How to treat esophageal strictures

Abstract

Disclosed herein is a method for locally treating stenosis by oral administration of a corticosteroid. Dosages, formulations and methods for administration of the corticosteroid are provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 177,064, filed April 20, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Esophageal stricture is an abnormal pinching or narrowing of the esophagus. Stricture narrows the esophagus, making it difficult for food to move down the tube. Stricture results from damage to the esophagus that causes scarring and symptomatic narrowing of the esophagus. The main symptom of esophageal stricture is dysphagia, which is already a main symptom of inflammatory disease of the esophagus. As a result, stricture can worsen dysphagia in patients with inflammatory disease of the esophagus.

[0003] Strictures are notoriously difficult to treat. Currently, there is no cure for strictures. Strictures also do not occur in all patients with esophageal inflammatory disease. As a result, patients with severe strictures are generally excluded from treatment.

[0004] There is a need in the art for methods to effectively treat strictures while controlling side effects such as fungal infections, including oral, oropharyngeal, and esophageal candidiasis. The present disclosure addresses that need. Summary of the Invention

[0005] The present disclosure provides methods for reducing the severity of a stenosis.

[0006] In some embodiments, the present disclosure provides a method of locally treating an esophageal stricture with a corticosteroid in a patient in need thereof, comprising: (a) detecting an esophageal stricture; and (b) orally administering a corticosteroid. In embodiments, about 1.5-3 mg of fluticasone propionate is administered. In embodiments, the corticosteroid is administered at an equipotent dose to about 1.5-3 mg of fluticasone propionate. In embodiments, a therapeutically effective amount of oral corticosteroid contacts the esophageal stricture, thereby reducing the severity of the esophageal stricture. In embodiments, the detecting in step (a) comprises inserting an endoscope into the esophagus of the patient. In embodiments, the endoscope has a diameter of about 9 mm. In embodiments, the esophageal stricture is detected visually using a video display of the endoscope. In embodiments, the stricture is detected due to the inability of the endoscope to pass down the esophagus of the patient. In embodiments, the patient also has a ring. In embodiments, the ring is a grade 2 or grade 3 ring. In an embodiment, administration of the corticosteroid reduces the grade of the ring by at least 1. In an embodiment, the corticosteroid is administered while the patient is lying down or immediately before the patient lies down. In an embodiment, the patient is in a supine position. In an embodiment, the corticosteroid is administered within about 5, 4, 3, 2, or 1 minutes before the patient lies down. In an embodiment, the corticosteroid is administered at bedtime. In an embodiment, the corticosteroid is administered about 30 minutes or less before a target sleep time. In an embodiment, the corticosteroid is administered once a day.

[0007] In some embodiments, the present disclosure provides a method of locally treating an esophageal stricture with a corticosteroid in a patient in need thereof, comprising orally administering the corticosteroid, wherein the stricture is detected visually using a video display of an endoscope or the stricture is detected due to the inability of the endoscope to pass through the patient's esophagus. In embodiments, the stricture is detected due to the inability of the endoscope to pass through the patient's esophagus. In embodiments, the endoscope has a diameter of about 9 mm. In embodiments, about 1.5-3 mg of fluticasone propionate is administered. In embodiments, the corticosteroid is administered at an equipotent dose to about 1.5-3 mg of fluticasone propionate. In embodiments, a therapeutically effective amount of the corticosteroid contacts the esophageal stricture, thereby reducing the severity of the esophageal stricture. In embodiments, the patient also has a ring. In embodiments, the ring is a grade 2 or grade 3 ring. In embodiments, administering the corticosteroid reduces the grade of the ring by at least 1. In embodiments, the corticosteroid is administered while the patient is lying down or immediately before the patient lies down. In embodiments, the patient is in a supine position. In embodiments, the corticosteroid is administered within about 5, 4, 3, 2, or 1 minutes before the patient lies down. In embodiments, the corticosteroid is administered at bedtime. In embodiments, the corticosteroid is administered about 30 minutes or less before the target sleep time. In embodiments, the corticosteroid is administered once a day.

[0008] In some embodiments, the disclosure provides a method of treating stenosis in a patient in need thereof, comprising orally administering to the patient about 0.5 mg to about 6 mg of fluticasone propionate or an equipotent dose of a corticosteroid once daily for at least 12 weeks. In embodiments, during said 12 weeks, the patient has less than about 10% risk of candidiasis, and the patient shows improvement in at least one of the following outcomes compared to patients receiving corticosteroids twice daily: (i) at least one symptom score measured using the Patient-Reported Outcomes Symptom Evaluation (PROSE) instrument after an episode of dysphagia, (ii) EoE Endoscopic Reference (EREF) score, (iii) EoE Activity Index (EEsAI) Avoidance, Modified and Slow Swallowing (AMS) score, (vi) Global EoE score, (v) Global Impression Scale-Severity (PGIS), and (vi) Global Impression Scale-Change (PGIC).

[0009] In some embodiments, the symptom score is one or more of: (i) the number of dysphagia-free days over a 14-day period, (ii) the average daily episode severity score over a 14-day period, or (iii) the symptom burden over a 14-day period. In some embodiments, the symptom score is the number of dysphagia episodes over a 14-day period.

[0010] In some embodiments, after treatment according to the methods of the present disclosure, patients demonstrate improvement in at least one of the following outcomes compared to patients receiving corticosteroids twice daily: (i) at least one symptom score measured using the Patient-Reported Outcomes Symptom Evaluation (PROSE) instrument after an episode of dysphagia; (ii) EoE Endoscopy Reference (EREFS) score; or (iii) global EoE score.

[0011] In some embodiments, the disclosed methods include administering 1.5 mg, 3.0 mg, or 6 mg of fluticasone propionate, or an equipotent dose of a corticosteroid, hi some embodiments, 3.0 mg of fluticasone propionate, or an equipotent dose of a corticosteroid, is administered.

[0012] In some embodiments, the fluticasone propionate or corticosteroid is administered at bedtime or overnight.

[0013] In some embodiments, fluticasone propionate or an equipotent dose of a corticosteroid is administered while the patient is reclining or immediately before the patient is reclining.

[0014] In some embodiments, the method of the present disclosure reduces the patient's risk of candidiasis to 5% or less. In some embodiments, the candidiasis is oral candidiasis or esophageal candidiasis. In some embodiments, the patient's risk of oral candidiasis is less than about 10%. In some embodiments, the patient's risk of oral candidiasis is less than about 4%, less than about 3%, less than about 2%, or less than about 1%. In some embodiments, according to the method of the present disclosure, the patient's risk of oral candidiasis is about 4.8%.

[0015] In some embodiments, the patient's risk of esophageal candidiasis is less than about 10%. In some embodiments, the patient's risk of esophageal candidiasis is about 9% or less, about 8% or less, about 7% or less, about 6% or less, or about 5% or less.

[0016] In some embodiments, the methods of the present disclosure include utilizing a symptom score, the symptom score including: (i) difficulty swallowing food on a scale ranging from 0 to 10; (ii) worst discomfort due to food on a scale ranging from 0 to 10; (iii) worst pain due to food on a scale ranging from 0 to 10; (iv) the average score of any combination of (i), (ii), and (iii); (v) number of dysphagia episodes; (vi) proportion of daily dysphagia episodes; or (vii) number of dysphagia-free days.

[0017] In some embodiments, the symptom score is the average of two or more symptom score measurements. In some embodiments, the average score is the average of (i) difficulty swallowing food on a scale ranging from 0 to 10, (ii) worst discomfort from food on a scale ranging from 0 to 10, and (iii) worst pain from food on a scale ranging from 0 to 10. In some embodiments, the average score is calculated for one or more dysphagia episodes over a predetermined period of time. For example, the average score may be calculated for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 6 The scores for each episode of dysphagia over 3, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks can be calculated. In some embodiments, the average score can be calculated from the scores for each episode of dysphagia over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months. The average scores for (i) difficulty, (ii) discomfort, and (iii) pain may be referred to as the "episode severity score." An episode severity score can be assigned for one dysphagia episode. Alternatively or additionally, an episode severity score can be assigned for each day as a "daily episode severity score". The daily episode severity score is the average of the episode severity scores of all dysphagia episodes occurring on a single day. In some embodiments, the daily episode severity scores are averaged over a 14 day period. In some embodiments, the method of the present disclosure utilizes an average score of the symptom scores, and if a patient has experienced more than one dysphagia episode, an average score is calculated for the worst dysphagia episode or the worst symptom.In some embodiments, the methods of the disclosure utilize a mean symptom score, where the mean score is (a) the daily average of (i), (ii), and (iii) over a 14 day period; (b) the mean score of the worst dysphagia episode over a 14 day period of (i), (ii), and (iii); (c) the worst dysphagia symptom score over a 14 day period; (d) the number of dysphagia episodes; (e) the proportion of daily dysphagia episodes; or (f) the number of dysphagia free days.

[0018] In some embodiments, the methods of the present disclosure result in an improvement in symptom scores of 0.5 to 4 points.

[0019] In some embodiments, the symptom score, average score, worst episode score, or worst symptom score is determined using data from the two week entries immediately preceding weeks 12 and 26 of treatment.

[0020] In some embodiments, the methods of the present disclosure improve the EREFS score by about 0.3 to 1.5 points.

[0021] In some embodiments, the methods of the present disclosure improve overall EoE score by 1-4 points.

[0022] In some embodiments, the methods of the disclosure shift the PGIS score toward an improvement of about 1-5 severity categories.

[0023] In some embodiments, the methods of the present disclosure improve EEsAI scores by about 2-15 points.

[0024] In some embodiments, the methods of the present disclosure result in patients showing improvement in the Eosinophilic Esophagitis Quality of Life Questionnaire (EoO-QoL-A).

[0025] In some embodiments, the methods of the present disclosure result in patients exhibiting an improvement of about 1-3 points on the Eosinophilic Esophagitis Quality of Life Questionnaire (EoO-QoL-A).

[0026] In some embodiments, the methods of the present disclosure reduce the patient's eosinophil count in the patient's esophagus as compared to the patient's baseline eosinophil level.

[0027] In some embodiments, the methods of the present disclosure result in a reduction in eosinophil count to 6 or less eosinophils per high power field (hpf).

[0028] In some embodiments, the methods of the present disclosure include measuring eosinophil counts in the distal portion of the esophagus, the proximal portion of the esophagus, or both.

[0029] In some embodiments, the methods of the disclosure result in eosinophil counts in the distal portion of the esophagus reaching 6 eosinophils or less per hpf.

[0030] In some embodiments, the methods of the present disclosure result in proximal eosinophil counts of 6 or less eosinophils per hpf.

[0031] In some embodiments, the methods of the disclosure result in a reduction in the number of dysphagia episodes compared to patients receiving corticosteroids twice daily.

[0032] In some embodiments, the methods of the disclosure result in an increase in dysphagia-free days compared to patients receiving corticosteroids twice daily.

[0033] In some embodiments, the methods of the disclosure provide for a measurement of risk of candidiasis and an improvement in at least one of the outcomes at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and / or 12 weeks.

[0034] In some embodiments, the methods of the present disclosure measure the risk of candidiasis and improvement in at least one of the outcomes again at 26 weeks and / or 52 weeks.

[0035] In some embodiments, the methods of the present disclosure provide for administration of a corticosteroid in an amount ranging from about 1 mg to about 5 mg, including 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, and 5 mg.

[0036] In some embodiments, the fluticasone propionate or corticosteroid is administered for about 12 weeks to at least 1 year.

[0037] In some embodiments, 1.5 mg of fluticasone propionate is administered. In some embodiments, 3.0 mg of fluticasone propionate is administered.

[0038] In some embodiments, the corticosteroid is budesonide. In some embodiments, the budesonide is administered for about 12 weeks to at least one year. In some embodiments, 0.5 to 2 mg of budesonide is administered.

[0039] In some embodiments, the corticosteroid is formulated as a solid composition. In some embodiments, the solid composition is in the form of a gel, a lozenge, a lollipop, an effervescent tablet, a powder, a granule, an oral disintegrating composition, or an oral dispersion composition. In some embodiments, the oral disintegrating composition is a tablet, a wafer, a film, an effervescent, or a lyophilized matrix. In some embodiments, the oral dispersion composition is a tablet, a wafer, a film, an effervescent, or a lyophilized matrix.

[0040] In some embodiments, the methods of the disclosure result in an improvement in Visual Dysphagia Questionnaire (VDQ) composite score compared to patients receiving corticosteroids twice daily.

[0041] In some embodiments, the methods of the disclosure result in an improvement in EEsAI total score compared to patients administering corticosteroids twice daily. [Brief description of the drawings]

[0042] [Figure 1] FIG. 1 shows the study design comparing fluticasone propionate (FP) orally disintegrating tablets with placebo in adults with eosinophilic esophagitis ("EoE"). [Diagram 2] 1 shows endoscopy scans showing various degrees of esophageal stricture. [Diagram 3] 1 shows bar graphs depicting histology, symptomatic response rate, and endoscopic response rate in treatment groups. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Disclosed herein is a method for locally treating esophageal strictures and rings. These fibrostenosing features are not present in all patients with inflammatory esophageal disease, and thus prior treatment with oral corticosteroids for inflammatory esophageal disease does not necessarily treat the fibrostenosing features, e.g., strictures. Furthermore, treating fibrostenosing features is known to be difficult. In fact, patients with these fibrostenosing features, especially severe strictures, are generally excluded from clinical trials. Applicants have surprisingly and unexpectedly discovered that orally administering corticosteroids according to the methods disclosed herein not only reduces strictures and rings. In some embodiments, once-daily administration (e.g., at night, e.g., while lying down or immediately before lying down) improves treatment of fibrostenosing features compared to patients treated with corticosteroids twice daily. Surprisingly, once-daily administration also reduces the risk of candidiasis and improves symptom scores as measured herein. Thus, once-daily treatment results in better clinical outcomes compared to twice-daily treatment. In some embodiments, the total daily dose for once-daily and twice-daily administration is the same. For example, patients administered 3 mg fluticasone propionate once-daily according to the methods described herein have improved symptom scores and reduced risk of candidiasis compared to patients administered 1.5 mg twice-daily (BID) for a total daily dose of 3 mg. In some embodiments, the total daily dose for twice-daily administration is greater than the total daily dose for once-daily administration. For example, patients administered 3 mg corticosteroid once-daily at bedtime according to the methods described herein have improved symptom scores and reduced candidiasis compared to patients administered 3 mg corticosteroid twice-daily (i.e., a total daily dose of 6 mg).

[0044] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "corticosteroid" can refer to a corticosteroid or mixture of corticosteroids, reference to a "process" includes references to equivalent steps and / or methods known to those skilled in the art, and so forth.

[0045] As used herein, the term "about" or "approximately" when preceding a numerical value indicates a plus or minus variation of the value within the accepted degree of the art. In some embodiments, "about" indicates a value within a range of plus or minus 10%. For example, "about 100" includes 90 and 110.

[0046] As used herein, "treat," "treatment," or "treating" refers to an approach for obtaining beneficial or desired results, such as clinical results. For purposes of this disclosure, beneficial or desired results can include inhibiting or suppressing the onset or progression of EoE, ameliorating or reducing the manifestations or symptoms of EoE, or a combination thereof.

[0047] As used herein, the terms "diagnose," "diagnosis," and "diagnosing" refer to identifying, assessing, evaluating, or classifying the presence or characteristics of a pathological condition, e.g., diagnosing whether a subject referred to in accordance with the methods of the present disclosure has an esophageal stricture or ring.

[0048] Fibrostenosis Characteristics and Treatment Methods In some embodiments, the present disclosure provides a method for treating fibrostenotic features in the esophagus, such as strictures or rings. Esophageal strictures represent fixed scarring of the esophagus secondary to long-term inflammation. Esophageal strictures are often caused by the accumulation of scar tissue due to various conditions or events that cause esophageal inflammation, such as eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD), endoscopic injury, extensive use of nasogastric (NG) tubes, swallowing toxic substances, esophageal scleroderma, and during or after the treatment of esophageal varices. Rings refer to abnormal rings of tissue in the esophagus that cause esophageal stricture. Rings may be caused by the same conditions and events that cause strictures.

[0049] Several diagnostic methods can be used to detect esophageal strictures and / or esophageal rings characteristic of fibrostenosing. In embodiments, esophageal strictures and / or esophageal rings can be detected by running an endoscope down the esophagus to look for esophageal rings or narrowings. In embodiments, esophagoscopy, esophageal manometry, modified barium swallow study (MBS), and / or flexible endoscopic evaluation of swallowing (FEERS) can be utilized to detect strictures or rings.

[0050] In an embodiment, the esophageal stricture is detected by using an endoscope, hi an embodiment, an esophageal stricture is detected when the endoscope is inserted into the patient's esophagus but is unable to pass through the patient's esophagus. In embodiments, the endoscope has a diameter in the range of about 7 mm to about 11 mm (e.g., 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm, 8.0 mm, 8.1 mm, 8.2 mm, 8.3 mm, 8.4 mm, 8.5 mm, 8.6 mm, 8.7 mm, 8.8 mm, 8.9 mm, 9.0 mm, 9.1 mm, 9.2 mm, 9.3 mm, 9.4 mm, 9.5 mm, 9.6 mm, 9.7 mm, 9.8 mm, 9.9 mm, 10.0 mm, 10.1 mm, 10.2 mm, 10.3 mm, 10.4 mm, 10.5 mm, 10.6 mm, 10.7 mm, 10.8 mm, 10.9 mm, 11.0 mm, including all values ​​and ranges therein). In an embodiment, the inserted endoscope has a diameter of about 8-10 mm. In an embodiment, the inserted endoscope has a diameter of about 9 mm. In an embodiment, the endoscope provides a visual image or video showing a portion or the entire esophagus. Esophageal strictures can be detected visually using a video display or radiography.

[0051] In some embodiments, stenosis and / or rings are diagnosed using the EoE Endoscopic Reference Score (EREFS), which measures edema (e.g., decreased vascularity or pulse), present rings, exudates (e.g., white plaques), wrinkles and / or stenosis in the esophagus as described in Table 1. In embodiments, the patient also has Grade 2 or Grade 3 rings. [Table 1]

[0052] Fibrostenosing features represent permanent scarring of the esophagus that occurs with continued inflammation, and the methods of the present disclosure can resolve this scarring. The resolution of scarring is independent of pathology or disease, and therefore the methods of the present disclosure are suitable for use in any disease or condition in which fibrostenosing features occur. In some embodiments, patients with fibrostenosing features have an inflammatory condition of the upper gastrointestinal tract, such as the esophagus. In some embodiments, the inflammatory condition is eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), erosive esophagitis, Barrett's esophagus, eosinophilic gastroenteritis, hypereosinophilic syndrome, caustic (corrosive) chemical esophagitis, radiation-induced esophagitis, chemotherapy-induced esophagitis, transient drug-induced esophagitis (also known as drug esophagitis), persistent drug-induced esophagitis, Crohn's disease of the esophagus, postoperative resection of the esophagus, and pseudomembranous esophagitis. In some embodiments, the patient has eosinophilic esophagitis (EoE). In some embodiments, the patient has gastroesophageal reflux disease (GERD). In some embodiments, the patient has non-erosive reflux disease (NERD). In some embodiments, the patient has erosive esophagitis. In some embodiments, the patient has Barrett's esophagus. In some embodiments, the patient has eosinophilic gastroenteritis. In some embodiments, the patient has hypereosinophilic syndrome. In some embodiments, the patient has corrosive (corrosive) chemical esophagitis. In some embodiments, the patient has radiation-induced esophagitis. In some embodiments, the patient has chemotherapy-induced esophagitis. In some embodiments, the patient has transient drug-induced esophagitis (also known as drug-induced esophagitis). In some embodiments, the patient has persistent drug-induced esophagitis. In some embodiments, the patient has Crohn's disease of the esophagus. In some embodiments, the patient undergoes post-operative resection of the esophagus. In some embodiments, the patient has pseudomembranous esophagitis. In some embodiments, the disclosure includes methods for treating a patient having one or more of the above gastrointestinal disorders, wherein the patient also has a lactose allergy and / or a starch allergy.

[0053] In some embodiments, the corticosteroid disclosed herein is administered until the stenosis and / or annulus is treated. In some embodiments, the corticosteroid disclosed herein continues to be administered after the stenosis and / or annulus is treated.

[0054] In some embodiments, following oral administration, the corticosteroid contacts and / or is deposited near the esophageal fibrostenosing features. In some embodiments, the corticosteroid contacts and / or is deposited at the distal portion of the esophagus. In some embodiments, the pharmaceutical composition contacts and / or is deposited at the proximal portion of the esophagus. In some embodiments, a therapeutically effective amount of the corticosteroid contacts and / or is deposited at the distal and proximal portions of the esophagus.

[0055] Treatment of stenosis and rings can be measured by any means known in the art. For example, treatment can be evaluated by visual inspection using an endoscope equipped with a video display. Tests used to evaluate patients with esophageal inflammation, such as EoE, include, but are not limited to, biopsy, symptom evaluation (e.g., patient-reported outcomes (PROs) or physician questionnaires), quality of life measurements, determining the number of days the patient was free of dysphagia, endoscopy (e.g., EREFS), improvement in esophageal compliance and / or esophageal remodeling (e.g., using a suitable diagnostic test, such as EndoFLIP available from Crospon Inc.), biomarker evaluation, reduction in peak eosinophil count, reduction in food impaction, EEsAI, Severity Dysphagia Index (DSQ), MDQ-30, EoE-QOL-A, VDQ (Visual Dysphagia Questionnaire), Avoidance Modification and Slow Meal (AMS) score, and / or histology.

[0056] Eosinophilic Esophagitis (EoE) In some embodiments, the methods of the present disclosure are utilized to treat fibrostenosing features (strictures and / or rings) in patients with EoE. Not all EoE patients have esophageal strictures. Generally, EoE is not diagnosed by imaging alone, and some EoE patients report normal esophagus during barium swallow studies. Although featureless narrow esophagus, circular esophagus, and isolated esophageal strictures can be seen in EoE, none of them have been classified as pathologies specific to EoE (Ahmed, M. et al., Eosinophilic esophagitis in adults, World J Gastrointest Pharmacol Ther, 2016 7(2):207-231).

[0057] EoE has been described in children and adults with dysphagia and other esophageal symptoms, either alone (typical symptoms) or as a manifestation of eosinophilic gastroenteritis (unusual symptoms). In its isolated form, the disease exhibits symptoms and histology similar to those of gastroesophageal reflux disease (GERD) (e.g., dysphagia, food impaction, nausea, vomiting, and weight loss), and thus was initially diagnosed as GERD when EoE first appeared in the 1960s (Furuta et al. 2007). Over time, the fact that EoE patients do not undergo reflux and typically do not respond to anti-reflux therapy called the similarity into question, and it was subsequently considered as a separate clinical entity.

[0058] EoE affects people of all ages and ethnic backgrounds. EoE is predominant in non-Hispanic whites. The majority of EoE patients are male and usually present with EoE symptoms in childhood or in their 30s or 40s. Pediatric EoE usually presents between the ages of 5-10, with 70% of pediatric EoE persisting into adulthood. The clinical presentation of EoE may vary with age, with more differences in symptoms between infants and young children compared to younger adults and adults. Older children, unlike younger children, typically present with symptoms of heartburn or dysphagia. Younger people present with food impaction in the esophagus. Patients with atopic background or food allergies have been shown to present with more severe esophageal symptoms and food impaction. In some embodiments, a common symptom of EoE in adolescents is symptoms similar to GERD. In some embodiments, children aged 11 years and older largely report dysphagia and food impaction, which is also the most common indication for endoscopy in adult patients.

[0059] In some embodiments, EoE is defined as a primary clinicopathologic disorder of the esophagus, characterized by esophageal and / or upper gastrointestinal (GI) tract symptoms associated with esophageal mucosal biopsy specimens containing ≧15 intraepithelial eosinophils (EOS) / high power field (HPF) in one or more biopsy specimens, and the absence of pathologic GERD, as evidenced by normal pH monitoring studies of the distal esophagus or lack of response to high-dose proton pump inhibitor (PPI) medications.

[0060] In some embodiments, EoE patients may be diagnosed using any suitable measure in the art. In some embodiments, patients are diagnosed with EoE based on scores from evaluations using symptoms, patient-reported outcomes (PRO) questionnaires, histology, and / or records of failure on proton pump inhibitors. In some embodiments, patients were on proton pump inhibitor (PPI) therapy prior to administration of corticosteroids. In some embodiments, patients showed poor improvement after 8 weeks of high-dose (e.g., 40 mg) PPI. Lack of response to PPI therapy may be defined as a peak eosinophil count above 15 / HPF in at least one biopsy site after 8 weeks of treatment with high-dose PPI. In some embodiments, failure of PPI therapy is documented prior to administration of a pharmaceutical composition of the present disclosure. In some embodiments, patients are not on PPI therapy prior to administration of corticosteroids.

[0061] The inventors have surprisingly and unexpectedly found that once-daily administration of corticosteroids is more effective than twice-daily administration in treating stenosis and / or rings in EoE symptoms, even though the total daily dose of once-daily administration is the same as that of twice-daily administration. Not only is once-daily administration of corticosteroids effective in treating EoE (e.g., by reducing eosinophils), but once-daily administration significantly reduces the risk of candidiasis compared to twice-daily administration. Thus, patients receiving once-daily administration of corticosteroids have a surprisingly improved symptomatic outcome compared to patients receiving twice-daily administration.

[0062] Corticosteroids and further therapeutic agents In some embodiments, the method of the present disclosure comprises administering one or more corticosteroids to a patient with esophageal stricture or ring. Suitable corticosteroids include, but are not limited to, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, etc. or mineralocorticoids (e.g., arsosterone), budesonide, fluticasone, flunisolide, ciclesonide, mometasone, beclomethasone, tixocortol and their salts, or esters and mixtures. In some embodiments, the corticosteroid is budesonide. In some embodiments, the corticosteroid is fluticasone or its ester. In some embodiments, the corticosteroid is fluticasone propionate.

[0063] Fluticasone propionate (FP) is a medium-potency synthetic corticosteroid with the chemical name S-(fluoromethyl)-6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propanoate. The molecular formula for fluticasone propionate is C 25 H 31 The chemical structure of fluticasone propionate is: [ka]

[0064] Fluticasone propionate (also referred to herein as "FP") is a white to off-white powder. It is freely soluble in dimethylsulfoxide and dimethylformamide, sparingly soluble in acetone, dichloromethane, ethyl acetate and chloroform, slightly soluble in methanol and 95% ethanol, and practically insoluble in water. FP decomposes without melting. The onset of decomposition occurs at about 225°C. Fluticasone propionate is a moderate-potency glucocorticoid with anti-inflammatory properties, including antieosinophil activity in vitro and in vivo.

[0065] In some embodiments, the pharmaceutical composition used (or for use) in the methods described herein can be in any dosage form that allows for local administration of the corticosteroid to the esophagus. Non-limiting examples of suitable dosage forms include liquid compositions (e.g., solutions, suspensions, and slurries), gels, and solid compositions that form a liquid or gel after oral administration. For example, orally disintegrating compositions (e.g., ODTs, effervescent, film, lyophilized matrix, or wafers), lozenges, and lollipops can be placed in the patient's oral cavity from a solution, suspension, or gel containing the therapeutic agent, and after the solution or suspension is swallowed, the corticosteroid dissolved or suspended therein contacts the esophagus as the liquid passes through the esophagus. In a preferred embodiment, the pharmaceutical composition is in the form of an ODT.

[0066] The wafers can include dry or lyophilized compositions, such as oral disintegrating or dissolving dosage forms prepared using Zydis® freeze-drying technology (e.g., as described in U.S. Pat. No. 6,316,027) that include a corticosteroid as the active pharmaceutical ingredient. Film dosage forms can include, for example, edible films, as described in U.S. Pat. No. 6,596,298 or U.S. Pat. No. 6,740,332, that contain a corticosteroid as the active pharmaceutical ingredient. In some embodiments, the solid composition includes a lyophilized matrix, which includes a corticosteroid, a carrier, and an excipient. Suitable excipients include, but are not limited to, mannitol, xylitol, sorbitol, maltol, maltitol, lactose, sucrose, maltose, and combinations thereof.

[0067] Effervescent tablets and effervescent orodispersible tablets may include those disclosed in U.S. Patent No. 9,867,780 and U.S. Patent No. 8,580,300. Such formulations contain a weak acid or a salt of a weak acid, such as tartaric acid, acetic acid, lactic acid, or citric acid, or a pharma- ceutically acceptable salt thereof, such as magnesium, calcium, or sodium salts. These formulations may also contain pharma- ceutically acceptable excipients that release CO2, such as carbonate ions, and salts of carbonate ions and bicarbonate ions, such as sodium and potassium salts, upon contact with water (e.g., saliva). In some embodiments, such effervescent tablets are formulated to dissolve in solution prior to oral administration. Such formulations may further contain polyvinylpyrrolidone.

[0068] In some embodiments, fluticasone propionate is formulated as an orally disintegrating tablet (also called oral dispersion or orodispersible) containing a mixture of excipients consisting of crospovidone, mannitol colloidal silicon dioxide, silicified microcrystalline cellulose, sucralose, and sodium stearyl fumarate. In some embodiments, the orally disintegrating tablet contains about 1.5 mg or 3.0 mg of fluticasone propionate. In some embodiments, ODTs are described in U.S. Patent No. 8,771,729 or U.S. Patent No. 10,471,071, each of which is incorporated herein by reference.

[0069] In some embodiments, one or more additional therapeutic agents may be co-administered with the corticosteroid, including proton pump inhibitors (PPIs), including, but not limited to, omeprazole, lansoprazole, dextransoprazole, rabeprazole, pantoprazole, and esomeprazole.

[0070] In some embodiments, the additional therapeutic agent comprises one or more immunosuppressants. Suitable immunosuppressants include, but are not limited to, cyclosporine, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolic acid, methotrexate, basiliximab, daclizumab, rituximab, mepolizumab (anti-IL-5), reslizumab (anti-IL-5), QAX576 (anti-IL-13), omalizumab (anti-immunoglobulin E), inflimab (anti-TNF-α), antithymocyte globulin, and antilymphocyte globulin.

[0071] In some embodiments, the pharmaceutical compositions disclosed herein are co-administered with one or more antibodies. Suitable antibodies include, but are not limited to, IL-4, IL-5 and IL-13 antibodies. Non-limiting examples include basiliximab, daclizumab, rituximab, mepolizumab (anti-IL-5), reslizumab (anti-IL-5), QAX576 (anti-IL-13), and omalizumab (anti-immunoglobulin E).

[0072] In some embodiments, one or more therapeutic agents may be "co-administered", i.e., coordinately administered to a subject together, either as separate pharmaceutical compositions or mixed into a single pharmaceutical composition. By "co-administered", one or more therapeutic agents may also be administered simultaneously with the pharmaceutical composition, or may be administered separately, such as at different times and with different frequencies. One or more therapeutic agents may be administered by any known route, e.g., orally, intravenously, intramuscularly, nasally, subcutaneously, etc., and the therapeutic agents may also be administered by any conventional route.

[0073] In some embodiments, the therapeutic agents in the previous paragraphs can be combined.When multiple drugs are used in combination, the dosage of each drug is generally the same as the dosage of the drug when used independently.If a drug inhibits the metabolism of another drug, the dosage of each drug is appropriately adjusted.Each drug may be administered simultaneously or separately at appropriate time intervals.

[0074] In some embodiments, the therapeutic agents for use in the present methods can be formulated in any suitable dosage form, such as orally, parenterally, by inhalation spray, or topically, in formulations containing pharma- ceutically acceptable carriers, adjuvants, and vehicles. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, and intra-arterial injections, with a variety of infusion techniques.

[0075] dose In some embodiments, the methods of the present disclosure include administration of a therapeutically effective dose of fluticasone propionate. In some embodiments, the therapeutically effective dose is about 0.5 mg to about 5 mg of fluticasone propionate. In some embodiments, the fluticasone propionate is about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg , about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, or about 5.0 mg. In some embodiments, 1.5 mg of fluticasone propionate or an equivalent dose of a corticosteroid is administered. In some embodiments, 3.0 mg of fluticasone propionate or an equivalent dose of a corticosteroid is administered.

[0076] Although the compositions and methods described herein use or refer to a dose of fluticasone propionate, the disclosure contemplates the use of other corticosteroids to achieve substantially similar efficacy in treating fibrostenosing features. The disclosure contemplates the use of such corticosteroids at equipotent doses to fluticasone propionate to achieve efficacy. In embodiments, the corticosteroid has an equipotent dose to fluticasone propionate of 1.5 mg or 3.0 mg. One skilled in the art can determine an equipotent dose based on the relative glucocorticoid receptor binding affinity of the corticosteroid or the relative potency of the anti-inflammatory activity of the corticosteroid. In some embodiments, the equipotent dose is calculated based on the relative glucocorticoid receptor binding affinity of the corticosteroid of the relative glucocorticoid activity. Glucocorticoid receptor binding affinity provides a measure of the dose required to occupy 50% of the glucocorticoid receptors. Table 2 shows the relative glucocorticoid receptor binding affinity for several corticosteroids. In some embodiments, pharmacokinetic / pharmacodynamic modeling is used to estimate the equipotent dose of a corticosteroid. The following article, which describes how to calculate the equipotent dose, is incorporated herein by reference in its entirety: Daley-Yates, Br J Clin Pharmacol. 2015 Sep;80(3):372-380. [Table 2]

[0077] In some embodiments, the disclosed methods provide for administration of a corticosteroid in an amount ranging from about 1 mg to about 5 mg, e.g., 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, and 5 mg. In some embodiments, an equipotent dose of a corticosteroid is 0.05 mg to 20 mg. In some embodiments, the equipotent dose of the corticosteroid is from about 0.05 mg to about 20 mg, e.g., about 0.05 mg, or about 0.1 mg, or about 0.15 mg, or about 0.2 mg, or about 0.25 mg, or about 0.30 mg, or about 0.35 mg, or about 0.40 mg, or about 0.45 mg, or about 0.50 mg, or about 0.55 mg, or about 0.60 mg, or about 0.65 mg, or about 0.70 mg, or about 0.75 mg, or about 0.80 mg, or about 0.85 mg, or about 0.9 mg, or about 0.95 mg, or about 1.0 mg, or about 1.5 mg, or about 2.0 mg, or about 2.5 mg, or about 3.0 mg, or about 3.5 mg, or about 4.0 mg, or about 4.5 mg, or about 5. 0.0 mg, or about 5.5 mg, or about 6.0 mg, or about 6.5 mg, or about 7.0 mg, or about 7.5 mg, or about 8.0 mg, or about 8.5 mg, or about 9.0 mg, or about 9.5 mg, or about 10.0 mg, or about 10.5 mg, or about 11.0 mg, or about 11.5 mg, or about 12.0 mg, or about 12.5 mg, or about 13.0 mg, or about 13.5 mg, or about 14.0 mg, or about 14.5 mg, or about 15.0 mg, or about 15.5 mg, or about 16.0 mg, or about 16.5 mg, or about 17.0 mg, or about 17.5 mg, or about 18.0 mg, or about 19.0 mg, or about 19.5 mg, or about 20.0 mg, including all ranges therebetween. Non-limiting examples of corticosteroids include hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, and the like or mineralocorticoids (e.g., arsosterone), budesonide, fluticasone, flunisolide, ciclesonide, mometasone, beclomethasone, tixocortol and salts, or esters and mixtures thereof.

[0078] In some embodiments, the disclosed method includes administration of a total daily dose. As defined herein, the "total daily dose" is the total amount of fluticasone propionate or an equipotent dose of corticosteroid administered in a day. As described herein, by administering a corticosteroid once a day, the fibrostenosing features are treated according to the disclosed methods, and the patient's symptom scores are improved (if described herein), while the patient's risk of candidiasis is also reduced. The total daily dose for once-daily administration may be the same or different from the total daily dose for twice-daily administration. In some embodiments, the total daily dose for twice-daily administration is the same as the total daily dose for once-daily administration. For example, the total daily dose for once-daily and twice-daily administration may be 1.5 mg or 3.0 mg of fluticasone propionate. In some embodiments, the total daily dose for twice-daily administration is greater than the total daily dose for once-daily administration. For example, a patient can be administered 1.5 mg fluticasone propionate once daily and their symptom scores and risk of candidiasis can be compared to patients administered a total daily dose of 3.0 mg, 4.5 mg, or 6 mg fluticasone propionate twice daily. As another example, a patient can be administered 3 mg of a corticosteroid once daily and their symptom scores and risk of candidiasis can be compared to patients administered a total daily dose of 4.5 mg or 6 mg fluticasone propionate twice daily.

[0079] Medication Regimen In some embodiments, the corticosteroid (e.g., fluticasone propionate) is administered once a day. In some embodiments, the corticosteroid (e.g., fluticasone propionate) is administered once a day at bedtime or overnight (HS). As defined herein, bedtime is the time when the patient wishes to fall asleep. In some embodiments, the corticosteroid (e.g., fluticasone propionate) is administered within 30 minutes, or 1 hour, or 1.5 hours, or 2 hours, or 2.5 hours, or 3.0 hours of the patient's bedtime. In some embodiments, the corticosteroid (e.g., fluticasone propionate) is administered within 30 minutes of the patient's bedtime. In some embodiments, the corticosteroid (e.g., fluticasone propionate) is administered while the patient is lying down or just before the patient lies down. As used herein, "just before the patient lies down" means within 30 minutes of the patient lying down, e.g., within 25, 20, 15, 10, or 5 minutes of the patient lying down. In embodiments, the oral corticosteroid is administered within about 5, 4, 3, 2, or 1 minutes before the patient lies down. In embodiments, the fluticasone propionate is administered within about 5, 4, 3, 2, or 1 minutes before the patient lies down. In some embodiments, the fluticasone propionate is administered once a day at about 6:00 PM, about 6:30 PM, about 7:00 PM, about 7:30 PM, about 8:00 PM, about 8:30 PM, about 9:00 PM, about 9:30 PM, about 10:00 PM, about 10:30 PM, about 11:00 PM, or about 12:00 AM. In some embodiments, fluticasone propionate is administered to the patient on an empty stomach (eg, at least 2 hours after a meal, or at least 1 hour before a meal, or at least 30 minutes before or after a meal).

[0080] In some embodiments, the corticosteroid (e.g., fluticasone propionate) is administered for a defined length of time. In some embodiments, the methods of the present disclosure provide for administration of the corticosteroid (e.g., fluticasone propionate) for a period of about 12 weeks to at least 1 year. In some embodiments, the period is at least 12 weeks, or at least 13 weeks, or at least 14 weeks, or at least 15 weeks, or at least 16 weeks, or at least 17 weeks, or at least 18 weeks, or at least 19 weeks, or at least 20 weeks, or at least 21 weeks, or at least 22 weeks, or at least 23 weeks, or at least 24 weeks, or at least 25 weeks, or at least 26 weeks, or at least 27 weeks, or at least 28 weeks, or at least 29 weeks, or at least 30 weeks, or at least 31 weeks, or at least 32 weeks, or at least 33 weeks, or is at least 34 weeks, or at least 35 weeks, or at least 36 weeks, or at least 37 weeks, or at least 38 weeks, or at least 39 weeks, or at least 40 weeks, or at least 41 weeks, or at least 42 weeks, or at least 43 weeks, or at least 44 weeks, or at least 45 weeks, or at least 46 weeks, or at least 47 weeks, or at least 48 weeks, or at least 49 weeks, or at least 50 weeks, or at least 51 weeks, or at least 52 weeks or more (e.g., 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, etc.).

[0081] In some embodiments, treatment of the esophageal stricture or ring with a corticosteroid is stopped for a defined period of time to allow the patient to recover from the treatment. In some embodiments, the period is at least 1 week, or at least 2 weeks, or at least 3 weeks, or at least 4 weeks, or at least 5 weeks, or at least 6 weeks, or at least 7 weeks, or at least 8 weeks, or at least 9 weeks, or at least 10 weeks, or at least 11 weeks, or at least 12 weeks, or at least 13 weeks, or at least 14 weeks, or at least 15 weeks, or at least 16 weeks, or at least 17 weeks, or at least 18 weeks, or at least 19 weeks, or at least 20 weeks, or at least 21 weeks, or at least 22 weeks, or at least 23 weeks, or at least 24 weeks, or at least 25 weeks, or at least 26 weeks, or less. or at least 27 weeks, or at least 28 weeks, or at least 29 weeks, or at least 30 weeks, or at least 31 weeks, or at least 32 weeks, or at least 33 weeks, or at least 34 weeks, or at least 35 weeks, or at least 36 weeks, or at least 37 weeks, or at least 38 weeks, or at least 39 weeks, or at least 40 weeks, or at least 41 weeks, or at least 42 weeks, or at least 43 weeks, or at least 44 weeks, or at least 45 weeks, or at least 46 weeks, or at least 47 weeks, or at least 48 weeks, or at least 49 weeks, or at least 50 weeks, or at least 51 weeks, or at least 52 weeks, or longer.

[0082] In some embodiments, treatment is stopped for a specified period of time and then resumed. In some embodiments, treatment is stopped for 1 week, or at least 2 weeks, or at least 3 weeks, or at least 4 weeks, or at least 5 weeks, or at least 6 weeks, or at least 7 weeks, or at least 8 weeks, or at least 9 weeks, or at least 10 weeks, or at least 11 weeks, or at least 12 weeks, or at least 13 weeks, or at least 14 weeks, or at least 15 weeks, or at least 16 weeks, or at least 17 weeks, or at least 18 weeks, or at least 19 weeks, or at least 20 weeks, or at least 21 weeks, or at least 22 weeks, or at least 23 weeks, or at least 24 weeks, or at least 25 weeks, or at least 26 weeks, or at least 28 weeks, or at least 29 weeks, or at least 30 weeks, or at least 31 weeks, or at least 32 weeks, or at least 33 weeks, or at least 34 weeks, or at least 35 weeks, or at least 36 weeks, or at least 37 weeks, or at least 38 weeks, or at least 39 weeks, or at least 40 weeks, or at least 41 weeks, or at least 42 weeks, or at least 43 weeks, or at least 44 weeks, or at least 45 weeks, or at least 46 weeks, or at least 47 weeks, or at least 48 weeks, or at least 49 weeks, or at least 50 weeks, or at least 51 weeks, or at least 52 weeks, or at least 53 weeks, or at least 54 weeks, or at least 55 weeks, or at least 56 weeks, or at least 57 weeks, or at least 58 weeks, or at least 59 weeks, or at least 60 weeks, or at least 61 weeks, or at least 62 weeks, or at least 63 weeks, or or at least 28 weeks, or at least 29 weeks, or at least 30 weeks, or at least 31 weeks, or at least 32 weeks, or at least 33 weeks, or at least 34 weeks, or at least 35 weeks, or at least 36 weeks, or at least 37 weeks, or at least 38 weeks, or at least 39 weeks, or at least 40 weeks, or at least 41 weeks, or at least 42 weeks, or at least 43 weeks, or at least 44 weeks, or at least 45 weeks, or at least 46 weeks, or at least 47 weeks, or at least 48 weeks, or at least 49 weeks, or at least 50 weeks, or at least 51 weeks, or at least 52 weeks, or more. Temporarily discontinuing corticosteroids is known as a drug "holiday" and, in some embodiments, can be helpful in reducing cortisol suppression and other side effects associated with long-term corticosteroid use.

[0083] Outcome In some embodiments, after administration of fluticasone propionate or an equipotent dose of a corticosteroid, the stenosis is resolved. In some embodiments, the number of patients with stenosis after 12 weeks of treatment is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95, or 100%. In some embodiments, administration of fluticasone propionate or an equipotent dose of a corticosteroid reduces the annulus grade by 1 or 2. In some embodiments, the patient does not develop a new stenosis or annulus during treatment. In some embodiments, the change in annulus grade and / or stenosis severity is measured after 12 weeks of treatment.

[0084] In some embodiments, administration of fluticasone propionate or an equipotent dose of a corticosteroid once daily results in an improvement in one or more outcomes compared to patients receiving fluticasone propionate or an equipotent dose of a corticosteroid twice daily. Non-limiting examples of patient outcomes include reduced risk or incidence of candidiasis, at least one symptom score measured using the Patient-Reported Outcomes Symptom Evaluation (PROSE) instrument after each episode of dysphagia (see, e.g., WO2019 / 165138) or a 24-hour diary (see, e.g., U.S. Patent Application Publication No. 2016 / 0078186), EoE Endoscopy Reference (EREF) score, EoE Activity Index (EEsAI) avoidance, modified and slow swallowing (AMS) score, global EoE score, Eosinophilic Esophagitis Quality of Life Questionnaire, Global Impression Scale-Severity (PGIS), and Global Impression Scale-Change (PGIC).

[0085] A patient's risk of candidiasis is determined from the incidence rate in the clinical trial population. The incidence rate of candidiasis is the number of patients who reported candidiasis infection divided by the total number of patients treated with corticosteroids during treatment.

[0086] In some embodiments, outcomes are assessed within 1 week, or 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks, or 6 weeks, or 7 weeks, or 8 weeks, or 9 weeks, or 10 weeks, or 11 weeks, or 12 weeks, or 13 weeks, or 14 weeks, or 15 weeks, or 16 weeks, or 17 weeks, or 18 weeks, or 19 weeks, or 20 weeks, or 21 weeks, or 22 weeks, or 23 weeks, or 24 weeks, or 25 weeks from the start of treatment with the methods of the disclosure. or 26 weeks, or 27 weeks, or 28 weeks, or 29 weeks, or 30 weeks, or 31 weeks, or 32 weeks, or 33 weeks, or 34 weeks, or 35 weeks, or 36 weeks, or 37 weeks, or 38 weeks, or 39 weeks, or 40 weeks, or 41 weeks, or 42 weeks, or 43 weeks, or 44 weeks, or 45 weeks, or 46 weeks, or 47 weeks, or 48 weeks, or 49 weeks, or 50 weeks, or 51 weeks, or 52 weeks, or or 53 weeks, or 54 weeks, or 55 weeks, or 56 weeks, or 57 weeks, or 58 weeks, or 59 weeks, or 60 weeks, or 61 weeks, or 62 weeks, or 63 weeks, or 64 weeks, or 65 weeks, or 66 weeks, or 67 weeks, or 68 weeks, or 69 weeks, or 70 weeks, or 71 weeks, or 72 weeks, or 73 weeks, or 74 weeks, or 75 weeks, or 76 weeks, or 77 weeks, or 78 weeks, or 79 weeks, or 8 or 90 weeks, or 91 weeks, or 92 weeks, or 93 weeks, or 94 weeks, or 95 weeks, or 96 weeks, or 97 weeks, or 98 weeks, or 99 weeks, or 100 weeks, or 101 weeks, or 102 weeks, or 103 weeks, or 104 weeks or more.In some embodiments, the methods of the disclosure may be administered 1 week, or 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks, or 6 weeks, or 7 weeks, or 8 weeks, or 9 weeks, or 10 weeks, or 11 weeks, or 12 weeks, or 13 weeks, or 14 weeks, or 15 weeks, or 16 weeks, or 17 weeks, or 18 weeks, or 19 weeks, or 20 weeks, or 21 weeks, or 22 weeks, or 23 weeks, or 24 weeks, or 25 weeks after initiation of treatment with the methods of the disclosure. weeks, or 26 weeks, or 27 weeks, or 28 weeks, or 29 weeks, or 30 weeks, or 31 weeks, or 32 weeks, or 33 weeks, or 34 weeks, or 35 weeks, or 36 weeks, or 37 weeks, or 38 weeks, or 39 weeks, or 40 weeks, or 41 weeks, or 42 weeks, or 43 weeks, or 44 weeks, or 45 weeks, or 46 weeks, or 47 weeks, or 48 weeks, or 49 weeks, or 50 weeks, or 51 weeks, or 52 weeks, or is 53 weeks, or 54 weeks, or 55 weeks, or 56 weeks, or 57 weeks, or 58 weeks, or 59 weeks, or 60 weeks, or 61 weeks, or 62 weeks, or 63 weeks, or 64 weeks, or 65 weeks, or 66 weeks, or 67 weeks, or 68 weeks, or 69 weeks, or 70 weeks, or 71 weeks, or 72 weeks, or 73 weeks, or 74 weeks, or 75 weeks, or 76 weeks, or 77 weeks, or 78 weeks, or 79 weeks, or 80 weeks or 81 weeks, or 82 weeks, or 83 weeks, or 84 weeks, or 85 weeks, or 86 weeks, or 87 weeks, or 88 weeks, or 89 weeks, or 90 weeks, or 91 weeks, or 92 weeks, or 93 weeks, or 94 weeks, or 95 weeks, or 96 weeks, or 97 weeks, or 98 weeks, or 99 weeks, or 100 weeks, or 101 weeks, or 102 weeks, or 103 weeks, or 104 weeks, or more. In some embodiments, the methods of the present disclosure provide an improvement in any of the outcomes described herein for at least 52 weeks.

[0087] In some embodiments, the risk of candidiasis and improvement in at least one outcome is measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and / or 12 weeks.

[0088] In some embodiments, the improvement in risk of candidiasis and at least one outcome occurs again at week 26 and / or week 52 (or any week in between).

[0089] In some embodiments, the disclosed method leads to a reduction in the patient's risk of candidiasis, a potential adverse effect of oral steroid use. In some embodiments, the disclosed method leads to an improvement in oral candidiasis, esophageal candidiasis, and / or oropharyngeal candidiasis. Oral, oropharyngeal, and esophageal candidiasis infections are known side effects of corticosteroid ingestion, such as budesonide and fluticasone propionate, used to treat EoE. Oral candidiasis is one of the most common fungal infections affecting the fungal mucosa. Oral candidiasis is described by Agrawal et al. in the following citation: Agrawal, A., Singh, A., Verma, R., & Murari, A. (2014). Oral candidiasis: An overview. Journal of Oral and Maxillofacial Pathology, 18(4), 81. doi:10.4103 / 0973-029x.141325, which is incorporated herein in its entirety. Oral candidiasis is caused by Candida albicans, Candida glabrata, Candida gillermondii, Candida krusei, Candida gillermonidii, Candida krusei, Candida parapsis, Candida pseudotropicalis, Candida stellatoidea, and Candida tropicalis. Candida can also infect the esophagus. Esophageal candidiasis is most often caused by Candida albicans. Esophageal candidiasis is detailed by Nishimura et al. in the following citation: Nishimura, S., Nagata, N., Shimbo, T., Asahima, N., Akiyama, J., Ohmagari, N., Uemura, N. (2013). Factors Associated with Esophageal Candidiasis and Its Endoscopic Severity in the Era of Antiretroviral Therapy. PLoS ONE, 8(3). doi:10.1371 / journal.pone.0058217, which reference is incorporated herein in its entirety.Without being bound by theory, it is hypothesized that patients who receive steroids may experience candidiasis due to suppression of local cellular immunity and phagocytosis. The methods described herein reduce immunosuppression. In some embodiments, the risk of oral candidiasis in patients according to the methods disclosed herein is less than about 10% (e.g., about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1% or less).

[0090] Candidiasis is diagnosed according to methods known to those skilled in the art. In some embodiments, oral specimens are grown on agar. Briefly, specimens are collected under sterile conditions from active lesions. Specimens are kept moist and stored in a refrigerator at 4°C. Smears are taken from infected oral mucosa, lagardo, and the wearing side of dentures, preferably with a wooden spatula. Smears are immediately fixed in ether / alcohol 1:1 or by spray fixation. Dried preparations can be examined by Gram staining and Periodic Acid Schiff (PAS) techniques. Various agar substrates are inoculated with swabs to grow yeast species. Pagano-Levin agar or Littman substrate are useful supplements, as they allow yeasts to be differentiated from differences in colony color.

[0091] In some embodiments, the imprint culture technique is utilized for quantitative assessment of yeast growth in different regions of the oral mucosa. Sterile square plastic foam pads are soaked in peptone water and placed under test in the restricted area for 30-60 seconds, then placed directly on top of the Pagano-Levin or Sabouraud agar. The density of Candida at each site is then measured by Galenkamp colony counter and expressed as colony forming units per mm 2 (CFU mm -2 ) This technique is useful for localizing the site of infection.

[0092] In some embodiments, the number of colony forming yeast units is estimated using the impression culture technique: maxillary and mandibular alginate impressions are captured and cast onto 6% fortified agar, embedded in Sabouraud's dextrose broth, and grown at 37°C for 48-72 hours to estimate the yeast CFU.

[0093] In some embodiments, the number of Candida in the patient's saliva is estimated by counting the resulting growth on Sabouraud's agar using either spiral plating or the surface viable counting technique of Miles and Misra. Patients who show clinical signs of oral candidiasis usually have greater than 400 CFU / mL.

[0094] In some embodiments, candidiasis is identified using commercially available identification kits, including the Microstix-Candida system, the O Yeast-I dent system, and the Ricult-N dip slide method.

[0095] In some embodiments, fungi in biopsy specimens are identified histologically. Hematoxylin and eosin do not stain Candida species well. Specific fungal stains, such as PAS stain, Grocott-Gomori methenamine silver (GMS) stain, and Gridley stain, are widely used to depict fungi in tissues that are highly stained with these stains.

[0096] In some embodiments, physiological tests are used for definitive identification of Candida species. These tests involve the ability of Candida species to assimilate and ferment individual carbon and nitrogen sources (see Tables 3 and 4). [Table 3] [Table 4]

[0097] In some embodiments, serological tests are used to detect invasive candidiasis, including detection of antibodies, immunodiffusion, slide agglutination, phytohemagglutination, co-electrophoresis, immunoprecipitation, A and B immunofluorescence, non-specific Candida antigens, latex agglutination, immunoblotting, β-(1,3)-d-glucan, cell wall mannoproteins, cell wall components, and Candida enolase antigen tests.

[0098] In some embodiments, especially if the candidiasis is esophageal candidiasis, an upper endoscopy is necessary for diagnosis. A yellowish white plaque can be seen on upper endoscopy. The plaque and exudate adhere to the mucosa and do not wash away with water irrigation. There may also be mucosal damage or ulceration. Hematoxylin and eosin staining of biopsies or brushings of esophageal candidiasis shows pseudohyphae, which are useful in diagnosing esophageal candidiasis. Pathology may demonstrate acute inflammation and / or intraepithelial lymphocytosis.

[0099] In some embodiments, patients treated according to the disclosed methods exhibit a risk of candidiasis of less than about 10%. In some embodiments, patients treated according to the disclosed methods exhibit a risk of candidiasis of less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%. In some embodiments, the disclosed methods lead to a reduced incidence of candidiasis. In some embodiments, the incidence of candidiasis is reduced by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%, including all values ​​and ranges therein, as compared to otherwise similar patients treated with a corticosteroid twice daily.

[0100] In some embodiments, the method of the present disclosure reduces the patient's risk of oral candidiasis by less than about 4%, less than about 3%, less than about 2%, or less than about 1%. In some embodiments, the method of the present disclosure reduces the patient's risk of oral candidiasis by about 4.8%. In some embodiments, the instances of oral candidiasis are reduced by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%, including all values ​​and ranges therein, compared to an otherwise similar patient treated twice daily with a corticosteroid.

[0101] In some embodiments, the method of the present disclosure reduces the risk of esophageal candidiasis in a patient by less than about 10%. In some embodiments, the method of the present disclosure reduces the risk of esophageal candidiasis in a patient by less than about 10%, or 9%, or 8%, or 7%, or 6%, or 5%, or 4%, or 3%, or 2%, or 1%. In some embodiments, the instances of esophageal candidiasis are reduced by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%, including all values ​​and ranges therein, compared to an otherwise similar patient treated twice daily with a corticosteroid.

[0102] In some embodiments, the methods of the present disclosure allow patients to show improvement in at least one symptom score measured using the Patient Reported Outcome Evaluation (PROSE) instrument after a dysphagia episode. The PROSE instrument calculates several items, such as the number of real-time episode entry (RTE) dysphagia episodes, the number of dysphagia episodes recorded at the end of the day, the total number of dysphagia episodes, the percentage of RTE dysphagia episodes, the total duration of dysphagia, the total estimated duration of dysphagia, the number of days without dysphagia, the worst difficulty recorded in the RT episode, the worst pain recorded in the RT episode, the worst discomfort recorded in the RT episode, the worst composite symptom summary score, the worst difficulty recorded in the EOD episode, the worst pain recorded in the EOD episode, the worst discomfort recorded in the EOD episode, the worst composite symptom summary score, the greatest difficulty response reported, the greatest pain response reported, the greatest discomfort response reported, and the worst composite symptom summary score. In some embodiments, the PROSE calculates the average of all ratings over the 14-day period. In some embodiments, the symptom score is the number of dysphagia episodes over the 14-day period. This is sometimes referred to as the frequency of dysphagia.

[0103] In some embodiments, PROSE provides a symptom summary assessment based on the following questions: (i) on a scale of 1 to 10, how difficult was it to swallow food and / or pills, (ii) on a scale of 1 to 10, what was the worst pain felt while trying to swallow food and / or pills, and (iii) on a scale of 1 to 10, what was the worst discomfort felt while trying to swallow food / pills. In some embodiments, the PROSE Symptom Score is the average score of any combination of (i), (ii), and (iii). In some embodiments, the average score of (i), (ii), and (iii) is referred to as the "episode severity."

[0104] An episode severity score can be assigned for a single dysphagia episode. Alternatively or additionally, an episode severity score may be assigned for each day as a "daily episode severity score." The daily episode severity score is the average of the episode severity scores of all dysphagia episodes occurring on a single day. In some embodiments, the daily episode severity scores over a 14 day period are averaged.

[0105] In some embodiments, the methods of the present disclosure result in an improvement in the average daily episode severity score over a particular time period. The average daily episode severity score over a particular time period is the sum of the daily episode severity scores for each day that a dysphagia episode is reported divided by the number of days in the period that a dysphagia episode is reported. The episode severity score is the average of the PROSE symptom scores (i), (ii) and (iii). In some embodiments, the average daily episode severity score is calculated over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, or 2 years. In some embodiments, the average daily episode severity score is calculated over a period of 14 days. For example, if an average daily episode severity score is calculated over a 14-day period and a patient experiences episodes of dysphagia on 12 days of the 14-day period, the average daily episode severity score over the 14-day period is the sum of the reported daily episode severity scores for the 12 days divided by 12.

[0106] In some embodiments, the methods of the present disclosure improve symptom burden. Symptom burden is the average daily episode severity score over a particular period of time, including days with no reported dysphagia episodes. As discussed herein, the daily episode severity score is the episode severity score divided by the number of dysphagia episodes in a day. The episode severity score is the average of the PROSE symptom scores (i), (ii) and (iii), where a day without a dysphagia episode is assigned a daily episode severity score of 0. In some embodiments, the symptom burden is calculated over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, or 2 years. In some embodiments, the symptom burden is calculated over a period of 14 days. For example, symptom burden calculated over a 14-day period is the sum of the daily episode scores for each of the 14 days divided by 14, with a daily episode score of 0 being assigned to days on which no dysphagia episodes are reported.

[0107] In some embodiments, the daily episode severity score is the episode severity score of the worst episode of dysphagia. The worst episode of dysphagia occurring on a given day has the highest episode severity score. The method of calculating the severity score id described herein.

[0108] In some embodiments, the methods of the present disclosure result in an improvement in the score of the worst symptom of dysphagia reported over a certain period of time. In some embodiments, the worst symptom of dysphagia has the highest PROSE symptom score. For example, if a patient assigns (i) a score of 9, (ii) a score of 5, and (iii) a score of 1, (i) is the worst symptom.

[0109] In some embodiments, the PROSE symptom score includes the number of dysphagia episodes. In some embodiments, the PROSE symptom score includes the proportion of dysphagia episodes of the number of dysphagia episodes per day. In some embodiments, the PROSE symptom score includes the proportion of dysphagia episodes per day of the number of dysphagia episodes per day, the number of dysphagia-free days. In some embodiments, PROSE provides a daily average composite score (e.g., for all reported dysphagia incidences), a daily worst composite score (e.g., for daily reported dysphagia incidences) over 14 days, a daily worst composite score over 14 days, the number of episodes over 14 days, the proportion of daily episodes over 14 days, or the number of dysphagia-free days over 14 days.

[0110] In some embodiments, the disclosed methods improve the PROSE score (e.g., the episode severity score described above) by about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 80%, or about 85%, or about 90%, or about 95%, or about 100%, or more. In some embodiments, the disclosed methods reduce the number of dysphagia episodes as determined by the PROSE device. In some embodiments, the methods of the disclosure provide a PROSE score of about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6 , about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, or more, including all ranges between these values.

[0111] In some embodiments, the PROSE device is described in International Publication No. WO2019 / 165138, the contents of which are incorporated herein by reference in their entirety. The 24-hour diary refers to a device used to record various events related to dysphagia (e.g., related to EoE) at the end of a 24-hour period, i.e., once a day. At the end of the 24-hour period, the patient recalls all events related to dysphagia that occurred in the past 24 hours, including, among others, (i) the severity, intensity, duration, pain, discomfort, difficulty, and / or frequency of the dysphagia, (ii) the type (including dosage form and agent), and timing of treatment, and (iii) any avoidance measures. In some embodiments, the patient fills in the 24-hour diary after the last meal. In some embodiments, the patient records an entry in the 24 hour diary at about 6 pm, about 6:30 pm, about 7 pm, about 7:30 pm, about 8 pm, about 8:30 pm, about 9 pm, about 9:30 pm, about 10 pm, about 10:30 pm, about 11 pm, or about 12 am.

[0112] In some embodiments, the methods of the present disclosure cause improvements as indicated by 24-hour diary outcomes. U.S. Patent Application Publication No. 2016 / 0078186 details 24-hour diary outcomes and is incorporated by reference in its entirety for all purposes.

[0113] In some embodiments, the disclosed methods improve the patient's EoE Endoscopic Reference Score (EREFS). The EREFS identifies the severity of five endoscopic findings: edema, ring, exudation, wrinkles, and strictures. The EREFS classification system assesses the severity of each endoscopic finding. The severity of edema is assessed on a scale of 0 to 2. The severity of ring is assessed from 0 to 3. The severity of exudation is assessed from 0 to 2. The severity of wrinkles is assessed from 0 to 2. The severity of stricture is assessed from 0 to 1. The absence of a finding corresponds to a score of 0. The presence of one finding corresponds to a score of 1, 2, or 3. Higher scores correlate with higher severity. In some embodiments, a composite EREFS score, or the sum of the individual scores, is utilized to indicate the severity of EoE. In some embodiments, an inflammatory EREFS score, or the sum of the individual edem, exudation, and wrinkle scores, is utilized to indicate the severity of EoE. In some embodiments, a higher inflammatory or composite EREFS score corresponds to the severity of EoE. In some embodiments, the inflammatory or composite EREFS score is decreased following treatment with a corticosteroid according to the methods of the present disclosure.In some embodiments, the inflammatory or composite EREFS score is 0.1, or about 0.2, or about 0.3, or about 0.4, or about 0.5, or about 0.6, or about 0.7, or about 0.8, or about 0.9, or about 1.0, or about 1.1, or about 1.2, or about 1.3, or about 1.4, or about 1.5, or about 1.6, or about 1.7, or about 1.8, or about 1.9, or about 2.0, or about 2.1, or about 2.2, or about 2.3, or about 2.4, or about 2.5, or about 2.6, or about 2.7, or about 2.8, or about 2.9, or about 3.0, or about 3.1, or about 3.2, or about 3.3, or about 3.4, or about 3.5, or about 3.6, or about 3.7, or about 3.8, or about 3.9, or about 4.0, or about 4.1, or about 4.2, or about 4.3, or about 4.4, or about 4.5, or about 4.6, or about 4.7, or 4.8, or about 4.9, or about 5.0, or about 5.1, or about 5.2, or about 5.3, or about 5.4, or about 5.5, or about 5.6, or about 5.7, or about 5.8, or about 5.9, or about 6.0, or about 6.1, or about 6.2, or about 6.3, or about 6.4, or about 6.5, or about 6.6, or about 6.7, or about 6.8, or about 6.9, or about 7.0, or about 7.1, or 7.2, or about 7.3, or about 7.4, or about 7.5, or about 7.6, or about 7.7, or is decreased by about 7.8, or about 7.9, or about 8.0, or about 8.1, or about 8.2, or about 8.3, or about 8.4, or about 8.5, or about 8.6, or about 8.7, or about 8.8, or about 8.9, or about 9.0, or about 9.1, or about 9.2, or about 9.3, or about 9.4, or about 9.5, or 9.6, or 9.7, or 9.8, or about 9.9, or about 10.0, or more, including all ranges between these values.In some embodiments, the EREFS score is reduced by 1%, or 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or more, including all ranges between these values. The following article, which is incorporated herein by reference in its entirety, describes the EREFS score: Wechsler, Clin Hepatol. 2018 Jul;16(7):1056-1063.

[0114] In some embodiments, the patient's symptom score is assessed using the Visual Dysphagia Questionnaire (VDQ). The VDQ addresses the severity of dysphagia when ingesting foods of eight different densities. The eight food compositions and examples of foods that illustrate these compositions are: 1) solid meats (steak, chicken, turkey, lamb, etc.); 2) soft foods (pudding, jelly, applesauce, etc.); 3) dry rice or sticky Asian rice; 4) ground meat (hamburger, meatloaf); 5) fresh, untoasted white bread or similar foods (donuts, muffins, cakes, etc.); 6) grits, congee (oatmeal), or rice pudding; 7) raw fibrous foods (apples, carrots, celery, etc.); and 8) french fries. The perceived difficulty in eating a given food consistency is graded from 0 for "no difficulty" to 3 for "very difficult." A VDQ composite score is calculated using the individual grades for a given food consistency. The VDQ composite score is the sum of the grades for each food consistency divided by the maximum sum of the individual grades for each food consistency that can be achieved. The maximum sum of grades depends on the number of food consistencies that the subject consumes in a given recall period. In some embodiments, after treatment with the method of the present disclosure, the VDQ composite score improves. The improvement of the VDQ composite score is a reduction in the VDQ composite score. In some embodiments, the VDQ composite score improves between about 1 and about 24 points, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 points.

[0115] In some embodiments, the outcome of the disclosed methods is assessed using the EoE Activity Index (EEsAI) Avoidance Modulation and Slow Swallowing (AMS) score. In some embodiments, the EEsAI is improved by about 2 to 15 points. In some embodiments, the EEsAI score is about 2.0, or about 2.1, or about 2.2, or about 2.3, or about 2.4, or about 2.5, or about 2.6, or about 2.7, or about 2.8, or about 2.9, or about 3.0, or about 3.1, or about 3.2, or about 3.3, or about 3.4, or about 3.5, or about 3.6, or about 3.7, or about 3.8, or about 3.9, or about 4.0, or about 4.1, or about 4.2, or about 4.3, or about 4.4, or about 4. 5, or about 4.6, or about 4.7, or about 4.8, or about 4.9, or about 5.0, or about 5.1, or about 5.2, or about 5.3, or about 5.4, or about 5.5, or about 5.6, or about 5.7, or about 5.8, or about 5.9, or about 6.0, or about 6.1, or about 6.2, or about 6.3, or about 6.4, or about 6.5, or about 6.6, or about 6.7, or about 6.8, or about 6.9, or about 7.0, or about 7.1, or about 7.2, or about 7.3 , or about 7.4, or about 7.5, or about 7.6, or about 7.7, or about 7.8, or about 7.9, or about 8.0, or about 8.1, or about 8.2, or about 8.3, or about 8.4, or about 8.5, or about 8.6, or about 8.7, or about 8.8, or about 8.9, or about 9.0, or about 9.1, or about 9.2, or about 9.3, or about 9.4, or about 9.5, or about 9.6, or about 9.7, or about 9.8, or about 9.9, or about 10.0, or about 10. 1, or about 10.2, or about 10.3, or about 10.4, or about 10.5, or about 10.6, or about 10.7, or about 10.8, or about 10.9, or about 11.0, or about 11.1, or about 11.2, or about 11.3, or about 11.4, or about 11.5, or about 11.6, or about 11.7, or about 11.8, or about 11.9, or about 12.0, or about 12.1, or about 12.2, or about 12.3, or about 12.4, or about 12.5, or about 12.6, or about 12.7, or about 12.8, or about 12.9, or 13.0, or 13.1, or about 13.2, or about 13.3, or about 13.4, or about 13.5, or about 13.6, or about 13.7, or about 13.8, or about 13.9, or about 14.0, or about 14.1, or about 14.2, or about 14.3, or about 14.4, or about 14.5, or about 14.6, or about 14.7, or about 14.8, or 14.9, or about 15 points, including all ranges therebetween.

[0116] In some embodiments of the present disclosure, the overall EoE score is utilized to evaluate the outcome of the method of the present disclosure. In some embodiments, the EoE score is improved by 1 to 4 points. In some embodiments, the EoE score is improved by about 1 point, or about 2 points, or about 3 points, or about 4 points. In some embodiments, the EoE score is improved by 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or 95%, or 100%, or about 125%, or about 150%, or about 175%, or about 200%, or about 225%, or about 250%, or about 275%, or about 300%, or more, including all ranges between these values.

[0117] In some embodiments, the Adult EoE Quality of Life Questionnaire (EoE-QoL-A) is utilized to assess the outcome of the methods of the present disclosure. The EoE-QoL-A) provides a measure of health-related quality of life. The EoE-QoL-A is a self-report questionnaire designed to assess disease-specific health-related quality of life in adults with EoE. The questions are designed to assess established domains of health-related quality of life, including the impact of the disease on social functioning, emotional functioning, and experiences of daily living. The EoE-QoL-A includes 47 questions on a 5-point scale. Higher scores indicate better quality of life. In some embodiments, the methods of the present disclosure result in an improvement in the EoE-QoL-A. In some embodiments, the EoE-QoL-A score is improved by about 1 to about 3 points.

[0118] In some embodiments, the Global Impression Scale-Severity (PGIS) is utilized to assess the outcome of the disclosed method. The PGIS is a global index that can be used to assess the severity of EoE. The PGIS is measured on a scale of 1 to 7. A score of 1 corresponds to normal and a score of 7 corresponds to very bad. A score of 4 corresponds to slightly unwell. In some embodiments, the disclosed method results in a reduction in the PGIS score. In some embodiments, the PGIS score shifts to an improvement of about 1 to 5 severity categories (e.g., about 1, 2, 3, 4 or 5 categories). In some embodiments, the PGIS is reduced by 1 point, or 2 points, or 3 points, or 4 points, or 5 points. In some embodiments, the PGIC is reduced by about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%, or 100%, including all ranges between these values.

[0119] In some embodiments, the outcome of the disclosed method is evaluated using Global Impression Scale-Change (PGIC). PGIC is a global index that can be used to evaluate the improvement or deterioration of clinical condition. PGIC is measured on a scale of 1 to 7. A score of 1 corresponds to a very significant improvement, and a score of 7 corresponds to a very significant deterioration. A score of 4 corresponds to no change in the patient's condition. In some embodiments, the disclosed method results in a decrease in PGIC score. In some embodiments, PGIC is reduced by 1 point, or 2 points, or 3 points, or 4 points, or 5 points, or 6 points, including all ranges between those values. In some embodiments, the PGIC is reduced by about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%, or 100%, including all ranges between these values.

[0120] In embodiments, the reduction in eosinophil count is associated with an improvement in EoE-associated stenosis. In some embodiments, the disclosed method results in a reduction in the patient's eosinophil count compared to the patient's baseline eosinophil level. In some embodiments, the disclosed method results in a reduction in the eosinophil count to 6 or less eosinophils per high power field (hpf). In some embodiments, the disclosed method results in a reduced eosinophil count to 5 or less eosinophils per high power field (hpf), or 4 eosinophils per high power field (hpf), or 3 eosinophils per high power field (hpf), or 2 eosinophils per high power field (hpf), or 1 eosinophil per high power field (hpf). In some embodiments, the disclosed method includes measuring the eosinophil count in the distal portion of the esophagus, the proximal portion of the esophagus, or both. In some embodiments, the disclosed method results in an eosinophil count in the distal portion of the esophagus to 6 or less eosinophils per hpf. In some embodiments, the disclosed method results in an eosinophil count in the distal portion of the esophagus reduced to 5 eosinophils per high power field (hpf) or less, or 4 eosinophils per high power field (hpf), or 3 eosinophils per high power field (hpf), or 2 eosinophils per high power field (hpf), or 1 eosinophil per high power field (hpf). In some embodiments, the disclosed method results in an eosinophil count in the proximal portion of the esophagus of 6 eosinophils or less per hpf. In some embodiments, the disclosed method results in an eosinophil count in the proximal portion of the esophagus reduced to 5 eosinophils per high power field (hpf), or 4 eosinophils per high power field (hpf), or 3 eosinophils per high power field (hpf), or 2 eosinophils per high power field (hpf), or 1 eosinophil per high power field (hpf).

[0121] In some embodiments, the symptom of EoE is dysphagia.In some embodiments, the method of the present disclosure results in a reduction in the number of dysphagia episodes compared to patients who administer corticosteroids twice a day.In some embodiments, the method of the present disclosure results in an increase in the number of dysphagia-free days compared to patients who administer corticosteroids twice a day. EXAMPLES

[0122] Example 1 A clinical trial was conducted to evaluate the effects of orally disintegrating tablets ("ODT") containing fluticasone propionate (FP). It was a randomized, double-blind, placebo-controlled, multicenter, dose-ranging, and maintenance study of FP in subjects (>18 years and <75 years) with stenosis and / or annulus and EoE. The study tested four doses of FP to define an exposure response to FP, testing the lowest effective dose to minimize significant effects on the hypothalamic-pituitary-adrenal (HPA) axis. The study (shown in Figure 1) was designed as follows: (a) Screening: Patients with a definite or presumptive diagnosis of EoE (including identification of stenosis and / or annulus) were selected for the study. The diagnosis of EoE was confirmed by symptoms, histology, and prior documentation of failed treatment with high-dose proton pump inhibitors (PPIs) for ≥8 weeks. High-dose PPIs were defined as a total dose of 20-40 mg of commercially available PPIs administered once or twice daily. Demographics of treatment groups are outlined in Tables A and B. [Table 5] [Table 6] (b) 4-week single-blind placebo run / baseline symptom assessment: To assess baseline symptoms, all subjects who passed the screening part of the study received placebo (at bedtime) 30 minutes after breakfast and before sleep (pre-sleep; HS). (c) Part 1 (Run-in) (study of the efficacy of FP over 14 weeks): Patients entering Part 1 of the study had evidence of EoE defined as ≥15 peak eosinophils / HPF. At least 5–6 biopsies should be performed, including both proximal and distal samples.

[0123] Subjects enrolled in Part 1 of the trial were randomized to receive one of the following treatments: (a) 1.5 mg HS: placebo, 30 minutes after breakfast and 1.5 mg HS (at bedtime), (b) 1.5 mg BID: 1.5 mg 30 minutes after breakfast and at bedtime, for a total daily dose of 3 mg; (c) 3mg HS: placebo, 30 minutes after breakfast, 3mg at bedtime, and (d) 3 mg BID: 3.0 mg 30 minutes after breakfast and at bedtime, for a total daily dose of 6 mg.

[0124] In Part 1 (induction therapy, days 1-week 14), subjects received randomized treatment for 14 weeks. At week 12, subjects underwent response evaluation, including esophagogastroduodenoscopy (EGD) to evaluate endoscopic and histologic status. Histologic responders and non-responders (week 12) began Part 2.

[0125] Patient Population: 105 subjects received at least one dose of study drug in Part 1 of the study safety analysis set (SAF population), with 92 subjects (86.8%) completing Week 14. The SAF population included all subjects who were randomized and did not meet any of the following criteria: subjects who did not receive any study drug, subjects who received an incorrect dose, or subjects who were incorrectly randomized. Subjects were classified according to randomized treatment.

[0126] Primary Objective: The primary objective of the study was to evaluate the efficacy (histological response) of FP in adults with EoE.

[0127] Secondary objectives: The secondary objectives were to evaluate the effect of ODT including FP on dysphagia episodes and to assess the change in EREFS, change in global EoE symptom score and change in frequency of dysphagia.

[0128] Evaluation items: The primary endpoint was the histologic responder rate at week 12 in Part 1, defined as the proportion of subjects with ≤6 peak eosinophils / HPF after evaluation of at least 5-6 (approximately 3 each) biopsies from the proximal and distal esophagus in which the HPF area was 235 square microns (40x lens with 22 mm oculars).

[0129] The following secondary endpoints were assessed at 12 weeks: (a) EoE sustained response: Percentage of subjects who met the primary endpoint (histology) at Week 12 and maintained the primary endpoint at Weeks 26 and 52; (b) Change from baseline Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) at Weeks 12, 26, and 52: Endoscopic changes were similar to EREFS assessments based on the following endoscopic features: edema, rings, effusion, wrinkles, strictures, and multiple variable features (crepe paper esophagus, thin esophagus, and esophageal erosions); (c) Percentage of subjects with peak eosinophils / HPF counts <1 and <15 at Weeks 12, 26, and 52; (d) Change from baseline global EoE symptom score assessed prior to randomization, assessed over the 7 days prior to the following study visits: Week 4, Week 8, Week 12, Week 14, Week 18, Week 22, Week 26, Week 28, Week 36, Week 44, and Week 52; (e) Dysphagia: Change in number of dysphagia episodes at baseline (14-day period prior to randomization) compared to the 14-day period prior to the time points of interest (Weeks 12, 26, and 52); (f) Change from baseline Day 7 Eosinophilic Esophagitis Activity Index (EEsAI) total score assessed before randomization to those assessed at Weeks 12, 26, and 52; (g) Change from baseline day 7 EEsAI subscore to EEsAI subscores assessed at weeks 12, 26, and 52; (h) Percentage of subjects with a mean Day 7 EEsAI total score <20 assessed at Weeks 12, 26, and 52; (i) change from baseline Global Impression Scale-Severity (PGIS) assessed prior to randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52; (j) Global Impression of Clinical Indication-Change (PGIC) at weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52; (k) Assessment of treatment failure and relapse included: proportion of non-responders by dose at weeks 12, 26, and 52; (l) The proportion of subjects requiring urgent endoscopic food removal prior to 14 weeks, between 14 and 28 weeks, and between 28 and 52 weeks of treatment, and the proportion of subjects requiring esophageal dilation by treatment group and study subset.

[0130] Exploratory efficacy outcomes were also analyzed. Exploratory efficacy outcomes included: (a) Change from baseline in dysphagia-free days during the 14 days prior to the following study visits: Weeks 12, 26, and 52; (b) EoE Sustained Response (Dysphagia): Proportion of all subjects who met the dysphagia secondary endpoint at Week 12 and maintained a dysphagia-related response at Weeks 26 and 52; (c) Assessment of PK / PD (cortisol) and exposure-response (efficacy) relationships; symptom assessments by subject at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, 52, and the Early Termination visit (if applicable) compared to the previous visit; and (d) Health-related quality of life (HRQoL) assessment based on the Eosinophilic Esophagitis Quality of Life Questionnaire in Adults (EoO-QoL-A) at randomization, weeks 12, 26, and 52 for all subjects by treatment and subgroup.

[0131] Subjects receiving single-blind treatment (3 mg twice daily [BID] in Part 2) will be tabulated separately: percentage of subjects classified as histological non-responders at Week 12 with ≦6 peak eosinophils / HPF in all esophageal sites biopsied at Weeks 26 and 52; change from baseline dysphagia episodes in the preceding 14-day period at Weeks 26 and 52 for subjects classified as non-responders at Week 12; percentage of subjects classified as histological non-responders at Week 12 who met the primary endpoint at Weeks 26 and 52.

[0132] A score structure and various assessment items were derived from the PROSE, the psychometric properties of the PROSE were evaluated, and anchor and distribution analyses were conducted to assess significant change in the PROSE.

[0133] Safety endpoints were measured, including frequency of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, treatment-emergent serious adverse events (SAEs), proportion of subjects with serum cortisol levels ≤5 μg / dL (≤138 nmol / L) or abnormal adrenocorticotropic hormone (ACTH) stimulation test (serum cortisol <16 μg / dL [≤440 nmol / L] at 60 minutes), number of subjects discontinuing in response to HPA axis suppression were recorded, and frequency of oroesophageal candidiasis.

[0134] Part 1 of the SP-1011-002 study has been completed, and efficacy and safety results after 12 weeks of treatment with FP (1.5 mg HS, 1.5 mg BID, 3 mg HS, or 3 mg BID) or placebo are summarized below.

[0135] result As shown in Figure 3 and Table C, resolution of EoE features in patients receiving FP versus placebo was accompanied by higher histologic (79% vs. 0%; P < .001) and endoscopic (88% vs. 38%; P < .001) response rates. Surprisingly, a post-hoc analysis performed on the subgroup of patients with stenosis and / or grade 2 rings from the total treatment group (i.e., FP 1.5 mg or 3 mg at bedtime and fluticasone 1.5 mg or 3 mg twice daily) reported a reduction in stenosis symptoms after FP treatment compared with placebo. Patients receiving FP had lower rates of persistent stenosis and / or annulus at week 12 versus placebo: stenosis (21% vs. 46%; P = .075), annulus (7% vs. 46%; P < .001), either stenosis or annulus (28% vs. 77%; P = .002), and combined stenosis and axis (0% vs. 15%). A summary of response rates at week 12 is presented in Table D. A summary of treatment-emergent adverse events (TEAEs) that occurred during the study is presented in Table E. [Table 7] [Table 8] [Table 9]

[0136] conclusion The data suggest that ODT containing FP at a 3 mg HS (bedtime) dose provides the best balance of safety and efficacy in inducing histological remission, symptomatic improvement over 52 weeks with lower candidiasis rates. Furthermore, once-daily bedtime dosing may promote better treatment compliance. In a post-hoc analysis of patients with baseline stenosis and / or grade 2 esophageal rings, FP showed improvement or resolution of these features in the majority of patients, especially for the 3 mg HS dose group. This is an important outcome in which fibrostenosis is associated with poorer response to treatment. The results showed that FP is effective in treating stenosis, including severe stenosis and rings, in a variety of conditions.

[0137] Example 2. Diagnosis of esophageal stricture Esophageal strictures are detected in patients by performing endoscopy (EGD) and / or modified barium swallow study (MBSS). EGD is performed with a long flexible tube, approximately 9 mm in diameter, attached to a video camera at the end of the scope. Prior to inserting the tube, the patient may choose to undergo minimal sedation, moderate sedation, deep sedation or general anesthesia. During EGD, the tube is introduced into the patient's mouth and guided into the esophagus, stomach and intestines. Sample collection for biopsy may be performed when symptoms of strictures, rings, or other esophageal abnormalities are detected. The video display of the endoscope is used to visually detect esophageal strictures or esophageal rings, as shown in Figure 2. If the endoscope cannot pass through the patient's esophagus, the patient is considered to have severe esophageal strictures.

[0138] In a modified barium swallow study (MBSS), a patient sits in a chair and swallows food or liquid containing barium while being monitored by a doctor or other medical professional. The swallowed barium material is visualized by x-rays, and the movement of the swallowed food or liquid is recorded and analyzed.

[0139] Example 3. Diagnosis and treatment of patients suffering from esophageal strictures A method for locally treating esophageal strictures is described. A patient is first diagnosed by a physician who observes for the presence or symptoms of esophageal strictures after inserting an endoscope into the patient's esophagus. The endoscope is attached to a camera or video to provide immediate visualization of the esophageal lumen.

[0140] Esophageal strictures are detected when an endoscope does not pass easily through the esophagus. A patient is diagnosed with severe esophageal stricture when an endoscope does not pass from the proximal to the distal esophagus. After diagnosis of esophageal stricture, patients are given fluticasone propionate 1.5 mg or 3 mg orally in an orally disintegrating tablet before bedtime.

Claims

1. 1. A method for locally treating esophageal stricture with a corticosteroid in a patient in need thereof, comprising: (a) detecting said esophageal stricture; and (b) orally administering the corticosteroid; a therapeutically effective amount of the oral corticosteroid contacts the esophageal stricture, thereby reducing the severity of the esophageal stricture. The method.

2. The method of claim 1 , wherein the detecting in step (a) includes inserting an endoscope into the patient's esophagus.

3. The method of claim 2, wherein the endoscope has a diameter of about 8-10 mm or about 9 mm.

4. 4. The method of claim 2 or 3, wherein the esophageal stricture is detected visually using a video display of the endoscope.

5. The method of claim 2 or 3, wherein the esophageal stricture is detected due to an inability of the endoscope to pass through the patient's esophagus.

6. The method of any one of claims 1 to 3, wherein the patient also has an annulus.

7. The method of claim 6 , wherein the annulus is a grade 2 or grade 3 annulus.

8. 8. The method of claim 7, wherein administering the corticosteroid reduces the grade of the annulus by at least one grade.

9. 4. The method of any one of claims 1 to 3, wherein the corticosteroid is administered while the patient is lying down or immediately before the patient is lying down.

10. 10. The method of claim 9, wherein the lying down is in a supine position.

11. 10. The method of claim 9, wherein the oral corticosteroid is administered within about 5, 4, 3, 2, or 1 minutes before the patient lies down.

12. 10. The method of claim 1, wherein the oral corticosteroid is administered no more than about 30 minutes before a target sleep time.

13. 4. The method of any one of claims 1 to 3, wherein the corticosteroid is administered once daily.

14. 4. The method of any one of claims 1 to 3, wherein the corticosteroid has a systemic bioavailability of about 20% or less of its dose.

15. 4. The method of any one of claims 1 to 3, wherein the corticosteroid is budesonide, fluticasone, flunisolide, ciclesonide, mometasone, or beclomethasone, or a pharma- ceutically acceptable salt, solvate, ester, polymorph, or prodrug thereof.

16. The method of any one of claims 1 to 3, wherein the corticosteroid is budesonide, fluticasone, or a pharma- ceutically acceptable ester thereof.

17. The method of any one of claims 1 to 3, wherein the corticosteroid is fluticasone propionate.

18. The method of any one of claims 1 to 3, wherein the corticosteroid is formulated as a solid composition.

19. 20. The method of claim 18, wherein the solid composition is in the form of a gel, a lozenge, a lollipop, an effervescent tablet, a powder, a granule, or an orally disintegrating composition.

20. 20. The method of claim 19, wherein the orally disintegrating composition is a tablet, wafer, film, or lyophilized matrix.

21. The method of claim 20, wherein the orally disintegrating composition is a tablet.

22. The tablet is a. the corticosteroid in an amount from about 1.0 mg to about 7.5 mg; b. a pharma- ceutically acceptable carrier in combination with said corticosteroid, and c. comprises rapidly dispersing fine particles; The orally disintegrating tablet disintegrates within 60 seconds when tested using the USP <701> method for disintegration time.

22. The method of claim 21.

23. 4. The method of any one of claims 1-3, wherein the corticosteroid provides a mean maximum plasma concentration (Cmax) of about 500 pg / mL or less following oral administration of about 0.5 mg to about 20 mg of the oral corticosteroid.

24. The corticosteroid has a mean AUC of about 3000 pg*h / mL or less following an oral dose of about 0.5 mg to about 20 mg of the oral corticosteroid. ０～２４ The method according to any one of claims 1 to 3, wherein

25. 4. The method of any one of claims 1 to 3, wherein the patient has a Cmax of the corticosteroid of about 200 pg / mL or less following an oral dose of about 1 mg to about 7.5 mg of the corticosteroid.

26. 2. The method of claim 1, wherein the patient has eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), erosive esophagitis, Barrett's esophagus, eosinophilic gastroenteritis, hypereosinophilic syndrome, corrosive chemical esophagitis, radiation-induced esophagitis, chemotherapy-induced esophagitis, transient drug-induced esophagitis, persistent drug-induced esophagitis, Crohn's disease of the esophagus, postoperative resection of the esophagus, or pseudomembranous esophagitis.

27. 4. The method of any one of claims 1 to 3, wherein the corticosteroid is administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks, or for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

28. After administration of the corticosteroid, the patient has a reduced eosinophil count, no dysphagia, and no dysphagia.

4. The method of any one of claims 1 to 3, which shows improvement in symptoms as measured by an increase in dysphagia score, a reduction in dysphagia episodes, an improvement in EREFS score, EndoFLIP documentation of improved esophageal compliance, evaluation of biomarkers, a reduction in episodes of food impaction, an improvement in EEsAI scores (patient, physician, endoscopy, pathology scores), EoE-QOL-A, Visual Dysphagia Questionnaire (VDQ), Avoidance Modification and Tardive Eating (AMS) score, or histology, at least one symptom score measured using the Patient Reported Outcomes Symptom Evaluation (PROSE) instrument after a dysphagia episode, Global EoE score, Global Impression Scale-Severity (PGIS), or Global Impression Scale-Change (PGIC).

29. The method of any one of claims 1 to 3, wherein the patient has EoE.

30. The method of any one of claims 1 to 3, wherein the patient's risk of candidiasis is less than about 10%.

31. 31. The method of claim 30, wherein the patient has a risk of candidiasis of about 5% or less.

32. 31. The method of claim 30, wherein the candidiasis is oral candidiasis or esophageal candidiasis.

33. 33. The method of claim 32, wherein the candidiasis is oral candidiasis.

34. 34. The method of claim 33, wherein the patient's risk of oral candidiasis is less than about 4%, less than about 3%, less than about 2%, or less than about 1%.

35. 31. The method of claim 30, wherein the candidiasis is esophageal candidiasis.

36. 36. The method of claim 35, wherein the patient's risk of esophageal candidiasis is about 4.8%.

37. The method of any one of claims 1 to 3, wherein the number of eosinophils in the patient's esophagus is reduced as compared to the patient's baseline eosinophil level.

38. 38. The method of claim 37, wherein the eosinophil count is reduced to 6 or less eosinophils per high power field (hpf).

39. 39. The method of claim 38, wherein the eosinophil count is measured in the distal portion of the esophagus, the proximal portion of the esophagus, or both.

40. 40. The method of claim 39, wherein the eosinophil count in the distal portion of the esophagus is less than or equal to 6 per hpf.

41. 40. The method of claim 39, wherein the eosinophil count in the proximal portion of the esophagus is 6 or less per hpf.

42. The method of any one of claims 1 to 3, wherein the EREFS score is improved by about 0.3 to 1.5 points.

43. The method according to any one of claims 1 to 3, wherein the EREFS score is 4 points or less.

44. The method of any one of claims 1 to 3, wherein the number of dysphagia episodes is reduced compared to a baseline period before treatment.

45. The method of any one of claims 1 to 3, wherein the number of dysphagia episodes is reduced by at least 50% compared to a baseline period before treatment.

46. 10. The method of claim 1, wherein the corticosteroid is fluticasone propionate and is administered at a dose ranging from about 3 mg to about 6 mg.

47. 10. The method of claim 1, wherein the corticosteroid is administered at an equieffective dose of about 3 to 6 mg of fluticasone propionate.

48. 10. The method of claim 1, wherein the corticosteroid is fluticasone propionate and is administered at a dose ranging from about 1.5 mg to about 3 mg.

49. 49. The method of claim 48, wherein the dose of fluticasone propionate is from about 1.5 mg to about 3 mg.

50. 10. The method of claim 1, wherein the patient does not develop new stenosis while being treated with the corticosteroid.

51. 10. The method of claim 1, wherein the patient does not develop new haloes while being treated with the corticosteroid.

52. 52. The method of any one of claims 46-51, wherein the fluticasone propionate is administered once daily.

53. 53. The method of claim 52, wherein the fluticasone propionate is administered at bedtime.

54. 53. The method of claim 52, wherein the corticosteroid is administered for at least 12 weeks and after 12 weeks, the endoscope is passed down the patient's esophagus.

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