 inhibitors, immunosuppressants, topical corticosteroids, oral corticosteroids (e.g., budesonide), systemic corticosteroids, inhaled corticosteroids, glucocorticoids, It can be an agent selected from the group consisting of proton pump inhibitors, decongestants, antihistamines, and non-steroidal anti-inflammatory drugs (NSAIDs). In certain embodiments, the IL-4/IL-13 pathway inhibitors of the present invention can be administered in combination with treatments including esophageal dilation, allergen removal, and dietary management. As used herein, the phrase "in combination" means that a pharmaceutical composition comprising an IL-4/IL-13 pathway inhibitor is administered simultaneously with, immediately before, or immediately after administration of a second therapeutic agent. means to be administered to a subject. In certain embodiments, the second therapeutic agent is administered as a co-formulation with an IL-4/IL-13 pathway inhibitor. In a related embodiment, the invention includes a method comprising administering to a subject on a background anti-allergy treatment regimen a therapeutically effective amount of a pharmaceutical composition comprising an IL-4/IL-13 pathway inhibitor. Background anti-allergy treatment regimens may include, for example, routes of administration of steroids, antihistamines, decongestants, anti-IgE agents, and the like. IL-4/IL-13 pathway inhibitors (eg, anti-IL-4R antibodies) can be added on top of the background anti-allergy treatment regimen. In some embodiments, the IL-4/IL-13 pathway inhibitor is added as part of a "background step-down" scheme, where the background anti-allergy therapy is reduced over time (e.g., step-down). The subject is gradually withdrawn from the drug, while the IL-4/IL-13 pathway inhibitor is administered to the subject at a constant dose or in increasing or decreasing doses over time. In certain embodiments, the IL-4/IL-13 pathway inhibitor is administered as a monotherapy.

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

According to certain aspects of the invention, a method for treating EoE, comprising: (a) selecting a subject exhibiting a level of at least one EoE-related biomarker before or during treatment indicative of disease status; (b) administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4/IL-13 pathway inhibitor. In certain embodiments of this aspect of the invention, subjects are selected based on elevated levels of IgE or eotaxin-3.

According to another aspect of the invention, a method for treating EoE comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an IL-4/IL-13 pathway inhibitor. administration of the pharmaceutical composition to the subject increases the level of EoE-related biomarkers (e.g., esophageal eosinophils, eotaxin -3, IgE, etc.).

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

According to certain embodiments of the invention, a subject has increased levels of IgE and/or eotaxin-3 after administration of a pharmaceutical composition comprising an IL-4/IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody). A reduction in one or more levels can be indicated. For example, about 1 day, 4 days after administration of a first, second, third, or fourth dose of a pharmaceutical composition comprising about 75 mg to about 600 mg of an anti-IL-4R antibody (e.g., dupilumab); On the 8th day, 15th day, 22nd day, 25th day, 29th day, 36th day, 43rd day, 50th day, 57th day, 64th day, 71st day or 85th day, the target is approximately 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% from baseline, according to the present invention. , 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more reduction in eotaxin-3 ('baseline' being the period immediately before the first dose). (defined as the level of eotaxin-3 in a subject). Similarly, about 1 day, 4 days after administration of a first, second, third, or fourth dose of a pharmaceutical composition comprising about 75 mg to about 600 mg of an anti-IL-4R antibody (e.g., dupilumab). , on the 8th day, 15th day, 22nd day, 25th day, 29th day, 36th day, 43rd day, 50th day, 57th day, 64th day, 71st day or 85th day, Subjects, according to the present invention, may be approximately 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% from baseline. %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more ('baseline' is the time immediately before the first dose). (defined as the level of IgE in a subject).

The invention also includes a method for determining whether a subject is a suitable subject who would benefit from administration of a pharmaceutical composition comprising an IL-4/IL-13 pathway antagonist. For example, if an individual exhibits a level of an EoE-related biomarker indicative of a disease state prior to receiving a pharmaceutical composition comprising an IL-4/IL-13 pathway antagonist, then the individual will therefore receive a pharmaceutical composition of the invention ( A composition comprising an anti-IL-4R antibody) is identified as a suitable patient who would benefit from administration. In a related embodiment, the invention includes a method for treating a suitable subject, where the suitable subject is more susceptible to EoE, e.g., due to food allergy or an atopic disease. There is. For example, the invention includes a method comprising administering an IL-4/IL-13 pathway antagonist to a subject with food allergy, atopic dermatitis, asthma, allergic rhinitis, or allergic conjunctivitis. In another example, the present invention provides IL -4/IL-13 pathway antagonist. Such subject populations may have elevated levels of EoE-related biomarkers.

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

Eosinophilic Esophagitis Related Parameters The present invention includes a method of improving one or more eosinophilic esophagitis (EoE) related parameters in a subject in need thereof, the method comprising: 4/IL-13 pathway inhibitor to the subject.

Examples of "EoE-related parameters" include (a) Straumann dysphagia measurement (SDI); (b) eosinophilic esophagitis activity index (EEsAI); (c) eosinophilic esophagitis edema ring exudate (d) Eosinophilic Esophagitis Tissue Scoring System (EoE-HSS); (e) Esophageal Intraepithelial Eosinophils; and (f) Esophageal Distensibility. "Improvement in EoE-related parameters" means a decrease from baseline in one or more of SDI, EEsAI, EoE-EREFS, EoE-HSS, or esophageal intraepithelial eosinophils. Improvement in esophageal distensibility refers to an increase from baseline. As used herein, the term "baseline" with respect to EoE-related parameters means the value of the EoE-related parameter of a subject before or at the time of administration of the pharmaceutical composition of the invention.

To determine whether an EoE-related parameter has been "improved," the parameter is quantified at baseline and at one or more time points after administration of a pharmaceutical composition of the invention. For example, EoE-related parameters can be determined on days 1, 2, 3, 4, 5, 6, 7, and 8 after initial treatment with the pharmaceutical composition of the present invention. , 9th day, 10th day, 11th day, 12th day, 14th day, 15th day, 22nd day, 25th day, 29th day, 36th day, 43rd day, 50th day, 57 day, 64th day, 71st day, 85th day, or 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks , at the end of weeks 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or longer. Ru. The difference between the parameter's value at a particular time point after treatment initiation and the parameter's value at baseline is used to determine whether there has been an "improvement" (eg, decrease) in the EoE-related parameter.

Straumann Dysphagia Instrument (SDI). The SDI is an unvalidated patient-reported outcome (PRO) used in clinical studies to determine the frequency and intensity of dysphagia (Straumann 2010). SDI has a one week recall period. The frequency of dysphagia events is graded on a 5-point scale: 0 = never, 1 = once a week, 2 = several times a week, 3 = once a day, and 4 = several times a day. . and the intensity of the dysphagia event is graded on a 6-point scale: 0 = unrestricted swallowing, 1 = slight resistance, 2 = slight retching with delayed passage, 3 = intervention (e.g., drinks, 4 = long-term persistent obstruction that can only be removed by emesis; and 5 = long-term complete obstruction requiring endoscopic intervention. Total SDI scores range from 0 to 9. According to certain embodiments of the invention, administration of an IL-4/IL-13 pathway inhibitor to a patient results in a reduction in SDI score of 3 points from baseline. For example, the invention includes treatment methods that result in a reduction from baseline in SDI score of 1, 2, 3, 4, 5, 6 or more reductions from baseline in SDI. In certain exemplary embodiments, administration of the IL-4/IL-13 pathway inhibitor to the patient occurs after administration of the IL-4/IL-13 pathway inhibitor (e.g., about 300 mg of anti-IL-4R antibody). or on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 after subcutaneous administration of an antigen-binding fragment thereof, or at least about 10%, 15 %, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more. In certain exemplary embodiments of the invention, administration of an IL-4/IL-13 pathway inhibitor to a subject results in a reduction from baseline in SDI of at least 40%.

Eosinophilic Esophagitis Activity Index (EEsAI). The EEsAI is an unvalidated multimodular index being developed at the University Hospital Incellspital (Berne, Switzerland), part of the international EEsAI research group (Schoepfer 2014). The EEsAI PRO module (questionnaire) used in this study includes information on the intensity and frequency of dysphagia, the influence of specific food groups on dysphagia symptoms, and other symptoms that are not dependent on eating or drinking (i.e., heartburn, acid vomiting). Contains items related to breast cancer, chest pain, and chest pain. The total EEsAI PRO score ranges from 0 to 100 (Figure 1), with higher scores indicating worse symptoms. The score consists of five parts: frequency of dysphagia, duration of dysphagia, pain on swallowing, visual dysphagia question, avoidance, modification, and delayed eating (AMS). According to certain embodiments of the invention, administration of an IL-4/IL-13 pathway inhibitor to a patient results in a decrease in the EEsAI score. For example, the present invention provides that 4,8,15,22,25 , 29, 36, 43, 50, 57, 64, 71, 85 days, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or more. EEsAI score from baseline. In certain exemplary embodiments of the invention, administration of an IL-4/IL-13 pathway inhibitor to a subject results in a reduction in EEsAI score from baseline of at least 30% after administration.

Eosinophilic esophagitis edema ring exudate grooves and strictures (EoE-EREFS). EoE-EREFS (edema, rings, exudates, grooves, strictures) was used to measure endoscopically identified EoE esophageal mucosal inflammation and remodeling features. This instrument includes a total of 17 items related to the presence and severity of esophageal function. Specific esophageal features include: rings (concentric rings around the esophagus - absent, mild, moderate, severe, not applicable); strictures (esophageal narrowing - yes, no, not applicable); strictures diameter (if applicable); exudate (see white spots - absent, mild, severe), grooves (vertical line of the esophagus - absent, present); edema (loss of vascular markings on the mucosa - absent, present); Crepe paper esophagus (absent, present); overall incorporating all EoE findings identified on endoscopy (i.e., fixed rings, strictures, whitish exudate, grooves, edema, and crepe paper mucosa) exterior. Additionally, mucosal changes associated with gastroesophageal reflux disease were also recorded using the Los Angeles classification system for erosions (no erosions or LA classification A, B, C, D). EoE esophageal characteristics are analyzed based on the EoE-EREFS, a validated scoring of the inflammatory and remodeling features of the disease using both an overall score and a score of each individual characteristic. system (Hirano 2014). According to certain embodiments of the invention, administration of an IL-4/IL-13 pathway inhibitor to a patient results in a decrease in EoE-EREFS score. For example, the present invention provides that 4,8,15,22,25 , 29, 36, 43, 50, 57, 64, 71, 85 days or later at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, Includes treatment methods that result in a reduction from baseline in EREFS score of 50%, 55%, 60%, 65%, 70%, 75% or more.

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

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

Esophageal distensibility. 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 sites along the esophagus while simultaneously recording intraluminal pressure during volume expansion of the esophagus. Analysis of the esophageal cross-sectional area versus pressure relationship allows determination of esophageal compliance as well as distensibility plateau (DP). DP has been shown to be significantly decreased in patients with EoE compared to healthy controls (Kwiatek 2011). According to certain embodiments of the 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 provides that 1, 2, 3, 4, 5 , baseline esophageal distensibility of at least about 5%, 10%, 15%, 20%, 25% or more at the end of Weeks 6, 7, 8, 9, 10, 11, 12, or later. including treatment methods that result in an increase in In certain exemplary embodiments of the invention, administration of an IL-4/IL-13 pathway inhibitor to a subject results in an increase of at least 10% from baseline in esophageal distensibility as measured by impedance planimetry. bring about.

Quality of life (EoE-QoL-A) questionnaire for adults with eosinophilic esophagitis. The EoE-QOL-A questionnaire is a validated disease-specific measure of health-related quality of life in patients with EoE (Taft 2011). The instrument used in this study, the EoE-QOL-A v. 3.0 includes 30 items related to established domains such as social functioning, emotional functioning, and the impact of illness on daily life experiences. EoE-QOL-A has a one-week recall period. Items are rated on a 5-point scale of "not at all," "slightly," "moderately," "quite a bit," and "very much." According to certain embodiments, administering an IL-4/IL-13 pathway inhibitor to a patient results in an increase in a quality of life parameter for the patient.

IL-4/IL-13 Pathway Inhibitors The methods of the invention include administering a therapeutic composition comprising an IL-4/IL-13 pathway inhibitor to a subject in need thereof.

As used herein, "IL-4/IL-13 pathway inhibitor" (also herein "IL-4/IL-13 pathway antagonist", "IL-4/IL-13 pathway blocker", etc.) (i) 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) ) Any agent that inhibits or attenuates at least one of the downstream signaling/activities resulting from binding of IL-4 and/or IL-13 to their respective receptors. Exemplary IL-4/IL-13 pathway inhibitors include, but are not limited to, anti-IL-4 antibodies (e.g., U.S. Pat. No. 7,740,843 and U.S. Pat. (antibody disclosed in US Pat. , U.S. Pat. No. 8,691,233, U.S. Pat. No. 9,605,065, U.S. Pat. bispecific antibodies that bind (e.g., antibodies disclosed in U.S. Pat. 4 receptor (IL-4R) inhibitors (described below).

As used herein, "IL-4R inhibitor" (herein "IL-4/IL-13 pathway inhibitor", "IL-4Rα antagonist", "IL-4R blocker", "IL-4R 4Rα blocker) binds to or interacts with IL-4Rα or IL-4R ligand and disrupts the normal biological signaling function of IL-4 receptors type 1 and/or type 2. Any drug that inhibits or attenuates. Human IL-4R 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 are stimulated by both IL-4 and IL-13. Therefore, IL-4R inhibitors that can be used in the methods of the invention block IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4 and IL-13-mediated signaling. It can function by doing. In this way, the IL-4R inhibitors of the invention can prevent the interaction of IL-4 and /IL-13 with type 1 or type 2 receptors.

Non-limiting examples of categories of IL-4R inhibitors include IL-4 muteins (e.g., pitrakinra), small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors. (e.g., a "peptibody" molecule), a "receptor body" (e.g., a genetically engineered molecule containing the ligand-binding domain of an IL-4R component), and an antibody or antigen binding of an antibody that specifically binds to human IL-4Rα. Fragments are mentioned. As used herein, IL-4R inhibitors also include antigen binding proteins that specifically bind to IL-4 and/or IL-13.

Anti-IL-4Rα Antibodies and Antigen-Binding Fragments Thereof According to certain exemplary embodiments of the invention, the IL-4/IL-13 pathway inhibitor is an anti-IL-4Rα antibody or antigen-binding fragment thereof. The term "antibody" as used herein refers to an immunoglobulin molecule that contains four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, as well as its including multimers (eg, IgM). In a typical antibody, each heavy chain includes a heavy chain variable region (abbreviated herein as HCVR or _VH ) and a heavy chain constant region. The heavy chain constant region contains three domains, C _H 1, C _H 2, and C _H 3. Each light chain includes 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 (C _L 1). The V _H and V _L regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FR). . Each V _H and V _L is composed of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the invention, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. Amino acid consensus sequences can be defined based on comparative analysis of two or more CDRs.

The term "antibody" as used herein also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc. refer to any naturally occurring enzyme that specifically binds and forms a complex with an antigen. synthetic, synthetic, or genetically engineered polypeptides or glycoproteins. Antigen-binding fragments of antibodies can be obtained from intact antibody molecules using any suitable standard technique, such as, for example, proteolysis or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. can be derived from. Such DNA is known and or readily available from, for example, commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or using molecular biology techniques, e.g., to place one or more variable and/or constant regions in the appropriate configuration, or to introduce codons. However, cysteine residues can be created and amino acids can be modified, added or deleted.

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

Antigen-binding fragments of antibodies typically contain at least one variable domain. Variable domains can be of any size or amino acid composition and generally include at least one CDR adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a V _H domain associated with a V _L domain, the V _H and V _L domains can be arranged relative to each other in any suitable arrangement. For example, the variable region may be dimeric and may contain V _H -V _H , V _H -V _L or V _L -V _L dimers. Alternatively, antigen-binding fragments of antibodies can include monomeric V _H or V _L domains.

In certain embodiments, an antigen-binding fragment of an antibody can include at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found within antigen-binding fragments of antibodies of the invention include (i) V _H -C _H 1; (ii) V _H -C _H 2; iii) V _H -C _H 3; (iv) V _H -C _H 1-C _H 2; (v) V _H -C _H 1-C _H 2-C _H 3; (vi) V _H -C _H 2 -C _H 3; (vii) V _H - C _L ; (viii) V _L - C _H 1; (ix) V _L - C _H 2; (x) V _L - C _H 3; (xi) V _L - C _H 1-C _H 2; (xii) V _L -C _H 1-C _H 2-C _H 3; (xiii) V _L -C _H 2-C _H 3; and (xiv) V _L -C _L include. In any of the configurations of variable and constant domains, including any of the above exemplary configurations, the variable and constant domains can be directly linked to each other or connected by a complete or partial hinge or linker region. be able to. The hinge region has at least two (e.g., 5, 10, 15, 20, 40 , 60 or more amino acids). Additionally, antigen-binding fragments of antibodies of the invention may be bonded non-covalently to each other and/or to one or more monomeric V _H or V _L domains (e.g., by disulfide bond(s)). Homodimers or heterodimers (or other multimers) of any of the variable domain and constant domain configurations listed above can be included in non-covalent association.

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

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

The antibodies used in the methods of the invention may be recombinant human antibodies. The term "recombinant human antibody" as used herein refers to any human antibody that is prepared, expressed, produced or isolated by recombinant means, e.g., a recombinant antibody that is transfected into a host cell. Antibodies expressed using expression vectors (described in detail below); antibodies isolated from recombinant, combinatorial human antibodies (described in detail below); animals transfected with human immunoglobulin genes; (e.g., from mice) (e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or any other method involving the splicing of human immunoglobulin gene sequences into other DNA sequences. is intended to include antibodies prepared, expressed, produced or isolated by means of. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis if animals transgenic for human Ig sequences are used). and thus the amino acid sequences of the VH and VL regions of the recombinant antibody, while derived from and related to human antibody germline _VH and _VL sequences, are naturally occurring within the human antibody germline repertoire in vivo. This is an array that may not exist in .

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

According to certain exemplary embodiments of the invention, the IL-4/IL-13 pathway inhibitor is an anti-IL-4Rα antibody, or a heavy chain It is an antigen-binding fragment of the above-mentioned antibody, comprising a variable region (HCVR), a light chain variable region (LCVR), and/or a complementarity determining region (CDR) comprising any of the amino acid sequences of an anti-IL-4R antibody. In certain exemplary embodiments, anti-IL-4Rα antibodies or antigen-binding fragments thereof that can be used in connection with the methods of the invention have a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1. The light chain complementarity determining region (LCDR) of the heavy chain complementarity determining region (HCDR) and the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2. According to certain embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where HCDR1 is of SEQ ID NO:3. HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 contains the amino acid sequence of SEQ ID NO:8. In yet other embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO:1 and a LCVR comprising SEQ ID NO:2. In certain embodiments, the methods of the invention include the use of an anti-IL-4R antibody, the antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:10. An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 is a fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the invention include the use of dupilumab or a biological equivalent thereof. The term "bioequivalent," as used herein, refers to the rate of absorption and/or when administered at the same molar dose in either a single or multiple doses under similar experimental conditions. or an anti-IL-4R antibody or IL-4R binding protein or a fragment thereof that is a pharmaceutical equivalent or pharmaceutical substitute that does not show a significant difference in extent compared to that of dupilumab. In the context of the present invention, this term refers to an antigen binding protein that binds to IL-4R that has no clinically meaningful difference in safety, purity and/or potency compared to dupilumab.

Other anti-IL-4Rα antibodies that can be used in connection with the methods of the invention are, for example, the antibody designated AMG317 and known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796) or MEDI 9314 or US Pat. No. 7,186,809, US Pat. No. 7,605,237, US Pat. No. 7,638,606 or US Pat. , 092,804, US Pat. No. 8,679,487, or US Pat. No. 8,877,189.

Anti-IL-4Rα antibodies used in connection with the methods of the invention can have pH-dependent binding properties. For example, anti-IL-4Rα antibodies for use in the methods of the invention may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody of the invention can exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The expression "acidic pH" refers to a pH value less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65 , 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5 .0 or less. As used herein, the expression "neutral pH" means a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

In a specific example, "decreased binding to IL-4Rα at acidic pH compared to neutral pH" means that the K D value of antibody binding to IL-4Rα that binds to IL-4Rα at neutral pH relative to the K _D value for antibody binding to IL-4Rα at acidic pH It is expressed by the K _D value (or vice versa) of the binding antibody. For example, if an antibody or antigen-binding antibody thereof exhibits an acidic/neutral K _D ratio of about 3.0 or greater, the antibody or antigen-binding fragment thereof is defined as "compared to neutral pH may be regarded as exhibiting "decreased binding to IL-4Rα at acidic pH." In certain exemplary embodiments, the acidic/neutral K _D ratio for antibodies or antigen-binding fragments of the invention is about 3.0, 3.5, 4.0, 4.5, 5.0, 5. 5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60. 0, 70.0, 100.0 or more.

Antibodies with pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for decreased (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. In addition, modification of the antigen binding domain at the amino acid level can yield antibodies with pH-dependent properties. For example, by replacing one or more amino acids in an antigen-binding domain (e.g., within a CDR) with a histidine residue, one can obtain an antibody with reduced antigen binding at acidic pH compared to neutral pH. . As used herein, the expression "acidic pH" means a pH of 6.0 or less.

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

A variety of delivery systems are known and can be used to administer the pharmaceutical compositions of the invention, for example liposomes, microparticles, microcapsules, encapsulation in recombinant cells capable of expressing the mutant virus, Receptor-mediated endocytosis (see, eg, Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The compositions can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and by absorption into other organisms. Can be administered together with biologically active agents.

Pharmaceutical compositions of the invention can be delivered subcutaneously or intravenously with standard needles and syringes. Furthermore, for subcutaneous delivery, pen-shaped delivery devices readily have utility in delivering the pharmaceutical compositions of the present invention. Such pen-shaped delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. Pen delivery devices can be reused. In disposable pen delivery devices, there are no replaceable cartridges. Rather, the disposable pen delivery device is prefilled with a pharmaceutical composition held within a reservoir within the device. Once the reservoir is emptied of pharmaceutical composition, the entire device is discarded.

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

Injectable preparations can include intravenous, subcutaneous, intradermal and intramuscular injections, drops, and the like. These injection preparations can be prepared by known methods. For example, an injectable preparation can be prepared, for example, by dissolving, suspending, or emulsifying the above-mentioned antibody or a salt thereof in a sterile aqueous medium or an oily medium commonly used for injections. Aqueous vehicles for injection include, for example, saline, isotonic solutions containing glucose and other adjuvants, such as alcohols (e.g. ethanol), polyhydric alcohols (e.g. propylene glycol, polyethylene glycol) , nonionic surfactants [eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. As the oily medium, for example, sesame oil, soybean oil, etc. are used, and this can be used in combination with a solubilizer such as benzyl benzoate and benzyl alcohol. The injection thus prepared is preferably filled into suitable ampoules.

Advantageously, the oral or parenteral pharmaceutical compositions described above are prepared in unit dose dosage forms suitable for adapting the dosage of the active ingredient. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories.

Exemplary pharmaceutical compositions containing anti-IL-4R antibodies that can be used in connection with the present invention are disclosed, for example, in US Pat. No. 8,945,559.

Dosage Regimens The present invention provides for administering an IL-4/IL-13 pathway inhibitor to a subject about four times a week, twice a week, once a week, once every two weeks, once every three weeks, or about four times a week. once, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently as long as a therapeutic response is achieved. include. In certain embodiments involving administration of an IL-4/IL-13 pathway inhibitor (e.g., an anti-IL-4R antibody), once weekly in an amount of about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 300 mg. Medication is employed. In certain embodiments involving administration of anti-IL-4R antibodies, biweekly dosing in amounts of about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 300 mg is employed.

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

The terms "primary dose," "secondary dose," and "tertiary dose" refer to the chronological order of administration of an IL-4/IL-13 pathway inhibitor. Thus, a "primary dose" is the dose administered at the beginning of a treatment regimen (also called the "baseline dose"); a "secondary dose" is a dose administered after the first dose; a "tertiary dose" is the dose administered after the first dose; ” is the dose administered after the second dose. The primary, secondary, and tertiary doses can all contain the same amount of IL-4/IL-13 pathway inhibitor, but generally can differ from each other in frequency of administration. However, in certain embodiments, the amounts of IL-4/IL-13 pathway inhibitor included in the primary, secondary, and/or tertiary doses vary from one another (e.g., up or down as needed). adjusted). In certain embodiments, the primary dose comprises a first amount of the antibody or antigen-binding fragment thereof, and the one or more secondary doses each comprise a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of antibody or fragment thereof (primary dose) is 1.5×, 2×, 2.5× of the second amount of antibody or antigen-binding fragment thereof (secondary dose). , 3×, 3.5×, 4×, or 5×. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered as a "loading dose" at the beginning of a treatment regimen, and then on a less frequent basis. Subsequent doses (eg, "maintenance doses") are administered. For example, the IL-4/IL-13 pathway inhibitor is administered to a patient in need thereof at a loading dose of about 300 mg to about 600 mg, followed by one or more maintenance doses of about 25 mg to about 400 mg. be done. In one embodiment, the primary dose and the one or more secondary doses are each 10 mg to 600 mg of an IL-4/IL-13 pathway inhibitor, such as 100 mg to 400 mg of an IL-4/IL-13 pathway inhibitor. eg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg or 500 mg of an IL-4/IL-13 pathway inhibitor. In one embodiment, the primary dose is 2x the secondary dose.

In an exemplary embodiment of the invention, each secondary and/or tertiary dose is 1 to 14 (e.g., 1, 1 1/2, 2, 2 1/2, 3 , 3 and 1/2, 4, 4 and 1/2, 5, 5 and 1/2, 6, 6 and 1/2, 7, 7 and 1/2, 8, 8 and 1/2, 9, 9 and 1/2, 10, 10 1/2, 11, 11 1/2, 12, 12 1/2, 13, 13 1/2, 14, 14 1/2, or more) weeks administered at As used herein, the phrase "immediately preceding dose" refers to IL-4/IL-4 administered to a patient prior to the administration of the immediately next dose in a series of multiple doses in sequence without an intervening dose. 13 pathway inhibitor dose.

Methods according to this aspect of the invention may include administering to the patient any number of secondary and/or tertiary doses of the IL-4/IL-13 pathway inhibitor. For example, in certain embodiments, only a single 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 certain embodiments, only a single 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.

In embodiments with multiple sub-doses, each sub-dose is administered with the same frequency as the other sub-doses. For example, each secondary dose is administered to a patient 1 to 6 weeks after the previous dose. Similarly, in embodiments with multiple tertiary doses, each tertiary dose is administered with the same frequency as the other tertiary doses. For example, each tertiary dose is administered to a patient 2 to 4 weeks after the previous dose. Alternatively, the frequency with which secondary and/or tertiary doses are administered to a patient may vary over the course of the regimen.

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

For example, when administered “before” the IL-4/IL-13 pathway inhibitor, the CS may be administered for more than 72 hours, about 72 hours, about 60 hours, or more before administration of the IL-4/IL-13 pathway inhibitor. 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 Administered minutes before. When administered “after” the IL-4/IL-13 pathway inhibitor, the CS is administered at about 10 minutes, about 15 minutes, about 30 minutes, about 1 minute after administration of the IL-4/IL-13 pathway inhibitor. time, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 8 hours, approximately 10 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 60 hours, approximately 72 hours later, or 72 hours Administered later in the day. “Co-administration” with an IL-4/IL-13 pathway inhibitor means that the CS is administered in a separate dosage form less than 5 minutes (before, after, or simultaneously) with the administration of the IL-4/IL-13 pathway inhibitor. or as a single combination dosage formulation containing both CS and an IL-4/IL-13 pathway inhibitor.

Dosage The amount of IL-4/IL-13 pathway inhibitor (eg, anti-IL-4Rα antibody) administered to a subject according to the methods of the invention is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means: (a) reducing the severity or duration of symptoms of eosinophilic esophagitis; (b) reducing the number of eosinophils in the esophagus. (c) increased esophageal distensibility; (d) decreased incidence of dysphagia; (e) prevention or mitigation of allergic reactions; (f) decreased use or need for conventional allergy treatments (e.g., antihistamines); , reduction or elimination of the use of decongestants, nasal or inhaled steroids, anti-IgE therapy, epinephrine, etc.).

In the case of anti-IL-4Rα antibodies, a therapeutically effective amount is about 0.05 mg to about 600 mg, such as about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, of anti-IL-4R antibody. 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 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg , about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about It can be 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg or about 600 mg. In certain embodiments, 300 mg of anti-IL-4R antibody is administered.

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

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

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

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

In embodiment 4, the invention provides a method for treating active eosinophilic esophagus comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an IL-4/IL-13 pathway inhibitor. including methods of treating, preventing or ameliorating at least one symptom or sign of inflammation of the earth (EoE).

In embodiment 5, the invention provides that the patient: (1) has 15 or more eosinophils per high power field (hpf) in the esophagus before or at the time of treatment ("baseline"); (2) prior treatment with at least one of high-dose PPI, esophageal dilatation, corticosteroids, allergen withdrawal, and/or dietary modification; (3) patient had one or more episodes of dysphagia per week; (4) the patient is unresponsive or refractory to previous treatment with high-dose PPIs or esophageal dilatation; (5) the patient has a Straumann Dysphagia Instrument (SDI) score of 2 or higher. (6) the patient has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score of 30 or higher, 40 or higher, or 50 or higher; (7) the patient has had EoE for at least 3 years; (8) the patient is suffering from food allergy, atopic dermatitis, asthma, allergic rhinitis, and allergic conjunctivitis before or at the time of administration of the IL-4/IL-13 pathway inhibitor; (9) the patient has or has been diagnosed with a disease or disorder selected from the group; A biomarker selected from the group consisting of thymic and activation-regulated chemokines (TARC), thymic stromal lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP), and eosinophil-derived neurotoxin (EDN). The method of any one of embodiments 1-4, wherein the method has one or more characteristics selected from the group consisting of increased levels of.

In embodiment 6, the invention includes the method of any one of embodiments 1-5, wherein the administration of the IL-4/IL-13 pathway inhibitor comprises: (a) Straumann Dysphagia Instrument (SDI) at least a 40% reduction from baseline in the frequency and severity of dysphagia, as measured by score; (b) a 3 point reduction from baseline in SDI score; (c) proximal, middle, and/or esophageal (d) an increase of at least 10% from baseline in esophageal distensibility as measured by impedance planimetry; (e ) a greater than 50% reduction from baseline in disease severity and extent as measured by the EoE Histological Scoring System (HSS) score; and (f) eosinophilic esophagitis severity and activity. resulting in an improvement in an EoE-related parameter selected from the group consisting of a greater than 30% reduction from baseline in dysphagia, as measured by the Index (EEsAI) score.

In Embodiment 7, the invention relates to embodiments 1 to 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). including any one of the following methods.

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

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

In embodiment 10, the invention provides that the IL-4/IL-13 pathway inhibitor is administered in a first dose, followed by one or more secondary doses, each secondary dose The method of any one of embodiments 1-7, wherein the method is administered 1 to 4 weeks after the dose.

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

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

In embodiment 13, the invention provides the method of embodiment 10, wherein the first dose comprises 600 mg of the IL-4/IL-13 pathway inhibitor and each secondary dose comprises 300 mg of the IL-4/IL-13 pathway inhibitor. to 12 methods.

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

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

In embodiment 16, the invention provides that the symptoms or signs of EoE are
The method of any one of embodiments 4 to 15 is selected from the group consisting of eosinophil infiltration of the esophagus, thickening of the esophageal wall, anorexia, vomiting, abdominal pain, heartburn, regurgitation, dysphagia, and food fragment injection. .

In embodiment 17, the invention provides that the patient consumes dairy products, eggs, wheat, soybeans, corn, fish, shellfish, peanuts, tree nuts, beef, chicken, oats, barley, pork, green beans, apples, and pineapples. The method of any one of embodiments 1 to 16 includes exhibiting an allergic reaction to a food allergen contained in a food selected from the group.

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

In embodiment 19, the invention includes the method of any one of embodiments 1-18, wherein administration of the IL-4/IL-13 pathway inhibitor results in a reduction in EoE-related biomarker levels in the subject.

In embodiment 20, the invention provides that the EoE-related biomarkers are from eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum TARC, TSLP, serum ECP, and EDN. The method of embodiment 19 is selected from the group consisting of:

In embodiment 21, the invention provides that an IL-4/IL-13 pathway inhibitor is administered in combination with a second therapeutic agent or therapy, the second therapeutic agent or therapy being an IL-1 beta 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 selected from the group consisting of anti-inflammatory agents, immunosuppressants, topical corticosteroids, oral corticosteroids, systemic corticosteroids, inhaled corticosteroids, glucocorticoids, proton pump inhibitors, NSAIDs, esophageal dilatation, allergen removal, and dietary management. Embodiments 1 to 20 include the method of any one of embodiments 1-20.

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

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

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

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

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

In embodiment 27, the invention provides that the IL-4/IL-13 pathway inhibitor binds to IL-4Rα and inhibits the interaction between IL-4 and/or IL-13 and the type 1 or type 2 IL-4 receptor. Includes the method of any one of embodiments 1-23, wherein the antibody or antigen-binding fragment thereof interferes with the interaction.

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

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

In embodiment 30, the invention provides that the antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 has the amino acid sequence of SEQ ID NO:3. HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 7; 29. The method of embodiment 28, comprising the amino acid sequence number 8.

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

In embodiment 32, the invention provides the method according to 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. Includes one method.

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

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

The following examples are set forth to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and to the extent that the inventors regard them as their invention. is not intended to limit. Efforts have been made to ensure accuracy of quantities used (eg, amounts, temperatures, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

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

Purpose of the Study The primary purpose of this study was to determine the clinical efficacy of multiple subcutaneous (SC) doses of dupilumab compared to placebo to alleviate symptoms in adult patients with active, moderate to severe EoE. It was to evaluate.

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

The exploratory purpose of the study was to evaluate the effects of dupilumab on other esophageal biopsy pathological features associated with EoE.

Study Design This was a multicenter, double-blind, randomized, placebo-controlled trial investigating the efficacy, safety, tolerability, PK, and immunogenicity of dupilumab in adult patients with EoE.

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

Patients received concomitant medications (excluding prohibited drugs [see below]) as needed while continuing study treatment. Samples for efficacy, safety, and laboratory evaluations, dupilumab concentrations and potential anti-drug antibody (ADA) responses to dupilumab, and study samples were performed or collected at specific time points throughout the study.

Study Population The target population included adult (18-65 years) male or female patients with active EoE.

Inclusion criteria: Patients had to meet the following criteria to be eligible for inclusion in the study:
(1) Male or female, 18-65 years old;
(2) Documented diagnosis of EoE by endoscopy before or at screening. Note: Intraepithelial eosinophils from endoscopic esophageal biopsy specimens performed within 2 weeks after at least 8 weeks of treatment with high-dose (or twice-daily) proton pump inhibitors (PPIs) Demonstration of infiltration (peak cell count ≥15 eosinophils/high power field [eos/hpf] [400×]) should be included;
(3) an average of at least two episodes of dysphagia (when taking solid foods from anti-inflammatory therapy) per week during the 4 weeks before screening (as per patient report) and once per week during the week between screening and baseline; History of an average of at least two recorded episodes of dysphagia; dysphagia is defined as patient-reported difficulty swallowing solid food or ingesting solid food sticks;
(4) Must maintain a stable 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 single or multiple elimination diets or previously eliminated food groups; defined as the reintroduction of;
(5) SDI PRO score at screening and baseline is 5 or higher;
(6) History or presence of any one or more of the following: allergic disease (e.g. allergic asthma, allergic rhinitis, AD, or food allergy), peripheral eosinophil count ≥0.25 GI/L, serum Total immunoglobulin E (IgE) ≧100kU/L;
(7) willing to comply with all hospital visits and study-related procedures; able to understand and complete study-related questionnaires; provide signed informed consent; and (8) completed at screening. With photographic endoscopy and demonstration of intraepithelial eosinophilic infiltration (peak cell count ≧15 eos/hpf) in at least two of the three biopsied esophageal regions (proximal, middle, or distal).

Exclusion criteria: Patients who met any of the following criteria were not eligible to participate in this study: (1) previous participation in a dupilumab (anti-IL-4R) clinical trial; (2) esophageal eosinophilia or other causes of the following diseases: hypereosinophilic syndrome, Churg-Strauss vasculitis, and eosinophilic gastroenteritis; (3) achalasia, active Helicobacter pylori infection, Crohn's disease, ulcerative Colitis, celiac disease, and history of previous esophageal surgery prior to screening; (4) standard diagnostic adult (9-10 mm) upper endoscopy or any significant esophageal stricture requiring dilation at screening; (5) history of bleeding disorders or esophageal varices; (6) use of chronic aspirin, nonsteroids, or anticoagulants within 2 weeks before screening. Patients should not stop these drugs just to be eligible for participation in this study; (7) within 2 months or 5 half-lives (if known), whichever is longer, before screening. Treatment with investigational drug; (8) use of systemic corticosteroids within 3 months before screening or topical corticosteroids swallowed within 6 weeks; (9) use of inhaled or nasal corticosteroids within 3 months before screening and during the study. Use of costosteroids. (10) treatment with oral immunotherapy (OIT) within 6 months before screening; (11) allergens; Immunotherapy (sublingual immunotherapy [SLIT] and/or subcutaneous immunotherapy [SCIT], if not on stable medication for at least 1 year before screening; (12) within 3 months before the screening visit; The following treatments or conditions that, in the opinion of the investigator, are likely to require such treatment during the 3 months of study treatment: systemic immunosuppressive/immunomodulatory drugs (e.g., omalizumab, cyclosporine, mycophenolic acid); (13) Active parasitic infection and diagnosed; clinical and (if necessary) non-laboratory evaluation of suspected parasitic infection excludes active infection before randomization; (14) systemic infection within 1 month before screening; Chronic or acute infection requiring treatment with antibiotics, antivirals, or antifungals; (15) Use of oral antibiotics/antiinfectives within 2 weeks prior to screening; (16) Known immunosuppression. history of invasive opportunistic infections despite resolution of infection (e.g., tuberculosis, non-tuberculous mycobacterial infections, histoplasmosis, listeriosis, (17) history of 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 [ (20) History of malignancy within 5 years before screening, provided that fully treated in situ cervical (21) Patient-reported history of alcohol or drug abuse within 6 months prior to screening; (22) In the opinion of the investigator, the study patient's participation in this clinical trial may pose an unreasonable risk to the study patient, indicating a new and/or poorly understood disease, and may pose a risk to the patient. other medical or psychological conditions, including relevant laboratory abnormalities at the time of screening, that may reduce the reliability of participation or interfere with study evaluation. The specific justification for patients being excluded under this criterion will be documented in the study documentation (e.g., chart notes, case report form [CRF]); (23) in the judgment of the investigator (24) Planned or anticipated use of any prohibited drugs and procedures (see below) during study treatment; (25) Childbirth within 3 months prior to screening; treatment with (attenuated) vaccines; (26) patients or their families are members of the research team; (27) women who are pregnant or breastfeeding, or who plan to become pregnant or breast-feed during the study; (28) ) Women who are fertile ^* and sexually active but who do not wish to use adequate contraception.

Study Treatment Study Drug: Dupilumab SC, 600 mg loading dose on day 1, then weekly doses of 300 mg from week 1 to week 11.

Placebo: Placebo (same formulation as dupilumab without active substance, anti-IL-4R monoclonal antibody) SC, volume matching dupilumab loading dose on day 1, then weekly dose volume of dupilumab from week 1 to week 11 Weekly doses that match.

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

Permitted (Concomitant) Medications Treatment with concomitant medications was permitted during the study. This includes contraceptives, stable doses of proton pump inhibitors (PPIs) (patients on PPIs at screening did not discontinue or change their medication regimen before the end of treatment [EOT] visit); stable doses of proton pump inhibitors (PPIs); treatment with systemic leukotriene inhibitors, topical, nasal, and/or inhaled corticosteroids (at least 3 months prior to screening); oral antihistamines for any period of time; and oral antibiotics for up to 2 weeks. Ta.

Restricted Medications and Procedures Restricted medications during the study period included: (1) Medications used to treat EoE (these were considered rescue medications): swallowing topical corticosteroids; Systemic corticosteroids, initiation or dose changes of systemic leukotriene inhibitors, topical, nasal, and/or inhaled corticosteroids, and immunosuppressive/immunomodulatory agents (including but not limited to omalizumab, cyclosporine, mycophenolate mofetil, azathioprine) (2) allergen immunotherapy (SCIT and SLIT were allowed if the dose was stable for more than 1 year, but OIT (3) Patients who had not used a PPI in the 8 weeks prior to screening were prohibited from starting PPI therapy before the EOT visit; (4) Live (attenuated) vaccines ( Chickenpox (varicella), FluMist-influenza, nasal influenza, measles (rubella), measles-mumps-rubella combination, measles-mumps-rubella-varicella combination, mumps, oral polio ( (5) clinical trials Treatment with drugs (other than dupilumab).

The following concomitant procedures were prohibited during study treatment (until week 12): (1) major elective surgical treatments; (2) esophageal dilatation (considering rescue procedures); and (3) dietary changes. (Patients were to maintain a stable diet for at least 6 weeks prior to screening and during the course of the study; a stable diet was defined as no initiation of one or more elimination diets or prior elimination. There were no reintroductions of food groups).

Study Endpoints The primary efficacy endpoint was change in Straumann Dysphagia Instrument (SDI) Patient Reported Outcome (PRO) score from baseline to Week 10.

Secondary endpoints were: percent change in weekly Eosinophilic Esophagitis Activity Index (EEsAI) PRO score from baseline to week 10; weekly EEsAI PRO score from baseline to week 10. Change in score; 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; Base Percent change in SDI PRO score from baseline to week 12; Change in SDI PRO score from baseline to week 12; Adult eosinophilic esophagitis quality of life (EoE-QOL-A) from baseline to week 12 ) (Questionnaire) Change in PRO score; Proportion of patients with SDI PRO response at week 10; Response is defined as a decrease of at least 3 points in SDI compared to baseline; Week 10 from baseline Proportion of patients achieving ≥40% improvement in EEsAI score from baseline to week 12; Percent change in overall peak esophageal intraepithelial eos/hpf (400X) from baseline to week 12; Eosinophilia from baseline to week 12 Change in bulbar esophagitis-endoscopic reference score (EoE-EREF) (endoscopic visual anatomical score); proportion of patients using rescue medications or procedures (e.g., esophageal dilatation) by week 12; and Incidence of treatment-emergent adverse events (TEAEs).

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

Procedures and Evaluations Screening/Baseline Procedures: The following procedures were performed only at screening and/or baseline visits for the sole purpose of determining study eligibility or characterizing the baseline population: Serum FSH (menopausal status for confirmation), serum total IgE, HBsAg, and hepatitis C antibodies.

Efficacy procedures: Efficacy was determined using the Straumann Dysphagia Instrument (SDI), Eosinophilic Esophagitis Activity Index (EEsAI), and Eosinophilic Esophagitis Quality of Life (EoE)-QOL-A) Questionnaire. , and patient-reported outcomes (PROs), including esophageal biopsies and photographs (endoscopy procedures), were assessed during the study at specific visits. Measurement of inflammatory and remodeling esophageal features based on the Eosinophilic Esophagitis Edema Ring Exudate Sulcus and Stricture (EoE-EREFS) score was included as part of the endoscopy procedure. An endoscopic functional lumen imaging probe (EndoFLIP) procedure to measure esophageal distensibility was performed during the endoscopy procedure. Eight histological features of EoE were measured using the EoE Histological Scoring System (HSS).

Straumann Dysphagia Measurement - Patient-Reported Results The SDI is an unvalidated PRO used in clinical studies to determine the frequency and intensity of dysphagia (Straumann 2010). SDI has a one week recall period. The frequency of dysphagia events is graded on a 5-point scale: 0 = never, 1 = once a week, 2 = several times a week, 3 = once a day, 4 = several times a day. The intensity of dysphagia events is graded on a 6-point scale: 0 = unrestricted swallowing, 1 = slight resistance, 2 = slight retching with delayed passage, 3 = intervention (e.g., drinking, breathing). ), 4 = long-term persistent occlusion that can only be removed by emesis, and 5 = long-term complete occlusion requiring endoscopic intervention. Total SDI scores range from 0 to 9. In the Straumann study, clinical response (improvement) was defined as a reduction in SDI score of at least 3 points from baseline.

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

Activity indicators for eosinophilic esophagitis - patient-reported outcomes It is not a multi-modular index. The EEsAI PRO module (questionnaire) used in this study includes information on the intensity and frequency of dysphagia, the influence of specific food groups on dysphagia symptoms, and other symptoms that are not dependent on eating or drinking (i.e., heartburn, acid vomiting). Contains items related to breast cancer, chest pain, and chest pain. The total EEsAI PRO score ranges from 0 to 100 (Figure 1), with higher scores indicating worse symptoms. The score consists of five parts: frequency of dysphagia, duration of dysphagia, pain on swallowing, visual dysphagia question, avoidance, modification, and delayed eating (AMS). EEsAI PRO utilizes a 24 hour and one week recall period.

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

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

This assessment was recorded by patients on a medical questionnaire at baseline and monthly thereafter until study termination or early termination.

Esophageal Biopsy and Photographic Endoscopy Esophageal biopsies were obtained by endoscopy at screening and at the 12 week visit. Screening endoscopy was performed during the screening period and results were made available for eligibility assessment -1 day in advance. A total of nine mucosal pinch biopsies were collected at each time point from three esophageal regions: three proximal, three intermediate, and three distal. Two samples from each area were used for histology (required for study inclusion criteria and secondary endpoints). To participate in this study, patients had to exhibit peak intraepithelial eosinophil counts of 15 eos/hpf (400X) or higher in at least two of the three esophageal regions sampled. Change in peak esophageal eos/hpf (400X) from baseline to week 12 was a secondary endpoint; This was determined by counting acid globules and calculating the change in peak counts for each site obtained at baseline compared to counts obtained at 12 weeks. As an exploratory purpose, the mean of all three peak counts, i.e. the mean change in peak counts in each of the three esophageal regions for each patient at each time point (screening and week 12), was calculated. The tissue blocks remaining after histological evaluation were kept for exploratory studies.

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

Assessment of esophageal distensibility utilizing an endoscopic functional lumen imaging probe (EndoFLIP, Crospon, Ireland) is also performed to measure esophageal lumen diameter and pressure (e.g., esophageal stiffness), and measurements Values were taken at screening and as part of the endoscopy performed at 12 weeks. The EndoFLIP device is a catheter-based procedure that measures cross-sectional area at multiple sites along the esophagus while simultaneously recording intraluminal pressure during volume expansion of the esophagus. Analysis of the relationship between esophageal cross-sectional area and pressure allows determination of esophageal compliance as well as distensibility plateau (DP). DP has been shown to be significantly decreased in patients with EoE compared to healthy controls (Kwiatek 2011). Furthermore, esophageal distensibility has been associated with both the consequences of food fragment intrusion and the need for esophageal dilatation (Nicodeme 2013).

The EoE-HSS produced separate severity (grade) and range (stage) disease scores. The score was used to measure eight histological features (parameters) of EoE from three different regions of the esophagus (proximal, middle and distal) (Collins et al., 2017). The eight parameters include eosinophil density, basal hyperplasia, eosinophil abscess, eosinophil surface stratification, intercellular space expansion, surface epithelial changes, dyskeratotic cells, and lamina propria fibrosis. is included. For both grade and stage, a scale of 0 to 3 was used for each parameter (0 being minimal inflammation, normal). The total score range for each domain in this study was 0-21 (excluding lamina propria parameters). Evaluation of the lamina propria was excluded because 50% of pinch biopsies were not deep enough for evaluation of the lamina propria. The total score per patient was calculated as (0-21 score x 3 regions = 63 total possible scores per time point). Two scores were generated for each patient at each time point. One each for grade (severity) and stage (extent).

Photographs were taken at the site as part of the endoscopic procedure and biopsy retrieval.

Safety Procedures: An AE is an untoward medical occurrence in a patient receiving an investigational drug, which may or may not have a causal relationship to the investigational drug. Therefore, an AE is any untoward, unintended sign (including abnormal laboratory findings), symptom, or disease that is temporarily associated with the use of an investigational drug, whether or not considered to be related to the investigational drug. It is. AEs also include any worsening of a pre-existing condition (i.e., clinically significant change in frequency and/or intensity) that is temporally associated with use of the investigational drug.

Serious Adverse Events (SAEs) are those that result in death at any dose, are life-threatening, require hospitalization of the patient, result in permanent or significant disability/incapacity, are congenital anomalies/defects of birth; and/or is a serious medical event (e.g., such an event may jeopardize the patient or require intervention to prevent one of the other serious outcomes listed above) ) is an adverse medical occurrence.

Safety and tolerability were assessed by physical examination, vital signs, electrocardiogram (ECG), clinical laboratory tests, and clinical evaluation. Patients were asked to monitor all AEs experienced from the time of informed consent to the last study visit.

Pharmacokinetics and antibody procedures: Serum samples were collected for assay of dupilumab levels and PK parameters were calculated using dupilumab concentration data. Serum samples were collected for ADA assay and exploratory analysis.

Results Baseline characteristics: Patients were randomized in a 1:1 ratio to receive subcutaneous (SC) 600 mg dupilumab or SC placebo loading dose and then weekly SC 300 mg dupilumab or SC placebo during a 12-week double-blind treatment period. It was randomized. Randomization was stratified by baseline Straumann Dysphagia Instrument (SDI) PRO score (≧5 and ≦7 vs. >7). Baseline demographic and disease characteristics were generally balanced between the two groups, with the exception of mean total IgE (dupilumab 217.8 kU/L, placebo 468.2 kU/L) (Table 1-2).

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

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

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

Dupilumab numerically reduced EEsAI scores vs. placebo through week 10 (-34.6% vs. -11.3%, P=0.085) (Table 4, Figure 4).

By week 12, dupilumab significantly reduced peak eosinophil count (eos/hpf) from baseline compared to placebo [-94.1 (-91.8%) vs. -7. 4 (+15.1%), P<0.0001] (Tables 4 and 6). A reduction in eosinophil tissue infiltration was observed in all patients in the dupilumab group (Table 5). Dupilumab effects were similar in the proximal, middle, and distal esophagus.

Dupilumab significantly reduced EREFS compared to placebo at week 12 (LS mean change p=0.0006, LS mean percent change p=0.0004) (Table 4). Dupilumab significantly reduced the total EREFS score as well as the effusion and sulcus subcomponents, with trends observed in the edema, rings, and stenosis subcomponents (Figure 5).

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

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

Table 6 summarizes the effects of dupilumab on subjective patient-reported outcomes of dysphagia and clinician-rated objective measures.

Safety results: Dupilumab was well tolerated in EoE patients. The most common treatment-emergent adverse events (TEAEs) were injection site erythema (Dupilumab 34.8%, Placebo 8.3%) and nasopharyngitis (Dupilumab 17.4%, Placebo 4.2%). there were.

Conclusions Compared to placebo, dupilumab demonstrated a statistically significant reduction in the primary endpoint, change from baseline in the Straumann Dysphagia Measure (SDI) at week 10. The LS mean difference in change from baseline at week 10 between the dupilumab and placebo groups was -1.7 (p=0.0304). Improvements in other subjective dysphagia measures were also observed, including EEsAI (Week 10) and EOE-QOL (Week 12). Finally, there was a significant statistical improvement in both histological and visual endoscopic objective assessment of disease activity. This includes percent change from baseline in peak eosinophils, absolute change from baseline in eosinophilic esophagitis edema, rings, effusions, grooves and strictures (EoE-EREFS) score at week 12. Contains changes. Dupilumab treatment was generally safe and well tolerated. The most common TEAEs were mild ISR and viral upper respiratory tract infections and nasopharyngitis.

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

Claims (12)

A medicament for increasing esophageal distensibility in a patient, the medicament comprising an interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibitor;
The IL-4/IL-13 pathway inhibitor is an antibody or antigen-binding fragment thereof that binds to IL-4Rα, and the antibody or antigen-binding fragment thereof binds to three HCDRs (HCDR1, HCDR2 and HCDR3) and three HCDRs (HCDR1, HCDR2 and HCDR3). LCDRs (LCDR1, LCDR2 and LCDR3), HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6. LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8;
The antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2;
the patient has eosinophilic esophagitis (EoE) and has been previously treated with a high dose proton pump inhibitor (PPI);
The above medicine. (a) The patient is 12 years of age or older;
(b) the patient is 18 years of age or older;
2. The medicament of claim 1, wherein (c) the patient has previously undergone esophageal dilatation at least once; and/or (d) the patient exhibits at least two weekly episodes of dysphagia. Patients:
(1) Previous treatment with at least one of corticosteroids, allergen withdrawal, and/or dietary modification;
(2) the patient is unresponsive or resistant to previous treatment with PPIs;
(3) the patient has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI) score of 30 or higher;
(4) the patient has had EoE for at least 3 years;
(5) The patient is selected from the group consisting of food allergy, atopic dermatitis, asthma, allergic rhinitis, and/or allergic conjunctivitis before or at the time of administration of the IL-4/IL-13 pathway inhibitor. Having or being diagnosed with a disease or disorder;
and/or (6) the patient receives eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, serum thymic and activation-regulated chemokines (TARC), thymic stromal lymphopoietin ( TSLP), serum eosinophilic cationic protein (ECP), and/or eosinophil-derived neurotoxin (EDN). Medicament according to claim 1 or 2, having at least one characteristic selected from the group. Any one of claims 1 to 3, wherein administration of the IL-4/IL-13 pathway inhibitor results in an increase of at least 10% from baseline in esophageal distensibility as measured with a functional luminal imaging probe. Medicines listed in section. (a) the IL-4/IL-13 pathway inhibitor is administered at a dose of about 50 to about 600 mg; or (b) the IL-4/IL-13 pathway inhibitor is administered at a dose of about 300 mg. ;
A medicament according to any one of claims 1 to 4, wherein each dose is administered one week or two weeks after the immediately preceding dose. The IL-4/IL-13 pathway inhibitor is administered in a first dose, followed by one or more secondary doses, each secondary dose being administered 1 to 4 weeks after the previous dose. , the medicament according to any one of claims 1 to 5. 7. The primary dose comprises 50-600 mg of IL-4/IL-13 pathway inhibitor and each secondary dose comprises 25-400 mg of IL-4/IL-13 pathway inhibitor. Medicine. the first dose comprises 600 mg of the IL-4/IL-13 pathway inhibitor, and each of the secondary doses comprises 300 mg of the IL-4/IL-13 pathway inhibitor;
8. A medicament according to claim 7, wherein each sub-dose is administered one week after the previous dose, or wherein each sub-dose is administered two weeks after the previous dose. The IL-4/IL-13 pathway inhibitor is administered in combination with a second therapeutic agent or therapy, said second therapeutic agent or therapy being an IL-1 beta inhibitor, an IL-5 inhibitor, an IL- 9 inhibitors, IL-13 inhibitors, IL-17 inhibitors, IL-25 inhibitors, TNF alpha inhibitors, eotaxin-3 inhibitors, IgE inhibitors, prostaglandin D2 inhibitors, immunosuppressants, topical corti Claim 1 selected from the group consisting of costosteroids, oral corticosteroids, systemic corticosteroids, inhaled corticosteroids, glucocorticoids, proton pump inhibitors, NSAIDs, esophageal dilation, allergen removal, and/or dietary management. 8. The medicament according to any one of items 8 to 8. The medicament according to any one of claims 1 to 9, wherein the IL-4/IL-13 pathway inhibitor is administered subcutaneously. 2. The medicament according to claim 1 , 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. The medicament according to any one of claims 1 to 11 , wherein the IL-4/IL-13 pathway inhibitor is dupilumab.

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