NZ790981A - Methods of treating eosinophilic esophagitis - Google Patents

Abstract

The present disclosure provides methods of treating inflammation of the upper gastrointestinal tract, especially the esophagus, by administering an oral corticosteroid. In some cases, the methods include treating eosinophilic esophagitis (EoE) by administering an oral corticosteroid in an induction phase and a maintenance phase to improve peak eosinophilic counts and symptoms. In some embodiments, the methods include treating EoE by administering the oral corticosteroid at nighttime and/or while the patient is lying down. phase and a maintenance phase to improve peak eosinophilic counts and symptoms. In some embodiments, the methods include treating EoE by administering the oral corticosteroid at nighttime and/or while the patient is lying down.

Description

METHGBS OE 'l‘ihEA’l‘iNG EGSKNOPHELEC ESQE’HAGE’I‘ES (IRGSSEREFERENCE T0 RELATED APPLKTATEGNS {Will} The t application claims priority to US Provisional Application No. 62/376,703, filed August l8, 20l6; US. Provisional Application No. 62/46l3l7, filed February 2i and , 20l7, US Provisional ation No. 62/489,292, filed April 24, EM 7, the entire contents of each of which are hereby incorporated by reference in its entirety for all purposes.

BACKGRGUND {(130392} Esophageal ation disorders such as eosinophilic esopliagitis (EOE), a disease characterized by high levels of eosinophils in the esophagus, as well as basal zonal hyperplasia, is increasingly being diagnosed in children and adults. Many s of the disease remain unclear including its etiology, l history, and l therapy. EoE affects all age groups but most frequently individuals between 20 and 50 years of age. Symptoms of EOE often inirnic those of gastroesophageal reflux e (GERD) and include vomiting, dysphagia, pain and food impaction. The disease is painful, leads to difficulty swallowing, and predisposes patients to other complications. EoE is often misdiagnosed for GERD, causing delay in adequate treatment for EOE patients {Wild} Currently, no topically administered anti-inflammatory medications are approved for the ent of ions associated with inflammation of the upper portion of the gastrointestinal tract, particularly the inflammatory conditions of the esophagus, such as EoE. .Altl’iougli systeinic treatments with corticosteroids such as prednisolcne are ett‘ective, these therapeutics are ated with significant adverse etiteets such as suppression of the hypothaiainopituitaiye-idreuai {EPA} axis as reflected in salivary Cortisol laws generalised suppression of immune turretion, and paiticularly in en, troubling ttects from long term systemic exposure ii‘telude growth retardation.

SUhih/EARY OF THE INVENTIGN {9994} The present disclosure provides methods of administering pharmaceutical compositions comprising a ose topically active corticosteroid to treat, prevent, ameliorate, or delay the symptoms and/or inflammation ated with a gastrointestinal inflammatory disorder. In some ments, the gastrointestinal inflammatory disorder is in the gus. In some embodiments, the gastrointestinal inflammatory er is eosinophilic esophagitis.

{M1395} In some embodiments, the present disclosure provides methods of treating eosinophilic esophagitis (EoE) in a patient in need thereof, comprising administrating an oral corticosteroid in an induction phase and a maintenance phase. In some embodiments, the induction phase results in improvement in I’eak eosinophilic (Hos) counts in at least one esophageal , and the treatment (e. g. during the induction phase) results in no worsening of patient mean weekly scores in a patient— reported outcome assessment which includes the assessment of dysphagiamfree days. ln some embodiments, the patient ts substantial improvement in esophageal function and morphology, including lessening of esophageal furrows, lessening of esophageal focal narrowing, increased esophageal diameter, increased geal compliance, sed esophageal body distensibility, increased ease swallowing, reduced edema, ed vascularity, reduction of rings, decrease or absence of exudate, and/or absence of stricture. {none} In some embodiments, the present disclosure provides methods of treating eosinophilic esopliagitis (EOE) in a patient in need thereof, comprising administrating an oral corticosteroid in an induction phase and a maintenance phase, wherein the induction phase does not result in substantial improvement in Peak eosinophilic counts in at least one esophageal biopsy. In some embodiments, the patient experiences at least one episode offood ion in the induction phase.

In some embodiments, the patient exhibits active ms ofEoE during the induction phase. In some embodiments, the induction phase results in a histological response offwl 5 peak eosinophils per high power field (EFF), In some embodiments, the patient exhibits no substantial improvement in esophageal function and/or morphology during the induction phase. In some embodiments, following the ineffective induction phase, treatment is continued resulting in the patient exhibiting an improvement in Peak eosinophilic counts in at least one esopl'iageal biopsy, and the ued treatment results in no worsening of t mean weekly scores in a patientureported outcome assessment, which includes the assessment of gia~free days. {8897} In some embodiments, the maintenance phase comprises a dose at least equal to, more than or less than the induction phase. ln some embodiments the ion and maintenance doses are between about l.5mg and about 3mg, e. g. administered once or twice daily. {8898} In some embodiments, the induction phase comprises administration for at least about a weeks, for at least about 8 weeks, for at least about it) weeks, or for at least about 12 weeks. In some embodiments, stration occurs twice per day. In some embodiments, the induction phase results in a ogical response of <6 pealr Eos per HI’E. In some embodiments, the induction phase results in no episodes of food, impaction. {9999} In some embodiments, the patient in maintenance therapy does not relapse with active symptoms of EoE. In some ments, the maintenance does is substantially the same or less than the induction dose. In some embodiments, the maintenance dose is higher than the induction dose. In some embodiments, the patient in the withdrawal phase does not relapse with active symptoms of EoE In some embodiments, the patient remains in withdrawal phase until active symptoms of EoE recur. In some embodiments, after recurrence of active symptoms of EoE, the patient receives an ion dose of an oral corticosteroid. in some embodiments, after recurrence of active symptoms of EoE, the patient receives a maintenance dose of an oral corticosteroid. In some embodiments, after recurrence of active symptoms oonE, the patient receives an induction dose of an oral corticosteroid followed by a maintenance dose.

{Iltlltl} In some embodiments, the present disclosure provides for administering the oral coiticosteroid composition to a patient while laying down. In some embodiments, the corticosteroid is administered to the t while laying down and prior to going to sleep (eg, about l minute, about 5 s, about l0 minutes, about l5 minutes, or about 30 minutes, inclusive of all values therein). In some embodiments, the pharmaceutical composition is administered to the patient at least about 2 hours after the evening meal. in some ments, the corticosteroid is stered to the patient at least about 4 hours after the evening meal, {8811} In some embodiments, the corticosteroid is ated in an orally dissolving dosage form, In some embodiments, the corticosteroid is selected from the group consisting of budesonide, Iluticasone, Ilunisolide, ciclesonide, mornetasone, beclomethasone, tixocortol and salts, or esters and mixtures thereof. In some embodiments, the orally dissolving dosage form is a tablet or wafer.

In some embodiments, the corticosteroid is deposited lly in the upper gastrointestinal tract.

In some embodiments, the patient has usly been administered proton pump inhibitor (PEI) therapy. ln some ments, the patient has previously been administered PI’l therapy for eight weelrs. In some embodiments, the I’l’I therapy was not effective to substantially improve one or more symptoms of EoE. In some embodiments, the patient has previously not been administered PPI therapy. {8812} in some embodiments, the present disclosure provides methods for assessing the suitability of subiects for a clinical trial to measure the effect of an oral corticosteroid on EoE after stration in both an induction phase and a maintenance phase, n the recruitment of subjects into the clinical trial is assessed based on (i) patients having Peak eosinophil counts per HP]? of greater than l5, and (ii) prior treatment with a PM over at least about 8 weelts had not been effective to ntially improve one or more symptoms of EoE. lillllldl in some embodiments, the t disclosure provides for a method of treating EoE in a t in need thereof, sing administering an oral corticosteroid to the t, wherein the patient is lying down when the oral corticosteroid is administered or the patient lays down immediately after administration of the oral corticosteroid in other embodiments, the present disclosure provides for a composition comprising an oral corticosteroid for use in the treatment of EoE in a patient in need thereof, n the patient is lying down when the composition is stered or the patient lays down after immediately after administration of the composition, in still other embodiments, the present disclosure provides for the use of composition comprising an oral corticosteroid for the manufacture of a medicament for the therapeutic application in EoE in a patient in need thereof, wherein the patient is lying down when the medicament is administered or the patient lays down immediately alter administration of the medicament {Mlle} In various embodiments, the present disclosure provides for methods (or compositions for use in methods) for lly treating EoE in patient in need thereof with an oral corticosteroid, said methods comprising: (a) administering the oral corticosteroid while the patient is lying down or immediately prior to the patient lying down. in embodiments, a therapeutically effective amount of the oral corticosteroid contacts the esophagus, thereby topically treating EoE {Gilli} ln embodiments, the lying down is in a supine, prone, or laterally recumbent on. In ments, the oral corticosteroid is administered about 30 minutes or less before target sleep time. ln embodiments, the oral corticosteroid is administered at least about 30 minutes after a meal. ln embodiments, the patient does not eat or drink for at least about 30 s after stration the oral corticosteroid. {8816} hi embodiments, the oral corticosteroid is administered: (i) once daily, or (ii) twice daily, wherein the first daily dose is administered while the subject remains upright. in embodiments, the corticosteroid has a systemic bioavailability of less than or equal to about 20% of its dose. ln embodiments, the oral corticosteroid provides an average maximum blood plasma concentration (Cmax) of less than or equal to about 500 pg/mL after oral administration of about Gill mg to about 20 mg of the oral corticosteroid. ln ments, the oral corticosteroid provides an average AUCazi of less than or equal to about 3,000 pg*h”ntL after oral stration of about 0.01 mg to about 20 mg of the oral corticosteroid. ln embodiments, the oral corticosteroid is budesonide, fluticasone, tlunisolide, ciclesonide, mometasone or beclomethasone, or a pharmaceutically acceptable salt, solvent, ester, polyinorph or prodrug thereof. In embodiments, the oral corticosteroid is formulated: (i) as a liquid composition; (ii) as a solid, composition; (iii) to form a solution or suspension prior to oral stration; or (iv) to form a on, sion or gel after oral stration, wherein (it—(iv) delivers a therapeutically effective amount of the oral corticosteroid to the esophagus. ln embodiments, (i) the liquid composition is in the form of a solution, suspension or slurry; and (ii) the solid composition is in the form of a gel, lozenge, lollipop, etlervescent tablet, powder, granules or an orally disintegrating ition. in embodiments, the orally disintegrating composition is a tablet, wafer, film, or lyophilized matrix, in embodiments ,the orally disintegrating composition is a tablet comprising: (a) the oral corticosteroid in an amount of from about l5 mg to about 7.5 mg; (b) a pharmaceutically acceptable carrier combined with the corticosteroid; and (c) rapidly dispersing n'iicrogranules, wherein the orally disintegrating tablet disintegrates within 60 s wl'ien tested using the USP <70l > method for disintegration time, {(3817} in embodiments, the patient has a Cmair of the oral corticosteroid of less than or equal to about 200 pg/mL ing oral stration l5 mg to about 7.5 mg of the oral osteroid. ln embodiments, the oral corticosteroid is lluticasone propionate, and the lying down patient has a Cmax within the range of about 80% to about l25% of about l5 pg/mL to about 45 pg/mL following oral administration of 6 mg fluticasone propionate or 3 mg of fluticasone propionate to a lying down patient. ln embodiments, the CmaX of the corticosteroid for the laying down t is lower than the Cmax ol‘ the oral corticosteroid for a fed patient that is upright and does not lay down immediately after administration of the oral corticosteroid. ln embodiments, the Cmax of the oral corticosteroid for the lying down patient is lowered by about l0% to about 30% compared to the Cmax of the oral corticosteroid for a fed patient that is upright and does not lay down immediately after administration of the oral corticosteroid. {(130318} In embodiments, the e time to reach a maximum blood plasma concentration ('l‘maa) is in the range of about 80% to about 1259/6 of about l2 h to about l5 h. in embodiments, the 'l‘inax of the corticosteroid for the lying down patient is delayed ed to the Tina}: of the oral corticosteroid for a patient that is upright and does not lay down immediately after administration of the oral osteroid. ln embodiments, the 'l‘max of the corticosteroid for the lying down patient is delayed by at least about l hour compared to the average TmaX of the oral corticosteroid for a patient that is upright and does not lay down immediately after administration of the oral osteroid. in embodiments, the 'l'max of the corticosteroid, for the lying down patient is delayed by an amount of time in the range of about 4 h to about 9 h compared to the Tniax oi‘ the oral corticosteroid for a patient that is upright and does not lay down immediately after administration of the oral corticosteroid. {9919} in embodiments, after l2 weeks of daily administration of the oral corticosteroid, esophageal inflammation is reduced as measured by a reduction in eosinophil count, an increase in dysphagia—free days, a reduction in episodes of dysphagia, ement in EREFS score EndoFLlP documentation of improved esophageal compliance, evaluation of hicmarlrers, a decrease in es of food impaction, an improvement in EEsAl scores (patient, ian, endoscopy, ogy scores), Eo’E—QOL—A, Visual Dysphagia Questionnaire (VDQ), Avoidance Modification and Slow Eating (Ah/l8) scores, or histology In ments, the patient’s eosinophil count is reduced by at least about 50%, {(3829} in embodiments, the patient has a lactose allergy or starch allergy.

BRIEF DESCRIPTEQN 0F THE S {dint} Figure 1 shows an exemplary schematic overview of Parts 1 and 2 of a Phase 2h study design and depicts screening and run—in in Part l (induction stage), and randomized withdrawal in Part 2 {8822} Figure 2 shows an ary schematic overview of Part 3 (maintenance) and followup of a Phase 2b study. {8823} Figure 3 shows another an exemplary schematic overview of Parts 1 and 2 of a Phase 2h study design and depicts screening and run—in in Part 1 (induction stage), and randomized withdrawal in Part 2. 24} Figure 4 shows another shows an exemplary schematic overview of Part 3 enance) and follow—up of a Phase 2h study. {(130325} Figure 5 shows a study schematic providing an overview of the treatment each subject will receive throughout the FLUTE study. {(130326} Figure 6 shows the Mean Linear Plasma Concentrationu'l‘ime Profile of APTulOll (Fluticasone Proprionate) for fed, fasted, and HS administration. {(130327} Figure ‘7 shows the Mean Logarithmic Plasnia Concentration~Tinie Profile of AP'l‘ul Ol l (Fluticasone Proprionate) for fed, , and, HS administration. {(130328} Figure 8 shows tti Plots of AF'lFlOll {Fluticasone onate) (Fasted conditions). {(130329} Figure El shows Spaghetti Plots of APP—1011 (Fluticasone Proprionate) (Fed conditions) {8839} Figure ill shows Spaghetti Plots of AP'f—lOll (Fluticasone Proprionate) (HS conditions).

DE'E‘AELED F’FEGN {(130331} Gastrointestinal inflammatory disorders, such as philic esophagitis (Eoli‘), an allergic/immune condition where the suhject suffers from inflammation and/or swelling of the esophagus, affect a patient’s ability to swallow food and can consequently cause malnutrition and e to thrive. Typically, eosinophils are not found in the esophagus, hut in EoE these cells accumulate and produce swelling that reduces the interior diameter of the esophagus mahing swallowing and eating very difficult. Often patients experience episodes of food impaction where food becomes , in the patient’s esophagus, which can require emergency treatment. Because of the difficulty swallowing, and fear of food impaction, many ts with Eol'i limit themselves to eating soft foods such as yogurt, soups, and smoothies. in severe cases of EoE patients receive parenteral ion (: e. g. intravenous feeding), which can provide required sustenance hut limits the patient’s activities and can lead to increased infection at the site of the catheter. {(130332} EoE most commonly occurs in Caucasian males and can occur at any age, with the symptoms varying with age. lnfants and toddlers suffering from EoE may refuse food, fail to thrive, or experience “reflux” and/or vomiting. Young children typically report hearthurn/retlux, ahdominal pain, vomiting, food avoidance, and/or poor growth. Eor adults, the hallmark symptom is dysphagia (trouble swallowing), and EoE is ated in over 50% of food impactions. Adult patients less commonly exhibit heartburn or chest pain. Adults with EoE also exhihit altered eating behavior such as dietary modifications, slow eating, excessive chewing, and increased consumption of liquids with food. {@933} While the causes of EoE are not known, many EoE patients have a family history of ies, asthma, and/or symptoms of allergic- disorders (eg. asthma, allergic rhinitis, atopic dermatitis, and food allergy). Additionally, environmental allergens such as dust mites, animals, pollen, and molds may play a role in the pment of EoE, Because of the link between EoE and allergies, especially food allergies, ation of the en may help alleviate symptoms, However, these types of ation can be ult to achieve. {9934} While there are no medications currently approved to treat EoE, some tions such as glucocorticosteroids, leukotriene antagonists, mast cell stabilizers, immunomodulators, hiologics, and small molecules can help alleviate symptoms. Proton Pump lnhihitors (PEI) which control the amount of acid produced, have also been used to treat patients’ symptoms, but may not reduce the amount of inflammation in the patient r, recent studies have linked longeterm PPl use to dementia, making their use in EoE patients less desirable. Endoscopic therapy (dilation) may also he used to alleviate symptoms, but this too has no effect on the underlying inflammation causing the geal swelling, {8835} While these therapies may help alleviate symptoms in some ts for a time, they often fall short of treatment of EoE. For example, current topical steroid medications are not optimal, with 5—5096 of patients fied as nonuresponders. Similarly, diet elimination which requires significant endoscopic surveillance of the t shows about 3 % non—response rate. {8836} New methods of not only alleviating the symptoms of esophageal inflammatory disorders such as EoE, but also addressing the inflammation causing the symptoms are required. The present disclosure provides methods ol‘administering pharmaceutical compositions comprising a topically active corticosteroid to treat the symptoms and/or inflammation associated with a gastrointestinal matory disorder. Pharmaceutical compositions comprising a topically active corticosteroid for use in such methods are also herein disclosed.

{NEW} ln various embodiments, the methods disclosed herein include at least two phases: an ion phase and a maintenance phase. During the induction phase, patients are administered a dosage of a ceutical ition of the disclosure. Based upon patient response at the end of the induction phase (eg. a histologic response and no ing of ms or episodes of food impaction), the patient may enter the maintenance phase. The dose of the pharmaceutical ition may he the same or different during the maintenance and induction phases. Upon an amelioration or decrease of symptoms, the patient may also enter a withdrawal phase, and receive no doses of the pharmaceutical composition until symptoms recur. {9933} The present disclosure provides methods of treating eosinophilic esophagitis (Hot?) in a patient in need thereof, comprising administrating an oral corticosteroid in an ion phase and a maintenance phase? where the induction phase results in improvement in Peak philic counts in at least one esophageal biopsy and the treatment results in no ing of t mean weekly scores in a t—reported outcome assessment which includes the assessment of dysphagia-l‘ree days~ {(3839} Unless defined ise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

Although any methods and materials, similar or equivalent to those described herein, can he used in the practice or testing of the present disclosure, the preferred methods and materials are described herein. {8849} it should he understood that singular forms such as “a” ‘an,” and “the” are used throughout this application for convenience, however, except where context or an explicit statement indicates otherwise, the singular forms are intended to include the plural. All numerical ranges should he understood to include each and every numerical point within the numerical range, and should he interpreted as reciting each and every numerical point individually. The endpoints of all ranges directed to the same component or property are inclusive, and intended to be independently cornhinable. lilllléll} As used herein, the word de,” and its variants, is intended to be nonulimiting, such that tion of items in a list is not to the exclusion of other lilre items that may also be useful in the materials, compositions, devices, and methods ot‘tliis technology. Similarly, the terms “can” and “may” and their variants are ed to he nonulirniting, such that recitation that an embodiment can or may se certain elements or features does not exclude other embodiments of the present technology that do not contain these elements or features. Although the opennended term ising,” as a synonym of terms such as including, containing, or having, is used herein to describe and, claim the disclosure, the present technology, or ments thereof, may alternatively be described using more limiting terms such as “consisting of” or “consisting essentially of” the recited ingredients.

{W42} The term "drug", "active" or "active pharmaceutical ingredient" as used herein includes a pliarmaceutically acceptable and topically acting corticosteroid, pharmaceutically acceptable salts, esters, solyates (including hydrates), polymorphs, stereoisomers, and/or prodrugs, and mixtures thereof. The terms “salts” refers to the product formed by the reaction of a le inorganic or organic acid with the "free base“ form of the drug. Suitable acids include those having ient acidity to form a stable salt, for example acids with low toxicity such as the salt approved for use in humans or animals Non—limiting examples of acids that may be used to form salts of an orally active drug, include inorganic acids, e. g, HCl HEPOr-‘l H2804. Non-limiting examples of organic acids include all<yl sulfonic acids and propionic acid. {llllrlfé} The terms “pharmaceutical composition” and aceutical dosage form,” are used interchangeably herein to refer to an oral dosage form (suspension, solution, powder, solid, etc.) which can he used to administer a corticosteroid. Non—limiting examples of dosage forms include an orally disintegrating composition, such as a tablet, a lyopl’iilized matrix, a film, and a wafer, liquid composition, a gel, a slurry, a lozenge, a lollipop, , an effervescent tablet, and the like. {(3844} The term “oral corticosteroid” and “corticosteroid” are used interchangeably to refer to a corticosteroid which is administered orally, e. g. in a pharmaceutical composition described herein. {(130345} The terms “orally egrating dosage form”, ”orally egrating tablet”, ”orally dispersing tablet", or "QDT" refer to a solid dosage ablet ol'" the present disclosure, wliich egrates rapidly in the oral cavity of a patient after administration, without chewing, to form a suspension comprising the corticosteroid. The rate of oral disintegration can vary, hut is icantly faster than the rate of oral disintegration of conventional solid dosage forms or chewable solid dosage forms tie, tablets or capsules) which are intended to be swallowed immediately after administration. {9946} As used herein, the terms ing, )9 LCtreatment” and “treat” include (i) preventing a particular disease or disorder from occurring in a suhj ect who may be predisposed to the disease or disorder but has not yet been diagnosed as having it; (ii) curing, treating, or inhibiting the disease, ie, arresting its development; or (iii) ameliorating the disease by reducing or eliminating symptoms, conditions, and/or lay causing regression of the disease. ln some embodiments, “treating,” “treatment” and “treat” may include administering a eutically ive regimen as d herein. {ltd/4'7} The term ”abou .”, as used herein to refer to a numerical quantity, includes "exactly” plus or minus up to l0% of that referenced numeric indication. When the term " is used in reference to a range of values, the term “about" refers to both the minimum and maximum value of the range (eg, "about l~50 um" means ”about l pm to about 50 pm”). The term "intimately associatet ”, as used herein to describe the spatial relationship between two or more components of a composition refers to components that are intimately mixed, such as, for example, in mixtures, gs and matrices. {@1948} Unless indicated otherwise, all percentages and ratios are calculated by weight, Unless indicated ise, all percentages and ratios are calculated based on the total composition.

} The term "having no significant systemic glucocorticoid or mineralocorticoid activity", as used herein refers to corticosteroid compositions which do not provide a generalized effect in the body through absorption into the circulation, but do provide local effects through topical contact with a diseased tissue. Examples include fluticasone, flunisolide, hudesonide, circlesone, asone, tixocortol, and heclomethasone. Corticosteroids which have high systemic glucocorticoid potencies when administered orally include e.g ortisone, prednisone, prednisolone, lprednisolone, dexamethasone, hetamethasone, etc. or mineralocorticoid potencies (eg, alsosterone). Corticosteroids which typically have systemic glucocorticoid or mineralocorticoid activity when administered orally can also he used in the diluted compositions of the present disclosure, wherein the systemic uptalte of the corticosteroid is reduced or suppressed. {8859} A “histologic responder” may be defined as a subject who achieves a histologic se of peak eosinophils/lll’F number :6 (as primary determinant}. l-lPF may be d as a standard area of 0237 square millimeters in a microscope with 40x lens an 22mm ocular. {9931} A “histologic non—responder” may be defined as a sub} ect who does not have a histologic response (i.e., do not achieve a histologic response of pealr eosinophils/HPF number 36). {9932} Subjects who develop food impaction with or without esophageal dilatation anytime during a study may be considered “treatment failures”.

Pharmaceutical Compositions andAdministration {WEE} The ceutical compositions used in (or for use in) the methods described herein can be any dosage form which can be used to topically ster a therapeutic agent (eg, corticosteroid) to the esophagus. Suitable dosage forms include liquid compositions (_ e.g solutions, suspensions, and es), gels, and solid compositions which form a liquid or gel after oral administration. For example, orally disintegrating compositions (eg, ODT, film, lyophilize matrix, or water), lozenges, and lollipops can from a on, suspension, or gel comprising the therapeutic agent in the oral cavity of the patient, and after the solution or suspension is swallowed, the osteroid dissolved or suspended therein contacts the esophagus as the liquid traverses the esophageal tract. lo a preferred emhodiinent, the pharmaceutical composition is in the form of an {8854} in some embodiments, the present disclosure provides an oral solid pharmaceutical composition comprising a corticosteroid (eg, about it) mg or less, including 7.5 mg, 6.0 mg, 4.5 mg, 3.0 mg, l5 mg, or 075 mg) and at least one pharmaceutically acceptable carrier, wherein the osteroid is combined with (e.g ed onto or suspended in) the pharrnaceutically acceptable carrier In some embodiments, the drug is present in an amount of less than about 5% t of drug/weight of composition), particularly less than 3% by weight, The pharmaceutical compositions disclosed herein can be formulated as an orally disintegrating tablet (hereafter referred to as an CDT) that disintegrates within 60 seconds (eg within 30 seconds) when tested using the USP <701> egration , and/or disintegrates within 60 seconds when placed in the oral cavity of a human. {8855} in some embodiments, the corticosteroid used in the compositions and methods described herein is a topically acting corticosteroid. ln some embodiments, the osteroid has low or substantially no systemic effect. ln some embodiments, corticosteroids that have low or no systemic effects are those which have no significant systemic glucocorticoid or mineralocorticoid ty after oral administration in . Corticosteroid with “no significant systemic glucocorticoid or mineralocorticoid ty after oral administration in humans” refer to corticosteroids, or pharmaceutical compositions comprising corticosteroids, which have less than about 20% ic glucocorticoid or mineralocorticoid activity after oral administration, e. g, less than about l5%, less than about 10%, less than about 5%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about l %. Systemic glucocorticoid or mineralocorticoid activity can be determined using methods known in the art, such as by measuring morning cortisol . {9956} lo some embodiments, corticosteroids for use in the s and compositions described herein have a systemic bioavailability of less than or equal to about 20% of the administered dose, Nonmlimiting examples of oral corticosteroids that have a bioavailability of less than or equal to about 20% include llutieasone, flunisolide, budesonide, circlesone, sone, tixocortol, and beclomethasone, and pharmaceutically acceptable salts, solvates, esters, polyrnorphs or prodrugs thereof. ln preferred embodiments, the oral corticosteroid used in the methods and compositions described herein is l‘luticasone propionate, {@1957} In some embodiments, the oral corticosteroids for use in the methods and compositions described herein are formulated to provide a pharmacoltinetic profile which reduces the hood that a patient will experience side effects ated with systemic corticosteroid administration, including, but not d to, osteoporosis, weight gain, immune system suppression (i.e., increased incidence of infections), high blood pressure, hyperglycaemia, muscle weekness, skin problems {e.g, poor healing of injuries, thinning of skin, easy bruising, stretchmarks, etc.) mood and behavioral changes, increased rislr of developming cataracts, and increased rislr of al ulcers.

That is, the pharmacokinetic profile of a corticosteroid can be modified to provide an average maximum plasma concentration (Cmax), an average time to reach the maximum plasma concentration (Tmax), and/or AUC that reduces systemic side effects. Pharmacokinetic profile can be measured by methods known in the art, for example the methods described in Example 5. {0058} in some embodiments, oral corticosteroids for use in the s and compositions described herein are formulated to provide an average maximum blood plasma concentration (Cmax) of less than or equal to about l0,000 pg/mL after oral administration of about 0.0l mg to about 20 mg of the oral osteroid, e.g about 9,000 pg/mL, about 8,000 pg/mL, about 7,000 pg/mL, about 6,000 pg/mL, about 5,000 pg/mL, about 4,000 pg/mL, about 3,000 pg/mL, about 2,000 pg/mL, about 1,000 pg/mL, about 900 pg/mL, about 800 pg/mL, about 700 pg/fllL, about 600 pg/mL, or about 500 pg/mL, inclusive of all values and, subranges therebetween. In preferred embodiments, the oral corticosteroid is formulated to provide a Cniax of less than or equal to about 500 pg/mL after oral stration of about 0.01 mg to about 20 mg of the oral corticosteroid. {0050} In some embodiments, oral corticosteroids for use in the s and compositions described herein are formulated to provide an average AUCma ofless than or equal to about l5,000 pgl'h/ml, after oral administration of about 0.0 l mg to about 20 mg of the oral corticosteroid, eg, about l4,000 pg’lh/mlc, about l3,000 13g*h,/"inl_,, about 12,000 pg*lt/ml.., about ll,000 pgl‘hu/mlr, about l0,000 pgl‘h/mL, about 9,000 pg’l‘li/ml_,, about 8,000 pg*h/mL, about 7,000 13g*h,/"inl_,, about 6,000 pg*h/nil_., about 5,000 pg*h/mL, about 4,000 pg’lh/mlc, about 3,000 13g*h,/"inl_,, about 2,000 pg*lt/ml.., about 1,000 pg‘l‘h/niL, inclusive of all values and subranges therebetween. in preferred embodiments, oral corticosteroids for use in the methods and itions described herein are formulated to e an average AleOQ/t of less than or equal to about 3,000 r3g*li,”ml_.. after oral administration of about 0,0l mg to about 20 mg of the oral osteroid. {0060} In some ments, the pl’iarmaceutical compositions described herein can be formulated to reduce systemic ilability, glucocorticoid activity, and/or mineralocorticoid activity (or combinations thereof) of the oral corticosteroid ing oral administration.

Reducing systemic bioavailability may allow the corticosteroid to exhibit local therapeutic s, rather than being absorbed systemically. For example, a corticosteroid which otherwise has high systemic bioavailability (systemic bioavailability of e.g., > 20%) can be formulated in an ion~ ge resin to reduce systemic bioavailability while increasing local therapeutic effects. {0061} Salts, solvates, polymorphs, and prodrugs can be used to modify corticosteroids that otherwise have a systemic bioavailability of greater than about 20% to provide a “topically activing corticosteroid” having less than about 20% systemic activity and greater than about 80% local effect by decreasing the systemic ilahility of tlie osteroid. {8862} miting examples of corticosteroids which can be modified (eg, by forming a salt or prodrug, or formulating the oral corticosteroid in an ion~exchange resin) to reduce systemic bioavailability and increase local effects, include hydrocortisone, prednisone, prednisolone. methylprednisolone, rlexamethasone, betametliasone, alsosterone, and the like.

{W63} The compositions of the present disclosure may include a water soluble or water" swellable pliarmaceutically acceptable ent, such as lling or hioadhesive r that will enhance hioarlherence of the corticosteroid to the inflamed esophageal mucosa. {9964} Suitable topically acting corticosteroids which may be included in the pharmaceutical ition of the t disclosure include hudesonide, fluticasone, flunisolide, ciclesonide, mometasone, beclornethasone, tixocortol and salts, esters, solvates,polymorphs, or prodrugs, and mixtures thereof. {(3965} In preferred embodiments, the composition of the present disclosure comprises fluticasone (eg. asone propionate), In preferred embodiments, the pharmaceutical composition is an ODT comprising tluticasone or a pharmaceutically acceptable salt thereof (eg fluticasone propionate). In other embodiments, the composition of the present disclosure comprises hudesonide, In certain other embodiments, the composition of the present disclosure comprises ciclesonide. {dildo} In some embodiments, the corticosteroid may be in the form of crystals having a mean particle size of about lOO am or less, about 75 pm or less, about 50 pm or less, more particularly about 25 pm or less, or about l5 pm or less. Particular embodiments of the disclosure provide the corticosteroid is micronized in order to e a mean particle size ot‘less than about It) um, less than about 8 pm or less, less than about 6 am, or particularly, less than about 4 pm. {8367} Alternatively, such crystals may have an average size in the sub—micron range (e.g, average particle size of about <l um), i.e., may be as nanoparticles (eg, average le size in the range of about l ulOO nm). In some embodiments, the corticosteroid may be present in an amorphous form, for example in association with a stabilizing agent which limits drug recrystallization, eg, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose , hydroirypropyl cellulose, hydroxyethylcellulose; Soluplus®, Kollidon® VAéL’l, sodium lauryl sulphate, Tween surfactants, it® EPO polymer, and mixtures thereof. {8868} The amount of corticosteroid t in the pharmaceutical compositions of the present disclosure is selected so as to ze the therapeutic benefit from topical administration while minimizing side effects from ic absorption. in the case of solid pharmaceutical compositions of the present disclosure, the amount of corticosteroid in the composition is less than about 5% w/w (weight of drug/ weight of composition). In some embodiments the amount of corticosteroid in the pharmaceutical composition is less than about 4%. in another embodiment it is less than about 3%. in some ments it is less than about 2%, less than about 15%, less than about l%, less than about 0.5% by weight or less. in some embodiments the amount of corticosteroid in the pharmaceutical composition is n about 0.50 mg and about 18 mg. 1n some embodiments the amount of corticosteroid in the pharmaceutical composition is between about 0.75 mg and about l2 mg, in some embodiments the amount of corticosteroid in the pharmaceutical composition is between about 1.5 mg and about 9 mg. in still other embodiments, the amount of corticosteroid is about 0.01 mg about 0.05 mg, about 0.1 mg, about 0. l5 ing, about 0.1 mg, about 02 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0,5 ing, about 0,6 ing, about 07.7 mg, about 0.75 mg, about 0.8 mg, about 1 mg, about 15 mg, about 2 mg, about '3 mg, about 4 ing, about 4.5 mg, about 5 mg, about 6 mg, about ’7 mg, about 8 mg, about 9 mg, about 10 mg, about l2 mg, about 18 mg, inclusive of all ranges and sub—ranges there between. {(1869} in preferred embodiments, the amount of corticosteroid in the ceutical composition disclosed herein (e.g ()DT) is the range of from about l5 mg to about 7.5 mg, including about 3.0 mg, about 4.5 mg, and about 6.0 mg, in preferred embodiments, the pharmaceutical composition is an ODT and the corticosteroid is present in an amount of about 1.5 mg. in other red embodiments, the pharmaceutical composition is an GDP and the corticosteroid is present in an amount of about 3.0 mg. in still other preferred embodiments, the pharmaceutical composition is an ODT and the corticosteroid is present in an amount ot‘about 4.5 mg. in yet other preferred ments, the pharmaceutical composition is an ()DT and the corticosteroid is present in an amount of about 6.0 mg. in some other preferred embodiments, the pharmaceutical composition is an OD”? and the corticosteroid is present in an amount of about 7.5 mg. {8879} ln some embodiments, the rapidly disintegrating composition of the disclosure may comprise pharmaceutically acceptable excipients which swell, dissolve or otherwise facilitate disintegration of the orally disintegrating dosage form t: e. g. an DDT, film, lyophilized matrix, or wafer) providing a smooth viscous suspension containing micronized corticosteroid particles to coat inflammatory esophageal mucosa to treat eosinophilic esophagitis. Examples of such pharmaceutically acceptable excipients e disintegrants or rapidly dispersing ranules as described herein. As used , the term “rapidly dispersing niicrogranules” refers to granules comprising particles of at least one sugar alcohol and/or saccharitle in combination with particles of at least one disintegrant, which are formed in a granulator. ln embodiments, the osteroid (e.g micronized corticosteroid particles) may be granulated, with the alcohol and/or saccharide particles. Alternatively, in some embodiments, the corticosteroid (e.g, ized corticosteroid particles) can be combined with the pharmaceutically acceptable carrier, and then blended with the rapidly sing rnicrogranules comprising particles of at least one sugar l and/or saccharide in combination with particles of at least one disintegrant, {9971} ln certain embodiments of the t disclosure the total weight of the dosage form is kept in the range of from 300 to 900 mg to incorporate as much y dispersing rnicrograriules comprising at least one sugar alcohol and/or ride in combination with at least one disintegrant as possible to maximize eosinophilic esophagitis surface coating with micronized corticosteroid In some embodiments, the rapidly dispersing microgranules comprise at least one egrant in combination with a sugar alcohol and/or a ride. The amount of sugar alcohol and/or saccharide in the rapidly dispersing granules ranges from about 9996—9092), or about 95%— 90% of the total weight ofthe disintegrant—containirig granules, including all ranges and sub—ranges there between. ln some embodiments, the average particle size ol‘a sugar alcohol and/or saccharide is about 30 pm or less, for example about l —30 um, about 5—30 um, about 5—25 pm, about 5—20 um, about S—l 5 um, about S—lO um, about lO—BO um, about ill—25 um, about lO— 20 um, about l0— l5 um, about lS—BO um, about l5—25 um, about l5—20 um, about 20—30 um, about 20—25 pm, or about 25—30 pm. {8872} ln some embodiments, the dosage form has total weight of 300 mg and contain about 0.05 mg ( O.lo%), about 0.75 mg (0.25% w/w), about l5 mg (0.5% w/w), about 3 mg (l% w/w), about 4.5 mg (l 5%) about 6 mg (2% w/w}, about 7.5 mg (2.5% w/w}, about 9 mg (3% w/Wy), about l2 mg (4% w/Wy), about lo mg (5%) of the corticosteroid. {0073} ln some embodiments, the dosage forms has total weight of 600 mg and contain about 0.75 mg (0.l25% w/w), about l5 mg (0.25% w/w), about 3 ing (0.5% w/w}, about 4.5 mg (075%), about 6 mg (0.l% w/w), about 7.5 mg (1.25% w/w), about 9 mg (15% WW), about l2 mg (2% w/w), about l8 mg (3% w/w) of the corticosteroid. In some embodiments, the topically acting corticosteroid is fluticasone propionate and it is in the range of about 0.05 to about l5 mg in the pharmaceutical composition at a drug content of from about 0.16% to 5% by weight of the composition. {0074} ln some embodiments, the lluticasone propionate is in the range of about 0.75 to about 7. 5 mg in the composition at a drug t offrom about 0.25% to 2. 5% by weight in the composition. {0075} ln some embodiments, the tluticasone propionate is in the range of 0.05 to about l8 mg in the composition at a drug content of from about 0. l25% to 5% by weight in the composition. {0076} The pharmaceutical ly acceptable carrier used in the mixture of the present disclosure is suitable for combining with the drug (eg, adsorption ot‘tbe drug, or dissolution of suspension of the drug in the pharmaceutically acceptable carrier), it should have the properties of an excellent carrier for dry blends providing blend llowability and workability and preventing the segregation. lt may concur in providing osteroid content uniformity. Suitable pharmaceutically acceptable carriers include, but are not limited to, microcrystalline ose, silicified rystalline cellulose, pregelatinized starch, corn starch, colloidal silica, or amorphous magnesium um silicate (commercially available as VEEGUMTM or NEUSlLlNTM). In red embodiments, the pharmaceutical r for the adsorption of the corticosteroid is silicified mi crociystalline cellulose. lt is preferably silicil’ied rystalline cellulose wl'iich is composed of intimately associated microcrystalline cellulose and colloidal silicon dioxide particles, (PROSOLVCE‘J SMCC: MCC, 9 % and CSD, 2%). The use ofthis ingredient in the composition of the disclosure es the llow and blending ties of the corticosteroid mixture, improved blend uniforinity/homogeneity and physical stability of the formulations during storage until their final processing into finished dosage forms such as tablets or es, i.e., to avoid or minimize ial de—mixing and segregation of corticosteroid microparticles is also achieved. The presence of this carrier in admixture with the active also ensures reproducibility of preparations of the WO 35393 composition of the disclosure (in ular with the applied technology of direct tableting). in some embodiments, a low—dose corticosteroid blend with the carrier showing high blend uniformity, low—segregation potential and excellent flowability is disclosed. This blend is particularly suitable for producing a rapidly disintegrating diluted corticosteroid composition. in some embodiments, of the disclosure the blend comprises fluticasone propionate adsorbed on silicifietl microcrystalline cellulose, and rapidly dispersing microgranules.

{W77} ln embodiments, the ceutically acceptable carrier for absorption of the corticosteroid is micronized. ln some embodiments, the izetl pharmaceutically acceptable carrier has a diameter of less than about 20 microns, eg, less than about l5 s, less than about l0 microns, less than about 9 microns, less than about 8 s, less than about 7 s, less than about 6 microns, less than about 5 microns, less than about 4 microns, less than about 3 microns, less than about 2 microns, or less than about l micron ln particular embodiments, the niicronized pharmaceutically acceptable carrier has a diameter of less about 5 microns. {9978} ln some embodiments, the pharmaceutically acceptable carrier is present in the pharmaceutical composition (cg, ODT) an amount in the range of about l % W/w to about 20% “Ii/"W; eg., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about l0%, about ll%, about 12%, about l3%, about l4%, about l5%, about 16%, about l7%, about l 8%, or about l 9%, inclusive of all values and ges therein. in preferred embodiments, the pharmaceutically carrier is present in the pl’iarmaceutical composition (Leg, ODT) an amount in the range of about l0 % WW. {(3879} in some ments, combining the corticosteroid with the pharmaceutically acceptable carrier provides a batch of orally disintegrating compositions having a corticosteroid content mity within the range of about 85% to about l l 5% of the corticosteroid dosage on the label (eg, l.5—7.5 mg, including l5 mg, 3.0 mg, 4.5 mg, 6.0 mg, and 7.0 mg). ln some ments, the batch has a corticosteroid content uniformity within the range of about 90% to about ll0% or" the corticosteroid dosage on the label, or within the range of about 95% to about lOS‘E/u, or about 96% to about l04%, or about 7% to about l03%, or about 98% to about 102%, or about 99% to about 101%. {(130380} ln some embodiments, the rate of disintegration of the disintegrating compositions of the present disclosure (cg, OUT, wafer, lyophilized matrix, film, etc) in the oral cavity of an individual can he on the order of about 60 seconds or less, about 50 seconds or less, about 40 seconds or less, about 30 seconds or less, about 20 seconds or less, or about l0 seconds or less. {8881} in some embodiments, the rate of disintegration of the disintegrating compositions of the present disclosure (cg OUT, wafer, lyophilized matrix, t‘ilm, etc) measured using the USP <70l> Disintegration Test is about 60 seconds or less, about 45 seconds or less, about 39 seconds or less, about 20 seconds or less, or about l0 seconds or less. illlle} ln addition to the corticosteroid and the r, the blend of the compositions or the oral dosage forms of the present sure may contain further pharmaceutically acceptable ingredients which swell, dissolve or otherwise facilitate disintegration. Such ingredients can e, but are not limited to, a disintegrant, a sugar l, a saccharide, or a mixture thereof, a water—soluhle polymeric hinder, a bio—gelling or a bioadhesiye polymer, which can retain the corticosteroid particle adhered onto the inflamed esophageal tissues longer than in its absence. {9983} ln some embodiments, the present disclosure es a solid pharmaceutical composition comprising a corticosteroid and a ceutically acceptable bio—gelling polymer which enables longer retention of the corticosteroid at the inflamed esophageal tissues. The ingredient herein called "bio—gelling polymer” or "hio—adhesive agent" is an agent which promote on of the corticosteroid to biological es, especially the inflamed mucosa. through gelling under Gl tract physiological conditions, for example, upon contact with physiological fluids and/or at physiological temperature, and includes, but is not limited to, the bio—gelling polymers listed below. {(3884} The bio—gelling polymer may be a tl'iermosensitiye polymer. Suitable thermosensitive polymers e polyacrylamides, such as poly(N—isopropylacrylamide), as well as polytether— ester) copolymers, such as poly/(ethylene glycol—(DL—lactic acid—co~glycolic acid) ethylene glycol). Such thermosensitiye polymers can partially or fully cover the inflamed esophageal s while lteeping the corticosteroid particle(s) close or in intimate contact with the inflamed s, y increasing the topical contact of tlie corticosteroid witli the inflamed tissues. {8385} lo some embodiments, the itions of the present disclosure include a bioadhesive agent such as a lipid or a polymer. Examples of such lipids are glycerphospholipids such as pliosphatidyl choline, and diacyl glycerols such as glycerol dioleate. Examples of bioadhesive polymers include chitosan, polyorthoesters, and copolymers, ymers and mixtures thereof.

WO 35393 {8886} in some embodiments, the solid pharmaceutical compositions of the present disclosure include an adhesive agent. le adhesive agents include, but are not limited to, sucrose aluminum sulfate complex, cliitosan and derivatives such as trimethylchitosan, polyvinylpyrrolidone, methylcellulose, liydroxypropyl cellulose, cross—linked polyacrylic acid copolymers, nylpyrrolidone, yrrolidonenpolyvinyl acetate copolymer leg, on® VA 64 from BASF), Soluplus®, poly(ethylene glycol 6000 — vinylcaprolactam m vinyl acetate) (8:57:30) copolymer from BASE), polyvinyl alcohol, polyethylene oxide, polyamide, alginic acid, and its salts, carrageenan, xanthan gum, ammoniomethacrylate copolymers, CARBOPOL polymers, maltodextrins, pectins, sucralose, and combinations thereof. ln certain embodiments of the solid, pharmaceutical compositions of the present disclosure, the corticosteroid and the adhesive agent are intimately associated. ln some embodiments, the solid pharmaceutical composition comprises osteroid surrounded or encapsulated by the adhesive agent, ln some embodiments, the solid pharmaceutical composition comprises corticosteroid disposed on the surface of the adhesive agent, in still other embodiments, the solid pharmaceutical composition comprises corticosteroid mixed or granulated with the adhesive agent. {9987} in certain embodiments, the solid pharmaceutical composition includes any solid dosage form which disintegrates rapidly in the mouth to form a suspension of powdered corticosteroid, which is hypothesized to coat or adhere onto the inflamed esophageal mucosa when swallowed. {(3888} in some embodiments, the composition of the present sure is in the form of an GUT.

The ()DT comprises the drug in an amount less than about 5% (weight of drug/weight of composition) and a pharmaceutically acceptable carrier, wherein the composition has no significant systemic orticoid or mineralocorticoid activity alter oral administration in humans. The drug les, (eg, a corticosteroid as described herein optionally coated or optionally ed with an adhesive agent as described ) are combined with rapidly dispersing ranules. Rapidly dispersing microgranules comprise a sugar alcohol, a saccharide, or a mixture thereof and a egrant alone or a egrant in combination with a aceutically acceptable additive with multi—functional activity (eg, pregelatinized starch, hydroxypropylcellulose or the like). {8889} A miting list of suitable disintegrahts for the y dispersing inicrogranules includes crospoyidone (cross—linked PVP), sodium starch glycolate, cross—linked sodium yinethylcellulose, calcium silicate, and low substituted hydroxypropyl cellulose. {(130390} The amount of disintegrant in the ()DT is typically in the range of about l% to about lO'l/ia by weight. {9991} Sugar alcohols are hydrogenated forms of ydrates in which the carbonyl group (re, aldehyde or ketone) has been reduced to a primary or secondary hydroxyl group. Non— limiting examples of suitable sugar alcohols for the rapidly dispersing granules of the pharmaceutical itions of the present disclosure include e.g., arabitol, t, erythritol, glycerol, lactitol, mannitol, ol, xylitol, maltitol, and mixtures thereof.

{W92} The term g*saccharide“ is synonymous with the term "sugars", and includes but is not limited tot monosacoliarides such as glucose, fructose and ribosee and disaccharides such as sucrose? lactose, maltose, trehalose, and cellobiosei Non—limiting examples ot‘suitable saccharides for use in the compositions of the present disclosure include eg, lactose? sucrose, maltose and mixtures thereof. In red embodiments? the composition does not include lactose, In some embodiments? the rapidly sing granules comprise at least one disintegrant in combination with a sugar alcohol) ln some enihodiinenta the y dispersing granules comprise at least one egrant in combination with a saccharide. In some embodiments, the egrant—containing granules comprise at least one disintegrant in combination with a sugar alcohol and a saccharide.

} The amount of sugar alcohol and/or saccharide in the rapidly dispersing granules ranges from about 9996—9096,, or about 9596-9096 of the total weight of the disintegrant—conraining granules, including all ranges and sub—ranges there between. {8894} The amount of sugar alcohol and/or saccharide in the CDT ranges from about 30% to about 70% by weight. {8095} Tn some embodiments, the average particle size of a sugar alcohol and/or saccharide is 30 pm or less, for example about l —30 um, about 5—30 um, about 5—25 um, about 5—20 pm, about 5— l5 um, about 5—l0 um, about lO—3O um, about l0—25 urn, about l0—2O urn, about lO—l 5 um l5—30 urn, about 15—25 um, about l5—20 um, about 20—30 pm, about 20—25 mm, or about 25—30 pm. {8096} The ratio of the disintegrant to the sugar alcohol, saccharide, or mixture thereof in the y dispersing inicrogranules ranges from about 90/l O to about 99/0l for example about 90/ l 0, about 9l/9, about 92/8, about 93/7, about 94/6, about 95/5, about 96/4, about 97/3, about 98/2, about 99/l inclusive of all values, , and suhuranges there between. {9997} The rapidly dispersing microgranules present in the OUT help rapid disintegration of the tablet when placed in the oral cavity, creating a smooth suspension ning the corticosteroid drug particles. It is desirable to incorporate ient amount of rapidly dispersing microgranules to coat extensively the esophageal mucosa. This creates a content uniformity problem in these low— dose OD'l‘s (for example, 300 mg 031‘ containing l2 mg or less of a corticosteroid). Typically, this problem is overcome by granulation, which involves spraying a dilute solution of the corticosteroid on to an excipient powder bed. The drug particles are ed in the es and consequently may not become exposed to the inflamed , resulting in being poorly efficacious. It has been surprisingly observed that it is possible not only to achieve desired t uniformity but also to enhance the probability of largely g the osteroid drug particles exposed to the inflamed mucosa by adsorbing micronized topically acting corticosteroid drug particles onto the phar‘rnaceutically acceptable carrier” (such as silicified niicrocrystalline cellulose) prior” to blending with rapidly dispersing nticrogranules and other excipients and compressing into GETS. {9993} The dosage form as described herein rnay also include pharmaceutically acceptable excipients typically used in egrating tablet formulations such as fillers, diluents, glidants, egran ts, binders and lubricants. {@1999} Examples of suitable fillers, diluents and/or hinders include, but are not limited to, lactose (eg spray—dried e, such as FAST—FLOG‘D), rnicrocrystalline cellulose (various grades of Avicel®, CEOLU9‘19) hydroxypropylcellulose, oxypropylcellulose (low substituted), low molecular weight hydroxypropyl methylcellulose (l-lPMC) (e,g, l‘vlethocelTM E, F and K from Dow Chemical, Metholoseli Sl—l from itsu, Ltd), hydroxy ethylcellulose, sodium carhoxyrnethylcellulose, carhoxyniethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, niannitol, dextrins, nialtodextrins, starches or modified starches ding potato starch, niaize starch and rice starch), calcium phosphate (eg, basic calcium phosphate, calcium hydrogen ate, dicalciuni phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate and collagen. The preferred filler for the composition of the disclosure is niannitol such as spray dried niannitol.

WO 35393 lillllllltl} Examples of suitable disintegrants include, but are not limited to, crospovidone {cross—linked PVP), sodium starch ate, cross—linked sodium carbosymethylcellulose, calcium silicate, and low substituted hydroxypropyl cellulose. The preferred disintegrant for the composition of the disclosure is crospovidone. lillllltlll Specific examples of glidants and lubricants include stearic acid, magnesium stearate, calcium stearate or other metallic stearates, talc, glyceryl behenate, colloidal silica, com starch, and optionally ium stearate or sodium steaiyl furnarate (lubricant intragranularly mixed or used externally to lubricate die and punch es). The preferred t for the composition of the disclosure is colloidal silica and preferred lubricant is sodium stearvl fumarate. {99192} In some embodiments, the methods and compositions described herein can be used to treat a patient suffering from Eol'i who also has a lactose allergy and/or a starch allergy.

Pharmaceutical formulations comprising lactose can ate a lactose allergy in a patient suffering from such, and this can cause increased discomfort in patients also suffering from EoE. in certain embodiments, the pharmaceutical compositions described herein do not include lactose.

Similarly, pharmaceutical formulations comprising starch can aggravate a starch allergy in a patient suffering from such, and this can cause increased discomfort in ts also suffering from EoE, ln certain embodiments, the pharmaceutical compositions described herein do not include starch. in further preferred embodiments, the pharmaceutical compositions bed herein do not include lactose and sucrose. {$49193} The solid ceutical compositions of the present sure can include other dosage forms besides an ODT, a wafer, a film, or other solid dosage form which disintegrates rapidly in the mouth to form a suspension or dispersion of a corticosteroid, which can readily be swallowed to coat the niucosal e of eosinophilic esophagitis, } For example, wafers can include dried or lyophilized compositions such as orally disintegrating or ving dosage forms prepared using Zydis® lyophilization technology (e.g as described in US Pat. No. 6,3l6,02’7}, containing a corticosteroid as the active pharmaceutical ingredient. Film dosage forms can include edible films such as those bed in US Pat. No. 6,596,298 or US. Pat. No. 6,740,332, containing a corticosteroid as the active ceutical ingredient. ln some embodiments, the solid composition comprises a lyophilized matrix, wherein the lyophilized matrix comprises corticosteroid, the carrier and ent. Suitable excipients include, but are not limited to, mannitol, xylitol, sorhitol, nialtol, inaltitol, lactose, sucrose, maltose, and combinations f. {@8195} Topical administration ot‘a corticosteroid to the oral cavity of individuals has been associated with candidiasis infection and oral thrush. While the sure is ed so as to he less prone to promoting such infections, in some embodiments of the disclosure, the pharmaceutical composition may include an antifungal agent. Suitable antifungal agents include, but are not limited, to mitotic inhibitor antifungals, pyrimidine analog antifungals, polyene antifungals, henzimidazole antifungals, imidazole ngals, polyene antifungals, triazole antifungals, thiazole antifungals, allylamine ngals, echinocandin antifungals, and other ”uncategorized” antifungals recognized in the art that do not fall Within any of the above categories (e. g, tolnaflate and ciclopirox). For example, suitable antifungal agents which may he included in the solid pharmaceutical compositions of the present disclosure include, but are not limited to, ahai‘ungin, ainorolfine, anidulai‘ungin, bifonazole, butenafine, hutoconazole, candicin, caspot‘ungin, ciclopirox, clotrirnazole, econazole, fenticonazole, filipin, tluconazole, flucytosine, griseofulvin, isavuconizole, isoconazole, nazole, ketoconazole, micafungin, azole, rnieonazole e, naftit‘ine, natamycin, nystatin, azole, posaconazole, pramiconazole, ravuconazole, riniocidin, setaconizole, sulconazole, ‘ine, terconazole, tioconazole, tolnaftate, lenic acid, and voriconazole. {(38196} in some embodiments, pharmaceutical compositions of the present disclosure include an antiviral agent. Antiviral agents wl'iich may be included in the solid pharmaceutical compositions of the present disclosure include interferons, nucleoside and nucleotide reverse transci'iptase inhibitors, non—nucleoside reverse transcriptase inhibitors, protease inhihitors, integrase inhibitors, fusion inhibitors, tion inhibitors, guanosine analogs, puridine s, pyrimidine analogs, and other egorized" antiviral drugs recognized in the art which do not fall within any of the above s (e. g, foscarnet and iniltefosine). For example, suitahle antiviral agents which may he included in the solid pharmaceutical compositions of the present disclosure include, but are not limited to, ahacavir, aciclovir (also known as acyclovir), adefovir, aniantadine, anidoxovir, ainprenavir, aplaviroc, apricitabine, arhiclol, atazanavir, heviriniat, EMS—488043, hoceprevir, hrivudine, cidofovir , DCMZGS, clocosanol, delavirdine, didanosine, vir, efavirenz, elvitegravir, el'vucitahine, citabine, enfuvirtide, epigallocatecliin gallate, etravirine, l‘amcielovir, fosaniprenavir, gancioloovir, globoidnan A, griffithsin, ibalizumab, idoxuridine, indinavir, lamivudine, lopina'vir, loviride, maraviroo, nellinavir, nevirapine, oseltami'vir, pegylated interferon alpha—2a, pegylated interferon alphau2b, penoiolovir, peramivir, plerixafor, PKG MO, racivir, raltegrvir, ritonavir, ribavirin, rirnantadine, rlipivirine, saquinavir, stampidine, ine, tenofotrir, tipranavir, 'l‘NX~355, trifluridine, tromantadine, elovir, valgancielovir, VioriViroe, bione, Virainidine, Viveeon, zaleitabine, zanamivir, and zidovudme. lilllllll’?) Tablet dosage forms, including ODT dosage forms, comprising the low dosage strength of a topic-ally acting oortioosteroid (eg, corticosteroids having systemie bioavailability of less or equal to about 20% of the dose, or corticosteroids which are formulated to reduoe systemic- bioavailabihty, each of which are described above) and a pharmaceutically able carrier, wherein the drug is in amount less than about 5% (_weight drug/weight of composition), disintegrate in less than about 30 see (US? method), and have a low triability in order to have sufficient durability to withstand handling, shipping, and/or packaging in push~through blister packaging. in some embodiments, friability of the GET dosage form described herein is less than about 1%, e,g less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0. 59/5, less than about 04%, less than about 0.3%, eto. , inclusive of all ranges and nges there between). {99198} In red embodiments, the DDT used in (or for use in) in the s described herein comprises: a corticosteroid in an amount of from about 0, 25 % to about 26% w/w (or about 0.75 mg to about 76 mg); a phai'niaeeutioally able carrier in an amount of from about 5% to about lSli/e W/w (or about 20 mg to about 40 mg); and rapidly dispersing n'iiorogranules in an amount of from about 40 % to about 60% w/w (or about l25 mg to about l75 mg), wherein the rapidly dispersing miorogranules comprise a ratio of sugar aleohol/saooharide to disintegrant of about 90: l0 to about 99: l. ln ments, the DDT ally further comprises: a disintegrant in an amount of about 5% to about l0% w/w (or about 5 mg to 20 mg to about 30 mg); a sugar alcohol or saooharide in an amount of about 2 % to about 40% w/w (or about 80 mg to about lOO mg); and optional exoipients. {@8199} Preferred embodiments of the ceutical formulation disclosed herein are described in Table l or Table 2, Table 1: Compositions of ssible blends of Fiutioasone ODIN, 1.5 and 3 mg Ingredients Fiuticasone OUTS 1.5 mg Colloidal n Dioxide NF Siiioified Mioromysmiiine Coiiulose NF emspovidone NF Suoi'aiose NF 1.20 S m '—dri€:d Mannitoi USP Ingredients asone OUTS ODT g 4.13mi; 60mg : mg/tabiet) mg/mbkt) mg/tablet) Mic-ionized Fiuticasone 0.75 4.50 6.00 Propionate USP : : Colloidal Silicon Dioxide NF 0.90 0.90 Siiicifiod Microcrystalline 10.00 30.0 30.00 30.00 Cefluiose NF Ciosovidone NP 7.50 22. 50 22. 50 1.20 1.20 Spi‘ayvdried Mamiitol USP 86.40 84.90 2000mm “0001200 ________________________________________________________________________ __________ Sodium Steawl Fumarate NP 1.50 4.50 4.50 4.50 300.00 No.0 No.0 No.0 Gastrointermini] Inflammation and diatomic almem 9} Treatment with topically acting corticosteroid (eg, fluticasone propionate) results in fewer sideueffects than other treatments, for example a highly systemically acting corticosteroid.

Upon administration of a pharmaceutical composition of the present disclosure to a patient, the composition disintegrates in the patient‘s oral cavity, and contacts the esophagus without being absorhed ically, thus limiting systemic effects.

{Will} in some embodiments, the present disclosure es s of treating the symptoms ated with an inflammatory disorder of the intestinal tract. in some emhodiments, the present disclosure provides methods of treating mation associated with an inflammatory gastrointestinal disorder. In some embodiments the present disclosure provides methods of treating both symptoms and inflammation associated an inflammatory gastrointestinal disorder. in some ments, the inflammatory gastrointestinal disorder affects the upper gastrointestinal tract. In some embodiments, the upper gastrointestinal tract is the esophagus. {99112} ln some embodiments, the oral corticosteroid contacts and/or is deposited in the upper part of the gastrointestinal tract In some embodiments, the oral corticosteroid contacts an d/or is deposited in the esophagus. In some embodiments, the oral corticosteroid contacts and/or is deposited in the distal n of the esophagus ln some enihodiments, the pharmaceutical ition contacts and/or is deposited in the proximal portion of the esophagus. In some embodiments, the oral corticosteroid contacts and/or is deposited in a substantially equivalent amount in the distal and proximal portion of the esophagus. {(38113} inflammatory intestinal disorders which may he treated according to the present disclosure include, but are not limited to, inflammation of the esophagus, inflammation of the glottis, inflammation of the epiglottis, inflammation of the tonsils, inflammation of the oropharynx, eosinophilic esophagitis , gastroesophageal reflux disease (SEED), non~erosive reflux disease (NERD), e esophagitis, Barrett's esophagus, philic gastroenteritis, hypereosinophilic syndrome, corrosive (caustic) chemical esophagitis, radiation—induced esophagitis, cheniotherapyuinduced gitis, transient druguinduced esophagitis (also lrnown as medication esophagitis}, persistent druguinduced esophagitis, Crohn’s disease of the esophagus, and pseudoniernbranous esophagitis. in some ments, the present disclosure includes a method for treating a food allergy with an fied allergen, eg, ”atopic 138", and ”atopic bowel". in some embodiments, the present disclosure includes a method for treating a patient having one or more of the above gastrointestinal disorders, wherein the t also has a lactose allergy and/or a starch allergy. ln some embodiments, the inflammatory gastrointestinal disorder is eosinophilio esophagitis (EOE). in some embodiments, the present disclosure includes a method for treating a patient EOE, wherein the patient also a lactose allergy and/or a starch allergy. iilllllld} In some embodiments, the pharmaceutical compositions disclosed herein are administered until symptoms and/or inflammation associated with gastrointestinal mation are treated. ln some emhodiments, the pharmaceutical compositions disclosed herein continue to be administered after symptoms and/or inflammation associated with gastrointestinal inflammation are treated. In some emhodiments, the symptom is dysphagia, episodes of food impaction, gs of having a lump in one’s throat, and/or increased eosinophil count in the esophagus.

} The treatment of gastrointestinal inflammation may he measured by any means known in the art For example, tests used to evaluate patients with esophageal mation such as EoE include, but are not limited to, biopsies, evaluation of symptoms (e. g. through patient reported outcome (PRO) or physician questionnaire), quality of life ements, determination of gia—Free—Days in a patient, endoscopy (eg. EREES), esophageal compliance and/or improvement in esophageal remodeling (eg. using a suitable stic test such as lP (available from Crospon lnc), evaluation of biomarlrers, decrease in peak phil count, decrease in food impaction, EEsAl Strong Dysphagia lndex (DSQ), MDQ~30, Eo’E-QOL—A, VDQ (Visual Dysphagia Questionnaire), Avoidance Modification and Slow Eating ) scores, and/or histology. {llllllo} In some embodiments, patient response to treatment is determined by measuring changes in one or more questionnaire scores with a biological response such as ogy score (eg. eosinophil count). Reliance on patient ed symptoms may yield false ve results as patients may modify their behavior to reduce incidents of dysphagia (eg. avoiding problematic foods or other behavior modifications such as increased chewing or liquid consumption} which can alter questionnaire score regardless of whether hiological symptoms have improved.

WO 35393 {00117} in some embodiments, patient se is eyaluated by assessing histology scores in a patient. ln some embodiments the histology score is ed by one or more different histologic features, including but not d to, eosinophil inflammation, basal zone hyperplasia, dilated intercellular spaces, lamina a is, eosinophil abscess, surface layering, surface epithelial alteration, and dyskeratotic epithelial cells. {00118} ln some embodiments, administration of the oral corticosteroid according to the methods disclosed herein reduces a histology score in a treated patient compared to an untreated t or the same patient before treatment. ln some embodiments, the histology score is measured in a treated patient between week l and year l0. ln some embodiments, administration of the pharmaceutical compositions disclosed herein reduces a histology score at about week l, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week ’9, about week l0, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week l00, about year l, about year 2, or about year 3 compared with the histology score in an untreated patient or the same patient before ent. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces a histology score for about l week, about l month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about l year, about 2 years, about 5 years, or about l0 years, or more compared with the histology score in an untreated patient or the same patient before treatment. {001”} In some ments, a histology score is reduced by about l%, about 5%, about l0%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about l 00% compared with the histology score in an untreated patient or the same patient before treatment. in some embodiments, administration of the pharmaceutical compositions disclosed herein reduces the histology score by about l%, about 5%, about l0%, about 20%, about %, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6 about week ’7, about week 8, about week 9, about week l0, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week l00, about year l, about year 2, or about year 3 compared with the histology score in an untreated t or the same patient before treatment. ln some embodiments, administration of the pharmaceutical compositions disclosed herein reduces the histology score by about l%, about fill/la, about ll %, about 2 %, about 30%, about 40%, about 50%, about 60%, about 70%, about St %, about 90%, or about “30% for about l week, about l month, about 2 , about 3 months, about 4 months, about 5 , about 6 months, about l year, about 2 years, about 5 years, or about ll) years or more compared with the histology score in an untreated patient or the same patient before treatment. litltlljlel In some embodiments, administration of the oral corticosteroid according to the s disclosed, herein reduces peak eosinophil (per high power field (EFF), eg, as described in Example 2) in at least one biopsy in a treated patient compared to peak eosinophil per HFF in an untreated patient or the same patient before treatment. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in at least one biopsy to less than l S/HPF. In some embodiments, administration of the pharmaceutical compositions sed herein reduces peak eosinophil m at least one biopsy in a treated patient to less than about l4/HFF, less than about l3/HPF, less than about lZ/HPF, less than about ll/HF’F, less than about , less than about QI’HFF, less than about 8/lélFF, less than about 7/HFF, less than about 6/llFF less than about S/HFF, less than about l/FlFF, less than about 3/HF‘F, less than about Z/HFF, less than about l/llFF or less (eg, 0) in the patient, In some embodiments, administration of the pharmaceutical compositions disclosed herein reduce peak eosmophil in at least one biopsy to less than l l-{F’F in the patient. in some embodiments, the reduction of peak eosinophil in at least one biopsy in a treated patient is measured between about week l and about year l0, in some embodiments, the ion of peak eosinophil is ed at about week l, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week l0, about week 20, about week 30, about week 40, about week 50, about week 60, about week '70, about week 80, about week 90, about week 100, about year l, about year 2, or about year 3. ln some embodiments, administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in at least one biopsy to less than about lil/l-lFF, less than about l3./'FlPF, less than about lZ/l-lFF, less than about ll/l-lFF, less than about lO/lll’F, less than about F, less than about S/l-lFF, less than about 7/l-ll’F, less than about o/Hl’F, less than about S/HFF, less than about ill/’l-lFF, less than about 3/"l:ll3F, less than about F, less than about l/l-ll’F or less (egg. 0) in the patient at about week l, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week l0, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week l 00, about year 1, about year 2, or about year '3. ln some embodiments, administration of the pharmaceutical compositions disclosed herein s peak eosinophil in at least one biopsy to less than about , less than about l3/HPF, less than about lZ/HFF, less than about ll/HFF, less than about l0/HPF, less than about 9,1’HFF, less than about S/HPF, less than about 7/lrlPF, less than about @llFF, less than about 5’HFF, less than about ail/HPF, less than about 3/HPF, less than about Z/HPF less than about l/HFF or less (e. g. 0) in the patient for about l week, about l month, about 2 months, about 3 months, about 4 , about 5 months, about 6 months, about l year, about 2 years, about 5 years, or about 10 years, or more 30011le In some embodiments, administration of the oral corticosteroid according to the s disclosed herein reduces peak eosinophil (per high power field (EFF), eg, as described in Example 2) in at least one biopsy in a treated patient compared to peak pliil per HPF in an untreated patient or the same patient before treatment by at least about 10%, eg, about l5%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 9l%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, in clusiye of all values and subranges th erebetween In particular ments, the peak eosinophil count is reduced by an amount in the range of about 50% to about 99%, eg, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, inclusive ol’all values and subranges therebetween, {08122} in some embodiments, administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in at least one biopsy from a treated patient at week l2, week 26, or week 52. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in at least one biopsy from a treated patient to less than about 6/ EFF at week l2, week 26, or week 52. in some embodiments, stration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in all tested biopsies from a d patient at week 12, week 26, or week 52. ln some embodiments, administration of the ceutical compositions sed herein s peak eosinophil in all tested biopsies from a d patient to less than about sure at week l2, week 26, or week 52.

} In some ments, administration of the pharmaceutical compositions disclosed herein reduce mean score in a patient questionnaire completed by the patient or a physician. In some embodiments, the questionnaire is Eosinophilic Esophagitis Activity Index (EEsAI), which can use either a 7—day recall period or a daily recall period to monitor the severity and frequency of dysphagia and any dietary modifications. In some embodiments, the questionnaire is Dysphagia Symptom Questionnaire (ESQ), which is a daily symptom diary used to monitor dysphagia frequency. In some embodiments, the questionnaire is a ized patient— reported outcome assessment which includes the assessment of dysphagianfree days. In some embodiments, the total score of a questionnaire such as the EEsAI or PROSE are used in combination with other patient assessments to measure patient response to treatment, In some ments, the correlation of questionnaire score with improvement in histological measurements (eg. eosinophil count) indicates patient response to treatment, {99124} In some embodiments, the mean questionnaire score is measured in a treated patient between week l and year it). In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces the mean questionnaire score at about week I, about week 2, about week '3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week I 0, about week 20, about week 30, about week 40, about week 50, about week 60, about week .70, about week 80, about week 90, about week l00, about year l, about year 2, or about year 3 compared with the mean questionnaire score in an untreated patient or the same patient before treatment In some embodiments, stration of the pharmaceutical compositions disclosed herein reduces the mean questionnaire score for about l week, about l month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about l year, about 2 years, about 5 years, or about 10 years or more compared with the mean questionnaire score in an untreated patient or the same patient before treatment. In some embodiments, the mean questionnaire score is reduced by about l%, about 5%, about l0%, about %, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with the mean questionnaire score in an untreated patient or the same t before treatment. In some embodiments, administration of the pharmaceutical compositions disclosed herein s the mean questionnaire score by about l%, about 5%, about 10%, about %, about 301%), about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week '70, about week 80, about week 90, about week l00, about year 1, about year 2, or about year 3 compared with the mean onnaire score in an untreated patient or the same patient before treatment. in some embodiments, administration of the ceutical compositions disclosed herein reduces the mean questionnaire score by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 909/5, or about 100% for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about l0 years or more compared with the mean questionnaire score in an untreated patient or the same patient before treatment. {00125} In some embodiments, the patient questionnaire is EEsAl. ln some embodiments, administration of the pharmaceutical compositions disclosed herein reduces mean EEsAI score to less than 20, ln some embodiments, administration of the pharmaceutical compositions disclosed herein reduces mean EEsAl score of a treated t to less than about 19, less than about l 8, less than about 17, less than about 16, less than about 15 less than about 14, less than about l3, less than about l2, less than about ll, less than about 10, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2, less than about l, or about 0. in some embodiments, the reduction of mean EEstl score in a treated patient is measured n about week l and about year 10. ln some embodiments, the reduction of mean Flask} score is measured at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year l, about year 2, or about year 3. in some embodiments, administration of the ceutical compositions disclosed herein reduces mean EEsAl score to less than about 20, less than about 19, less than about 18, less than about l7, less than about 16, less than about l5, less than about l4, less than about 13, less than about 12, less than about 11, less than about 10, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2, less than about l, or less (eg. 0) at about week l, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week , about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year l, about year 2, or about year 3. ln some embodiments, administration of the pharmaceutical compositions disclosed herein reduces mean EEsAl score to less than about , less than about l9, less than about 18, less than about l7, less than about 16, less than about , less than about l4, less than about 13, less than about l2, less than about ll, less than about , less than about 9, less than about 8, less than about '7, less than about 6, less than about 5, less than about 4, less than about 3 less than about 2, less than about l, or less (eg. 0) for about 1 week, about l month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 , about l year, about 2 years, about 5 years, or about l0 years, or more.

} In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces mean EEsAl score in a treated patient at week l2, week 26, or week 52, In some embodiments, administration of the pharmaceutical compositions disclosed herein s rnean EEsAl score in a treated patient to less than about 20 at week l2, week 26, or week {(39127} In some ments, administration of the pharmaceutical compositions sed herein reduce mean EoE Endoscopic nce Score (EREFS) in a treated patient, which measures edema (cg. decreased vascularity or pallet), rings present, exudates (eg. white plaques), furrows, and/or stricture in the esophagus according to Table 3. In some embodiments, the EREFS score in a patient correlates with histologic response (e. g. eosinopl’iil count) and EREFS score can be used in conjunction with histologic response to measure patient response to treatment.

Table 3:-—-- EREFS Score Assessment Grade 2 Grade 3 Decreased Absent ................................................................................................................................................................................................................................

Rings None Mild (ridges) Moderate Severe t (trachealization) (distinct rings) l endoscoiel Exudate (white None Severe (310% la ues ~ surface areal Eurrows (vertical i Severe (depth) linesi Structure } in some embodiments, the itions and methods disclosed herein reduce the EREES score for edema to l or 0. in some embodiments, the compositions and methods disclosed herein reduce the EREFS score for rings to 2, l or 0, in some embodiments, the con'ipositions and methods disclosed herein reduce the EREFS score for exudates to l, or O. in some embodiments, the compositions and methods disclosed herein reduce the EREES score for es to l, or O. In some ments, the compositions and methods disclosed herein reduce the EREES score for s to l, or 0. in some enibodirrients, the compositions and methods disclosed herein substantially remove strictures. {(38129} in some embodiments, administration of the pharmaceutical compositions disclosed herein reduces the mean EREES score to less than about l0, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about i, or about zero in a treated patient. in some embodiments, the mean EREES score is measured in a treated patient between week 1 and year l0. in some embodiments, administration of the pharmaceutical compositions disclosed herein s the EREFS score at about week l, about week 2, about week 3, about week 4, about week , about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 3t), about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3 in some embodiments, administration of the pharmaceutical compositions disclosed herein reduces the mean EREES score for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more in a treated patient. in some embodiments, administration of the pharmaceutical compositions disclosed herein reduces the mean EREES score to less than about it), about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about l, or about zero at about week l, about week 2, about week 3, about week 4, about week 5, about week a, about week ‘7, about week 8, about week 9, about week it), about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week ‘90, about week 106, about year l, about year 2, or about year 3. in some embodiments, administration of the pharmaceutical compositions disclosed herein reduces the mean EREES score to less than about l0, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about I, or about zero for about I week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 , about 6 months, about I year, about 2 years, about 5 years, or about l0 years or more in a treated patient. {@9139} In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces mean BRIEFS score in a treated t at about week 12, about week 26, or about week 52. {midi} In some embodiments, administration of the pharmaceutical compositions disclosed herein s episodes of gia in a d patient. In some embodiments, reduction of episodes of gia in a treated patient is measured by determining Dysphagian FreemDays in the patient. In some embodiments, improvement in DysphagiamllreemDays in a patient is measured in conjunction with other patient measurements such as improved histologic scores (eg. eosinophil counts) to measure patient response to treatment. In some embodiments, administration of the pharmaceutical itions disclosed herein reduce gia in it treated patient compared with episodes of dysphagia in an untreated subject or in the same patient before treatment In some ments, administration of the pharmaceutical compositions disclosed herein reduce episodes of dysphagia to fewer than about 6 per week In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces episodes of dysphagia to fewer than 6 per week over a time period of two weeks. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces episodes of dysphagia to fewer than about 6 per week, about 5 per week, about 4 per week, about 3 per week, about 2 per week, about one per week, or none per week. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces episodes ofdysphagia to fewer than about 6 per week, about per week, about 4 per week, about 3 per week, about 2 per week, about one per week, or none per week over a time period of two weeks. {@9132} In some embodiments, episodes of dysphagia are d by up to about 100%. In some embodiments, episodes of dy sphagia are reduced by up to about 1%, about 5%, about l0%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes ot‘dy sphagia in an untreated patient or the same patient before treatment. In some embodiments, dyspliagia is eliminated. In some embodiments, gia is assessed in a treated patient between week l and year l0. In some embodiments, administration of the ceutical compositions disoiosed herein reduces episodes of dysphagia at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year I, about year 2, or about year 3. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces dysphagia for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about a months, about 1 year, about 2 years, about 5 years, or about 10 years or more ed with the number of episodes of dysphagia in an untreated patient or the patient before treatment. In some embodiments, episodes of dysphagia are reduced by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes of dysphagia in an untreated patient or the same patient before treatment at about week 1, week 2, about week 3, about week 4, about week 5, about week 6, about week ‘7, about week 8, about week 9, about week 10, about week 20, about week '30, about week 11-0, about week 50, about week 60, about week 70, about week 80, about week ‘90, about week 100, about year 1, about year 2, or about year '3. In some embodiments, episodes of dysphagia are reduced by up to about 1%, about %, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes of dyspbagia in an untreated patient or the same t before ent for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more compared with the number of episodes of dysphagia in an untreated patient or the patient before treatment {00133} in some embodiments, administration of the pharmaceuticai compositions disciosed herein reduces episodes of dysphagia in a treated patient at week 12, week 26, or week 52 ed with es of dysphagia in an untreated patient or the same patient before treatment. {001341} 1n some embodiments, stration of the pharmaceutioai compositions disciosed herein reduces food impaction in a treated t ed with episodes of food impaction in an untreated patient or in the same patient before treatment. in some embodiments, administration of the pharmaceutioai compositions disoiosed herein reduces episodes of food impaction to fewer than 4 per week. in some embodiments, administration of the pharmaceutical compositions disciosed herein s episodes of food impaction to fewer than 4 per week over a time period of two weeks. in some embodiments, administration of the pharmaceutical compositions disclosed herein s episodes of food impaction to fewer than about 4 per week, about 3 per week, about 2 per week, about one per week, or none per week. In some ments, administration of the pharmaceutical compositions disclosed herein reduces episodes of food impaction to fewer than about 4 per week, about 3 per week, about 2 per week, about one per week, or none per week over a time period of two weeks. {00135} In some embodiments, episodes of food impaction are reduced by up to about 100%. in some embodiments, episodes of food impaction are reduced by up to about 1%, about %, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes of food impaction in an untreated patient or the same patient before treatment. in some embodiments, food impaction is eliminated, In some embodiments, episodes of food impaction are assessed in a treated patient between week l and year 1 0 in some embodiments, administration of the pharmaceutical compositions disclosed herein reduces episodes of food impaction at about week i, about week 2, about week 3, about week 4, about week 5, about week 6, about week ’7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year i, about year 2, or about year 3 In some embodiments, administration of the ceutical compositions disclosed herein reduces episodes of food impaction for about 3 week, about 3 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about l year, about 2 years, about 5 years, or about l0 years or more compared with the number of episodes of food ion in an untreated t or the same t before treatment. in some embodiments, episodes of food impaction are reduced by up to about l%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 709/6, about 80%, about 90%, or about 100% compared with episodes of food impaction in an untreated t or the same patient before treatment at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week l00, about year l, about year 2, or about year 3. in some ments, episodes of food impaction are d by up to about l%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about l00% compared with episodes of food ion in an untreated patient or the same patient before treatment for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about l year, about 2 years, about 5 years, or about 10 years or more compared with the number of episodes of food impaction in an untreated patient or the same patient before treatment. {00136} in some embodiments, administration of the ceutical compositions disclosed herein reduces episodes of food impaction in a treated patient at week 12, week 26, or week 52 compared with food impaction in an untreated patient or the same t before treatment. {00137} In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces Global EoE score in a treated patient compared with Global EoE score in an untreated patient or in the same patient before treatment. {00138} In some embodiments, the reduction of Global EoE score in a treated patient is measured between about week l and about year l0 In some embodiments, administration of the pharmaceutical compositions sed herein reduces Global EoE score at about week l, about week 2, about week 3 about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week l0, about week 20, about week 30, about week 40, about week 50, about week 60, about week .70, about week 80, about week 90, about week l00, about year 1, about year 2, or about year 3 compared with an untreated patient or the same patient before treatment, In some embodiments, administration of the pharmaceutical compositions disclosed herein s Global Eoli score for about l week, about l month, about 2 months, about 3 , about 4 months, about 5 months, about 6 months, about l year, about 2 years, about 5 years, or about l0 years compared with the Global EoE score in an untreated patient or the patient before treatment. in some embodiments, Global EoE score is reduced by up to about 1%, about 5%, about l0"%3, about 209/13, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about l00% compared with Global EoE score in an untreated patient or the same patient before treatment commenced.

} In some embodiments, administration of the pharmaceutical compositions disclosed herein s Global EoE score by up to about l%, about 5%, about l0%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about l00% compared with Global EoE score in an untreated patient or the same patient before treatment at about week l, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week l00, about year 1, about year 2, or about year 3. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces Global EoE score by up to about 1%, about %, about 10%, about 2 %, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about l00% compared with Global EoE score in an untreated patient or the same patient before ent for about l week, about l month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about l year, about 2 years, about 5 years, or about l0 years, or more. {00140} Global EoE is scored on a scale of 0 to l0, with 0 representing no EoE, symptoms, and l0 representing most severe EoE, symptoms, ln some embodiments, administration of the pharmaceutical compositions sed herein reduces Global EoE score in a treated subject to less than about 5. ln some ments, administration, of the pharmaceutical compositions disclosed herein reduces Global EoE score to less than about l0, less than about 9, less than about 8, less than about 7, less than about 6, less than about :3, less than about 4, less than about 3, less than about 2, less than about l, or about 0. in some embodiments, administration of the pharmaceutical compositions disclosed herein reduces Global EoE score in a treated t to less than about l0, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2, less than about l, or about 0 at about week l, week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week l0, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week l00, about year l, about year 2, or about year 3. ln some embodiments, administration of the pharmaceutical compositions disclosed herein reduces Global EoE score in a treated subject to less than about l0, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2, less than about l, or about 0 for about l week, about l month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about l year, about 2 years, about 5 years, or about l0 years, or more.

{M13141} ln some embodiments, stration of the pharmaceutical compositions disclosed herein reduces Global EOE score in a treated patient at about week 12, about week 26, or about week 52 compared with Global Eol'i score in an untreated patient or the same patient before treatment. {99142} ln some embodiments, administration of the pharmaceutical compositions disclosed herein improves characteristics as measured by endoscopy (eg. Endoli'lip) in a treated patient compared, with an untreated patient or the same patient before treatment commenced. These teristics include, but are not limited to esophagus diameter, esophageal compliance, focal narrowing ofthe esophagus, esophageal body sibility, esophageal body cross-sectional areas (CSA), and intra~luminal er. {99143} In some embodiments, the characteristics as measured by endoscopy are ed in a d patient between week l and year l0. In some embodiments, administration of the pharmaceutical compositions disclosed herein improves characteristics as measured by endoscopy at about week l, about week 2, about week 3, about week 4, about week 5, about week 6, about week ’7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3 compared with an untreated patient or the same patient before treatment. in some embodiments, administration of the pharmaceutical compositions disclosed herein es characteristics as measured by endoscopy for about l week, about l month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about l year, about 2 years, about 5 years, or about l0 years or more compared with an untreated patient or the same patient before treatment. ln some embodiments, characteristics as ed by endoscopy are improved by up to about l0t %. ln some embodiments, characteristics as ed by endoscopy are ed by up to about 1%, about 5%, about l0%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about l00% compared with an untreated patient or the same patient before treatment. in some embodiments, administration of the pharmaceutical compositions disclosed herein improves characteristics as WO 35393 measured by endoscopy by up by about 1%, about 51%;, about 10%, about 20%, about 30%, about 40%, about 50%, about 6 %, about 701%), about 80%, about 90%, or about 100% compared with an untreated patient or the same patient before ent at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week '7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3. in some embodiments, administration of the pharmaceutica1 compositions disclosed herein improves teristics as measured by endoscopy by up by about 1%, about 5%, about %, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with EndoFiip score in an untreated patient or the same patient before treatment for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more, {00144} in some embodiments, administration of the pharmaceutica1 itions dise1osed herein improves characteristics as measured by endoscopy in a treated patient at week 12, week 26, or week 52 compared with an untreated patient or the same patient before treatment. {00145} In some embodiments, administration of the pharinaceutieai compositions sed reduces the number of episodes associated with EOE experienced by a patient over a period of time. Nondimiting exampies of such episodes inciude u1ty swa11owing a pi11 or food. The ence of such episodes may be reported by the patient as a feeiing of discomfort after swaiiowing a piii or food, and may be measured after each instance of swaiiowing a pi1i or food or over a 24 hour period or more. Any method can be used to assess or report patient discomfort, inc1uding PROS}? {00146} In some embodiments, the number of episodes occurring over said period of time is reduced by at 1east 1 episode, at least 2 episodes, at 1east 3 episodes, at 1east 4 episodes, at 1east episodes, at 1east 6 episodes, at 1east 7 es, at 1east 8 episodes, at least 9 episodes, at 1east episodes, at least 11 episodes, at 1east 12 episodes, at 1east 13 episodes, at 1east 14 episodes, at least 15 es, at 1east 16 episodes, at 1east 17 episodes, at 1east 18 episodes, at least 19 episodes, or at 1east 20 episodes, 1east 21 episodes, at 1east 22 episodes, at 1east 23 episodes, at 1east 24 episodes, at 1east 25 es, at 1east 26 episodes, at least 27 episodes, at 1east 28 episodes, at least 29 episodes, or at least 30 es, least 3l episodes, at least 32 episodes, at least 33 episodes, at least 34 episodes, at least 35 es, at least 36 es, at least 37 episodes, at least 38 es, at least 39 es, or at least 40 es, least 4l episodes, at least 42 episodes, at least 43 episodes, at least 44 episodes, at least 45 episodes, at least 46 episodes, at least 47 episodes, at least 48 episodes, at least 49 episodes, or at least 50 episodes. ln some embodiments, the time period is about i week, about 2 weeks, about 3 weeks, about 4 weeks, about weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9, weeks about l0 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 1 year, about 2 years, or about 3 years.

Dosing andAdministration {@9147} The oral corticosteroids disclosed herein may be administered in any appropriate dose and using any suitable pharmaceutical composition. While one of skill in the art can determine the desirable dose in each case, a suitable dose of the therapeutic agent for achievement of therapeutic benefit, may, for example, be in a range of about l microgram (pg) to about lOO milligrams (mg) per kilogram body weight of the recipient per day, preferably in a range of about l0 pg to about 50 mg per kilogram body weight per day and most preferably in, a range of about l0 pg to about 50 mg per kilogram body weight per day, in some embodiments, the pharmaceutical composition is administered at a low dose, e~g about 20 mg or less, in some embodiments, the oral corticosteroid is administered at about l mg per kilogram body weight per day, about 3 mg per kilogram body weight per day, arid/or about 9 mg per kilogram body weight per day. The desired dose may be presented as one dose or two or more sub—doses administered at riate als throughout the day, These sub~doses can be administered in unit dosage forms, for example, containing from about l0 rig to about 1000 mg, preferably from about 005 mg to about mg, and most preferably from about 06 mg to about 75 mg. in some embodiments, the pharmaceutical composition is administered in a unit dosage form of 0.75 mg, l5 mg, 3.0 mg, 4.5 mg, 6.0 mg, or 75. {90MB} in some embodiments, the pharmaceutical composition described herein (eg, a liquid or solid composition comprising an oral corticosteroid) is administered to a patient once a day at bedtime (HS). in some embodiments, the pharmaceutical composition is administered to a patient twice a day (BlD). ln some ments, the pharmaceutical composition is administered to a patient once in the morning and once in the evening. in some embodiments, the pharmaceutical composition is administered on an empty stomach (e. g. at least 2 hours after eating or at least l hour before ; or at least 30 minutes before or after eating). in some embodiments, the pharmaceutical composition is administered to a patient 30 minutes before breakfast and, 30 minutes before bedtime. in some embodiments, administering the ceutical composition before bedtime decreases systemic tion of the oral corticosteroid compared, to systemic adsorption obseived after e dosing. lilltlldgl Thus, in some embodiments, the pharmaceutical composition is administered during the evening between about 7 pm and about ll) pm, e.g at about '7 pm, 7:30 pm, about 8 pm, about 8:30 pm, about 9 pm, or about 9:30 pm, inclusive of all values and subranges therebetween ln some ments, the pharmaceutical composition is administered about 30 minutes before the target sleep time. The term “target sleep time” can mean the time of day that the patient anticipates going to bed, {991%} inary investigations of therapeutic efficacy in treating Eel? ing conventional oral administration of the oral corticosteroid (re, while the patient is upright) revealed higher eosinophil clearance in the proximal portion esophagus (eg, closer to the oral cavity) and lower eosinophil clearance in the distal portion of the esophagus (eg closer to the stomach). Without being bound by theory, these results suggested increased contact of the corticosteroid with the proximal esophageal tissue, and decreased contact ofthe corticosteroid with the distal esophageal tissue. Various experiments were performed in an t to improve contact of the corticosteroid with the distal gus: lt was surprisingly discovered that administering the oral corticosteroid while the patient is lying down increases eosinophil clearance in the distal esophagus while maintaining high phil clearance in the proximal esophagus. Without being bound by theory, t of the corticosteroid with the distal esophagus is increased when the corticosteroid is administered while the patient is lying down, because drug transit through the esophagus is driven primarily by peristalsis, whereas adopting an upright position ses contact of the oral corticosteroid with the distal esophagus because drug transit is driven primarily by gravity and the uous flow of fluids down the esophagus. {9815i} t of the corticosteroid with the esophagus can be observed ly by conducting a scintigraphy study as bed in Example 6. Alternatively, contact of the corticosteroid with the esophagus can be determined indirectly by ing eosinophil clearance in the proximal and distal portions of the gus. For example, eosinophil clearance can be determined by measuring the eosinophil count in the proximal and distal esophagus before treatment (cells/mm?“ of the high power field) to establish a baseline and comparing said baseline to the eosinophil count in the proximal and distal esophagus measured after 8~weel<s of treatment, as bed in Example 2. gibblSZl Accordingly, in ular embodiments, the oral corticosteroid is administered once daily, at nighttime while the patient is lying down (or wherein the t lays down immediately after oral administration). ln other particular embodiments, the oral corticosteroid is administered twice daily, wherein the patient may remain upright during the first daily dose and the patient is lying down for the second daily dose (or the patient lays down immediately after oral administration). In firrther embodiments, the patient is lying down for both daily doses. {99153} In n embodiments, the pharmaceutical ition is stered to a patient while the patient is lying down or immediately prior to the patient lying down, eg, within about l second, about 2 seconds, about '3 seconds, about 4 seconds, about 5 seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, about l0 seconds, about l5 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 s, about 50 seconds, about 60 seconds, about ll minutes, about l ,2 minutes, about l3 minutes, about l4 minutes, about l5 minutes, about lo minutes, about l.7 minutes, about l8 minutes, about l9 minutes, about 2.0 minutes, about 2.5 minutes, about 3 minutes, about 4 minutes, or about 5 minutes prior to the patient lying down, inclusive of all yalues and ranges therebetween.

{M13154} ln various embodiments, the pharmaceutical composition is administered l-lS while the patient is lying down (or the patient lays down immediately following administration). in other embodiments, the pharmaceutical composition is administrated during daytime (e.g Ell) or QD administration), while the patient is lying down (or the patient lays down ately ing administration). In various embodiments, the patient remains lying down following administration for an amount of time sufficient for topical deposition and/or contact of the corticosteroid onto the WO 35393 esophagus to treat infiamination thereof (eg, a time ient to resuh in improvement of 13013 using the measurements described , such as a reduction in episodes of dysphagia). 1n some such embodiments, the patient rernains 1ying down fo11owing administration for an arnount oftime in the range of from about 1 minute to about 8 hours, inc1ut1ing about 5 minutes, about 10 s, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hr, about 1.1 hr, about 1.2 hr, about 1.3 hr, about 1.4 hr, about 1.5 hr, about 1.6 hr, about 1.7 hr, about 1.8 hr, or about 1.9 hr, about 2 hrs, about 2.1 hr, about 2.2 hr, about 2.3 hr, about 2.4 hr, about 2.5 hr, about 2.6 hr, about 2.7 hr, about 2.8 hr, or about 2.9 hr, about 3 hrs, about 3.1 hr, about 3.2 hr, about 3.3 hr, about 3.4 hr, about 3.5 hr, about 3.6 hr, about 3.7 hr, about 3.8 hr, or about 3.9 hr, about 4 hrs, about 4.1 hr, about 4.2 hr, about 4. 3 hr, about 4.4 hr, about 4.5 hr, about 4.6 hr, about 4.7 hr, about 4.8 hr, about 4.9 hr, about 5 hrs, about 5.1 hr, about 5.2 hr, about 5.3 hr, about 54- hr, about 5.5 hr, about 5.6 hr, about 5.7 hr, about 5.8 hr, about 5.9 hr about 6 hrs, about 6.1 hr, about 6.2 hr, about 6.3 hr, about 6.4 hr, about 6.5 hr, about 6.6 hr, about 6.7 hr, about 638 hr, or about 6.9 hr, about 7 hrs, about 7.1 hr, about 7.2 hr, about 73 hr, about 7.4 hr, about 7.5 hr, about 7.6 hr, about 7.7 hr, about 7. 8 hr, or about 7.9 hr, inchisive of a11 va1ues and subranges therebetween. 1n ments in which the 131iarrnatt-eutica1 composition is administered during daytime, the patient remains 1ying down for an amount of time in the range of from about 1 minute to about 60 minutes, ineiuding about 5 rninutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about rninutes, about '35 minutes, about 40 s, about 45 minutes, about 50 minutes, about 55 minutes, inehrsive of a11 vaiues and subranges therebetween. in certain embodiments, the patient remains 1ying down for about 5 to about 10 minutes. {(18155} As used , “1ying down,” “1ays down,” and derivations and variants thereof, refer to a patient adopting a supine, prone, or 1atera11y bent position, as on a bed or on the ground, or a substantia11y nta1 body position, whereby the corticosteroid (upon swa11owing) contacts the esophagus and topicahy deposits the corticosteroid on esophagus, eg,‘ at the site of inflammation. As used herein, “substantiaiiy horizontai” refers to a body position which at 1east ° 1ess than verticai, eg1ess than about 15°, 1ess than about 20°, 1ess than about 25°, 1ess than about 30°, 1ess than about 35", 1ess than about 40°, 1ess than about 45°, 1ess than about 50°, 1ess than about 55°, 1ess than about 65°, 1ess than about 76°, 1ess than about 75°, 1ess than about 80°, WO 35393 less than about 85°, or about 90° from vertical, inclusive of all values and ranges therebetween.

For example, when the composition is formulated as an CDT, the DDT rapidly disintegrates in the mouth ofthe supine patient to form a sion comprising the osteroid which is swallowed.

The suspension then traverses the esophagus of the patient, providing topical contact of the corticosteroid on the gus to topically treat inflammation thereof. As used herein, “upright” refers to a patient adopting essentially any other position, ing, but not limited to, standing or sitting. {99136} ln some embodiments, the pharmaceutical composition is administered, to a patient at bedtime. In some ments, the pharmaceutical composition is administered, to a patient at bedtime while the patient is lying down. ln some embodiments, the pharmaceutical composition is administered to the patient while lying down and prior to sleep (eg, about 1 minute to about 1 hour before going to sleep, eg, about l, minute, about 5 s, about l0 minutes, about l5 minutes, about 20 minutes, about 25 s, about 30 s, about 35 minutes, about 40 minute, about 45 minutes, about 50 minutes, about 55 minutes, inclusive of all values therein), in preferred embodiments, the pharmaceutical composition is administered to a lying down patient about 30 minutes before bedtime. In some embodiments, the pharmaceutical composition is administered to a patient after the evening meal, eg, from about l minute to about 5 hours after the evening meal (eg about 5 minutes, about l0 minutes, about l5 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minute, about 45 minutes, about 50 minutes, about :35 minutes, about l hour, about l5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 45 hours, inclusive of all values and subranges therebetween. ln preferred embodiments, the ceutical composition is administered at least about 30 s after the evening meal. {98157} in some embodiments, stering the pharmaceutical composition sing a corticosteroid while the patient is lying down increases contact of the corticosteroid with the upper gastrointestinal tract (e.g the esophagus), while also decreasing systemic absorption of the corticosteroid. Thus, in embodiments, administering the pharmaceutical composition while the patient is lying improves efficacy, and t:in further embodiments) reduces side effects associated with systemic administration of corticosteroids. {98158} 'l‘ransit time of a liquid pharmaceutical composition in the esophagus is generally in the range of about l to about 5 seconds. Without being limited by theory, administration of a pharmaceutical composition described herein while the patient is lying down increases the residence time (also referred to as dwell time) of the corticosteroid in the gus, which increases the time required for the corticosteroid to reach the stomach, and decreases the amount of the corticosteroid that reaches the stomach and is absorbed systemically. in some embodiments, increased residence time of the corticosteroid, in the esophagus increases contact of the corticosteroid with the esophagus. in some embodiments, residence time of the corticosteroid on the esophagus and/or contact of the corticosteroid, with the esophagus is sed in a lying down patient compared to the nce time of the corticosteroid when administering in a similar composition while the patient is upright. {(39159} In some embodiments, the residence time of the osteroid on the esophagus following administration While the patient is lying down is in the range ot‘froni about l second to about 5 minutes, e,g about 2 seconds, about 3 seconds, about 5 s, about 6 s, about ’7 seconds, about 8 seconds, about 9 seconds, about l0 seconds, about l5 seconds, about 20 s, about 25 seconds, about '30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 s, about 60 seconds, about 65 s, about 70 seconds, about ’75 seconds, about 80 seconds, about 85 seconds, about 90 seconds about 95 seconds, about lOO seconds, about lOS seconds, about 110 seconds, about llS seconds, about lZO seconds, about l25 seconds, about l30 seconds, about l35 seconds, about l40 seconds, about l45 seconds, about lSO seconds, about l55 seconds, about 160 seconds, about l65 s, about ”E70 s, about l75 seconds, about l80 seconds, about l85 seconds, about l90 seconds about l95 seconds, about 200 seconds, 205 seconds, about ZlO seconds, about 2l5 seconds, about 220 seconds, about 225 seconds, about 230 seconds, about 235 seconds, about 240 seconds, about 245 s, about 250 seconds, about 255 s, about 260 seconds, about 265 seconds, about 27 seconds, about 275 seconds, about 280 seconds, about 285 seconds, about 290 seconds, or about 295 seconds, inclusive of all values and subranges therebetween. In particular embodiments, the traverse tirne ot" the corticosteroid on the esophagus following administration while the patient is lying down is in the range ot" about 5 seconds to about 60 seconds. {11111611} 1n some embodiments, administering the pharrnaceuticai composition While the patient is lying down increases the residence time of the corticosteroid in the esophagus {0011119211661 to the residence time of the corticosteroid in the esophagus when the patient is upright) by about 5 seconds, about 10 seconds, about 15 seconds, about 20 s, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 61.1 seconds, about 65 seconds, about 70 seconds, about 75 seconds, about 80 seconds, about 85 seconds, about 90 seconds about 95 seconds, about 100 seconds, about 105 seconds, about 110 seconds, about 115 seconds, about 120 seconds, about 125 seconds, about 130 seconds, about 135 seconds, about 140 seconds, about 145 s, about 150 seconds, about 155 seconds, about 160 seconds, about 165 seconds, about 170 seconds, about 175 seconds, about 180 seconds, about 185 s, about 190 seconds about 195 seconds, about 200 seconds, 205 s, about 210 seconds, about 215 seconds, about 220 seconds, about 225 seconds, about 230 seconds, about 235 seconds, about 2-40 seconds, about 245 seconds, about 2511 seconds, about 255 seconds, about 260 s, about 265 seconds, about 270 seconds, about 275 seconds, about 280 seconds, about 285 s, about 290 seconds, about 295 seconds, or about 300 seconds. In particu1ar embodiments, the residence time of the corticosteroid on the esophagus ing administration whiie the patient is bring down is increased by an amount or" time in the range of from about 5 s to about 60 seconds. {1111161} 1n some embodiments, the average time to reach the m b1ood p1asrna concentration of the corticosteroid (Tim) for the 1ying down patient is the range of about 80% to about 125% of about 8 hr to about 20 hr, eg, about 4.0 hr, about 4.5 hr, about 5 hr, about 55 hr, about 6 hr, about 6.6 hr, about 7 hr, about 7.5 hr, about 8 hr, about 8.5 hr, about 9.0 hr, about 9.5 hr, about 10.0 hr, about 10.5 hr, about 11 hr, about 115 hr, about 12 hr, about 12.5 hr, about 13 hr, about 135 hr, about 14hr, about 145 hr, about 15 hr, about 155 hr, about 16 hr, about 16.5 hr, about 17 hr, about 17.5 hr, about 18 hr, about 185 hr, about 19 hr, about 195 hr, about 20 hr, about 205 hr, about 21 hr, about 215 hr, or about 22 hr, about 225 hr, about 23 hr, or about 23.5 hr, about 24 hr, about 24.5 hr, about 25 hr, about 25.5 hr, or about 26 hr, inc1usive of a11 vaiues and subranges therebetween. 1n red embodiments, the Tmax of the oral corticosteroid for the 1ying down patient is the range of about 80% to about 125% of about 14 hr :1: 6 hr, inc1usive of a11 vaiues and subranges therebetween. {1111162} 1n some embodiments, the lying down patients Tam of the oral corticosteroid is increased by an amount of time in the range of from about 1 hr to about 15 hr compared to the 1111” of an upright patent (egg, AM feel or fasted conditions), e.g about 1.5 hr, about 2.5 hr, about 3hr, about 3.5 hr, about 4 1n, about 4.5 hr, about 5 1n, about 5. 5 hr, about 6 hr, about 6.5 hr, about 7 hr, about 7.5 hr, about 8 hr, about 8.5 hr, about 9 hr, about 9.5 hr, about 10 hr, about 105 hr, about 11 hr, about 11.5 hr, about 12 hr, about 12.5 hr, about 13 hr, about 135 hr, about 14hr, about 14.5 bi, inclusive of all values and subranges etweeni {11111631 1n some embodiments, the Tmax of the oral corticosteroid when stered to an upright patient in a fed state (and the patient does not lay down immediately thereafter) is in the range of about 80% to about 125% of about 1 hr to about 10 hr, eg, about 1.5 hr, about 2.5 hr, about 3hr, about 3.5 hr, about 4 hr, about 4.5 hr, about 5 hr, about 5.5 hr, about 6 hr, about 6.5 hr, about ‘7 lit, about 75 hr, about 8 hr, about 8.5 hr, about 9 hr, about 9.5 hr, about 10 hr, about 105 hr, about 11 hr, about 11.5 hr, about 12 hr, about 125 hr, about 13 hr, ive of all values and ges therebetween. {1111164} In some embodiments, the Tina); of the oral corticosteroid when administered to an upright patient in a fasted state (and the patient does not 1ay down immediately thereafter) is in the range of about 80% to about 125% of about 2 hr to about 30 lit, e.g, about 1 hr, about 1.5 hr, about 1.5 hr, about 3hr, about 3.5 lit, about 11- hr, about 4.5 hr, about 5 hr, about 5.5 hr, about 6 hr, about 6. 5 hr, about 7 hr, about 7.5 hr, about 8 br, about 8.5 hr, about 9 hr, about 9.5 hr, about 10 hr, about 105 hr, about 11 hr, about 1 1.5 hr, about 12 hr, about 125 hr, about 1 3 hr, about 135 hr, about 14 hr, about 14.5 hr, about 15 hr, about 155 hr, about 16 hr, about 16.5 hr, about 1.7 hr, about 175 hr, about 18 hr, about 18.5 hr, about 19 hr, about 195 hr, about 20 hr, about 20.5 hr, about 21 hr, about 215 hr, about 22 hr, about 22.5 hr, about 23 hr, about 23.5 hr, about 24 hr, about 24.5 hr, about 25 hr, about 255 hr, about 26 hr, about 265 hr, about 27 hr, about 275 hr, about 28 hr, about 28.5 hr, about 29 hr, about 295 hr, about 30 hr, about 30.5 hr, about 31 hr, about 315 hr, about 32 hr, about 325 hr, about 33 hr, inclusive of all values and subranges therebetween. {11111651 Conventionally, food usually delays Two, and therefore Tmax for the fed state are usually larger than fasted state Til-ax. However, the pharmacokinetic studies revealed that fasted state Tmau vaiues are larger than fed state Tim. Thus, in some embodiments, fasted state Two are larger than fed state Tina); by about 1 hr, about 1.5 hr, about 2 hr, about 2.5 hr, about 3 1n, about 3.5 hr, about 4 hr, about 4.5 hr, about 5 hr, about 5.5 hr, about 6 hr, about 6.5 hr, about 7 hr, about 7.5 hr, about 8 hr, about 8.5 hr, about 9 hr, about 9.5 hr, about 10 hr, about 10.5 hr, about 1 1 hr, about 11.5 hr, about 12 hr, about 12.5 hr, about 13 hr, about 135 hr, about 14 hr, about 14.5 hr, about 15 hr, about 155 hr, about 16 hr, about 165 hr, about 17 hr, about 175 hr, about 18 hr, about 185 hr, about 19 hr, about 19.5 hr, about 20 hr, or more. {1191661 Due to the topicai contact of the orai corticosteroid with the esophagus, and, the use of corticosteroids having 1ow (or ed to have low) systeinic bioavaiiabihty, the s and compositions described herein are abie to treat EoE with biood piasma 1eve1s of the corticosteroid that are surprising1y 1ow. A benefit of 1ow biood piasma 1eve1s of the corticosteroid is a reduction or avoidance of side effects associated with systemic administration of corticosteroids. Thus, in some embodiments, the methods and compositions bed herein 11y administer a corticosteroid to the upper gastrointestinal tract (e.g.., the gus) in an effective arn ount of the corticosteroid to 11y treat inflammation thereof (eg, EoE). 1n some embodiments? the ora1 corticosteroid provides an average maximum b1ood p1asnta concentration (Cniax) of 1ess than or equa1 to about 1000 pg/mL after ora1 administration of about 0.01 nag to about 20 mg of the ora1 corticosteroid, eg 1ess than or equai to about about 950 pig/int“ about 900 pg/mL, about 850 pg/n11), about 800 pg/in1_,, about 750 Egg/1111.1, about 700 pg/rn1_., about 650pg/'n11_., about 600 pg/mL, about 550 , about 500 pg/mL, about 4.50 pg/ml..-, about 400 pg/inL, about 350 og/ihL, about 300 pg/mL, about 250 pg/niL, about 200 pg/mL, about 150 pg/rnL, about 100 pg/itiL, or about 50 pg/mL. 1n preferred embodiments, the ora1 corticosteroid provides a (Ethan ot‘1ess than or equai to about 500 rig/mi... after ora1 administration of about 0.01 mg to about 20 mg of the ora1 osteroid. {1111167} 1n preferred embodiments, the 1ying down t’s Cmax is within the range of about 80% to about 125% of about 15 bg/mL to about 40 pg/mL fo1iowing administration of 6 mg of fiuticasone propionate whiie the patient is 1ying down, e.g about 10 pg/mL, about 11 pg/mL, about 12 pg/mL, about 13 pg/mL, about 14 bg/inL, about 15 mg/mL, about 16 pg/mL, about 17 pg/mL, about 18 pox/min, about 19 pg/mL, about 20 pg/rnL, about 21 pg/mL, about 22 rig/mitt, about 23 pg/mL, about 24 rig/nth about 25 pox/mL, about 26 pg/mL, about 2'7 bg/mL, about 28 pg/mL, about 29 bg/mL, about 30 pg/mL, about 31 pg/hiL, about 32 pg/mL, about 33 pg/rnL, about 34 pg/mL, about 35 bg/rnL, about 36 bg/rnL, about 37 bg/mL, about 38 pg/mL, about 39 pg/mL, about 40 pg/mL, about 4l pg/niL, about 42 pg/mL, about 43 pg/mL, about 44 og/ntL, about 45 pg/rnL about 46 og/ntL, about 47 pg/mL, about 48 tog/nil, about 49 pg/rnL about 50 pg/inL, about 5i , about 52 pg/inL, about 53 pg/rnL, about 54 pg/mL, or about 55 pg/mL, inclusive of all values and ges therebetween. ln some embodiments, the low blood plasma levels achieved to treat EoE also reduces side effects associated with ic administration of corticosteroids.

For example, in embodiments involving HS administration, topical delivery of the corticosteroid decreases systemic- administration and, ated side effect even though HS administration is lly known to increase ic absorption. {00160} In some embodiments, a lying down patient’s Cit—ax of the oral corticosteroid is at least about l% lower compared to the fed patient’s Cmax of the oral corticosteroid for a fed patient that is upright and does not lay down immediately after administration of the oral corticosteroid, eg at least about 29/5, at least about 3%, at least about 4%, at least about 59/5, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about l0%, at least about ll%, at least about l2%, at least about l3%, at least about l4%,at least about l5%, at least about l6%, at least about l7%, at least about l8%, at least about l 9%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, inclusive of all values and subranges therebetween. {00169} In some embodiments, the oral corticosteroid provides and an average AUCo—m of less than or equal to about l 0,000 glib/ml, after oral administration of about 0,0l mg to about 20 mg of the oral corticosteroid, eg, about 9,000 pg*l1,/1’TIL, about 8,000 nila, about 7,000 pg’l‘h/inli, about 6,000 pg’l‘h/inli, about 5,000 pg’l‘h/inli, about 4,000 pg’l‘h/inli, about 3,000 pgl‘h/rnla, about 2,000 pg*h/mL, about l,000 pg’l‘l'i/rnl_.., about 900 pg’l‘li/rnls, about 800 pg’l‘h/rnls, about 700 pg*h/mL, about 600 pg*h/mL, about 500 pg’lhl’iriL, about 400 pg’lh/mL, about 300 pgl‘h/mL, about 200 pg*li/'mL, or about l00 pg*h«’mL. In particular embodiments, the oral corticosteroid provides and an average AUCuza of less than or equal to about 3,000 pg*b/mL after oral administration of about 0.0l mg to about 20 mg of the oral corticosteroid. {00170} ln some ments, the patient’ s t (:pgtl‘h/niL} is within the range of about 80% to about l25% of about 50 pg‘h/inL to about l,000 pg h/mL following administration of l5, 3.0, 4.5, 6.0 or 7.5 mg of fluticasone propionate while the patient is lying down, cg, about l0 pgh/niL, about 20 bgb/mL, about 30 pg'h/mL, about 40 nL, about 50 pgh/niL, about 60 pgb/mL, about 70 pgb/mL, about 80 , about 90 , about 100 pg b/mL, about 110 pg'b/mL, about 120 pgh/mL, about 130 pgb/mL, about 140 pg b/mL, about 150 pgb/mL, about 160 pgb/mL, about 170 pgb/mL, about 180 pg‘b/mL, about 190 pgh/mL, about 200 pgh/mL, about 210 pgh/mL, about 220 pgb/mL, about 230 pgb/mL, about 240 pgb/mL, about 250 pgb/mL, about 260 ogb/mL about 270 pgb/mL, about 280 pgb/mL, about 290 pgb/mL, about 300 pgb/mL, about 310 ogb/mL, about 320 pgb/mL, about 330 ugh/nth about 340 pgh/mL, about 350 ogh/mL, about 360 ogb/mL, about 370 pgb/mL, about 380 pgb/mL, about 390 ugh/mi, about 400 ogb/mL, about 410 pgb/mL, about 420 pgb/mL, about £130 ogb/mL, about 440 pgb/mL, about 450 pgb/mL about 460 pgb/mL, about 470 pgb/mL, about 480 , about 490 pgb/mL, about 500 pgb/mL, about 510 pgb/mL, about 520 pgb/mL, about 530 pgb/mL, about 540 ogb/mL about 550 , about 560 , about 570 pgb/mL, about 580 pgb/'mI_.r, about 590 pgb/mL, about 600 pgb/mh about 610 ugh/m1.“ about 620 pg1t/m1_,, about 630 pg1t/m1.,, about 640 pgb/mL, about 650 pgb/mL, about 660 pgb/mlt, about 670 pgb/mL, about 680 ngmL, about 690 pgb/mL about 700 pgb/1111.2 about 71, 0 pg1t/m1_,, about 720 pgb/mh about 730 ugh/m1_,, about 740 pgb/mlfl, about 750 pgb/ml..., about 760 pg-b/mL about 770 pg-b/mL, about 780 pgb/mh about 790 pgb/mL, about 800 pgb/mh about $10 pgb/mh about 820 4, about 830 , about 840 pgb/'mI_.-, about 850 pgb/mL, about 860 pgb/'mI_.r, about 870 pgb/mL, about 880 pgb/mh about 890 ugh/m1.“ about 900 pg1t/m1_,, about 910 _.., about 920 pg11/m1_.., about 930 pg11/tu1..., about 940 pgb/tuL, about 950 pgb/mL, about 960 pgb/mL, about 970 pgb/mL, about 980 pgb/mL, about 990 pgb/mL, about 1000 ugh/mtg about 1010 pgb/mL, about 1020 pgb/mL, about 1030 pgb/mL, about 1040 pgb/mL, about 1050 pgb/mL, about 1060 pgb/tuL, about 1070 pgb/mL, about 1080 pgb/mL, about 1090 pgb/mL, about 1100 pgb/mL, about 1 1 10 pgb/mL, about 1120 pgh/mL, about 1 130 pgb/mL, about 1140 pg‘b/mL, about 1150 pgb/mL, about 1160 pgb/mL, about 1 170 pgh/mL, about 1 180 pgb/mL, about 1190 pgb/mL, about 1200 pg b/mL, about 1210 pgh/mL, about 122 pgb/mL, about 1230 pg‘b/mL, about 1240 pgb/mL, about 1250 pgb/mL, about 1260 pgh/mL, about 1270 , about 1280 pgb/mL, about 1290 pg b/mL,about 1300 pgb/mL, too1usive of a11 va1uos and subranges thetebotweeu. {001711 to some ments, the patient’ 3 AUCo-24 (:pgtkb/mL} is within the tango of about 80% to about 12 % of about 50 pgb/mL to about 1000 pg b/mL fo11owiog administration of 1.5, WO 35393 3.0, 4.5, 6.0 or 7.5 mg of fluttoasoue ptopionato w1u1o the t is upright (Ab/1 closing in the fed or fasted state), eg, about 10 pgb/mL, about 20 pgb/mL, about 30 ogb/mL, about 40 pgb/mL, about 50 pgb/mL, about {30 , about 70 pgb/mL, about 80 pgb/mL, about 90 pgh/mL, about 100 pgh/mL, about 110 pgb/mL, about 120 pgb/mL, about 130 pgb/mL, about 140 ngmL, about 150 pg‘b/ij about 160 , about 170 pgb/mL, about 180 pgh/mL, about 190 pgb/mL, about 200 ogb/mL, about 210 pgb/mL, about 220 pgb/mL, about 230 ugh/1111;, about 240 bgb/mL, about 250 bgb/mL, about 260 pgb/mL, about 270 , about 280 ugh/mi, about 290 ogb/mL, about 300 ngmL, about 310 pg‘b/mL, about 320 bgb/mL, about 330 pgb/mL, about 340 pgbij about 350 pgb/mL, about 360 pgb/mL, about 370 pgb/mL, about 380 pgh/mL, about 390 pgb/mL, about 400 pgb/mL, about 410 pgb/mL, about 420 ngmL, about 430 j about 440 pgb/mL, about 450 pgb/mL, about 460 pgh/mL, about 470 pgb/m1_.r, about £180 pgb/mL, about 4190 pgb/mL, about 500 ogh/mLfi about 510 pg~1t/m1_,, about 520 pg1t/m1.,, about 530 pgb/m1.,, about 540 pgb/m1.,, about 550 ugh/mi, about 560 pg11/m1_.r, about 570 pgb/utL, about 580 pgb/mL about 590 pgb/m1.“ about 600 pg1t/m1_,, about 610 pgb/mh about 620 _,, about 630 pg11/m1_.r, about 640 pg~b/’u11_.., about 650 pg-b/mL about 660 pg-b/mL, about 670 pgb/mL about 680 pgb/mL about 690 , about 700 pgb/mh about 710 ugh/"1111,, about 720 pgb/mL, about 730 l..-, about 740 pg-b/mL, about 750 pgb/m1_.r, about 760 pgb/mL, about 770 pgb/mL, about 780 ogh/mLfi about 790 pg~1t/m1_,, about 800 pgb/m1_.., about 810 pg11/m1_.., about 820 pg11/tu1..., about 830 pgb/tuL, about 840 pgb/mL, about 850 pgb/mL, about 860 pgb/mL, about 870 pgb/mL, about 880 pgb/mL, about 890 pgb/mL, about 900 11.1, about 910 pgb/tuL, about 920 pgb/mL, about 930 pgb/mL, about 940 pgb/mL, about 950 pgb/mL, about 960 pgb/mL, about 970 pgb/mL, about 930 pgb/mL, about 990 , about 1000 pgb/tuL, about 1010 pgb/mL, about 1020 pgb/mL, about 1030 , about 1040 pg b/mL, about 1050 pgb/mL, about 1060 pgb/mL, about 1070 ngmL, about 1080 pgb/mL, about 1090 pgb/mL, about 1100 pgh/mL, about 1110 pgb/mL, about 1120 pgh/toL, about 1 130 pg b/mL, about 1140 pgb/mL, about 1 150 pgb/mL, about 1160 ngmL, about 1170 pgb/mL, about 1180 pgb/mL, about 1190 pgh/mL, about 1200 pgb/mL, about 1210 pgh/toL, about 1220 pg b/mL, about 1230 pgb/mL, about 1240 pgb/mL, about 1250 pgb/mL, about 1260 pgb/mL, about 1270 pgb/mL, about 1280 pgh/mL, about 1290 pgb/mL,about 1300 pgb/mL, indusivo of a11 valuos and subtaugos tbotobotweou. {98172} In some embodiments, the patient’ s AUCom (pg’l‘h/inL) is within the range of about 80% to about 125% of about 250 pg h/mL to about 475 pg‘h/mL following administration of 6 mg of flutioasone propionate While the patient is lying clown, eg about 150 pgh/mL, about I60 pg'b/inL, about l70 pgli/mL, about l 80 pg‘b/mL, about l90 pg h/mL, about 200 pgb/mL, about 210 , about 220 pgh/mL about 230 pgb/mL, about 240 pg~h./"niL, about 250 pg‘b/inL, about 260 pgb/mL, about 270 pgb/mL, about 280 pgb/mL, about 290 pgb/mL, about 300 pgb/mL, about 310 pg‘h/niLj about 320 ugh/ml), about 330 , about 340 pgb/mL, about 350 pg‘h/mL, about 360 pg‘h/mL, about 370 pg‘b/mL, about 380 pg‘h/niL about 39G pgb/mL, about 400 pgb/mL, about 410 nab/ml), about 420 ugh/ml), about 430 pg~lt/’mL, about 440 pglflmL, about 459 pgh’btb, about 460 L, about 470 L, about 480 pgb/mL, about 490 pgh/mL, about 500 pgh/mL about SlQ pgb/mL, about 520 pg~h./"niL, about 530 pg‘b/inL, about 540 pg-b/ntL about 550 pg~b,l’inL., about 560 pgb/mli, about 570 pgb/mh about 580 pg‘h/inlsfi about 590 pg-b/mli, about 600 pgh/mI... inclusive of all values and subtanges tbetebetween {99173} In some embodiments, the patient’ s AUCc-a4 'mI..-) is within the range of about 80% to about l25% of about 250 pgb/mL to about 475 ngmL following administration of 6 mg of flutioasone propionate while the patient is uptight, e.g about 150 pub/min about 160 pg-b/mL, about I70 pg-b/ntL about 180 pg~b,l’inL., about 190 pgb/mL about 200 pgb/mh about 210 pg’h/IUL, about 220 pg’li/mlo, about 230 pg'h/ml..., about 240 pg-h/mL, about 250 pgb/mL, about 260 pgh/mL, about 270 pgh/mL, about 280 pgb/mL, about 290 pg’li/tnL, about 300 pgb/inI..., about 3} O pgb/inI_.., about 320 pg-h/mI_.., about 330 pg'b/mi..., about 340 pg'h/mL, about 350 pgb/mL, about 360 pgh/niL, about 370 pgb/mL, about 380 pg’h/inIfi about 390 pgh/inL, about 400 pg'h/inL, about 4t 0 pgli/inti, about 420 pg'h/mL, about 430 pg-h/niL, about 440 pgb/mL, about 450 L, about 460 pg‘b/mL, about 470 pg‘b/mL, about 480 pg‘b/mL, about 490 pg'b/inL, about 500 L, about 510 pg‘b/mL, about 520 pg h/mL, about 530 pgb/mL, about 540 pgh/mL, about 550 , about 560 L, about 570 pgli/mL, about 580 pg‘h/inL, about 590 nL, about 600 pg‘h/mL inclusive of all values and subranges tlietebetween. {98174} In some embodiments, the pharmaceutical composition is administered to a patient at least about 2 hours after the evening meal (with no ) while the patient is lying down. In some embodiments, the ceutical composition is administered to a patient at least about 4 hours after the evening meal (with no snacks) while the patient is lying down. in some embodiments, the pharmaceutical composition is administered to a patient within about 2 hours after the evening meal (with no snacks) while the patient is lying down. In some embodiments, the ceutical composition is administered to a patient within about 4 hours after the evening meal (with no snacks) while the patient is lying down. in some embodiments, after stration of the ceutical composition while the patient is lying clown, the t goes to sleep. In some embodiments, after administration of the pharmaceutical composition while the patient is lying down, the patient does not rise for at least one hour. iilllll75} In some embodiments, the patient holds the pharmaceutical composition in the oral cavity for a length of time sufficient to swallow the composition leg, about 1 second, about 2 s, about 3 seconds, about 4 seconds, about 5 seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, or about l0 seconds). in other embodiments, the patient holds the pharmaceutical composition in the oral cavity for a length of time sufficient to allow the ceutical composition to dissolve in the saliva. One skilled in the art will appreciate that the length of time necessary for the ceutical composition depends, in part, on the dosage form, For example, orally disintegrating compositions disintegrate in saliva within about 60 seconds (eg, about 50 seconds, about 40 seconds, about 30 s, about 20 seconds, or about it) seconds) to form a suspension which is then swallowed. ln embodiments in which the pharmaceutical composition is a lozenge or lollipop, the lozenge or lollipop may remain in the patient’s oral cavity for about l minute, about 2 minute, about 3 minutes, about 4 minutes, about minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about if) minutes. {@8176} ln some embodiments, the pharmaceutical composition is administered to a patient from one to five times a day. in some embodiments, the pharmaceutical composition is administered to a patient at least once a day, at least twice a day, at least three times a day, at least 4 times a day, or at least five times a day. in some embodiments, the pharmaceutical composition is stered to a patient at least one to five times a day for one weel: to l0 years or more. ln some embodiments, the pharmaceutical composition is stered to a patient at least once a day, at least twice a day, at least three times a day, at least 4 times a day, or at least five times a day for at least one week, at least two weeks, at least three weeks, at least four weelrs, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least ten weeks, at least fifteen weeks, at least twenty weeks, at least thirty weeks, at least forty weeks, at least fifty weeks, at least fifty~two weeks, at least sixty weeks, at least seventy weeks, at least eighty weeks, at least ninety weeks, or at least one hundred weeks or more. in some ments, the pharmaceutical composition is administered to a patient indefinitely. ln some embodiments, the pharmaceutical composition is administered twice a day for at least about 6 weeks, at least about 8 weeks, at least about lt‘i weeks, or at least about l2 weeks. in some embodiments, the pharmaceutical composition is administered twice a day during the induction and/or maintenance phase. in some embodiments, the pharmaceutical composition is stered twice a day for at least about 6 weeks, at least about 8 weeks, at least about it) weeks, or at least about l2 weeks during the induction phase. 7} In some embodiments, the pharmaceutical composition is administered to a patient at 0.75 mg, l5 mg, 30 mg, 4.5 mg or 6.0 mg at least once a day, at least twice a day, at least three times a day, at least four times a day, or at least five times a. day, In some embodiments, the pharmaceutical composition is administered to a patient at the same dose multiple times a day. in some embodiments, the pharmaceutical composition is administered to a patient at the same dose at least twice a day, at least three times a day, at least Zl- times a day, or at least five times a day in some embodiments, the pharmaceutical ition is administered to a patient at the same dose two to five times a day for one week to l 0 years or more. in some ments, the ceutical composition is administered to a patient at least at the same dose at least twice a day, at least three times a day, at least 4 times a day, or at least five times a day for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least ten weeks, at least fifteen weeks, at least twenty weeks, at least thirty weeks, at least forty weeks, at least fifty weeks, at least fiftyutwo weeks, at least sixty weeks, at least seventy weeks, at least eighty weeks, at least ninety weeks, or at least one hundred weeks or more or indefinitely.

{M13178} ln some embodiments, the pharmaceutical composition is administered twice a day at different doses. ln some embodiments, the ceutical composition is administered twice a day, with the morning, dose being, greater than the evening dose. ln some embodiments, the pharmaceutical composition is administered twice a day, with the morning dose being less than the g dose.

{IIIII’79} In some ments, the patient is administered different doses of the pharmaceutical composition ing on the phase of the regimen. For example, the regimen may be divided into at least induction, treatment, withdrawal, or maintenance phase. In some embodiments, the regimen includes at least one ofthese phases. In some embodiments, the regimen includes a combination of one or more of these phases. In some embodiments, the regimen includes all of these phases. {nurse} In some embodiments, the regimen includes ion and withdrawal. In some embodiments, the regimen includes le cycles of induction and withdrawal as needed. In some embodiments, the regimen includes multiple cycles of induction and withdrawal ed nitely. In some embodiments, the induction period does not result in a recurrence of symptoms, {IIIIISI} The regimen phases may be any appropriate duration. In some embodiments, the induction phase lasts n about I and about IO weeks, about l2 weeks, about I5 weeks, about weeks, about 30 weeks, about 4-0 weeks, or about 50 weeks. In some embodiments, the induction phase lasts about l4 weeks. In some embodiments, the withdrawal phase lasts between about l and about IO weeks, about I5 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about :30 weeks, about I year, about 2 years, about 5 years, about IO years or indefinitely. In some ments, the withdrawal phase lasts until symptoms recur, In some embodiments, the witI'idraer phase lasts about l4 weeks. In some embodiments, the maintenance phase lasts between about l and about l5 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about I year, about 2 years, about 5 years, about IO years or more. In some ments, the maintenance phase lasts about 28 weeks. In some embodiments, the maintenance phase is an indefinite duration.

{IIIII82} In some embodiments, the patient is administered a greater dose in one or more regimen phases compared to the others. In some embodiments, the patient is administered the same dose in one or more regimen phases. In some embodiments, the patient is administered the same dose in every n phases. In some embodiments, the patient is administered no dose during, one or more phases. {98183} In some ments, the patient is administered a greater dose during the induction stage compared to the maintenance stage. In some embodiments, the patient is administered a smaIIer dose during the induction stage compared to the maintenance stage. In some embodiments, the patient is administered no dose during either the induction or maintenance stage.

In some ments, the patient is administered no dose during both the induction and maintenance stages. In some ments, the t is administered the same dose during the induction and nance stages. In some embodiments, the patient is administered suhstantiaiiy the same dose during the induction and maintenance . In some embodiments, the patient is stage. In some embodiments, the patient is administered 3.0 mg BID during the induction stage, and 1.5 mg IIS during the maintenance stage. In some embodiments, the patient is administered 1.5 mg BID during the induction stage, and 3.0 mg BID during the maintenance stage. In some embodiments, the patient is administered 15 mg IIS during the induction stage, and 30 mg BID during the maintenance stage. In some ments, the patient is administered IS mg BID during both the induction and maintenance stages, In some embodiments, the patient is administered 1.5 mg HS during the induction and nance stages. In some embodiments, the patient is administered 3,0 mg BID during the induction and maintenance stages, In some embodiments, the patient is administered 6.0 mg BID during the induction stage, and 3.0 or 15 mg BID during the maintenance stage, In some embodiments, the patient is administered 6.0 mg BID during the induction stage, and 3.0 or 1.5 mg I-IS during the maintenance stage. In some embodiments, the patient is administered 15 or 3.0 mg BID during the induction stage, and 60 mg BID during the maintenance stage. In some embodiments, the patient is administered IS or 3.0 mg IIS during the induction stage, and 6.0 mg BID during the maintenance stage. In some embodiments, the patient is administered 6.0 or 3.0 mg BID during both the induction and nance stages. In some embodiments, the patient is administered 6.0 or 3.0 mg IIS during the induction and maintenance stages. In some embodiments, the t is administered 6.0 mg BID during the induction and maintenance stages. {98184} In some embodiments, the patient is not inistered a strong cytochrome I’4503A4 inhibitor. In some embodiments, the patient is not co—administered ritonavir or ketoconazoie. {98185} In certain embodiments, the patient is a human, but in other embodiments may be a non—human mammal, such as a domesticated pet (cg dog or cat), or livestock or farm animal (erg, horse, cow, sheep, or pig).

Patient Populations {(38186} Any t diagnosed with, or presumed to be sulleririg from an inflammatory intestinal disorder, may be administered the pharmaceutical compositions of the present disclosure. In some embodiments, the patient is an adult. In some embodiments, the patient is an adolescent. In some embodiments, the patient is a child. ln some embodiments, the patient is an infant. {98187} In some embodiments, the inflammatory gastrointestinal disorder is EOE. The patient may be diagnosed using any appropriate measures in the art. In some embodiments, the patient is diagnosed with EoE based on symptoms, histology, and/or failed documentation on proton pump inhibitors. In some embodiments, the patient received I’PI therapy prior to stration of a pharmaceutical composition of the present disclosure. In some embodiments, the patient did not receive PI’I therapy prior to administration of a pharmaceutical composition of the present disclosure. ln some embodiments, the patient failed to improve after 8 weeks of high" dose (eg. 40 mg) PI’l. A laclr of response to PPI therapy may be defined as Peak eosinophil count 3 lS/HPF in at least one biopsied location after 8 weeks of treatment with a high dose PPI. In some embodiments, the failure of PPI y is documented before administration of a pharmaceutical composition of the t disclosure. In some embodiments, the e of PPI y is documented subsequently to administration of a pharmaceutical ition of the t disclosure. In some embodiments, patients which did not respond to previous PPI therapy are stered a high dose of the oral corticosteroid according to (or for use in) the s disclosed herein, such as (it) mg, 7.5 mg, or more (e.g about 9.0 mg to about 20 mg, including about 9 mg, about it) mg, about ll mg, about 12 mg, about l3 mg, about l4 mg, about l5 mg, about l6 mg, about l7 mg, about l8 mg, and about l9 mg, inclusive of all values and ges therebetween). {88188} In some embodiments, the patient diagnosed with EOE has an esophageal stricture.

In some embodiments, said patient is administered a high dose of the oral corticosteroid according to (or for use in} the methods disclosed herein, such as 6.0 mg, 7.5 mg, or more (eg, about 9.0 mg to about 20 mg, including about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, and about 19 mg, inciusive ot‘all values and ges therebetween). 31111189} 1n some embodiments, the patient diagnosed with EoE has a severe food allergy (e.g a 1actose or starch allergy). 1n some embodiments, said, patient is administered a high dose of the ora1 corticosteroid according to (or for use in) the methods disclosed herein, such as 6.0 mg, 7.5 mg, or more (eg, about 9.0 mg to about 20 mg, inc1uding about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, and about 19 mg, inclusive of all values and suhranges therebetween). 311111311} 1n some embodiments, the patient has been sed with EOE by histological analysis. 1n some embodiments, the patient is diagnosed as having gulf? peak eosinophil count per EFF (400x magnification) in at least one biopsy. 1n some embodiments, there are at minimum of 6 biopsies taken from the patient. in some ments, at least 3 biopsies are taken from each of the proximal and the distal gus. {1111191,} 1n some embodiments, the patient is diagnosed as having Hot? by their EEsAL G1oha1 EoE, EREFS, PROSE, and/or measurement of esophageal characteristics via endoscopy (e. g. EndoFlip). 1n some embodiments, the patient is diagnosed as having 130E based on a 7—day recali 1 score of >30, 1n some embodiments, the patient is diagnosed as having EoE based on a 7—day reca1l Glohai 13oF; score of: 5. in some embodiments, the patient is diagnosed has having EoE based on the EREFS score which scores endoscopic characteristics (see Tabte 3). 1n some embodiments 13013 is diagnosed in a patient scoring above Grade 0 in any of the five characteristics disclosed in Tabie 3. {1111192} 1n some ments, the patient is diagnosed as having EoE based on symptoms, inc1uding but not d to episodes of food ion, episodes of food impaction requiring endoscopy, food avoidance, vomiting, reflux, and/or dy spbagia. in some embodiments, the patient is diagnosed as having EoE based on dysphagia (difficulty swallowing). in some embodiments, the patient is diagnosed as having EoE based on experiencing dysphagia at least 3 times per week within 2 weeks. {@9193} Patient outcome and response to administration with a pharmaceutical composition of the present disclosure may be red or measured using any appropriate means in the art (eg endoscopy, histology, questionnaires}. {@9194} Patients who exhibit an improvement of symptoms and/or histologic response after treatment commences are categorized as Responders. in some embodiments, ts who exhibit < 15 peak eosinophiis/HPF are categorized, as Responders. in some embodiments, ts who exhibit < 6 peak eosinophils/HPF are categorized as Responders. in some embodiments, patients who exhibit < 6 peak eosinophils/HPF and no worsening of symptoms (eg. no increase in weekly EEsAI score compared, to baseline; stricture requiring dilation) are categorized as Responders. in some embodiments, patients who exhibit < 6 peali: eosinophils/BRF and no episodes of food impaction are categorized as Responders. in some embodiments, Responders exhibit evidence of inflammatory endoscopic remission such as an absence of white exudate and/or furrows in some embodiments, Responders t evidence offibrotic remission including an absence of strictures and rings or moderate. to severe rings, in some embodiments, Responders t improved vascularity. in some embodiments, ders t ed biomarkers (eg. lL—S, lgE levels). {99195} In some embodiments, patients who are categorized as Responders enter the maintenance stage of the regimen. in some embodiments, ts who are categorized as Responders are administered a. different dose of a, pharmaceutical composition of the present sure after categorization, in some ments, Responders receive a greater dose after categorization after categorization. in some embodiments, ders receive a smaller dose ai‘ter' categorization. in some embodiments, Responders receive the same dose after categorization, in some embodiments, Responders receive substantially the same dose ai‘ter' categorization. {981%} in some embodiments, the patient is classified as a responder if the pharmaceutical compositions disclosed herein are administered in an induction phase and a maintenance phase, and during the ion phase improvement in Peak eosinophilic counts in at least one esophageal biopsy and/or at least no worsening of patient mean weekly EESAl scores are o d, and where the nance phase comprises a dose at least equal to, more than or less than the induction phase.

} Patients who do not meet the definition of Responder as disclosed above are categorized as Non—Responders. Patients whose histologic score and/or symptoms worsen are categorized as Relapse. ln some embodiments, patients whose histologic score and/or symptoms worsen at any point during treatment are categorized as Relapse. ln some embodiments, patients who experience food impaction requiring endoscopy and/or clinicallymsignificant worsening of symptoms are rized as Relapse. ln some embodiments, patients who are categorized as Non— Responders or Relapsers are administered a different dose of a pharmaceutical composition of the t disclosure after categorization In some embodiments, NonmResponders and/or Relapsers e a greater dose after categorization ln some embodiments, NonnResponders and/or Relapsers receive a r dose after categorization ln some ments, Non—Responders and/or Relapsers e the same close after categorization. In some embodiments, Non" Responders and/or Relapsers receive substantially the same dose after categorization. {99198} In some embodiments, the patient is classified as a responder if the pharmaceutical compositions disclosed herein are administered in an induction phase and a maintenance phase, and during the induction phase no improvement in Peak eosinophilic counts in at least one esophageal biopsy and/or worsening of patient mean weekly EESAI scores are observed, and where the maintenance phase comprises a dose at least equal to, more than or less than the induction phase. {(38199} ln some embodiments, the present disclosure provides methods for assessing the suitability of subjects for a clinical trial to measure the effect of an oral corticosteroid on hold, after administration in both an induction phase and a maintenance phase. ln some ments, the recruitment of subjects into the clinical trial is assessed on patient’s eosinophil count and prior treatment. ln some embodiments, the ts selected for the clinical trial l'iave Peak eosinophil counts per l-ll?F of greater than about 6, greater than about l0, greater than about l5, or greater than about 20. ln some embodiments, the patients selected for the al trial have Peak eosinophil counts per l-ll’F of greater than about l5. ln some embodiments, the patients selected for the al trial have failed prior treatment. in some embodiments, the prior treatment was administration of a PM over at least about 8 weeks that had not been effective to substantially e one or more symptoms of Bali.

Purposewfiomid Products {@9299} in keeping with the foregoing, the present disclosure es an oral corticosteroid for use in a method of treating Bali in a patient, wherein the oral corticosteroid is administered immediately prior to the patient lying down or whilst the patient is lying down. ln embodiments, a therapeutically effective amount of the oral corticosteroid contacts the patient’s esophagus. The term “therapeutically effective amount” can mean an amount e of eliciting beneficial biological activity in vivo and, in an embodiment, e of treating EoE as measured using any of the metrics disclosed . The doses of oral corticosteroid disclosed herein suitably deliver a therapeutically effective amount of the oral corticosteroid to a patient. {99291} The oral osteroid, method of treating and t can all be as described herein. lndeed, any and all of the features as described herein for the disclosed compositions, methods of treatment, dosing, administration and patient populations can be employed in tion with the disclosed purpose—bound products. Any and all ations of such features are explicitly encompassed by the disclosed invention, except combinations where at least some of such features are mutually exclusive. {@9292} Thus, in embodiments, the lying down may be in a supine, prone or laterally recumbent on. {@9293} The oral corticosteroid may be administered about 30 minutes or less before target sleep time. The oral corticosteroid may be administered at least about 30 minutes after a meal. ln an embodiment, the patient may not eat or drink for at least about 30 s after administration of the oral corticosteroid. 94} The oral corticosteroid may be administered once daily. it may be administered twice daily, the first daily dose being administered wl'iilst the patient remains upright. {1949295} The oral corticosteroid may be administered in a dose of from about (till mg to about 20 mg, The oral corticosteroid may be thrticasone propiona‘te, administered in a dose of from about l5 mg to about 7.5 mg, and preferably about l6, 3.0, 4.5, 6,0 or 7.5 mg. {(38296} in an embodiment, the patient may have a lactose allergy or a starch allergy. {98297} The oral corticosteroid may have a systemic bioavailability of less than or equal to about 209/13, less than about l5%, less than about l0%, less than about 5% or less than about l% of its dose. 308208} The oral corticosteroid may provide an average maximum blood plasma concentration (Cmax) of less than or equal to about 500 pg/mL after oral administration of from about 0.0l mg to about 20 mg of the oral corticosteroid. {@9299} The oral corticosteroid may provide an average AUCoai of less than or equal to about 3,000 pg*h/mL of after oral administration of from about 0.01 mg to about 20 mg of the oral corticosteroid. lititlilell In embodiments the oral corticosteroid may be budesonide, fluticasone, flunisolide, ciclesonide, mometasone, tixocortol or beclomethasone, or a pharmaceutically acceptable salt, solvate, ester, polymorph or g thereof. {@9211} ln an embodiment, the oral corticosteroid may be formulated as a liquid composition. in r embodiment, it may be formulated as a solid composition. it may be formulated to form a solution or sion prior to oral stration. It may be formulated to form a solution, sion or gel upon oral administration. if formulated as a liquid composition, the oral corticosteroid may be in the form of a solution, suspension or slurry, If formulated as a solid composition, the oral corticosteroid may be in, the form of a gel, e, lollipop, effervescent tablet, powder, granules or an orally disintegrating composition The orally disintegrating composition may be in the form of a tablet, wafer, film or lyophilized matrix, {(39212} In an embodiment, the oral corticosteroid is formulated as an orally disintegrating tablet comprising the oral corticosteroid in an amount of from about l5 mg to about 76 mg, a pharmaceutically acceptable r combined with the corticosteroid, and rapidly dispersing mi crogran ules, wherein the orally disintegrating tablet disintegrates Within 60 seconds wl'ien tested using the USP <70l > Disintegration Test. {@8213} ln an embodiment, the patient may have a Cmax of the oral corticosteroid of less than or equal to about 200 pg/mL following oral administration of from about l5 mg to about 7.5 mg of the oral corticosteroid.

{MEN} The e time to reach a maximum blood plasma concentration (Tmax) of the oral corticosteroid may be in the range of from about 80% to about l25ll/ia of from about 12 h to about 15 h. {@9215} in an embodiment, the oral corticosteroid may be fluticasone propionate and the Cmar: may be within the range of from about 80% to about l25% of from about l5 pg/mL to about 40 pg/mL following administration of 6 mg of fluticasone propionate or 3 mg of fluticasone"t propionate. {982%} In embodiments, after l2 weeks of daily administration of the oral corticosteroid, esophageal inflammation may be reduced as measured by a reduction in eosinophil count, an increase in dysphagia—free days, a reduction in episodes of dysphagia, improvement in EREFS score, lP documentation of improved esophageal ance, evaluation of biomarhers, a decrease in episodes of food impaction, an improvement in EEsAl scores (patient, physician, endoscopy, pathology scores), EoE—QOLHA, Visual Dysphagia Questionnaire Q), Avoidance Modification and Slow Eating (AhlS) scores, or histology. r--« @9217} ln an embodiment, the patient’s eosinophil count may be reduced by at least about Combination Therapies {timid} The one or more therapeutic agents may be “co—administered”, i.e., administered together in a nated fashion to a subject, either as separate ceutical compositions or d in a single pharmaceutical composition. By “conadministered”, the one or more therapeutic agents may also be administered simultaneously with the present pharmaceutical compositions, or be stered separately, including at different times and with different frequencies. The one or more therapeutic agents may be administered by any known route, such as orally, intravenously, intramuscularly, nasally, subcutaneously, vaginally, intra~rectally, and the like; and the therapeutic agent may also be administered by any conventional route. {99219} When two or more medicines are used in combination, dosage of each medicine is commonly identical to the dosage of the medicine when used ndently, but when a medicine interferes with n'ietabolisin of other medicines, the dosage of each medicine is properly adjusted.

Each medicine may be stered simultaneously or separately in an appropriate time interval. 9} The pharmaceutical compositions disclosed herein may be co—adrninistered with various therapies used to treat, t, delay, and/or ameliorate intlan'iinatory conditions of the gastrointestinal tract, including but not limited to infl animation of the esophagus, inflammation of the glottis, inflammation of the epiglottis, iritlarriinatiriri of the tonsils, inflammation of the oropharynx, eosinophilic esophagitis (Eoli), gastroesophageal reflux disease (GERD), non~erosive reflux disease (NERD), erosive esophagitis, Barrett's esophagus, eosinophilic gastroenteritis, hypereosinophilic syndrome, corrosive (caustic) chemical esophagitis, radiationuinduced esophagitis, chemotherapyuinduced esophagitis, transient druguinduced esophagitis (also known as medication gitis), persistent drugninduced esophagitis, Crohn's disease of the esophagus, and pseudomemhranous esophagitis. {$821le The one or more therapeutic agents may he any compound, molecule, or substance that exerts therapeutic effect to a subject in need thereof. {$822} In some embodiments, the ceutical compositions disclosed herein are co— stered with one or more corticosteroids. Suitable corticosteroids include, but are not limited to hydrocortisone, prednisone, prednisolone, methylpredmsolone, dexamethasone, hetainetliasone, etc. or mineralocorticoid potencies (ego, alsosterone}, hudesonide, asone, tlunisolide, eiclesonide? mometasone, ethasone, tixocortol and salts, or esters and es thereof.

} In some embodimenta the pharmaceutical compositions disclosed herein are co— administered with one or more proton pump tors (PPI). Suitable PPIs include, but are not limited to, omeprazole, lansoprazole, dexlansoprazolei raheprazole, pantoprazolefi and esoineprazole In some embodiments the PPI is administered at high doses. {88224} In some embodiments, the pharmaceutical itions disclosed herein are co~ stered with an antifungal agent. Suitable antifungal agents include, but are not d to mitotic inhibitor antifungals, dine analog antil‘ungals, e antifungals, henzirnidazole antifungals, imidazole antit‘ungals, polyene antifungals, triazole antifungals, thiazoie antifungals, allylamine antifungals, echinocandin antit‘ungals, and other "uncategorized“ antifungais recognized in the art that do not fall within any of the above categories (eg, tolnaflate and ciclopirox}. For e, suitahle antifungal agents which may be included in the solid pharmaceutical compositions of the present disclosure include ahafungin, amoroit‘ine, anidulafungin, bifonazole, fine, hutoconazole, candicin, caspofungin, ciclopirox, clotrimazole, econazoie, fenticonazole, filipin, I‘luconazole, t‘lucytosine, griseofulvin, isavuconizole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, miconazole nitrate, naftit‘ine, ycin, nystatin, oxiconazole, posaconazole, pramiconazole, ravuconazole, riniocidin, setaconizole, sulconazole, terbafine, terconazole, tioconazole, tolnaftate, undecylenic acid, and voriconazole. {98225} ln other ments, pharmaceutical compositions disclosed herein are con administered with an antiviral agent. Antiviral agents which may be used in the present disclosure include, but are not limited to, interferons, nucleoside and nucleotide reverse transcriptase inhibitors, nonnnueleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, maturation inhibitors, ine analogs, puridine s, pyrimidine analogs, and other "uncategorized" antiviral drugs recognized in the art which do not fall within any of the above classes (ego, foscarnet and, fosine). For example, suitable antifungal agents which may be included in the solid ceutical compositions of the present disclosure include ahacavir, aciclovir (also known as acyclovir), adefovir, dine, arndoxovir, amprenavir, aplaviroe, aprioitahine, arhidol, atazanavir, imat, 8043, hoceprevir, brivudine, cidofo vii, DCMZOS, docosanol, delavirdine, didanosine, durunavir, efavirenz, elvitegravir, elvucitabine, enitricitabine, enfiwirtide, epigallocatechin gallate, etravirine, famciclovir, fosamprenavir, ganciclocvir, globoidnan A, tlisin, ihalizumah, idoxuridine, indinavir, lamivudine, lopinavir, loviride, maraviroc, neli‘inavir, nevirapine, oseltamivir, pegylated interferon alpha—2a, pegylated interferon alpha—2b, lovir, peraniivir, plerixai‘or, PRO ill-0, racivir, raltegrvir, ritonavir, rin, adine, rlipivirine, saquinavir, stampidine, stavudine, tenofovir, tipranavir, TT‘DQ :3, trilluridine, tromantadine, valaciclovir, valganciclovir, vicriviroc, vidarabione, virarnidine, vivecon, zalcitahine, zanamivir, and zidovudine. } lo some embodiments, the pharmaceutical compositions disclosed herein are co- stered with one or more iminunosuppressants. Suitable iminunosuppressants include, but are not limited to, cyclosporme, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolic acid, methotrexate, hasiliximah, daclizumab, rituximab, anti" cyte globulin, and anti~lymphocyte globulin. {88227} The disclosure also provides lrits for the treatment of gastrointestinal inflammatory disorders. in some embodiments, the lrits include a pharmaceutical composition of the t disclosure (lluticasone propionate, GUT) in unit dosage form, In some embodiments, the lrits include 1.5 mg or 3.0 mg of a pharmaceutical composition of the t disclosure. ln some embodiments, the l<its include a maintenance dosage of a pharmaceutical composition of the present disclosure. ln some embodiments, the ltits e an induction dosage of a pharmaceutical composition of the present disclosure. ln some embodiments, the ltits include both an induction and a maintenance dosage of a pharmaceutical ition of the present sure. The kit can further include a label or printed instructions instructing the use of described reagents. The kit can further include a treatment to be tested.

INCGRPURATTGN BY REE‘ERENCE {$828} All ations, patents, and patent publications cited are incorporated, by reference herein in their entirety for all purposes. {$8229} This application incorporates by reference the following publications and applications in their ties for all purposes: US 8,77l5729 filed October l, 2t‘il0; US 206627 filed September 5, 20M»: US 6l/S74/l—50 filed September 6, 2M3, ‘WO 20l5/034678 filed. August Ill, 2014, and } This disclosure is further illustrated by the following nonnliniiting examples.

EXAMPLES Elafampie 1~ A Randomized Double—Blind Daseui’ttmgmg Study ofiilzrrz’casone Programme Oral /mgr Tablet {@8231} This Phase 2h study will enroll 320 patients with eosinophilic esophagitis {EoE} between the ages of l4—75. To he eligible for the study, ts must have a diagnosis of EoE (> l5 peal: eosinophil per l-ll’E) after proyen failure of 8 weeks or more ofliighmdose (ie. 40 mg Ell) prazole) proton pump inhibitor (Pl’l). Pl’l therapy may he continued during the study only if the sub} ect was on PET therapy at the time of enrolling in the study. No new initiation of, nor alteration of PET therapy is allowed during the study. Sub} ects must also he symptomatic and have a 7mday recall Global EoE symptom score of 3: 5 and a 7nday recall EEsAl score of > ”‘0 to enter the placebo runnin, and an increased EEsAl score based upon a daily diary. {@8232} y Ghjectlves: Tn evaluate the efficacy of fluticasone propionate oral disintegrating tahlet {Al?"l'ul Ol l} in adolescents and adults with ensinnphilic esophagitis (EnE). {99233} Secnndary Glijectlves: Tn evaluate the safety of AP'l‘ulOll (fluticasone propionate, DDT) in adolescents and adults with EoE. Tn define the dose—response nf Al’fulOl 1. Te evaluate the pharmacohinetics (PK) nf APT—lOl l in patients with EnE. To evaluate the effect of Treatment" awal, including time to relapse and effect of te~treatment To evaluate maintenance of efficacy of treatment and long—term safety. To evaluate the effects on endoscopic ance using the EOE Endoscopic Reference Score (ERES) illlliZScll Study Rationale and Design: Doses from 1.5 mg HS to 3.9 Bill) will be explored to define the exposure—response of APT—10H and the minimum effective dose. This is a randomized, double—blind. placehoncontrolled dosenranging study of three daily doses (l .5 mg, 3 mg, and 6 mg) of APTm'lGll administered as 1.5 mg HS, l5 mg BIT), or 3f: mg fill) compared to ng placebo. The impact of treatment withdrawal, rentreatinent, and long—term maintenance will also be ted. illlliZSSl The formulations of Alyll—ltlll (fluticasone propicnate. OUT) used in the clinical trials are listed in the following tables.

Fluticasone ODTS l5 n10 —slate (mg/ea w Micrnnized Eluticasnne O. 50 l50 l’ropionate USP Colloidal Silicnn e NT Silicifiecl rystalline lOOO 30.00 Cellulose NF Crospovidone NT 22. 50 Sucralose NE (%/’tablet)j ueo ging/aueo jgmg/aua) blicronizedFluticasone 0.25 4.50 6.00 Fi‘opiouate USP l l Colloidal Silicon DioxideNF 0.30 0.00 0.00 0.00 ..................................................................................................................................................................................................................... fiedMicrocrystalline 10.00 30.0 30.00 30.00 Cellulose NF ! a (Mideast__________________________________________________742.0________220220 _________w________.1 SucraloseNF 0.40 1.20 1.20 1.20 Spray-dried Mannitol use 3005 90. 15 86.40 s4. 90 Rapidly Dispersing Granules 50.00 150.00 150.00 150.0 Sodium l Fumarate NF 4.50 4.50 00.00% woo woo mo {£39236} Dosing: For 3 dosing groups, AFT~lGl l will be provided as blinded tablets in dose strengths of l5 mg and 3.0 mg. For the fourth dosing group there will be a matching placebo.

Tablets will be administered Fill) — 30 minutes before breakfast and HS (at e). Note that in the l.5 nig dosing group, subjects will receive placebo tablets 30 minutes before breakfast, and l .5 mg AFTmlOll HS (at e). To maintain the blind, all tablets will be labeled for “before breakfast” and c‘bedtiriie” administration. {£39237} Screening: Subjects will be screened with upper endoscopy (FGD) at Z~4 weeks.

Subjects who meet other inclusion criteria and have 5: l5 peak eosinopbil per HFF and have a global symptom score of > 5 and a 7~day recall Eli‘s/kl score of > 20 may enter the placebo run~ in. Subjects wl'io have an sed FFsAl score based upon a, daily diary, > 80% compliance daily diary, and >90% compliance with study drug and meet all the other inclusion criteria will be ized. Subjects will be randomized l:l:l:l to 3 active doses and placebo. {98238} The study will be conducted in three parts as shown in Figures 1 and 2. Part l and Part 2 represent a Treatment—Withdrawal Design. ln Part l, treatment efficacy is assessed. in Part 2, the effect or" withdrawal is assessed including Time to Relapse and difference in relapse rates between active ent and placebo. {unseat Part 1: Treatment (Day 1 to week 14). ts will be stratified by age (<1 l8 and 2 l8 years) and by concomitant PPl use during the study (“yes” or “no”); then randomly assigned to l of the 4 dosing groups (ratio: l:l:l:l). {99249} All subjects will come in monthly for routine visits, and for unscheduled visits should, symptoms worsen n visits. Subjects will be treated for l2 weeks and, undergo an EGD to assess histologic and endoscopic improvement. Symptom improvement will be assessed on an ongoing basis. EoE Responders, defined, as subjects who achieve a histologic response of < 6 Peak Eos per HP}? and no worsening of symptoms (e, g. an increase in weekly EEsAl score compared to baseline) or episodes of food impaction will be re—randoinized to Part 2 at week l4, Non—Responders, defined as subjects who do not meet the definition of se, will receive open—label (0L) 3 mg BID until week 28 with an EGD‘ at week 28. EOE Responders at the end of the OL period will be eligible to enter Part '3. Non—responders to CL treatment will enter a 2—week follow—up period. {@9241} Part 2: Treatmenn‘Withdrawal (week 14 to week 28). Roll Responders from Part l will be ized to either continue their dose or receive placebo in a 3: l randomization Placebo responders, which are expected to be few? will remain on placebo. Subjects who experience a worsening of symptoms (eg. return to baseline weekly EEsAl score or complain of ms worsening) or food ion will undergo opy at an unscheduled visit: Subjects with food impaction requiring endoscopy or a stricture requiring dilation will enter the 2-week ~up period and exit the study. Subjects deemed to be a relapse will be returned to their previous dose, except those previously on placebo who will receive 3 mg Ell}. Subjects who relapse on Study Drug will also e 3 mg BlD to avoid unblinding the study. The relapsers will enter Part 3. All subjects in the study at weeks l2, 26 and 52 will undergo endoscopy. lioE Responders at week 28 will ue to Part 3. Nonuresponders at the end of Part 2 will receive 3 ing Ell) when they enter Part 3. {98242} Part 3: Maintenance {week 28 to week 54). Non—Responders from Part l who respond to openulabel 3 mg BED will continue on this dose in Part 3. Note that this group will not participate in Part 2. Eoli‘ responders from Part 2 will continue on the same dose. Relapsers and non" responders from Part 2 will receive 3 mg BED in Part 3. Subjects who e leg. experience food impaction requiring opy or clinicallymsignificant worsening of symptoms) in Part 3 will o an unscheduled endoscopy, enter the 2-week follow-up, and exit the study. All continuing sub} ects will undergo endoscopy at week 52 and complete their final on treatment visit at week 54. {99243} Follow—up: (lmweehs after last dose). All subjects must have a final endoscopy within 3 weeks prior to entering —up. Exceptions include withdrawal of consent or contra—indication to endoscopy. Reasons for entering follownup include completing week 54, adverse event ing early withdrawal including food impaction requiring endoscopy, failed to respond to opennlabel 3 mg Ell), or relapsed in Part 3 {$8244} Pharmacokinetics: All doses of APT—101 l will be administered twice daily 30 minutes before breakfast and bedtirne with the ion of the 1.5 mg dose, which will be administered HS at bedtime or 30 minutes before breakfast. A tion PK analysis will be performed based on a combination of serial and sparse plasma concentration data {$8245} Population PK: Sparse PK s will be collected from all subjects (excluding subject +/— 3 days) of repeat dosing On Week 4, Day I (+/’~ '3 days) of the repeat—dose period, PK samples will be collected no more than l5 s prior to the morning dose, and at 05, 1.5, and 3 hours following the morning dose. The time of the night—time dosing (eg. bedtime) along with actual PK sampling time will be documented. {(39246} Intensive PK Subset to he performed in Part 1: At selected sites, 24- evaluable sub} ects (6 subjects per dose group) will undergo intensive serial PK sampling following a single dose on Week l, Day I and following repeat—dose administration on Week 4, Day l (Jr/v 3 days} On the morning ofWeek 1, Day l, suhj ects will receive a single dose of APT—l Ol l and PK samples will be collected no more than l5 minutes prior to the AM dose and at 0.5, l, 2., 4, 8, 24, and 48 hours following dose administration. NOTE: the r sample should be collected following the single dose and prior to the start of the —dose period. This sample would be collected on the visit when subjects return to receive medication for the repeat~dose outpatient period. {£19247} The repeat—dose period will start following collection of the 48~hour PK sample on Week 1 Day 3. ()n Week 4, Day 1 (-t/u 3 days} of the udose period PK s will he collected no more than 15 minutes prior to AM dose and at 0.5, l, 2, 4, 8 and 12 hours post AM dose, immediately prior to PM dose. NO'llE: the 12—hour post AM dose PK sample is ‘Optional’.

The llmhour PK sample should he ted immediately prior to the PM dose. Time of dosing (bedtime the preceding night and, following morning) along with actual PK sampling times will he documented). {@9248} Study Duration: This study has an anticipated recruitment period, of 12 months.

Sub} ects who enter and complete the study (Part l, Part 2 and Part 3) will he in the study for up to months. litltlichgl Study Population: The study will enroll approximately 320 adolescent and adult subjects diagnosed with Eoli who meet the entry criteria and will randomize subjects into 1 of 4 dosing groups (including o) of 80 ts per dosing group. {@9259} Inclusion Criteria: Male and female subjects between the ages of l4 and 75 inclusive Patients must have a diagnosis or presumptive diagnosis ot‘EoE, ing those patients with relapse, must he med by symptoms and histology; by historical documentation of failed treatment on 8 weeks or more of high~dose (e g. 40 mg Elli) proton pump inhibitor (PPl) either prior to initial diagnosis or documented subsequently A lack of response to PPI therapy is d as a, pealr eosinophil count 335 per l-lPF in at least one biopsied location alter the 3 weeks of high dose treatment. PPI therapy i'nay be continued during the study only if the subject was on PPI therapy at the time of biopsies from the ing opy. No new initiation of, nor alteration ot‘P‘Pl therapy is allowed during the study. {@8251} Subjects must have evidence of eosinophilic esophagitis defined by the PEAK esophageal mucosal eosinophil count ‘5 15 per high—powered field (EFF, 400x magnification) in at least 1 of the esophageal sites biopsied {Z 3 biopsies from each the proximal and the distal esophagus; a minimum of 6 total biopsies). Biopsies are to he obtained no more than 30 days prior to the Screening Visit, and slides must he received by the central pathologist within 30 days alter the Screening Visit or 2 weelrs prior to randomization. Eligibility will he based solely on the central pathologist’s assessment. {98252} The subjects must have a 7—day recall Global EoE score 3 5, as measured on a scale from 0 to l0 (0 representing no symptoms and lil representing most severe symptoms). {@9253} Subjects must have 7uday recall EEsAl score 2> 20 to enter the placebo runnin. For randomization, an increased EEsAl score based upon a daily diary is required and al symptoms of dysphagia (difficulty swallowing) at least 3 times per week within 2 weeks. {@9234} Exclusion Criteria: Known contraindication, hypersensitivity or intolerance to corticosteroids; any physical, mental, or social condition, history of illness or laboratory abnormality that in the investigator’s judgment might ere with study procedures or the ability ofthe sub} ect to adhere to and, complete the study; ce of oral or geal mucosal infection of any type; any condition affecting the esophageal mucosa or altering geal motility other than EoE including erosive esophagitis, hiatus hernia longer than 3 cm, and Barrett’s esophagus; use of systemic, oral or parenteral corticosteroids within 30 days, or inhaled or extended use of high—potency dermal topical osteroids within 30 days prior to: the geal biopsy required for ce to this study or EGD if done during the reening period; morning (0700 to 0800 hours, or as close to that window as possible) seruin cortisol level :15 lug/ill... (l 38 nntol/L); a plasma cortisol level of < l8 ug/inlc (497 ninol/l...) at 60 minutes with adrenocorticotropic e (ACTH) stimulation test using 250 ug cosyntropin, consumption of grapefruit juice during the treatment is prohibited; use of biologic immunomodulators within the past a months; use of calcineurin inhibitors, purine analogues (azathioprine, 6—mercaptopurine) within the past 3 months; contraindication to EGD or esophageal biopsy or narrowing of the esophagus precluding EGD with a standard 9 mm endoscope; gastrointestinal bleeding within l month prior to the Screening Visit or between the Screening Visit and the ization Visit; current chronic infection, imn'iunosuppression, or deficiency; history or presence of (frol'ii'i‘s disease, celiac e, or other inflammatory disease of the gastrointestinal tract including eosinophilic enteritis; current alcohol or drug abuse; female subjects who are pregnant or breastfeeding; sexually active s of child—bearing potential who do not agree to follow highly effective contraceptive methods during the study including the follow—up period. (abstinence is acceptable for adolescents}; female subjects with surgical menopause or menopause confirmed by ESl—l do not require contraception or pregnancy testing during the study; participation in a clinical study involving an investigational drug within 30 days of tlie Screening Visit. {98255} Methodology/Study Procedures are shown in Tables 4—7.

{M13256} Primary Efficacy Endpoints: There are 2 co—priniary efficacy endpoints for EoE Response {@9257} The percentage of subjects with a PEAK phil count < 6 HTEF at all biopsied esophageal locations at Week l2 and change from baseline in mean weekly EEsAl score. EoE Endoscopic Response and no worsening of the mean weekly EEsAl score will be the basis for ng Part 2. {@9238} Secondary Efficacy Endpoints: EoE Response will be ed also at week 26 with comparisons to placebo to assess the impact of treatment—withrlrawal. EoE Response will also be assessed at week 52 by dose and subgroup. EoE Remission and, Response will also be assessed after 12 weeks of GE treatment in nonnresponders to Part l. {@9239} Sustained EoE Response will be assessed at Weeks 24 and 52 for subjects remaining on the same dose: ment of Relapse and Treatment Eailure; non-Response at each endoscopic endpoint; relapse on Placebo in Part 2; percentage of subjects requiring emergency endoscopic food disinipaction by dose and part of the study; percentage of ts requiring esophageal dilation. {oozes} The effect of re—treatrnent will be assessed by assessing EoE Response in Part 2 Relapsers at week, 52 by treatment group. {(38261} The percent of subjects with PEAK Eros per HPE < l and < 15 at all major time points where EoE Response is assessed {(38262} The t ofsubj ects with mean weekly EEsAl score < 20 at all maj or time points where EoE Response is assessed {@6263} Endoscopic changes will be based upon the EREES score based on 5 endoscopic es: edema, furrowing, exudates, rings, ures and physician assessment of overall disease activity (absent, mild, te, severe): the percentage of subjects with overall assessment of ‘improved’, ‘no change’ and ‘worsened’ from baseline (Screening Visit} at Week l2, 26 and 52 as well as at the end of GE treatment of nonuresponders from Part l; the change from baseline in 7~ day Global EoE Score which will be assessed before run—in, baseline, week l2, week 26 and week {98264} cohtnetlc Endpoints: Steady—state Population PK e PK and intensive PK) analyses; single—dose PK analyses. {98265} atory nts: Collin’s l-listologic Score for EoE for all biopsies performed, the change from baseline will be assessed; evaluation of quality of life based on the EoEmQOLnA at weelt l2, 26, 52 and week 12 of 0L treatment by dose and subgroup; patient’s assessment of symptoms compared to the previous visit. This Question will he assessed at weeks 8, l2, l8, 26, 30 and 52‘ {09266} Safety: Safety will be assessed by monitoring and recording all treatmentnemergent adverse events (lEALEs), 'l'EAEs leading to Withdrawal and serious adverse events (SALEs). All 'l'EAEs will be coded based upon the MedDRA version l4.0 classification of adverse events (ABS) and classified hy severity (mild, moderate, ) and relatedness to study drug (related, or not related) by the lnvesti gator TEAEs occurring within 2 days ofa dose change will he attributed to the previous dose. This time of attrihution may be altered based on the half—life of the dose. al ations will he performed to document the ne condition of the t and to highlight changes related. to AEs. Vital signs will also be assessed at all visits and clinically significant deviations will be reported. {£39267} Routine laboratory tests will he performed throughout the study including hematology, blood chemistry, urinalysis, electrocardiograms (ECGs) as ted in the Schedules of Assessments. Clinically icant s in laboratory tests or ECGs will be summarized. {$49268} (Tantra! Asians: Abnormal AM cortisol, urinary e or serum glucose would necessitate following the subject to resolution. CRFs should capture presence or absence Oflfl‘lO‘Wll glucocortieoid AEs such as rnoon taoies, acne, hirsutism, mood swings, insomnia or depression. lCF should highlight that stress steroids may he required during significant medical illnesses.

ACTH stimulation test (cosyntropin 250 mcg) should be performed at baseline and Week l2, early withdrawal and at week 52 for all subjects. ACTH test should he performed in all subjects with plasma cortisol > 5 L(l38 rnrnol/L). All subjects with positive tests should he excluded. Any positive results at the end of treatment should be followed to ry of adrenal function. The number of subjects discontinuing t‘or l-lllA suppression or positive AC'l‘l-l stimulation tests will be summarized. The Sponsor will provide each site and investigator with guidelines for safety follow~ up and document restoration of adrenal function in all subjects demonstrating evidence of hypercortieism or HPA axis suppression during the course of the study. ts under age l8 will be evaluated for growth parameters such as height, weight, body mass index (BMl) and ponding :zuscores. The safety endpoints of interest are: frequency of treatment emergent adverse events (TEAEs), TEAEs leading to withdrawal and ent—emergent serious adverse events , as well as the percentage of subjects with serum cortisol level 5' 5 u i/dL (l38 nmol/L) or positive ACTH stimulation test (serum ol < l8 ug/mL (497 nmol/L) at 60 minutes). The number of subjects discontinuing for HPA axis suppression will be recorded. {00269} Statistical ltlethods: Sample Size Detemzimztt’on; Eor Part l, sample size determination is based on the planned comparisons between each dosing group with respect to EOE Response: l) the percentage of subjects with a peat: eosinophil count < 6 Eosinophil/HPP at all biopsied esophageal locations at Week l2; and 2) Change from baseline in EEsAl score. lf for the present study, after l2 weeks of treatment, the tage of placebo treated subjects with a peak eosinophil count < 6 xllPE at all biopsied esophageal locations is assumed to he l5% for placebo and 6t % for active arms with an expected delta of 45. For the mean weekly EEsAl score, the EoE Response for symptoms at week l2, we assume a placebo rate of 35% with an expected efficacy of 65% in the active arms with an expected delta of 30%. Based upon an equal randomization, approximately 60% of subjects will enter Part 2 of the study. ln order to ensure that the sample size is sufficient to detect a delta of 30% in Part l and to ensure ient ts enter PART 2 for analysis assuming 20% of active and 80% of placebo develop a symptomatic relapse, a, minimum of 320 subjects will be enrolled (30 per arm), With 320 per arm, assuming and overall dropout rate of 20%, we assume that approximately 35 subjects per active arm will be evaluable for assessment of sustained remission at weelr 52. {(38279} The primary is population for efficacy is the ~to—treat (lTT) population, defined as all randomized subjects. The analysis population for safety is the safety population, defined as all subjects who receive at least one dose of study drug. The singleudose PK population will be defined as all subjects in the HT population of PART 1 who are randomized to one of the three AP'lll Oll dosing , take their first dose of APT—l Ol l, and have at least one PK sample included in the final singleudose population PK analysis. The ustate PK population will be defined as all subjects in the HT population of PART l who are randomized to one of the three ll arms, take their dose of APT—ldll that corresponds to the steadyustate PK sampling period, and have at least one PK sample included in the final stead ustate population PK analysis.

Additional per protocol analysis populations who complete Parts l, 2, and 3 and 0L treatment may be defined in the Statistical Analysis Plan (SAP). Baseline and aphic information will be summarized using descriptive statistics for continuous and ordinal variables (e.g age, weight, height) and counts and percentages for categorical variables (eg, sex, race). {00271} Primary Efficacyfor Part I {00272} There are two compriniary efficacy endpoints for l’AR’l‘ l: the percentage of subjects with a peal: eosinophil count < 6 /HPF at all biopsied esophageal locations at Week l2; and the change from baseline in mean weekly EEsAl score at weeli: l2. To preserve the overall level of icance at 0.05 for the study, each of the two co—primary efficacy endpoints will be assessed at the 0.05 level. {00273} For each co~prirnary endpoint, the y treatment comparisons of st are the comparisons of each APTdOl l dosing group versus placebo The efficacy hypotheses of APT— lOl l versus placebo will he tested in the ing order: {00274} H0: p ofAPT—lOll 30 mg Ell) = p ofplacebo {00275} Ho: _u of APT—lOll l5 rng Ell.) = p of placebo } Ho: ii of APT—l, Oll l5 mg HS = u of placebo {00277} where it denotes the proportion of subjects with a. peak eosinophil count < lS/HPF at all biopsied esophageal locations at Week l2 for one co~prirnaiy efficacy end—point and {i denotes the change from ne in mean weekly EEsAl score at Week l2 for the other co—primary efficacy endpoint. {00278} The statistical testing will begin with the comparison of APTd Ol l 30 mg BED vs. placebo with respect to each of the two mary efficacy endpoints, lf both comparisons are statistically significant at the 0.05 level, the next lower dose will he tested vs. placebo for both co— y efficacy nts. The procedure stops after the first pair—wise coinparison yields a non— statistically significant result for one or both of tlie comprirnary efficacy endpoints. Since statistical testing of treatment differences between Alff—lOl l and placebo is to he performed by means of a priori d hypotheses, no adjustment of the significance level for multiplicity is required. {00279} The pair~wise comparisons between each AP’lll Oll arm and placebo with respect to the proportion of subjects with a peak eosinophil count <16 .I’l-le‘ at all biopsied esophageal locations at Week l2 will he performed using the n—Mantel"llaenszel (Civil-l) test adj usting for the two randomization stratification factors: age group and Pl’l use, and also geographic region (North America; non~North America). The pairuwise comparisons between each AP’f—lOll arm and placebo with respect to the change from baseline in mean weekly EEsAl score at week 12 will be performed by comparing the corresponding least squares means from an analysis of covariance A) with treatment, the two randomization stratification factors, and the geographic region in the model as fixed effects and the baseline SQ score as a covariate. The method will be used to adjust for multiple comparisons. The sample size has been increased accordingly.

} If superiority of at least one of the APT—101 l dose groups over placebo is demonstrated for the two conprimaiy endpoints, the dosenresponse relationship will be assessed for the two co—primary endpoints with total daily dose among the explanatory les in the riate statistical models. {00281} Efficacyfiw (33L Treamzent {00282} A, similar approach will be taken as in Part l for non-responders from Part l who receive 0L treatment with 3.0 mg BID, {00283} Efficacy/for Part 2 {00284} There is one primary efficacy endpoint for PART 2, the tage of subjects who relapse on or before the end of the double—blind treatment in PART 2, d as a return to baseline in EEsI-‘tl score or a verbal complaint that “My symptoms have worsened and are about the same as when I entered the study”) and a peak eosinophil count }: lid-{PF in at least one biopsied geal location on or before the end of the assessment at week 26 Part 2, To ve the overall level of significance at O. 05 for the study, the statistical testing for the efficacy endpoint in PART 2 will be performed only if statistical significance in favor of at least one APT~l Oll dosing group over placebo is demonstrated for the two PART l couprirnary efficacy endpoints.

The efficacy hypothesis of APT—l Oll 3.0 mg QD versus placebo is as s: gasses; Ho: a at 'll l 3.0 mg on a of placebo {00286} where u denotes the proportion of subjects who e on or before the end of the 12—week doubleublind treatment in PART 2. The test will be conducted at the 0.05 level of significance using the CMl-l test adiusting for the two randomization stratification factors (from Part l), phic region, and the prior treatment the subject was on before being randomized into douhle—hlind treatment in PART 2. The prior treatments are placebo, APT—Kill l5 mg Ql), l5 rng Bil), and 3.0 mg Bill for randomized subjects in Part l. {@9287} Efficacy-for Part 3 {M13288} Sustained EoE. Response will he assessed in the subgroup of subjects who achieved EoE se in Part l and Part 2 and who complete the week 52 evaluations. {00289} Secondary and Empiomrorj! Efficacy {@1299} Statistical tests to compare each Alyl'nlOll dosing group to placebo will be performed for the secondary cy nts, but the corresponding p-values will he considered as descriptive rather than inferential. The secondary endpoints will he analyzed in the same manner as described above for the primary cy endpoints, , using CMH test for categorical endpoints and, ANCOVA for change or percentage change from baseline endpoints, except for the endpoint of time to relapse after initiation of douhle-hlind treatment in PART 2, which will he analyzed using Kaplan—Meier methods. No statistical testing of exploratory etiicacy endpoints will he performed. {coast} Safety {@9292} The incidence of TEAEs will he summarized by system organ class and preferred term. Separate summaries by maximum severity and relationship to study drug will he provided.

The nce of TEAEs leading to withdrawal from the study and treatment—emergent SAEs will also be summarized ln subjects who change dose groups, the TEAEs will he attributed to the previous dose, if they occur within 2 days of the change. The attribution period may he altered depending on the hall'llife of the dose. Clinically significant changes of ial clinical interest in clinical tests will he summarized including hematology, chemistry, urinalysis, ECG, ol, vital signs, growth—related assessments for adolescents, and hone mineral density. No tical testing of safety nts will he performed. Shift tahles may he performed, if needed. {(38293} Pharmacoitmeflcs and Pharmacodynamics Analysis {98294} In this study, all doses of AP'l‘ulOll will be administered twice daily e hrealrfast and at bedtime) with the exception of 1.5 mg daily, which will he administered QD at bedtime with placebo administered after ast. A population PK analysis will be performed based on a combination of serial and sparse plasma concentration data. Previous serial PK data for Al3'l"—lOl l may he included in this analysis to facilitate development ol‘a hase PK model. {@9295} Population PK analysis will he performed using the nonlinear mixedueffects software, NONE/HEM, Version 7.2.0 or later (lCON Development Solutions, Ellicott City, MD) or other appropriate nonlinear rnixed~effects modeling software. The structural PK model will include Clo/F and V/F as fixed~effect parameters. ln addition, the between—subject (intersuhject) ility in the parameter estimates and the random residual error in the data will he estimated with riate error models. The optimal base model will he ed according to the standard criteria such as minimum obj ective on value and diagnostic plots. Given the relatively small number of subjects in this study, a covariate analysis is not planned. The relevant information from hioanalytical and clinical datahases (eg dosing times and ng times) will be ted and integrated for generation of the population PK input file(s). All possihle efforts will he made to capture any missing information. Any additional information ohtained regarding missing data and the procedures followed to handle any missing data will he documented and discussed in the clinical study , After the final model is constructed, secondary parameters such as AUC and Cmax will be calculated to characterize the extent of FF systemic exposure. Additional simulations may he performed, as necessary, to inform decision making for future studies. in general, the tion step will e creation of data files using dummy suhjects with desired sampling times and dosing regimens, running simulation with desired numher of replicates using the final model output parameters in the control file, The output from the final population models including appropriate diagnostic plots, listings, and summaries of P’K parameters will be generated. in addition, graphical and tabular presentations of any PK simulations will he produced. {882%} As data permit, exploratory analyses assessing the relationship between systemic exposure to Fl? and changes in cortisol levels also may he performed as described above. ial atory PK/PD analyses will be used to tate selection ofsafe and effective doses for future studies.

Seiretiaie of Assesamerits: Screening through PAR 1 Asseasments i Procedures: ViSIfiI‘i‘ iSereeniag Ronv ization Weak Week Week Week Unsehe Eariy i in 4 a 12 14 daied Withdrawal“ informed consent si inciusion/excius ion criteria Demographics, medicai, surgioai history, medication itant exanniiation Vital signs ' I I g A , A , ,4 ,4 , i i , : , 1_______________________________________+____________________________________ _________________ . ________________ . _________________ _________________?_____________________________________________________ Chemistry; ' I r I I I I Hematology ; Serum cortisoi Resui i optional (AM fastin 39 tsf ‘ Urinaitsis Electrocardiogr arn Standard '5 Z—Eead Population nacokineii intensive PK Pie—Dose EGD with iiiuitipie esophageal es“ j EndoFiip will be peiformed at seieeted sites at the iiino of endoscopy as part of a substutiv Sehefinie 111.1111sneesn1en111: 8111111111111 1111111111 PART 1 Assessssnenm 111111 Frecedn 113s ing 111111~ 1R11ndemiza110n Week Week Week Week Unsehe E3113; 1 i ' ‘ (11111313 11‘11111111111211” [1111111 pregnancy test for women of Menopausal 11011113111131 111 5011111111110 01111 1 ACTH I1 . [10111101121 1112111011 test 11‘ (11013211 EOE See 1e EOEQOL-A 1111111110131111401 Sv 111 101115 "3911.63.53.83:____________‘1_______________________________________________________________________________________________________ ______________________________________ ); Drug Dispensed D1111; 121nd accountability (Study 13mg 1:01np1111nce assessment) Dz111y Dimy Compliance Assessment 21. EndeseepV may be perfermed at a sepa1a1e V1311 Results 11f 1113111111gy 11111 be 1equ1rec1 a1 randomization and 11eek 14 b. 9311:1111 3111111111 be seen 1n the 0111131: 111 7 (131501 1319191111111:111on 111 the need 11:1 whhdraw 11111 patient If 1111s is 1101 pess1b1e due to 1111 SAE (11 other unforeseen e1reun1s1a11ee, 111111 may he completed 111111 a phone 11111 the 11111113111; :11 famfiy member. Becamentanen efWhy the patient 131111111 1101 ceme 1n 5111111111 he placed 111 1he patient reeerd. c. The reason 1012111 unscheduled 171511 11111 guide procedures, at the (115011311011 of the P1. 11. Confinnatmn 111111 the 11111113111 S1111 meets 11s1011/exel1151011 11111131121 based upon Deny EEsAI 1n 211111111011 10 01he1 c111e1111 To be drawn as close as possible to {)8th hours. Patients must be fasting for an eight (8:)—hour period prior to the serum cortisol assessments. Blood may be drawn for AM Serum Cortisol +/- 2 days of scheduled visit to accommodate accurate g. Other blood draws scheduled for the visit may be done at, the same time. ll abnormal serum cortisol level is reported at liinal on treatment Visit; additional monitoring and ACTl-l test may he required.

A sample will he obtained at Weeli 4 in all subjects excluding those in the intensive PK subset; no more than l5 minutes prior to the AM dose and at 0.5, l5 and 3 hours ing the AM dose.

The time of the PM dose (_bedtime preceding) and AM dose along with actual PK ng will be documented h. Approximately 6 subjects per dose group will undergo ive PK at selected sites between Weeks 2 and 4: Phi samples will be collected no more than l5 s prior to Alvl dose and at 0.5, l, 2, 4, 8 and l2 hours post AM dose, immediately prior to NW dose. NOTE: the lZ—hour post AM dose PK sample is nal’. The lZuhour PK sample should be collected immediately prior to the PM dose. The time of the PM dose me preceding) and AM dose along with actual l’lfi sampling will be documented.

Can be done up to 30 days prior to Screening Visit (in absence of systemic or inhaled? intranasal or high-potency dermal topical corticosteroids within these 30 days prior to the Screening Visit). lf a previous ogy is considered not able, an additional Screening Visit must be scheduled to perform EGD and biopsies during the Screening Period, The results from the central pathologist must be available before randomization thlS must be available or able to be performed from an endoscopy report for any standard of care cndoscopies as well lf the t is withdrawing from the study due to lack of cy or other reasons, the investigator may perform an EGD, if clinically indicated.

All subjects o a ZSOng ACTl—l stimulation test at baseline and EST or at early withdrawal.

An ACTH simulation test will also be performed during the study at an optional visit for subjects whose seruin coitisol level is confirmed by two blood draws as 535 jig/(ll; G38 innol/L) or if they have signs and symptoms of hypercortism to assess for hypophyseal—pituitary—adrenal (HPA) axis suppression of potential clinical concern.

Bone age to be performed on all adolescents (<1 l8 years of age at randomization); exceptions include female subjects who have completed their linear growth or male subject who have :uot completed their liner growth by l8 years of age], at the discretion of the Pl.

Table 5 Schedule of Assessments: PART 2 Assessments and ‘6’1811‘ l’rnccdures EloE Responder in PART 1 No contraindications to continue Scheduie of Assessments: PART 2 Assessments 11:31} V351'? yrncedu res; W66}: 14 \NGE‘DR Wank Week \NGE‘DR Unschtxiuiefi Bari}; Ramnmizmim 3.8 22 26 221 Visit“: walb 1121117 E 98 + 3 19:: i 22113:;3 3 i E >80% compiiant with diary >9G% compiieantz with drug Concomitant niedication(s) TR ‘v‘v’ec‘k 12 ’i X X X X 7 X X X TR week I: X X X X Chemistry; Hematniogy', 1R week, 12. X X X X X LFTs : Scrum cortisol !AM TR week 12 X Rasnh‘sf Optional X 1615:1110? : X X X Ficctmcardm5121111 — X X Standard 12463143 Population I Phannztcokitietics d?) T 1 EGD with multipie TR Week 12 i geal biopsics'‘ EndoFlip at selected sites as rtrtoiwubbmdy . . _______________________________+ ACTH stimulation test (250 TR Week 12 X Results alk X i L )k 5 EOEQOLA and Global EGE SVmytoms i i i __________________________________________________________________________________________________________________________________________________________________+_______________________________§_____________________________.¢ 1 . .

. : Drug return and accountability (Study Drug comptiance assessment) WO 35393 Scheduia 0f Assassmmzs {It}; i eatmmt Assessments mm mefiums WSW Wfififik 14 Week Week Wee Wee EUnscheduk: 18 22 26 28 Visiic i Wiihdmfwaib ________________________________________________________________________12 $8 + 3 126 d; 154 i- 192 3: 220 j; 3 3 3 3 E E0E NONnRespOIidei' in PART Li X >80% compliant with diary >90% com iiant with studv dmo TR from Part 1 , TRfrom X X X X A , ~, A '1 ' “‘ ' ' Part 1 ‘r Part E i : TR from X X Part 1 E Part 1 : TR from X X Lnnaiy R15 ______;i::2_r_é__£________________________________________________________________________________________________________ Electrocardiogram Standard ER from iii—lead tion Pmmiacokinetics i awed? Intensive PK (Needed?) EGD with mufiiiiple esophagsal bicpsiesa"i EiidoFlip at selected sites as part of sub 511:de Urine pregnancy testfm women of CB? x . X "'X x X __—-— X _---><1 X Drug mium and accountabiiiiv X (Study Dmg compiiance ' : assessment) ________________________________n.

Schedule 0f Asgeasment: EEXRT 3 Asseesmenm VISIT and l’reeeainree Week 28 " I ' ' ' ' H 1e , Unseneeiuie Barfly Fniiowmp imiio ‘: d Withdrawn} Any Visitc “ n subject 0r assigned : g : wiin Erniy rinse ‘awa i a 1 220% 126283 154 192 220 2weeks i i 3 i i 3 j; 3 nfler last : (inse inclusion Criteria X for PART 30 j Concomitant TR week 26 X X X medication(s) Physical TR week 26 X X X Vital sins : TR week 26 X i Chemistry; TR week 26 X Hematology ; : Serum eni‘risni TR week, 26 X X (AM fastind e .

Urinaivsis TR week 26 X Eliectroeardiegra TR week, 26 X X In — Standard 12- lend E - Population Pharrnncokineiic s Needed?) g -- not: with TR week 26 Resuits X multipie : esophageai bio 35.1658” 1 Urine pregnancy X X X test for women of ACTH i Results Optionalk X stimulation test 7—dav EEsAI EIEZSAI Dan E Globe} EOE X Score L—A and X X X Giobal EOE , , 5211mm________________i______________________________________________________________i_______________e Seltednle of Assessment: PART 3 ments VISIT and Freewares Week 28 Wee Wee Unscliednie i Early Follow~up Raurlonrizatin l : . k 52 lrS-i Withdrawal. Any l l E l ‘5 n t : Drassigneri witlilfilarly dese Withdrawa a i : 220 + 3 1% 220 e- 3 l 4- Study Drug Dis ensed Drug return and accountability (compliance assessme at) am see previous footnotes or Subjects rnee’t Inclusion Criteria R'l‘ 3 Complete PART 2 as a Responder continue on same dose Complete PART 2 as a Non-Responder — Assigned to 3 mg BID Relapse en Placebo — return to prior dose in PART 3 Relapse in PART 2 on placebo — Assigned to 3 rug BID in PART 3 Complete 0L 'i‘reatnrent as a Responder Continue 3 mg BID Complete 0L Treatment as a Non—Responder Exit Study and enter —up Peiiod Earrmple 2_ A randemizerl doublewblmcl, placebowcom'rolled trial of a 'j’lm'icrrsone propiomrz‘e orally disintegrating tablet in Artlulr and Adolescent Patients: with Eosmapliilz‘c Esophagus.“ A Phase 1/ch Safety and Tolertrbilm’ ly {$9297} BACKGRGUNB dz. Alli/ES: Eesinophilic esophagitis (EOE) is a chronic immune" mediated disease characterized by ce of tissue philia and ms of esophageal dysfunction. This was the first al study at APT—1011, fluticasene prepionate (PP) a novel orally disintegrating tablet (DDT; that evaluated the telerahility and safety of 2 dosing regimens of APT- 1 O l l compared to placebo (P30) in ad oleseerit and adult EoE patients. {@9298} METHQDS: Subjects were randomized l:l:l t0 receive either APTmlOll l5 mg BID [‘8le (n=8), APT~lGl l 3.0 mg QD [QDl (11:8)a or P80 (n=8) Patients underwent esophage— gastrouduodenoscopy (EGD) with esophageal biopsy at ne (BL) and end of ent {EST} {week 8) to assess change in median eosinophil count. ary endpoints included improvement in endoscopic features as measured by the EoE opic nce Score (EREFS) and Patient Glohal Assessment of Disease Severity {PatGA}. Safety was also assessed. {some} RESULTS: Twenty four subjects (including 9 adolescent patients, 3 in each treatment arm) completed the 8—week double—blind period. Baseline and EOT median esophageal phil counts (cells/min?“ of the high power field), median EREFS score. as well as median PatGA for PEG: BID and Q1) groups are shown (Table 8). At EOT: the median geal eosinophil counts were significantly decreased from BL in biopsies of patients given Al’TnlOll (both regimens) but not in those of patients given placebo. There was a significant reduction in the l median EREFS (when compared to BE) in both groups of patients given AP'l‘m'lGll, but not plattebo. There was a significant improvement in Patient Global Assessment of Disease Severity in ts given APT-ml l BID (trend in group given QB)? but not placebo. Table 8 shows the median (and IQR) esophageal eosinophil counts as well as median EREES score. P~value of < 005 is considered to be significant.

Table 8 EREFS score PBO BL PEG EOT APT-tori 1.5mg are nor . . .. 0.5 0—2.5 ,. . 2.0 (in so; p—values Pee (Terr vs nor o. 3261 . .t iii i 67 p—Values Bio QBL vs not} ooooz . coma pvvalues on ’BL vs nor 0.0111 ‘ . 7 noses {@9399} The rates of treatment emergent adverse events ('l'EAEs} were 75% (PRO): 75% (APT—1011) (QB). All TEAEs were of mild intensity except for 1 each of moderate fatigue and moderate depression by l suhject in the placebo group. lllll3lll} CONCLUSEGNS: Eightuweel; treatment with Al’TulOll is well tolerated. Use of M9'l'ulOll in adult and adolescent EOE ts led to significant reduction in esophageal eosinophilia and improvements in the severity of EoEuassociatecl endoscopic findings. ple 3 w A Randomized, —Blind, Placebo"Controlled anging amid/faintemmce Study ofAPIL1 01 1 in Adolescents arid/ldulm with Easinophilic Esophagitis (EoE) {@392} Primary ()hjective: te the efficacy of APE—10H in adolescents and adults with eosinophilic esophagitis (EoE). iillll3ll3l Secondary ()hjectives: To evaluate the safety of APT—lOll in adolescents and adults with EOE; To define the dose—response of APT—Ml l; To select a tlose(s) for Phase 3; To te individual pharmacokinetics of AP'l‘~l0l l in a subset of adults and adolescents with EOE; To evaluate the population pliarmacohinetics (PtipPK) of APT—l Gl l in patients with EoE; Evaluate maintenance of efficacy and long~term safety; To evaluate the effects on endoscopic appearance using the EoE Endoscopic nce Score (EREFS) (Hirano ZOl 5; van Rhijii 20M); te change from baseline of the 7—day EEsAl and Global EOE Symptom Score. {@9394} Safety Objectives: To determine the safety profile of acute and chronic administration of El? and its effects on the HP axis. {99395} Exploratory ives: Evaluate the change from baseline in the EOE Histology Scoring System (EoEl-lSS) score (Collins 20%); To te Quality of Life via the Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE—QolmA). (Taft ZOl l); Evaluate Symptoms compared to prior s) (7 scale); To te PK/?D(cortisol) and exposure response (efficacy) relationships. {@8396} Study Rationale: Doses from l5 ing HS to 3.0 mg Ell) will be explored to define the exposure—response of Alyf—lOl l and the minimum effective dose while remaining below any clinically significant hypothalaniicupituitaiy—adrenal (EPA) axis effects. {$19397} Study Design {@0898} This is a randomized, uhlind, placebo—controlled dose~ranging study of 3 total daily doses (l5, 3 and 6 ing) of Al”l7—l0ll administered as l5 mg HS, l5 ing Ell), and 3.0 mg BID compared to matching placebo in 320 adult and adolescent subjects with EoE.

Maintenance of efficacy and long—term safety will also he evaluated. {98399} Eligible subjects will he l4u75 years of age sive) and have a diagnosis ot‘EoE (:_ lfi Peal; Eos per l-ll’F) after proveh failure of 8 weeks or more of high—dose (ie. twice daily dosing} proton pump tor (Pl’l). Subjects who have not had an adequate trial of Pl’l therapy should have this med BEFGRE screening for this study. l’Pl therapy may be continued during the study only if the subject was on PPI therapy at the time of signing an informed consent.

No new initiation of, nor alteration of Pl’l therapy is allowed during the study. Suhj ects must also be symptomatic with dysphagia and have a 7mday recall Global Eol'i symptom score of > 3 AND report at least 3 episodes of dysphagia in the past 7 days AND no exclusions for the study to enter the 2—week baseline symptom assessment. The subjects must report dysphagia at least 3 episodes per weelr for each of the two weeks of the baseline symptom assessment in the daily diary to he eligible for randomization. {99319} In PART L, subjects will he stratified by age (< l8 and 23; 'l 8 years) and by concomitant PPl use during the study (yes or “no”); then randomly assigned to l of the 1l- dosing groups : (l .7):l:l:l). lllllfill} All subjects will come in monthly for routine visits and for unscheduled visits should symptoms worsen hetween visits, {99312} The study will be conducted in several parts: {00313} Screening: {@8314} l-4 weeks including upper opy (EGD) {llllSlS} Baseline Symptom Assessment: 2 weeks {@8316} have a Global Eel? symptom score of> 3 AND report at least 3 dysphagia episodes in the past 7 days AND have no exclusions for the study may enter the baseline m assessment {983W} Randomization: Subjects must report at least 3 dysphagia es per week for each of the two weeks of the haseline m assessment in the daily diary, have 2> 75% compliance with daily diary and have 3 l5 Peal; Eos per l-lPF and meet all the other inclusion and exclusion criteria will he randomized. ts will be randomized l.7:3 for o to active doses. Response adaptive randomization will he used among the active doses which will be updated at each interim analysis. {983%} Subjects will he stratified by age and current Pl’l use.

WO 35393 {983%} The l protocol is shown in Ti‘igures 3 and 4. PART l represents induction of EoE response and PARTS 2 and 3 will assess maintenance. {98.3le} abel treatment will be offered to non—responders in PART l. {(130321} 1’2de 1.: ent (Day ,1 m Wéteir I4) {W322} Subjects will be treated for l2 weeks and undergo an EGD to assess histologic and endoscopic improvement. m improvement will be assessed on an ongoing basis. EoE Responders, defined as subjects who achieve a histologic response of =< 6 Peak Eos per HPF and no worsening of symptoms (ie. no increase in dysphagia based upon the daily diary compared to baseline) or episode of food impaction, will enter the PART 2 maintenance at week 14. This part will incorporate an adaptive sample size and response adaptive ization within active arms. interim analyses will he conducted frequently after lot) subjects are ized, in which ization probabilities are modified and early stopping criteria evaluated. {$9323} Qpen—Lebel (0L) Escarpment (Weeks 14 to 23) {(39324} Non~responders (suhj ects who do not have a histologic response and/or have worsening of their dysphagia) at week l4 will receive open—label (0L) 3 mg BID until week 28 with an EST) at weelc 28, and then if they are responders at the end of the UL period (same tion as above), they will be eligible to enter PART 3, Non-responders to 0L treatment will enter a < follow—up period and then exit the study, {@8325} PART 2: Maintenance (Week l4 to Week 28) {1949326} Hot? Responders (histologic se and no worsening of dyspliagia) from PART l will continue on their same dose as in PART l . Placebo responders, which are expected to be few, will remain on placebo. Either worsening of dysphagia or food impaction will prompt an endoscopy at an unscheduled visit. After the endoscopy, all “relapsers” will immediately enter PART 3 except those with food impaction requiring endoscopy or stricture requiring dilation.

Subjects with food impaction ing endoscopy or a stricture requiring dilatation will enter the 2—week t‘ollowutip period and exit the study. All subjects in the study at week 26 will undergo endoscopy. EoE Responders at weelt; 28 will continue to PART 3. Non—responders at the end of PART 2 or early relapsers will receive 3 mg Ell) when they enter PART 3. {(130327} 1’2de 3.: M’aintenance (Week 28 in Week 54) {99328} NonuResponders from PART l who respond to open—label 3 mg Bill) will continue on this dose in PART 3. Note that this group will not participate in PART 2. {98329} EoE Responders from PART 2 will ue on the same dose. {(130339} Non~responders and early relapsei's from PART 2 will e open—label 3 mg fill) in PART 3 {09331} Sub} ects who relapse (food impaction requiring endoscopy or clinicallynsignificant recurrent symptoms) in PART 3 will o an unscheduled endoscopy and enter the 2—week followmup and exit the study. 33%le All uing suhj ects will undergo endoscopy at week 52 and complete their final on treatment visit at week 54. {$9333} follow—up (2 weeks after inst dose) {99334} All subjects must have a final endoscopy within 3 weeks prior to entering follow~ up. ions include: withdrawal of consent or contra—indication to endoscopy. Reasons for ng follow—up: Completed week 54; e event requiring early withdrawal including food impaction ing endoscopy; Failed to respond to openmlahel 3 mg Till); Relapsed in PART 3. {00335} Pharmacokinetics: Tn this study, the l5 mg BID and 3.0 mg BIT) doses of APT~ lOl l will be administered at least 30 minutes AFTER breakfast and at bedtime, (at least 2 hours after the evening meal): The l . 5 mg dose will be administered at e (at least 2 hours after the evening meal). Subjects receiving the l (5 mg dose will receive placebo in the morning at least 30 minutes AFTER breakfast. No food or drink will be permitted for at least l hour alter dosing. {(38336} A combination of intensive PK sampling from a subset of subjects and sparse PK sampling from the remaining suhj ects will he collected to characterize FP exposure in the patient population Non cornpartrnental analysis (NCA) will he performed on the intensive PK data and a population PK analysis will he performed based on a comhination cl" intensive serial and sparse plasma tration data. {@8337} Intensive PK: Intensive PR serial sampling will he performed at baseline and at Steady—State in a subset of adult subjects (:8 per dose group) and in a subset of adolescent subjects (approximately 5 per dose group) at preuspecilied PK sites. These subjects will take the daily close {both tahlets} on Day l. Blood samples for determination of tluticasone plasma trations will he collected se and at 0.5, l, 2, 4, 8, and l2 hours following the morning dose on Day l and Week 4. Steady—state samples may he collected at the Week 8 or l2 visit if the subject cannot stay for l2 hours on Week 4. Collection of intensive PK samples over a l2~hour period is related to the BlD dosing le and the need to avoid an inpatient stay for these EOE patients. {@9338} Sparse PK; Sparse PK samples will be collected from all adult and adolescent sub} ects (excluding suhj ects in the intensive PK Subset). A baseline pre—dose sample will he taken prior to dosing on Day l. At Weeks 4, 8 and l2 of repeat dosing the suhj ects will take their AM dose at home and will have two samples taken during their scheduled visit. One sample will be taken upon arrival to the site and another sample taken l to 1.5 hours later ately prior to leaving the site. The time of dosing the prior evening (bedtime of preceding night) and the time of the morning dosing (_the day of planned visit) will he recorded. The actual PK sampling times also will be nted. Sites will he encouraged to vary site visits throughout the day. Due to the variability of site visits, the sparse PK samples will be taken to typically cover a large portion of the l2— hour post~dosing period.

} Study Emotion: This study has an anticipated recruitment period of approximately 12- l8 months. ts who enter and complete the study (PART l, PART 2 and PART '3) will he in the study for up to l/il months.

{MB/ill} Study Population: The study uses an adaptive sample size, with a range of l60 to 320 adult suhj ects diagnosed with EOE who meet the entry criteria. The study is expected to enroll approximately 25% females and 5% elderly subjects. {llllddl} Inclusion Criteria: {@8342} Male and female subjects P: l4 and S 75 years of age at the time of informed consent {@8343} Have signed the informed consent form (lCE) (parent or guardian must sign when applicable) and assent form ired for adolescents under ill or legal age of majority per local law) and willing and able to adhere to all study procedures. {@8344} sis or presumptive diagnosis olTEoE, must he confirmed by symptoms, and histology; and by historical documentation of failed treatment on 8 weeks or more of high—dose ) proton pump inhibitor (Pl’l). (ie. 20 mg BID omeprazole or 20—40 mg Ell) of an approved prescription Pl’l. Maintenance or OTC doses are too low) Documentation of PM failure prior to initial sis OR by documentation ot‘PPl failure at the time of screening. A lacl: of response to PFl therapy is defined as a peak eosinophil count 2 lS/l-lFF in at least one biopsied location AFl'ER the 8 weelts of high dose treatment. l’Fl therapy may be continued during the study only if the subject was on F‘Fl therapy at the time of biopsies from the screening endoscopy. Subjects on F’Fl’s may either stop them after the endoscopy or reduce the dose as long as this is BEFORE the baseline run in period. After this dose change the ts must remain on a stable dose after that. Once a Fill is stopped it may not be restarted. No new initiation of PM therapy is d during the study. {@9343} Have evidence of eosinophilic esophagitis d by the PEAK esophageal mucosal eosinophil count 2 l5 per highnpowered field (EFF, 40th ication (€13 min?) in at least l of the esophageal sites biopsied (>3 3 biopsies from each the proximal and the distal esophagus; a minimum of 6 total biopsies). Additional mid, esophageal biopsies may be taken at the igator’s tion es are to be obtained and must be received by the central pathologist within 30 days AFTER the Screening Visit or 2 weeks prior to randomization and before starting the baseline period. Eligibility will be based solely on the central pathologist’s assessment Optional biopsies may be taken and processed locally for local use if specified in the local ICE. The subjects must have a 7—day recall Global EoF. score > 3; Suhj ects must report at least 3 dysphagia episodes per week for each week of the Baseline Symptom Assessment; Willing and able to adhere to study d treatment regimens, procedures and Visit schedule {@8346} Exclusion Chagrin: Known contraindication, hypersensitivity or intolerance to corticosteroids” Any physical, mental, or social condition, y of illness or laboratory abnormality that in the investigator’s judgment might interfere with study procedures or the ability ol‘the subj ect to adhere to and complete the study. Presence of oral or esophageal mucosal infection of any type. Any mouth or dental condition that prevents normal . Any condition allecting the esophageal mucosa or altering esophageal inotility other than EOE including erosive esophagitis (LA grade B or higher), hiatus hernia longer than 3 cm, Barrett’s esophagus, and sia. Use of systemic, oral or parenteral corticosteroids within 30 days, or inhaled or extended use ol‘lriglnpotency dermal topical corticosteroids within 30 days prior to: The esophageal biopsy required for entrance to this study; EGD if done during the pre—screening period. Use of swallowed/topical steroids within 30 days. tion of an elimination diet or elemental diet within days of screening. No dietary therapy may be started during the study. Morning (0700 to 0800 hours, or as close to that window as possible) serurn cortisol level :45 ug/dL (138 nmol/L). A seruni cortisol level of < 18 ug/inL (497 nrnol/L) at 60 minutes with adrenocorticotropic hormone (ACTH) ation test using 250 pg ropin. Consumption of grapefruit juice during the treatment is prohibited. Use of ic iniinunomodulators within the past 6 . Use of calcineurin inhibitors, purine analogues (azathioprine, 6-mercaptopurine) within the past 3 months. Contraindication to esophagogastroduoendoscopy (BSD) or geal biopsy or narrowing of the esophagus precluding EGD with a rd 9 mm endoscope. Overt gastrointestinal bleeding within l month prior to the Screening Visit or between the Screening Visit and the Randomization Visit. Current chronic infection, nosuppression, or immunodeficiency. History or presence of Crohn’s disease. celiac disease, or other inflammatory disease of the gastrointestinal tract including eosinophilic gastroenteritis. Current alcohol or drug abuse. Female subjects who are pregnant or breastfeeding. Sexually active females of child bearing potential who do not agree to follow highly effective contraceptive methods during the study including the follow~up period. Abstinence is acceptable for adolescents Female subjects with surgical menopause or menopause confirmed by FSH do not require contraception or pregnancy testing during the study. Paiticipation in a clinical study involving an investigational drug within '30 days of the Screening Visit. {00347} ) Drug Administration: For 3 dosing groups? APT~lOll (fluticasone propionate, ()DT) will he provided as blinded tablets in dose strengths of 1.5 mg and 30 mg. For the fourth dosing group there will he a matching o Tablets will be administered BlD 30 minutes AFTER. breakfast and HS (at bedtime) at least 2 hours after the evening meal. Note that in the l5 mg dosing group, ts will receive placebo tablets 30 s AFTER ast, and l .5 mg Al’T-lOl l HS~ To maintain the blind, all tablets will be labeled for “AFTER breakfast” and “BED'l'lME” administration. The subjects should not eat or drinlt for l hour after study drug administration. The BEDTlME dose should be stered after all drinks and snacks and tooth ng and immediately before going to bed.

{M13348} PRIBEARY EFFICACY ENDPQENTS at ‘Weeh 12: {99349} There are two coupriniary efficacy endpoints for EOE RESPGNSE: PEAK eosinophil count 6 /l-ll’F at all biopsied esophageal locations and change from baseline in dysphagia episodes over the prior 14 clays {99359} SECQNDARY EFFECACY ENDEGEN'I‘S: {M13351} Change from baseline in DysphagiauEree Days over the previous l4 days; EoE ned Response will be assessed at Weeks 26 and 52 with the Co—Primary Endpoint; Change from baseline in 7~day Global EoE Score will be assessed before the baseline symptom assessment, baseline, Week l2, Week 26 and Week 52. 7~day Global EoE symptom score will be assessed at each visit. Change from baseline in EREES score at Weeks l2, 26 and 52. Endoscopic changes will be based upon the EREES score based on 5 endoscopic features: edema, furrowing, exudates, rings, strictures. t of sub} ects with PEAR Eos per HPE < l and <. 15 at all major time points where EOE Response is assessed Change from baseline in 7~day EEsAl score and t of subjects with mean weekly EEsAl score < 20 and change from baseline in sub scores will be ed at Weeks 12, 26 and 52. 7—day EEsAl will be assessed at each Visit. {00352} Assessment ofRelepse and erit Failure (a) Non—Response at each endoscopic time point (b) Percentage of subjects requiring emergency endoscopic food disirnpaction by dose and part of the study. (c) Percentage of subjects requiring esophageal dilation. {@8353} 032 Treatment: EoE Response (Coul’rimary above) will also be assessed after 12 weeks of GE treatment in sponders to PART l.

} PHARll/lAC0KENE'E‘EC ENDPQ1NTS } The following PK parameters will be calculated for the intensively~sampled PK subjects using nonconipartniental methods, as data permit: Cinax, 'l‘max, A’UCouz, CEss/E and Accumulation Ratio. lillllélSnll Population pharrnacokinetic parameters including oral nce (CL/E) and volume of distribution (VT/P) will be estimated, as data permit. Additional parameters will be estimated, as appropriate, based on the final structural pliarrnacolsinetic model. {00337} EXPLGRATQRY ENDPGlNTS: {99358} EoE Histology Scoring System for all biopsies performed. Change from baseline will be assessed Evaluation of quality of life based on the EoEonl_.r—A at Week l2, 26, 52 and Week l2 of GE treatment by dose and subgroup. Patient’s assessment of ms compared to WO 35393 the previous visit. This question will be assessed at Weeks 8, l2, l8, 2o, 36 and 52. Evaluation of Fifi/PD (cortisol) and exposureuresponse (efficacy) relationships. {@8359} Safety Endpoints: Safety will be assessed by monitoring and recording all treatment~ernergent adverse events (TEAEs), 'llEAEs leading to withdrawal and s adverse events (SAEs). All TEAEs will be coded based upon the MedDRA n 14.0 fication of adverse events (AEs) and classified by severity (mild, moderate, severe) and relatedness to study drug (related, or. not related) by the investigator. 'l'EAl'is occurring within 3 days of a dose change will be attributed to the previous dose. Physical examinations will be performed to document the baseline condition of the subject and, to highlight changes related. to Allis. Vital signs will also be assessed at all visits and, clinically significant deviations will he reported.

{W369} Routine laboratory tests will he med throughout the study including hematology, blood chemistry, urinalysis, electrocardiograms (ECGs) as indicated in the Schedules of Assessments. Clinically significant changes in laboratory tests or FCGs will be summarized. {(39361} Cortisol issues: Abnormal AM cortisol, y glucose or serum e would necessitate following the subject to resolution CRFs should capture presence or absence of known glucocoiticoid AF/s such as moon facies, acne, hirsutism, mood swings, insomnia. or depression lCF should highlight that stress steroids may be ed during significant medical ses.

ACTH stimulation test tropin 250 mcg) should be performed at baseline and Week l2, early withdrawal and at Week 52 for all subj ects~ ACTH test should he performed in all subjects with AM serum cortisol > 5 incg/dL U38 inniol/L) All subjects with positive tests should be excluded, Any positive s at the end of treatment should be followed to recovery of l function.

The number of subjects discontinuing for EPA suppression or positive ACTH stimulation tests will be summarized Subjects under age l 8 will be evaluated for growth parameters such as , weight, hody mass index (Eh/ll) and corresponding zuscores. Tanner stage and hone age will also be determined in adolescents less than 18 who have not completed their linear growth. {98362} The safety endpoints of interest are: frequency of treatment nt adverse events ('l'EAEs}, 'lEAEs leading to withdrawal and treatnientuemergent serious adverse events (SAEs), as well as the tage of subjects with serum cortisol level 5 5 ug/dl; (S l38 nrnol/L) or positive ACTH stimulation test (serum cortisol < l8 ug/rnL (497 nrnol/L) at 60 minutes). The nurnher of subjects discontinuing for HPA axis suppression will be recorded. {@9363} Statistical Methods {(130364} Sample Size Determination {@8365} PART 1 incorporates an adaptive sample size that ranges between l60 and 320 adult patients. Frequent interim analyses will he conducted after at least use subjects are randomized in which s and futility criteria are evaluated. Tf evidence of ent efficacy with respect to co-priniary outcomes is sufficiently low, the trial may stop early for futility If the predictive ility of obtaining sufficient evidence to demonstrate treatment efficacy is very high, the trial may stop accrual for expected success, with a decisive analysis performed when all enrolled patients have completed 12 weelrs of follow—up (Broglio 2014). Simulations are used to calculate the expected, sample size, Type l error, and, statistical power under a variety of assumed ent profiles (to he provided in SAP). {99366} It is pated that approximately 60% of subjects will enter PART 2 of the study.

Given a minimum of l 02 ts on active treatment in PART l, at least til patients are expected to enter PART 2, Approximately l7 placebo responders are expected to enter PART 2. Tt is anticipated that 70% ofthe placebo responders and approximately 20% oftliose on active ent may relapse prior to Week 26. Approximately 82 subjects on active treatment are expected to enter PART 3. {99367} In addition, assuming a 20% dropout rate into PART 3, at least 66 subjects (22 per dose) are expected to he ble on the active ti'eatn'ient arms for the assessment of sustained remission at Week 52., and at least 4 patients are expected on control This provides a minimum expected power of 73% for comparing sustained remission rates of 80% versus 20% for each active dose versus control, and a minimum expected power of 80% for comparing the pooled active treatment remission rates versus control l-Towever, the primary focus of PART 3 will he descriptive in nature. {@8368} Statistical [Methodology } y statistics will he presented in tabular form by dose group and subgroups, as able) or each PART of the study including the OL ent. {98379} The primary analysis population for efficacy is the intentdo~treat (lTT‘) population, d as all randomized subjects. The analysis population for safety is the safety population, defined as all subjects who receive at least one dose of study drug. The ~dose PK population will be defined as all ts in the HT population ot‘PAR'l" 1 who are randomized to one of the three AP'lll 011 dosing groups, take their first dose of APP—l Ol l, and have at least one PK sample included in the final singleudose population PK analysis. The steadyustate PK population will be defined as all subjects in the ill” tion of PART 1 who are randomized to one of the three APT—10M arms, take their dose of APP—1911 that corresponds to the steadynstate PK sampling , and have at least one PK sample included in the final steadynstate population PK analysis.

Additional per protocol analysis populations who complete PAR’l's l, 2, and 3 and CL treatment may be defined in the Statistical Analysis Plan (SAP). {$11371} Baseline and demographic information will be summarized using descriptive statistics for continuous and ordinal variables (eg, age, weight, height) and counts and percentages for rical variables (cg, sex, race). 72} Pharmacokinetics and Pharmacodymrmics Armiysis 73} in this study, the 1.5 mg Pill) and 3.0 mg BID doses will be administered at least minutes AFTER breakfast and at bedtime (at least 2 hours after the evening meal). The l5 mg HS dose will be administered at bedtime (at least 2 hours after the evening meal} Subjects ing l5 mg HS daily will also receive o at least 311 minutes after breakfast. {1111374} Using the PK data from the intensely sampled subjects, PK parameters for PP will be calculated by noncompartmental methods when possible? as s: {1111375} Cmax: Maximum observed concentration, observed by inspection of individual study participant plasma concentration time plots 76} Tniax: Time of maximum observed concentration, obtained directly from the observed concentration time data {1111 77} AU(20—12: The area under the plasma concentration time curve, from time 0 to the 12 hours postudose, calculated by a combination of linear and logarithmic oidal methods 1:Linear up/log down method). {1111378} CLss/F Apparent clearance at steady—state {11113179} Accumulation Ratio Accumulation ratio calculated from AU130—12 at steady state and AUCO—lZ after single dosing {98389} individual and mean plasma tration time curves (both linear and semi—log) will be generated. ed methodology for summary statistics oftlie concentration data and the PK parameters will be documented in the SAP. {@0881} A Population PK analysis will be performed based on a combination of serial and sparse plasma concentration data. Previous serial PK data for APT—10H (Studies l’RnOZS and Food—effect) may be included in this analysis to facilitate development of a base PK model.

{W382} Population PK parameters including oral clearance (CL/F) and volume of distribution (V/F) will be estimated, as data permit. Additional parameters will be estimated, as appropriate, based on the final structural PK model. {99383} The output from the final population models including appropriate diagnostic plots, listings, and ies of PK parameters will be generated. ln addition, graphical and tabular presentations of any PK simulations will be produced. 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{W386} Seem/idem) Objectives: The secondary objectives of the study are as follows: To define the esp0iise of APT—Ml l; To select a dose(s) of APT—10H for Phase 3; To evaluate the effect of APT-lGll on histology and opic appearance; To evaluate maintenance of efficacy and long—term safety of Al’lll Ol l; To evaluate the population pharmacolzinetics (Popl’li) of APT—1011; To evaluate the effect of Al’l'LlOll on dysphagia episodes. {@9387} Exploret‘my flbjectives: The exploratory objectives of the study are as follows: {(39388} To te the ett‘ect of APT—lull on dysphagia and other symptoms of EoE; To te quality of life; To evaluate symptomatology over time; To evaluate the cokinetic (PK)/pharmacodynamic (PD) relationship (with cortisol as the primary endpoint); To te the dose—response relationship for the histological response and symptom response; To derive a scoring structure; and various endpoints from the t Reported Outcome Symptoms of EoE (PRQSE); To evaluate the measurement properties of the PROSE, ing reliability, construct ty, sensitivity to change; To produce guidelines for interpreting clinically irieaningful change and derive the cutoff for treatment response on the PROSE, or a responder definition. {(38389} STUDY DESIGN {1949399} This is a randomized, double~hlihd, placebo-controlled dose—ranging study of 4 total daily doses of APTfil Ol l versus placebo in lOO adult subjects (Elli years of age) diagnosed with Eoli. {@0891} During the singleubhnd /baseline symptom assessment; the subjects will receive placebo 30 minutes after breakfast and hora somni (HS; at bedtime). Four doses of study drug will be administered: Placebo 30 minutes after breakfast and l5 ing hora somni (HS; at bedtime) AFT—ml l, 1.5 mg twice daily (ETD) {30 minutes after breakfast and at bedtime; total daily dose of 3 mg) APT—lOl l; Placebo 30 minutes after breakfast and 3 mg l-lS (at bedtime); and 3 mg Bill) (:30 minutes after breakfast and at bedtime; total daily dose of 6 mg} APT—lOl l, and matching placebo administered 30 minutes after ast and HS (at bedtime). {98392} The lOO subjects will be randomized in a l:l:l:l:l to receive placebo or one of the active doses into Part l of the study. As described below, the treatment that a subject receives in Part 2 depends on their histologic response status at Week l2. {99393} Randomization will occur in a double~blind manner using an integrated ctive Web Response System (lWRS), and will be stratified by the presence or absence of a history of or current esophageal strictures at Screening and y of a prior positive steroid response to any corticosteroid treatment previously received to treat the subject’s EOE captured with demography. {@9394} Efficacy (including sustained EoE response and patientnrepoited outcomes), safety, and PK of APTlell Will be examined. {(39395} FLUTE will he conducted in several parts (Screening [4 weeks}, followed by a 4~ weeh single—blind placebo run—in and Baseline Symptom Assessment, and 2 treatment parts [Part l and Part 2}), with a Follow~up Visit to occur 2 weeks after the final dose of study drug. Screening will take up to 28 days. The esophagogastrodnodenoscopy (EGD) to determine eligibility (lnclusion ion #7: evidence of EOE as defined by 3_>_:l 5 PEAK eosinophils/ highmpower field [HPPl with at least 5~6 es ing both al and distal specimens {3 eachl) will be completed during the Screening Period and the biopsies must be received by the central pathologist by the times noted in this inclusion criterion. To enter the 4—weelrs Baseline Symptom Assessment, the t must satisfy all eligibility criteria including the Global lioE score >3 (Inclusion Criterion #5), except those to be confirmed during this phase (li'iclusion Criterion #7: evidence of EOE as defined by :{l S PEAK eosinophils/HPF with at least 5-6 biopsies including both proximal and distal ens [3 each}; ion ion #8: in the daily diary, report episodes of dysphagia 23 days per week during the last 2 weeks of the 4~weel< Baseline Symptom Assessment; lnclusion Criterion #9: completion of episode entries on at least 5 of out of each 7 days during the lluweelr ne Symptom Assessment; and Exclusion Criterion #23: a serum cortisol level <Zl8 ug/dL (497 L) at 60 minutes with adrenocorticotropic hormone {AC’lll-ll stimulation test using 250 pg cosyntropin lie, a positive result on the ACTH stimulation testl}. The subiects will be dispensed placebo along with their electronic diary at the beginning of the zluweel; placebo run~ in/Baseline Symptom Assessment. {@8396} During the aluweelr; Baseline Symptom Assessment, baseline symptom severity will be determined and the ability of the subject to be compliant with diary s will be assessed.

The subjects must have 2 l5 PEAK eosinophils/l-lPF on their esophageal biopsies to be randomized. ln order to ensure that a diagnosis can be made, at least 5—6 biopsies from both the proximal and distal (3 each) should be taken. The presence or absence of a history of or current geal stricture on the EGD along with a y of a prior positive response to any corticosteroids treatment previously received to treat the subject’s EOE captured with demography will be stratifioation variables at randomization.

{W397} Following confirmation of these eligibility criteria, eligible ts may be randomized as described above.

{WES} During treatment, all subjects will return to the site imately monthly for soheduled visits and for unscheduled Visits due to significant adverse. events or worsening of symptoms ing food impaction } Definitions of Histologc Response Histoiogt'c Nomrespome, and Treatment {@9499} Response or nonmresponsive status will be assessed 2 weeks prior to the planned end of treatment for Part l (Week l2), and Part 2 (Weeks 26 and 52} {99491} A, histologie responder will be defined as a subject who achieves a histologie response of peak eosinophils/HPF number :6 (as primary determinant). HPF will be defined as a standard area of 0.235 square millimeters in a microscope with 40X lens and 22mm ocular. {88492} A histologie non—responder will be defined as a subject who does not have a histologie response (re, do not e a histologic response of pealr eosinophils/lthF number 316). {@9493} Subjects who develop food impaction with or t esophageal dilatation anytime during the study will be considered treatment failures and complete early termination assessments and exit the study after the 2 weel: postutr'eatment followuup period. Subjects who voluntarily withdraw from the study due to worsening symptoms before the week l2 evaluation or later in the study will also be considered treatment failures. Every effort should be made to perform an EGD in ts wishing to withdraw due to worsening symptoms. They also must complete the early termination assessments and exit the study after a 2~week post—treatment follow~up period. {99494} Part 1: Induction (Day 1 In Week 14) {@9495} During Part l, subjects will be treated for l4 weeks with study drug e 5). At Week 12, the ts will undergo a response assessment, including EGD to assess endoscopic and histologic status.

{W496} Histologic responders and histologie nonmresponders (at Week l2) will enter Part {tier-£97} Part 2: Adama‘enmme (week 14’ to ll’eekw?) {99498} ln Part 2, all suhjects fied as histologic responders at Week l2 will continue to be treated according to the dosing group to which they were randomized for Part l for an additional l4 weeks, beginning at Week l4 e 5). Subjects may continue on this dose for up to ‘9 months after the completion of Part l. {@9499} Subjects who are histologic non—responders at Week l2 will receive singleblind 3 nag Ell.) in Part 2‘ {@9419} At Week 26, suhj ects will undergo a response assessment, including EGD to assess histologic response Symptoms will also be assessed The l4 days prior Week 26 will be compared to the l4 days prior to Randomization. Subjects who are histologie non~responders will stop treatment at Week 23 and enter the 2 week follow~up and exit the study. l-{istologic responders will ue on the same dose. {@8411} Subjects who complete the study at Week 52 will undergo a se assessment, including EGD to assess endoscopic and histologic status. Symptoms will also be assessed The l4 days prior Week 52 will be compared to the l4 days prior to Randomization.

{Gilda} Subjects will te a Follow up Visit 2 weeks after the final dose of study drug. {(38413} Foll()w~np We”! {984M} Subjects will complete a Followuup Visit for l or more of the following reasons: Subject completed treatment at Week 52 (following EGD); Suhj ect experienced an adverse event (AB) requiring early discontinuation, including food impaction requiring EGD; Suhject with logic non—response at week 26 including subjects on ublind 3 mg Bil); Suhject with worsening ms who voluntarily withdraws during the study. The Followuup Visit will occur 2 weeks after the t talres the final dose of study drug. All ts must have a final EGD within 3 weeks prior to completing the Follow up Visit unless the subject withdraws consent or has a contraindication to EGD. {00415} Pitttrmawkirteries {00416} Sparse PK sampling will be performed to characterize fluticasone propionate (PP) exposure in the study population. PopPK is will be performed on sparse plasma concentration data. {00417} Pharmacokinetic samples will be collected, from subjects in all 5 closing groups to in the blind. Samples collected, from subjects in the placebo dosing group will not be analyzed. Samples collected, from the subjects on active doses will be analyzed for PopPK results.

} For this sparse PK sampling, a prendose sample will be collected on Day l. At Week r—‘lr Week 8, and Week l2? subjects will take their “after breakfast” dose as scheduled on the day of the visit (most likely at home) and 2 s will be taken during their scheduled visit: upon arrival to the site and approximately l to l5 hours after first sample (immediately prior to g the site). Sites will be encouraged to book subject visits throughout the day. Due to this variability, the sparse PK samples are expected to represent a large portion of the l2 hour post“ dosing interval {00419} Planned Number rngubjects {00420} Approximately lOO subjects will be randomized into Part l in a ltl : l : l :l fashion stratified by presence or absence of a, history of or current esophageal stricture and a history of a prior positive steroid response to any corticosteroids treatment previously ed to treat the subj ect’s Boll {00421} While both genders will be aged to enroll, it is expected that imately % of subjects enrolled will be female. Although subjects are allowed to be up to 75 years old, it is expected that 5% of enrolled subjects will be geriatric (265 years). {00422} No interim analyses are planned. {00423} Inclusion criteria: {00424} Subjects must satisfy all of the following criteria: {00425} Before entering Aluweek Baseline Symptom Assessment: Male or female n El 8 and :75 years of age at the time of ed consent; Signed the informed consent form (lit—7F) WO 35393 and willing and able to adhere to all study procedures; Diagnosis or presumptive diagnosis ofEoE; Diagnosis of EoE must be confirmed by symptoms, histology; and historical documentation of failed treatment on 28 weelrs of highudose proton pump inhibitors (Elli). For the purposes of FLUTE, high dose PM is defined as 20 mg Bil) omeprazole or 20 to 40 Bil) mg of any marketed PPl; maintenance doses of l’l’ls are not acceptable. A lack of response to PEI therapy is defined as >_>l5 PEAK eosinophils/HPE with at least 5 biopsies including both proximal and distal specimens after 8 weeks of high dose El’l treatment. {@9426} Documentation of PPI failure prior to initial diagnosis or by documentation of PPI failure at the time of ing is ed. The subjects may be pre~screened but should not be consented, sign an ICE, or he offered participation in FLUTE if they have not met the diagnostic criteria for EoE that requires that they fail an 8—week trial of high dose EEls EXCEP'l‘ those that have taken PEls for 8 weeks will use the EGD within the study for this documentation The investigator and potential subject must make the decision to complete a PPl trial independent of any considerations of the study. There is insufficient time to do the 8 week trial within the current study. Should a subject he consented in error and screen fails due to this point, they may he re— screened as described in the protocol Have a subject reported history oi‘Ei3 episodes of gia (difficulty with food going down) in the 7 days prior to ing; Have a 7—day recall Global EoE Symptom Score >3; at baseline (EoE score must remain >3 at each of Visits l, 2 and 3 before ization). This will be performed on paper during the Screening visit; Willing and able to adhere to study related treatment regimens, ures, and visit schedule; {@8427} Before randomization: To be determined prior to randoniizati on: have evidence of EoE as defined by }:l S PEAK eosinophils/l-fPF with at least 5-6 biopsies including both al and distal specimens (3 each); No EGDs and biopsies performed outside FLUTE are acceptable for meeting eligibility criteria. Optional biopsies may be talren and sed locally for local use if specified in the local lCE. Biopsies are to be obtained PRlGR to the 4—week Baseline Symptom Assessment. Eligibility from a histological perspective will be based solely on the central pathologist’s assessment. {98428} To be determined prior to randomization: in the daily diary, report at least 3 episodes of gia (difficulty with food going down) for each of the last 7 days during the last 2 weeks of tlie lt Baseline Symptom Assessment; {90429} To he determined prior to randomization: completion of episode s on at least out of each 7 days during the last 14 days of the iluweel; Baseline Symptom ment.

} Exclusion ia: {@0431} Sub} ects will not he entered in FLUTE for any of the following reasons: {W432} Before ng r Baseline Syniptoin Assessment: Have known contraindication, hypersensitivity, or intolerance to corticosteroids; Have any physical, mental, or social condition or history of illness or laboratory abnormality that in the investigator’s judgment might interfere with study ures or the ability of the sub} ect to adhere to and complete the study; Presence of oral or esophageal mucosal infection of any type; Have any mouth or dental condition that prevents normal eating; Have any condition affecting the esophageal mucosa or altering esophageal rnotility other than Bold, ing erosive esophagitis (grade B or higher as per the Los Angeles Classification of Gastroesophageal Reflux Disease), hiatus hernia longer than 3 cm, Barrett’s esophagus, and aohalasia; Use of systemic (oral or parenteral) osteroids within 60 days prior to Screening, use of inhale /swallowed corticosteroids within 30 days prior to Screening, or extended use of high-potency dermal topical osteroids within 30 days prior to Screening; Initiation of an elimination diet or elemental diet within 30 days before Screening; Morning (0700 to 0800 hours, or as close to that window as possible) seruni cortisol level :15 rig/(ll, (88 ninol/L); Use of biologic iminunoinodulators in the 24 weeks prior to Screening; Use of calcineurin inhibitors or purine analogues (azathioprine, 6 mercaptopurine) in the l2 weeks prior to Screening, Use of potent cytochrome P450 (CYP) 3A4 tors (e.g ritoriavir and ltetoconazole) in the l2 weeks prior to Screening; Have a contraindication to or factors that substantially se the risk of £61) or esophageal biopsy or have narrowing of the esophagus that precludes EGD with a standard 9 min endoscope; Have history of an esophageal ure requiring dilatation with the previous 12 weelrs prior to Screening, Suhjects who have initiated, discontinued or changed dosage regimen of PMS, HZ antagonists, antacids or antihistamines for any condition such as GERD for allergic rhinitis within 4 weelrs prior to ying endoscopy.

These drugs must remain constant throughout the study. infection with hepatitis B, hepatitis C, or human immunodeficiency virus (to he tested during Screening), {00433} The following parameters will be utilized to determine hepatitis B and hepatitis C infection: positive for hepatitis B surface antigen [lilies/lg], total hepatitis 8 core antibody {anti l-chl, or hepatitis C virus antibody. r; sub} ects who are positive for hepatitis B surface antibody; but negative for l-lBsAg and anti l-ch; will be eligible. {@8434} Have gastrointestinal (Gl) bleeding within 4 weelts prior to Screening or between the ing Visit and the Randomization Visit; l-lave current (>30 days) chronic infection, immunosuppression; or immunodeficiency; Have history or presence of Crohn’s disease, celiac disease. or other inflammatory disease of the GI tract, including eosinophilic gastroenteritis; Have current alcohol or drug abuse in the opinion of the lnvestigator; Female subjects who are pregnant, feeding, or planning to become pregnant during the study; Serum pregnancy test at Screening and urine pregnancy test during 4—week Baseline Symptom Assessment in women of childbearing potential must be negative. Sexually active females of childbearing potential who do not agree to follow highly effective contraceptive methods through the Follow up Visit; For systemic contraceptive use must be stable for 2:28 days prior to Screening. Female subjects with surgical menopause or menopause confirmed by le stimulating hormone/luteinizing hormone do not require contraception or pregnancy g during the study. Participation in a clinical study involving an investigational product within 30 days (or 5 half~lives; whichever is ) of Screening; {fill/435} Before randomization {00436} A, serum cortisol level <l8 ug/inL (-497 dL) at 60 minutes with adrenocorticotropic hormone (ACTl-l) stimulation test using 250 pg cosyntropin (ie, a positive result on the ACTH stimulation test). {@8437} Test t, dose and mode chrdmimstmliou: {$49438} APT—l 01 l is an orally disintegrating tablet that includes PP as its active ingredient. {(38439} For the purposes of this protocol, the term study drug is used to refer to any blinded medication administered (i.e.; any dosage of APT—lull or o). 49} Subjects will be instructed to talre the study drug orally, with no water or other liquids. The tablet should he placed in the mouth and manipulated between the tongue and the roof of the mouth and allowed to disintegrate completely on the subject’s . lt should be swallowed when fully disintegrated, without biting or chewing. No rinsing with water or liquids is to be allowed after administration. {98441} Dosing will occur in the morning (“after ast” 1:30 minutes after breakfast) and at bedtime (“at bedtime; at ‘52 hours after the evening meal). The “at bedtime” dose of study drug will be administered immediately prior to sleep, while lying in bed. All eating, ng, and tooth brushing should be completed prior to . {@0442} Study drug will be administered, BID (30 minutes after breakfast and at bedtime) in all parts of the study. During the placebo run—in; the subjects will receive placebo BID. in the HS groups; the subjects will receive placebo in the morning 30 minutes after ast and their closes at bedtime. Placebo sub} ects after randomization will receive placebo Ell). {$9443} ts in the 1.5 mg BID APTnlOl l, 3 mg BID APE—Ml l, and placebo dosing groups will take the same study drug for the “after breakfast” and “at bedtime” doses. ts in the id mg HS and, 3 mg HS AFT 1011 groups will take placebo “after breakfast” and l5 mg or 3 mg APT lGl l “at bedtime.” {till/444} Subjects should n from oral intake of solids or liquids for at hour after dosing. {00443} Criteriafar evaluation: {till/446} Efficacy will be assessed histologically (eosinophils per HPP) endoscopically (Eosinopliilic Esophagitis Endoscopic Reference Score [EREPsl), clinically as an exploratory endpoint (Via the PROSE completed for each dysphagia episode and at the end of each day), and the following additional patient~reported outcomes: Global EoE Symptom Secret Patient Global lnipression of Severity (PGIS) and t Global lnipression of Cl’iange , 7—day recall liosinopliilic Esophagitis Activity Index (EELS/ll) total and subscores, and subj ect’s assessment of symptoms. Health Related y of Life (l-lRQoL) will be assessed as an exploratory endpoint by the Adult Eosinophilic Esopl'iagitis Quality ofLife Questionnaire (EoE—QoL—A) {88447} fi‘irmzry y endpoint: The lbllowing primary y endpoint will be evaluated at Week l2 to assess EoE response: {(130448} Histology: percentage of ts with PEAK eosinopliils/HPF number :6 after assessing at least 5—6 biopsies from the proximal and distal esophagus ("“3 each) where the HPF area is 235 square microns (40 magnification lens with a 22 mm ocular). {@9449} Secondary efficacy endpoints: The following secondary efficacy endpoints will be evaluated: {98459} EoE sustained response: tage of subjects who met the primary endpoint at ‘Week l2 and maintained the primary endpoint at Week 26 and Week 52, {99451} Change from baseline EREFs at Week l2, Week 26, and Week 52, {@9452} Endoscopic changes will as per the EREFs evaluation based on the following opic features: edema, rings, eXiidates, furrows, stricture, and several miscellaneous features (crepe paper esophagus, narrow caliber esophagus, and esophageal ns).

{W453} Percentage of subjects with a peak eosinophils/lLH’lE' niiniher <l and <l5 at Week 12, Week 26, and, ‘Week 52, {W454} Change from baseline Global EOE Symptom Score ed prior to randomization, which will be assessed for the 7nday period prior to the following study Visits: Week 4, Week 8, Week l2, Week l8, Week 22, Week 26, Week 28, Week 36, Week 44, and Week {99455} Dysphagia: Change in the number of dysphagia episodes at baseline (lid-day period prior to randomization) compared with the lzlmday period prior to the time point of interest (Week l2, Week 26, and Week 52) {(39456} Change from, baseline 7~day reeall EEsAl total score at Week l2, Week 26, and Week 52; {(39457} Change from baseline 7—day recall EEsAl subscores at Week l2, Week 26, and Week 52; {1949458} Percentage of subjects with mean 7~day recall EEsAl total score <20 at Week l2, Week 26, and Week 52; 59} Change from baseline PGlS assessed prior to randomization to those assessed at Weeks 4, 3, i2, E4, is, 22, 26, 23, 36, 44 and 52-, {99469} PGlC at weeks 4, a, 12, 14, 18,22,263, 28, 36, 44, and 52.

} Assessment of treatment failure and relapse, including: {@8462} Percentage of histologic non—responders by dose at Week l2, Week 26, and Week {98463} Percentage of suhj eets requiring emergency opic food disimpactien by close before Week l4, between Week 14 and Week 28, and between Week 28 and Week 52; {98464} Percentage of subjects requiring esophageal dilation by closing group and part of the study. {@9465} Exploratory cy endpoints: The following exploratory efficacy endpoints will be evaluated: {W466} Dysphagia: Change in the number of dyspliagia episodes at baseline (l4~day period prior to randomization) compared, with the 14 day period prior to the time point of interest (Weeks 12, 26 and 52). {99467} Change from baseline in dysphagia—free days during the l4 day period prior to the following study visits: Week 12, Week 26, and Week 52; {99468} EoE sustained response (dysphagia): percentage of all subjects who met the dysphagia ary endpoint at Week l2 and, maintained a dysphagia—related se at Week 26 and ‘Week 52; {99469} Evaluation ot‘PK/PD (cortisol) and exposure—response (efficacy) relationships; {@9479} Subjects: assessment of symptoms compared with the us visit at Week 4, Week 8, Week l2, Week l4, Week lSfi Week 22, Week 26, Week 28, Week 36, Week 44, Week 52, and the Early Termination Visit (if applicable); {£39471} tion ofHRQoL based on the —A at ization, Week l2, Week 26, Week 52 for all, subjects by dose and subgroup; {@8472} Subjects receiving single~blind (to subject) treatment (in Part 2) will be tabulated separately {(38473} Percentage of subjects who were classified as histologic non—responders at Week 12 and have a peak eosinophiis/I—lPF number :6 at all biopsied esophageal locations at Week 26 and Week :32; {98474} Change from baseline dysphagia episodes during the M day period prior to Week 26 and Week 52 for subjects who were classified as nonuresponders at Week l2; {99475} Percentage of subjects who were classified as histologic nonuresponders at Week 12 and meet the primary endpoint at Week 26 and Week 52; {99476} A g structure, and various endpoints will be derived from the DEB}.

: Psychometric ement properties of the PROSE will be evaluated; {98478} Anchor and distribution analyses to evaluate meaningful changes on the PRGSE. {99479} Adverse events {@9489} Any Ali or rent illness experienced by a subject during any portion of FLUTE must be described in detail and be fully evaluated by the investigator. The investigator is responsible for recording all AEs observed or reported during the study, regardless of ity and/or clinical icance. {@9481} Safety will be assessed by monitoring and, recording all treatment—emergent adverse events ('i'EAEs), lEAEs leading to discontinuation, and serious adverse events (SAEs). All 'i'EAEs will be coded using the Medical Dictionary for Regulatory Activities version Mi) classification and classified by severity (mild, moderate, or severe). Relatetlness to study drug (related or not related) will be reported for SAEs only by the investigator. Treatmentneinergent adverse events occurring within 3 days of a dose change will be attributed to the previous dose. {(39482} APTdOll (fluticasone proprionate ODT) a lly absorbed corticosteroid is expected to act topically in the gus. Because of this, there is potential for decreased cy if the sub} ect swallows water soon after . Since the use of iluticasone has only been rarely associated with oral candidiasis, there will be no need to do swisli and spit since this could inadvertently be associated with swallowed water. {till/483} Oral and esophageal candidiasis will however be considered AEs of special interest.

Subjects may remain in the study during the treatment for these AEs. The investigator may allow swish and spit 30 minutes after dosing for these subjects. Subjects must be instructed not to swallow the rinsing water. {(38484} Symptoms of hypercorticism (See below are also AEs of special interest. {$19485} laboratory tests {(38486} Routine laboratory tests and assessments will be performed throughout the study, including hematology, blood chemistry, ysis, and electrocardiograms (ECGS). Clinically significant changes in laboratory tests or ECGs will be summarized. {@9487} Physical examination and vital signs {@9488} Physical ations will be performed to nt the baseline condition of the subject and to highlight changes related to [His Vital signs will also be ed and clinically significant deviations will be reported. {99489} Cortiso{wrelaletifindmgs {984%} All subjects will undergo a 250 pg ACTH stimulation test during the 4—week Baseline m Assessment following receipt of the g serum cortisol level during the Screening period. This test will also he administered at Week l2 (Visit 6), Week 26 (Visit l0), and ‘Week 52 (Visit l4}. dgll At all visits uled or duled), specific attention will be given to potential changes related to corticosteroids, as well as symptoms of hypercorticisin. Should a suhj ect undergo surgery or trauma during the study, particular care should be taken in observing subjects for evidence of inadequate adrenal response.

{W492} If liypercorticism or adrenal suppression are suspected, an adequate work—up should he performed to m or rule out these findings. ically, to monitor for hypothalamic pituitary adrenal (HPA) axis suppression of potential clinical concern, a 250 ug ACTH tion test will also he med after Screening if any of the following occur: {£39493} During routine laboratory testing completed for the study, the suhj ect has a. morning serum cortisol level :15 ug/dL (l‘S‘d nrnol/L) (confirmed by 2 blood draws), including at the last (in—treatment visit for a suhj ect and, if able, Early Termination Visit; {@9494} The subject reports symptoms of hypercorticism; {99495} The subject discontinues due to HPA axis ssion. {(39496} A, positive result for the ACTH stimulation test is defined as serum cortisol level <l8 ug/dL (497 l’ll’TlOl/L) at 60 minutes after treatment with 250 ug cosyntropin. This result is exclusionary if it occurs at Screening/4 week Baseline Symptom Assessment and requires follow— up through recovery of adrenal function if it occurs thereafter. Treatrn ent for l-TPA axis suppression is discussion in the full protocol The Sponsor will provide guidelines for safety follow—up and document of restoration of adrenal function in all subjects demonstrating evidence of hypercorticisni or l-i’llA axis suppression during the course of the study. {@8497} Electrocardiogram {98498} Electrocardiogranis signs will be assessed and clinically significant deviations will he reported. {@8499} Safety nts: The safety endpoints of interest are: {(130599} Frequency of TEAEs, {98591} TEAEs leading to discontinuation; {99592} 'l‘reatrnentmemergent SAEs; {(139593} Percentage of subjects with serum ol level :45 ug/dL (3138 nmol/L) or positive ACTl-l stimulation test (serum cortisol -<l 8 ug/mL [£497 nmol/L} at 60 minutes}; {@9594} The number of subjects discontinuing for EPA axis suppression will be recorded. {09595} Frequency of oral and, esophageal iasis. {99396} cokiaert’c variables: The following Popl’li parameters will be estimated using sparse sampling, as data permit: Oral nce; Volume of bution. Additional PopPK parameters will be estimated, as appropriate, based on the final structural PK model. {$9597} Statistical methods: {@9398} Sample size determination: Part l will include a sample size with a range of lGO subjects, in which 20 patients are randomized to 1.5 mg HS: l5 mg Bill), 3 mg HS 3 mg Bill), and placebo (l:l :l:l:l). Based on these randomization ratios, approximately 80 % of all subjects in Part l will be treated with an APT-ml, l dosing n and approximately 20% of all subjects in Part l will be treated with placebo lllllSll9l attransitizeizalaaeatI {99519} The All Enrolled Population includes all subjects who signs an lCF and are enrolled into the study. The Safety Population includes all subjects who receive 2: l dose oftbe study drug, The —to—treat (lTT) tion includes all subjects who receive Lil dose of study drug and have >_:l efficacy ment post—dose. A subject who is ed in the study and receives study drug, but fails to complete treatment will be considered a t. The Sparse PK Subgroup includes all subjects who have }:l quantifiable PK sample collected for sparse PK evaluations. {llllSl l} Additional analysis populations (cg, Per Protocol Populations including subjects who complete Part l, Part 2 Weeks 26 and 52) may be defined in the Statistical Analysis Plan. {llllSl 2} Statistical methodology: {(130513} Subject characteristics: Baseline and demographic information will be summarized using descriptive tics for continuous and ordinal variables (eg. age and weight) and counts and percentages for categorical variables (presence or absence of strictures, prior response to ds, sex and race). {(130514} Primary efficacy analysisjbr Part 1 } Let p0 be the proportion of patients who meet histology response for placebo, and let pj he the proportion of ts who meet histology response for dose j, with j====1,2,3,4 corresponding to 1.5 mg HS, 1.5 mg 1311), 3 mg HS and 3 mg 1311) doses, respectively. There are 4 hypotheses corresponding to the 4 active doses which will he tested using a eeping gy to ve Type 1 error for each analysis. {1111316} 1} Primary Hypothesis#-1 Ho: {34:90 Hi: p4=po {1111517} A Chi—square test of proportions will he used to test priniary hypothesis #1, i.e 3mg Ell) vs placebo. lf the corresponding pn"valueis less than or equal to 1.1.11 5.the null hypothesis will be rejected, and subsequently the following hypothesis will he tested: {0051.8} 2) Primary Hypothesis #2 Ho: psiipo Hi: p3=po {1111519} A Chi-square test of proportions will he used to test primary hypothesis #2, i.e 3mg HS vs. placebo. 11," the corresponding p—Value is less than or equal to 11115, the null hypothesis will be rejected, and subsequently the following hypothesis will he : {005211} 3) Primary Hypothesis #3 {1111521} 1-10: pzépo {1111522} 1-11: p2i===p0 23} A Chi~square test of proportions will be used to test prin'iary hypothesis #3 1e 1.5mg 1311) vs. placebo. 11‘ the corresponding p—yalue is less than or equal to 11.05, the null hypothesis will be rejected, and subsequently the following hypothesis will he tested: {11115261} 4) Primary Hypothesis #4 1:10: piépo 1-11: po {1111525} A Chi~square test of proportions will he used to test primary hypothesis #4, i.e 1.5n1g HS vs. placebo. 1f the corresponding p—vahre is less than or equal to 0.05, the null hypothesis will be rejected.

WO 35393 {00526} Note the gate—keeping strategy only allows formal hypothesis testing of l .Smg HS or l.5rng Bil) if the higher doses meet statistical significance.

} Efficacy analysisjbr Part 2 {00528} Sustained EoE response will be assessed in subiects who complete both Part l and Part 2 and complete Week 26 and 52 tions. This will be assessed hy the primary endpoint.

Other measures of efficacy will be assessed at Week 26. Efficacy will be summarized for histologic non—responders from Part 1 who are treated in Part 2. Other measures of efficacy will be assessed at Week 52. {00529} Secondary and exploratory efiimqy analysis {00330} Statistical tests to compare each Alyl‘nlt‘ill dosing group with placebo will he performed for the secondary cy endpoints, but the corresponding pnyalues will he considered as descriptive rather than ntial {00531} The secondary endpoints will be analyzed Via a Cochran~Mantel~Haenzel (CMH) test for categorical endpoints and analysis of covariance for change from, ne endpoints, except for the endpoint of time to e after initiation of double—blind treatment in Part 2., which will be analyzed using liaplan—Meier methods. {00532} No statistical testing of exploratory efficacy endpoints will he performed. {00533} Earthly analyses {00534} The incidence of TFAFLs will be summarized by system organ class and preferred term. Separate summaries by maximum severity (all AEs) and onship to study drug (SAEs only) will he proyided, The incidence of TFAFs leading to tinuation from the study and treatment—emergent SAEs will also he sumi'narized. ln subjects who change dosing groups, the TEAEs will be uted to the previous dose, if they occur within 3 days of the change. {00535} ally significant changes of potential clinical interest in clinical tests will be summarized including hematology, chemistry, urinalysis, ECG, cortisol, vital signs, and hone mineral density. No tical testing of safety endpoints will be performed. Shift tables may be produced, it needed. The number of ts discontinuing due to EPA axis suppression or positive ACTH stimulation tests will be summarized. {00536} Population pharmacokmelics {98537} A Popl’li analysis will he performed based on sparse plasma concentration data. it will he performed using the nonlinear mixed—effects software, NONMEM, Version 7.2.0 or later (lCON Development Solutions, Ellicott City, MD) or other appropriate nonlinear mixed—effects modeling, software. The structural PK model will include oral clearance and volume of distribution as fixedneffect parameters. Additionally, the ubj ect ility in the parameter estimates and the random residual error in the data will be estimated with appropriate error models. The l base model will be selected according to the standard criteria such as minimum objective function value and diagnostic plots. A separate Popl’K report will be generated as an appendix to the clinical study . {00538} Eaplomrory PEPD analysis {WEE} As data permit, exploratory Elli/PD analyses assessing the relationship between systemic exposure to FF and changes in cortisol levels also may be performed as described above, Additional atory PK/PD analyses may be performed to facilitate selection of safe and etive doses for future studies and clinical use. {@9543} STUDY RATIONALE AND RESKrBENEFlT ,ANALYSES {(39541} The purpose Ticasone in Eosinopltilic esophagitis (FLUTE) is to e 3 total daily doses of APT—lfill to define the exposureaesponse of APT~lOll and the minimum effective dose while minimizing any clinically significant HPA axis effects APT—l Ol l is expected to offer the following ages for patients with Eo’E: ()ral administration is generally more acceptable and more reliable in terms of accurate dose stration. Currently, the only available formulation of FF is a metered dose inhaler that is sprayed into the mouth and swallowed by the patient, Oral administration of APT-l fill has very low bioavailability even compared with similar compounds such as budesonide, which further reduces its ial for systemic corticosteroid toxicity, while it may be more potent on a mg basis. {@0642} The current study represents the first dose g study of Al’TulOl 1. Given its low hioavailability, it is unlikely that AP'l‘ul Ol l will have any significant systemic osteroid effects. fiwmfiw Amhwmm 9 fimgfiw Emma”, .................................4 3. Eamafiflfl fig m wan Em» nwmoammmmflw 38% m MS aa 3mg way? a3%wQawmmwmawa £5383 "Mm 4 wmpw Er», x33 mammmmmfivfig w mam,» Mafia Q m m 3%? Mfiamwfimgwmfififiw Mmefié N I “@803qu 39% 3 S an- R», magi wflmmmwmm ‘Egaghm memfimwfimmfi mm. 3%» M E? .m‘mmwnwflv ham flagm M mm- , 5 we @338me ........ n...................................... n................................. n............................................................ n......................... n............. n......... ..

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Pathology for EGD biopsies may also be assessed (or earlier ifpossible). {00552} Randomization {00553} ation osz’igibz’lz’zy; {00554} To be eligible for randomization. subiects must satisfy all inclusion/exclusion criteria, including the following ion criteria that are expected to be confirmed during the 4—week Baseline Symptom Assessment: lnclusion Criterion #7: evidence of EOE as defined by El 5 PEAK eosinophils/HPF; lnclusion Criterion #8: in the daily diary, report es ofdysphagia 2:3 days per 7 days during the last l4 days of the lit-“week Baseline Symptom Assessment; inclusion ion #9: completion ofthe daily diary on at least 5 out of each ‘7 days during the last 14 days ofthe Baseline Symptom ment and Exclusion Criteria #23: a serum cortisol level <l 8 rig/til. (497 nniol/l...) at 60 minutes with adrenocorticotropic hormone (ACTH) stimulation test using 250 ug cosyntropin tie, a positive result on the ACTH stimulation mst). {00555} if the lnvestigator coniirrns eligibility criteria are met? he or she will randomize the subject using the lnteractive W’eb se System (lW’RS), The lW'RS will confirm the eligibility of the subject pertaining to histology (iej contirrn histological evidence of the Eoli diagnosis as per ll'lCluSiOH Criterion #7: evidence of EOE as defined by El 5 PEAK SOS‘iI‘lOplfiilS/HPF)? and provide the randomization number to the lnvestigator and the Sponsor. {00556} ization Scheme; {00557} A total of lOO adult subiects will be randomized to l of 4 doses of APT—101 l (l .5 mg l-lS, 1.5 mg BID, 3 mg HS and 3 mg BlD) or placebo. Subjects in the HS treatment groups will receive placebo 30 minutes after breakfast in order to maintain the blind. {00558} ization will occur in a doublewblind manner using an ated l‘vVRS, and will be fied by the presence or absence of a history of or current esophageal stricture at ing and history of a prior positive steroid response to any osteroid treatment previously received to treat the t’s EoE capturedwith demography. Randomization for sub3 ects in Part 1 will he stratified by use, such that a comparahie percentage of subjects during the study wiii be ahocated to each of the 5 dosing . 59} Treatment gusset); Figure 3 provides an overview of the treatment each subject wiii receive is determined throughout FLUTE (based, on responder status). Symptom improvement or deterioration will be assessed on an ongoing basis {00561} Induction (Day 1' to What? 14) giddddz} During Part 1, subjects will receive their randomized treatment for 14 weeks {@9363} At Week 12, the ts will undergo a response assessment, including EGD to assess endoscopic and histoiogic status. The process overview in Section 6.2 wiii he foiiowed to determine responder status (as defined in Section 4.1.1) and inform the site thereof. Symptoms wiii also he assessed. The 14- days prior to Week 12 will be compared to the 14 days prior to Randomization. {£39564} Histoiogic ders and non—responders (at Week. 12) wii} enter Part 2 (see Section 421.62). {(39565} [Warmer/lance (Week I 4, to Week 52) {(39566} In Part 2., all ts classified as histologic responders at Week 12 will continue to he treated according to the dosing group to which they were randomized for Part E. Suhj ects may ue on this dose for up to 9 months after the completion of Part 1.

} Subjects who are histoiogic non~responders (see Section 4.1.3) at Week 12 wiii receive singie-hiind 3 mg BID in Part 2. {@8568} At Week 26, subjects wiii undergo an 13431) with biopsy, to assess histoiogic se. The process overview in Section 6.2 wiii he followed to determine responder status (as defined in Section 4.1.1) and inform the site thereof. Symptoms wiii aiso be assessed. Ali ts fied as histologic responders wiii continue to be treated according to the dosing group to which they were randomized for Part 1 up to Week 52. The 14 days prior to Week 26 wiii he compared to the 14 days prior to Randomization.

{M13569} Sub} ects who are histoiogic nonuresponders (see Section 4.1.1) at Week 26 wiii stop ent at Week 28 and enter the 2—week followuup period and exit the study. {@9578} Subjects who complete the study at Week 52 will undergo a response assessment, including EGD to assess endoscopic and histologic status. The s overview in Section 6.2 will be followed to determine responder status l:as defined in n 4. ll) and inform the site thereof. Symptoms will also be assessed. The subject will be treated with study drug through completion of the EGD associated with the Week 52 visit. The ld days prior to Week 52 will be compared to the l4 days prior to Randomization. lllll57ll Subjects will complete a Follow-up Visit 2 weeks after the final dose of study drug (see Section 4. l8). {9&572} EhFlCACY, SAFETY, ANB l’HARl‘l/LXCOKENE'E‘IC ASSESSl‘l/EENTS } Baseline and demographic data to be collected, include age, , weight, race sian, Black, Asian, Native American, or other), ethnicity (Hispanic, Non—Hispanic, or other), and smoking . {$9574} Efficacy and Patient—reported Outcome Assessments {99575} Esophagogastroduodenoscopy: For the purposes of the current study, it is expected that the esophagus will be the focus ofEGD procedures. {99576} Whenever possible, the same opist should be used for all EGDS performed for the study. {00577} ,Mtiin’pie Esrmhageai Biopsies } A minimum of 3 biopsies will be ed from both the proximal and the distal esophagus (total of 7/6 biopsies) during the BSD. Care should be taken to obtain biopsies that are of sufficient size and are opaque. Additional attempts should be made if suboptimal biopsies are taken. it is suggested that biopsies be obtained l at a time to e optimal results. {88579} All biopsies should be stored at room temperature. {llllSSll} Eosz'uophilic Esophagilis Histology {@9581} A central ogist will evaluate all esophageal biopsies and count the peak number of phils/l—lPF. Frorn a histological perspective, the eligibility requirements are described in inclusion Criterion (eg. have evidence of EoE, as defined by :lfi PEAK eosinophils/HPF with at least 56 biopsies including both proxirnal and distal specimens [3 eaclil). {(130582} Ii'osinophilz’c Esophagilis Endoscopic Reference Score {98583} The endoscopist will record the observed Eosinophilic Esophagitis Endoscopic Reference Score (EREli's)27 that assesses edema, fur‘r‘owing, exudates, rings, ures, several laneous features, and physician assessment of l disease activity (absent; mild; moderate; severe) at each EGD. The EREFS has been shown to be a reliable diagnostic tool to both diagnose EOE and, to assess the response to treatment.

} The opist will complete a worksheet for the EREFs and, data will he transferred to the appropriate eCRF by the site clinical staff/study coordinator. The worksheet should be retained at the site as a source document. {$9585} Daily Diary {@9386} A daily diary will he completed by the subject to assess the presence of dysphagia and questions related to its severity and associated pain. The diary will be completed hy the sub} ect daily throughout the study. {99587} These data will be eported electronically hy the subject, transferred automatically to the electronic t—reported outcome (ePRO) vendor, and transmitted thereafter to the clinical database. {00588} Global Eostnophtiic gttts Symptom Score {99589} For the Global EOE Symptom Score, the suhj ect will respond to the following: {995%} On a scale from 0 to l0 (0 representing no symptoms and ll) representing most severe symptoms), how severe were your eosinophilic esophagitis symptoms over the past 7 days? {llll59l} These data will be self—reported electronically by the suhj ect, transferred tically to the ePRG vendor, and transmitted thereafter to the clinical database, {$19592} 7~dtty Recall Eartttopiziit’c Esophagtlts m [Ilirsessmem Index {@8593} Symptoms will be assessed using the 7—day recall EEsAl questionnaire periodically and both total and subscores will he calculated. The res will include symptoms such as dysphagia, food avoidance and modification, and painful swallowing (:odynophagia). {98594} Additional questions used as anchors for the 7—day recall EEsAl score will also be assessed. These data will he self—reported on paper by the subject and transmitted thereafter to the al database by the site. {(130395}M Suhjecl Assessment QfSymptoms {005%} The following Patient Global lnipression ot‘Change (PGlC) questions will be asked to examine the subject’s assessment of symptoms: } Compared with the beginning of the study, before you started the treatment, your EoE symptoms today are: Much worse; Moderately worse; A little worse; Stayed the same; A little ed; Moderately improved; Much improved. Please think of all your symptoms due to EOE and make an overall statement by choosing l of the options above. {005%} Compared with the beginning of the study, before you started the treatment, your difficulty with food, or pills going down today is: Much worse; Moderately worse; A little worse; Stayed the same; A little improved; tely improved; Much improved. Please think of your difficulty with food or pills going down and make an overall statement by choosing l of the options above.

} These data will be self~reported electronically by the subject, transferred automatically to the ePRQ vendor, and transmitted thereafter to the clinical database. {00600} Griffin/act Assessment rom Severity {00601} The following questions about patient global impression of symptom severity (PGTS) will be asked to examine the subj ect’s assessment of severity: {00602} Please choose the response that best describes the ty of your EoE ms over the past week (check one se): None; Mild; Moderate; ; Very Severe. Please think of all your symptoms due to EoE and make an overall statement of their severity by choosing l of the options above. {00603} Please choose the response that best describes the severity of your difficulty with food or pills going down over the past week (check one response): None; Mild; Moderate; ; Very Severe. Please think of your difficulty with food or pills going down and make an overall statement of its ty by choosing l of the options above. {00604} These data will be self~r‘eported electronically by the t, transferred automatically to the el’RG vendor, and transmitted thereafter to the clinical database. {00605} Adair Easinophilz’c Esophagrris Qtarlz’ry ofere Questionnaire {00606} The Adult Eosinophilic gitis Quality of Life Questionnaire {EoE—QOL—Al29 is an assessment that may be administered directly to subjects to determine how EoE impacts their quality of life. it includes 30 questions on a 5—point Likert scale; questions represent 5 factors: eating/diet , social impact, nal impact, disease anxiety, and choking anxiety and has been validated to ate with established health related quality of life measures. Higher scores indicate better quality of life. {@96th These data will be self~reported electronically by the subject, transferred automatically to the el’RO , and transmitted thereafter to the clinical database. {@9698} Efficacy Endpoints {$9699} Primary Efficacy Endpoint: The following primary efficacy endpoint will be evaluated at Week l2 to assess EoE response: tillll Histology: percentage of sub} ects with a PEAK eosinophils/HPF number :46 after assessing at least 56 biopsies from the proximal and, distal esophagus where the EFF area is (3.235 square millimeters (40 magnification lens with a 22 mm ocular). {0061 1} Secondary Efficacy Endpoints {99612} The following secondary efficacy endpoints will be evaluated: EoE ned response: percentage of subjects who met, the primary nt (histology) at Week 12 and maintained the y endpoint at Week 26 and ‘Week 52, Change from baseline FREFs at Week 12, Week 26, and Week 52; Endoscopic changes will as per the EREFs evaluation based on the ing endoscopic features: ederna, rings, exudates, furrows, stricture, and several miscellaneous features (crepe paper esophagus, narrow caliber esophagus, and esophageal erosions); Percentage of subjects with a peak eosinophils/l-EPF number <l and <l 5 at Week l2, Week 26, and Week :32, Change from ne Global EOE; Symptom Score, which will be assessed for the 7 day period prior to the following study visits: Week l2, Week 26, and Week 52; Dysphagia: Change in the number of dysphagia es at baseline (Malay period prior to randomization) compared with the l4—day period prior to the time point of interest (Week l2, Week 26 and Week 52:); Change from baseline 7~day recall EEsAl total score at Week l2, Week 26, and Week 52, Change from baseline 7uday recall EEsAl subscores at Week l2, Week 26, and Week 52, Percentage of subjects with mean 7—day recall EEsAl total score <20 at Week l2, Week 26, and Week 52, Change from baseline PGlS assessed prior to randomization at Weeks 4, 8, l2, i4, is, 22, 26, 28, as, 44, and 52; edit: at Weeks 4, 8, l2, i4, is, 22, 26, 2s, 36, 44, and 52.

Assessment of treatment failure and relapse, including: Percentage of non—responders by dose at before Week l4, between Week l4 and 28, and between Week 28 and 52; Percentage of subjects WO 35393 requiring emergency endoscopic food disuirnpaction by close at Week l2, Week 26, and Week 52; Percentage of subjects requiring esophageal dilation by dosing group and part of the study. {@9613} Exploratory Efficacy Endpoints {66614} The following exploratory efficacy endpoints will be evaluated: {W615} Dysphagia: Change in the number of dyspliagia episodes at baseline (l4~day period prior to randomization) ed with the 14 day period prior to the time point of interest (Weeks 12, 26 and, 52). Change front baseline in dysphagia—free days during the 14 day period prior to the following study visits: Week 4, Week 8. Week l2, Week l4, Week 18, Week 22, Week 26, Week 28, Week 36 Week 44, and Week 52; EOE sustained response (dysphagia): tage of all subiects who met the dysphagia secondary endpoint at Week l2 and, maintained a dysphagia- related response at Week 26 and Week 52; Evaluation of PK/l’l) (cortisol) and re—response (efficacy) relationships; Subjeot’s assessment of symptoms compared with the previous visit at Week 4, ‘Week 8, Week l2, W’eek loll, ‘Week l8, Week 22, ‘Week 26, Week 28, ‘Week 36 Week 44, Week 52, and the Early Termination Visit (if applicable); Evaluation of HRQol... based on the Eol:3~Qol...—A at baseline, Week 12, Week 26, Week 52 for all ts by dose and subgroup; Subjects receiving single~blind (to subject) treatnient (Part 2) will be tabulated separately, {£39616} tage of subjects who were classified as ogic non responders at Week 12 and have a peak eosinophils/HFF nuniber :16 at all biopsied esophageal locations at Week 26 and Week 52, {llllélfl Change from baseline dysphagia episodes during the l4 day period prior to Week 26 and Week 52 for subjects who were fied as non responders at Week l2; {llllélal Percentage of subjects who were classified as histologic non~responders at Week l2 and meet the primary endpoint at Week 26 and W'eek 52. {99619} A scoring structure, and various endpoints will be d from the DEB}.

The populations to be analyzed will be detailed in the Statistical Analysis Plan (SAP). Subgroup analyses may be med based upon age gender, PM status and other study ulations, Example 5 ~ A Phase I igfilfb’ to Assess the Pharmacokmerics, Safety and Toi’embiliiy ofa Single Dose QfFIi/ztimsoiie propionate Administered under Fed or Faster/i ions or at Beri’iime in a Randomized Three—way Crossover Design {@8629} Primary adjective: The plasma pharmacolrinetics (PK) ol'" Fluticasone propionate (Fl?) after administration under Fed or Fasted conditions in the morning were ted. {996le Secondary fligieci‘ives: The plasma (PK) of FF after administration at bedtime (HS) were evaluated. The safety/tolerahility of the administration of a single dose of F? in male and female healthy adult volunteers when administered under fasted, fed, or HS conditions were evaluated. {$9622} Prinmiy Endpoint: FP Cmax, AUClast, and, 'l'max after stration ofFF tinder fed, and fasted conditions for morning dose stration were assessed. {$9623} ary Endpoints: FP AUCO—Zd, AUCinf, AUCext, la, tl/2, CL/ll, and V2,]? after administration of FF under fed and, fasted conditions were assessed. FP AUCO—Zd, AUCint‘, AUCext, AZ, tl/2, CL/ll, and Viz/”F after administration of PP under HS administration were assessed Additional PK parameters were calculated as needed to adequately terize the pharmacokinetics or??? following morning (fasted and fed) or HS dosing. incidence of treatment— emergent Adverse Events (All/s), AEs leading to withdrawal, and Serious Adverse Events (SAEs) grouped by system organ class (SOC) were calculated as needed Clinically significant ahnormal values for clinical laboratory, AM cortisol (:1 l38 nrnol/L), urinalysis, vital signs, and electrocardiogram (ECG) findings were measured as needed. {@9624} Study Design and Duration: This study was a randomized, single-dose, three~way crossover study evaluating the effects of 6 mg Fl? administered in the morning (AM) under fed or fasted ions or before bedtime (HS), 4 hours after the evening meal. A total of 2-4 subjects were enrolled and randomized to one of six sequences to receive each of the three treatments over the three s with a 7~day t between doses. The three treatments included administration of 6 mg of FF” (2 x 3 mg orally disintegrating tablets) under the following conditions: {@9625} A. : 6.0 mg of Al’TulOll (e. g. F?) (ll‘wo 3 mg oral dissolving tahlets) after an overnight fast (at least l0 hours), with last continuing 4 hours postudose {@9626} B. Fed; 6.0 mg lGll {Two 3 mg oral dissolving tablets) 30 minutes after the start of a higli fat breakfast. {@9627} C. HS: 6.0 mg APT—10H ('l‘wo 3 mg oral dissolving tahlets) at bedtime imately 4 hours after the standard evening meal. {99628} ° Subjects on the “Fasted” ent (Treatment A), were administered {3.0 mg of APP—1011 after an overnight fast of at least l 0 hours. These subjects ued fasting, for at least 4 hours post—dose. {(139629} =9 Subjects on the “Fed” treatment (Treatment B) began a highufat breakfast 30 minutes after an overnight fast of at least 10 hours. Subjects were administered 6.0 mg of APT" 101 l, 3i) minutes after initiation of the high-fat breakfast. {sense} it Subjects on the “HS” treatment (Treatment C) consumed a standard meal approximately 4 hours prior to bedtime. Subjects were administered 6.0 mg of A'l"l’~l0ll immediately prior to bedtime (4 hours following the standard meal). Subjects were administered the dose of PP while laying down. iitltltfill Randomizatien (Bay 1): Subjects were randomized to one of siX sequences (See Table 15) to receive a single dose of each treatment over three s, with a 7~day washout between doses.

Table 15 {1949632} Treatment Periods: For each period, subjects were inpatients for 5 days (Days 0— 4, Days 7~l l, Days 14—l 8) with PK samples ted over '72 hours following each dose. Subjects were checked—in to the CRU the evening prior to each dosing (Day 0, 7, and M) and received treatment according to the sequence on which they were randomized on Day l, APT—lOll was administered as single doses on Days l, 8, and l5. All meals (AM, and 4 hours prior to bedtime) were standardized for all ts and all s. Subjects completed these meals within 30 minutes. Serial plasma samples for PP Pl: were collected preudose and at 0.5, l, 2, 3, 4, 5, 6, 8, WO 35393 , l2, lb, 20, 24, 30, 36, 42, 48, 60, and 72 hours following each dose. Subjects dosed l-lS ed the sarne Pl: schedule with PK s scheduled relative to the bedtime dose. {99633} Subiects were rged from the CRU following PK sampling and safety assessments for each treatment period (Day 4, Day ll, Day l8).

{W634} Follow"Up (Day 25 3:2 days}: After Period 3, sub} ects returned, to the clinic within 7 days (:2 days) of discharge from the clinical research unit for follow—up criteria.

{W635} Inclusion Criteria: Female and, male subjects were eligible for inclusion in this study only if all of the following criteria applied: {W636} l. Subject was healthy based on evaluation of medical history, physical examination, clinical tory tests and lZ—lead ECG. Subjects with y of mild. acute or chronic medical s or laboratory parameters outside the norrnal reference range were included only if the Investigator agree that the finding is unlikely to introduce additional risk and will not interfere with study procedures. {66637} 2. An Institutional Review Board GEM—approved informed consent was signed and dated prior to any related activities. {66638} 3. Subject was between the ages of l8 and 55 years, inclusive. {69639} 4. Female sub} ect of childbearing potential had a negative urine pregnancy test or had surgical sterilization, had been diagnosed infertile, or was post~menopausal prior to randomization. Females of childbearing potential must have been willing to practice adequate birth control from at least 23 days prior to the first administration of the study drug, during the study and for at least 30 days after the last dose of the study drug to be eligible. {1949649} 5. Male subjects who engaged in sexual activity must have agreed to use a condom and spermicide during the study. {99641} 6. Body rnass index between l9 and 30 kg/rn2 (weight/{height}2), inclusive. {66642} 7. Norrnal (:or abnorrnal but clinically ificant} laboratory values present at Screening. {@6643} 8. Subiect had the y to understand the ements of the study and a willingness to cornply with all study procedures.

WO 35393 {99644} 9. Subject had not consumed and agrees to n from taking any dietary supplements, herbal therapies, or escription drugs (except as ized by the Investigator) for 7 days prior to lst CRU admission (for Period 1} through Follow~ljp {th645} l0. Subject had not consumed and agreed to abstain from taking any prescription drugs (except as authorized by the Investigator) for 28 days prior to lst CRU ion (for Period 1) h —Up.

{W646} ll. Subject had, not consumed alcohol—containing beverages for 3 days prior to lst CRU admission (for Period, 1) through Follomep.

{W647} l2. Subject agreed to n front consuming caffeine“ or chocolate~containing products from CRU admission to rge of each period.

{W648} l3. Subject agreed to abstain from strenuous physical activity frorn signing of the informed t form to the final follow up visit {title/49} Key Exclusion Criteria: A subject was not eligible for inclusion in this study if any of the ing criteria applied: {titlfiSl‘l} l. Had a history of asthma requiring occasional use of inhaled corticosteroids. {99651} 2. Had a recent (within 30 days) history of corticosteroid use, including hut not limited to intranasah inhaled, derrnal, ophthalmologioal, or intra~articular routes of administration. {99652} 3. Had a history of illicit drug abuse in the past year or current evidence of such abuse in the opinion of the Investigator based on criteria established in DSM—lV.

{W653} 4‘ Used tobacco products within 3 months before Day l of this study } 5. Had positive findings on urine drug screen or positive cotinine test. {tltl655} 6‘ Had a history of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >l 4 drinks/week for men or >l O drinks/week for wornen.

One drink is equivalent to l2 g alcohol 5 ounces (l 50 rnL) of wine or 12 ounces (360 niL} of beer or 1.5 ounces {45 mL) of EEO—proof distilled spirits. An ethanol breath test was administered twice and used to document laclr of ethanol use at Screening and Day 0 and was exclusionary if positive. {99656} 7. Was positive (re, evidence of current ion) for hurnan immunodeficiency virus (HIV), hepatitis 8 and/or hepatitis C on Screening assessnients. {98657} 8. Fenrale subject who was pregnant or lactating. {98658} 9. Male sub_iect whose partner was known to be pregnant. {@9659} 10. Had an acute illness within 28 days of first CRU adrnission. } l l. l-lad any history of ulosis and/or prophylaxis for tuberculosis {@9661} 12. Had donated plasma in the previous 7 days before Day l of this study {W662} l3. Had donated 500 in}; or more of blood ian Blood Services, Heman Quebec, clinical studies, etc.) in the previous 56 days before day l of this study {$9663} l4. Had taken an inducer or tor of Cytochrome P450 3A (CYP3A) enzymes within 28 days of the first dose.

{W664} l5. Had talren grapefruit juice within 7 days of the first dose , {99665; to. Bad participated in an investigational drug study within the 30 days prior to first CRU admission or subject has had less than 5 halfnlives washout of any prior investigational drug prior to first CRU admission (whichever is longer). {99666} l7. Had any physical, mental, or social condition, y of illness or laboratory abnormality that, in the investigator’s nt, might interfere with study procedures or the ability of the subject to adhere to and complete the study. {@9667} l8. Clinical laboratory tests indicated the presence of clinically relevant renal or hepatic insufficiency in the opinion of the Investigator. {99668} l9. Had a history of any gastrointestinal, renal, or hepatic conditions that could impact absorption or rnetabolism/elimination of the investigational compound. 9} 20. Could not or would not consume contents of standard high fat meal due to dietary preferences or restrictions {$49679} 2l. Had a history of sensitivity to the study medication (Fluticasone propionate or other corticosteroids) or components thereof, or a history of drug or other allergy (such as eggs) that, in the opinion of the lnvestigator, contraindicates participation. {@8671} cohfinetlcs : Derived plasma~Plearanteter descriptive statistics were ized by treatment. To assess the PK of F? in the fasted (reference) and fed (test) states, an analysis of variance (ANOVA) with fixed effect term for treatment (fed or fasted status), fixed effect ternt for Period t l, 2, 3), fixed effect term for sequence (ABC, BCA, CAB, CBA, ACB, BAG) and t within sequence as a random effect was performed on log—transformed AUClast, AUCGuZél, AUCinf, and Crnax. Relative hioavailability was estimated by ntiating the difference in leastusquares means (test reference) and the associated 90% confidence interval (Cl). Additional comparisons were assessed n HS desing and Fed and Fastecl administration.

Table 16 PK Parameter Description Maximum observed plasma concentration, ed directly from the observed concentration versus time data Time of maximum concentratien (n), obtained directly from the ebserved concentration versus time data Area under the plasma concentration—time curve from time 0 to time of last measurable plasma concentration AUCinf Area under the plasma concentration~tinie curve from O—tiine extrapolated ralJCext Th3 @3993ng cf the AUC that is extrapolated beyond the last measurable concentration AUCO—24 Area under the plasma concentrationutime curve from time 0 to 24 hours post-dose Apparent plasma terminal—phase elirmnatiori rate constant Apparent volume of distribution, terminal Apparent systemic clearance Additional PK parameters may be calculated as necessary to adequately characterize the PK profile of APT—1m l.

} PP concentrations were summarized using descriptive statistics (including in, mean, SD, cceffici ent of variation (CV93), median, minimum, and maximum) for each treatment. 73} The following PK parameters were estimated by nencompartmerital methods from plasma samples. Below limit of quantitation concentrations were d as zero for all PK analyses All deviations from the scheduled sampling time of 2 minutes or more were taken into eration for evaluation of the PK parameters. In the case where concentrations ofFP could not be determined due to clinical or hioanalytical reasons, these values were set to missing for the pharmacokinetic analysis. {@9674} The trapezoidal rule was used to te the area under the curve (linear trapezoidal linear interpolation) and the terminal phase were estimated by maximizing the coefficient of ination estimated from the log—linear sion model. However, disposition parameters were not ted for individual concentration—time profiles where the terminal leg— linear phase cannot be reliably terized. {98675} if a pre~dose concentration 3 was detected, the subject’s data was included in the pharmacokinetic analysis without adjustment, if the preudose concentratieh was equal to or less than 5% of the Cmax value of the ccrresponding peried. lf the pre—dose concentration was greater than 5% of the CmaX value, the sub} ect was dropped frcm all pharmacolriiietic evaluations.

{W676} Given the low expected systemic bioavailahility of Fl) (4%) it was possible that scme PK parameters were not reliably calculated due to low plasma PP ccncentrations (eg, concentrations that are BLQ). er le, PK parameters were calculated. {99677} d plasinanPKnpararneter descriptive statistics were tabulated by treatment.

Descriptive statistics for PK ters included the arithmetic and, geometric mean, CV94), SD cf the arithmetic mean, median, minimum, maximum, and n, as appropriate. {99678} To assess the PK of FF, an analysis of variance (ANOVA) with fixed effect term for treatment, fixed effect term for Peried (l , 2, 3), fixed effect term for sequence (ABC, BCA, CAB, CBA, ACE, BAG) and subject within sequence as a random effect was perfermed en loge— ormed AUClast, AUCG~Z4, AUCint‘, and Cmax. ve bicavailability was ted by expenentiating the difference in least-squares means (test — nce) and the associated 90% confidence interval (Cl), {(38679} Food Effect Analysis: The 90% confidence interval for the exponential of the difference in LSmeans between 8 (fed) and A (fasted) was calculated for the iii-transformed parameters (Test to Reference ratio of geometric LSrneans), {eases} HS vs Fasted Analysis: The 90% confidence interval for the exponential of the difference in LSmeans n C (HS) and A (lasted) was calculated for the lit—transformed parameters (Test to Reference ratio of geometric LSnieahs). {@9681} HS vs Fed is: The 90% confidence interval fer the experiential of the difference in LSineans between C (HS) and B (fed) was calculated for the iii—transformed parameters (Test to Reference ratio cf geometric LSmeans). {@9682} Statistical analyses were generated using SAS® t: version 9). {@9683} Sample Size: Using an estimate of 54% as determined by using an overall estimate of variability cf 60%, and assuming the intra—subj ect variability is estimated to be about l0% less.

Then for a twousided 90% confidence interval for a normal mean, a sample size of 24 yields a half— width of at most 0.25 with a conditional probability of 0.98. {98684} Rationale for the Current Study: The approach to treatment of EoE. with oral administration of APTml Oll was to provide topical esophageal exposure of PP while minimizing systemic exposure and associated systemic cologic effects. Previous studies demonstrated a significantly decreased exposure when the drug was administered, after breakfast; for example administration of APTmlGll after a highnfat meal icantly decreased systemic re compared to administration in the fasted state. Additionally, administration of Al’llltlll as 6 mg QT) resulted in approximately the same dosemnorinalized, steadynstate systemic exposure (A’UCtau.®ose) as a 3 mg Ell) regimen. However: the data were highly variable, with the between— subject variability (Cl/94') Geo mean) of PP AUCt'O—Zalh) following singlemdose administration >55%. {99685} The us PK study demonstrated significantly lower drug levels with QT) administration compared to the same dose d and administered BID. The reason for this is unclear {(39686} The current study assessed the effect of food on APT-l O l l pharmacokinetics, APT~ lOl l res were compared when a g dose is administered in either the fasted state or minutes after initiating a high fat meal. Additionally, the current study characterized the pharmacokinetics ofAPT—lOOl when administered as a single dose at ne (HS). {1949687} This study provides guidance on administration of the drug relative to food and time of day of dosing.

TREATMENTS {(38688} Treatments Administered: Study drug was administered by ied study staff only in accordance with the procedures described in this ol. All doses of “ were be 6 mg, administered as two 3 mg orally disintegrating tablets. All subjects were instructed to talre the study drug tablet orally without water or other liquids. Subjects placed hoth study drug tablets on the upper surface of the tongue and gently massaged the study drug tablet between the tongue and the roof of the month until it disintegrated sufficiently to allow normal swallowing with saliva over the course of one to five minutes. Subjects were instructed not to chew or crush the study drug tahlet and not to swallow any portion of the intact study—drug tablet before it has fully dissolved. ts did not drink for at least l hour after dosing and did not eat for at least 4 hours after dosing. {@8689} Due to the low ilahility of AP’lll Cl 1, a dose of 6 mg was selected for this study. Based on previous data, FF concentrations following a 6 mg dose provide detectable plasma levels of F? at most time points using the proposed hioanalytical assay.

Selection and Timing Qf’Dosejhr Each Subject {name} All doses of APE—1011 were 6 mg, administered as two 3 mg orally disintegrating tablets simultaneously. For the Fasted ent (Treatment A). sub} ects were dosed following an overnight fast of at least 10 hours. A standard meal was provided 4 hours after dosing. For the Fed treatment (Treatment B), ts started a highnfat, high—calorie meal after an overnight fast of at least l0 hours, and 30 minutes prior to dosing. The meal was consented within 3t) minutes or less. {99691} For the HS treatment, suhj ects were administered 1 1 approximately r—‘l hours after a standard meal with no snacks after dinner. After administering the drug, the suhj ect ately laid down and did not get up for at least l hour.

Pimrmrtcnkimztics {£39692} Collecting, Processing and Shipping Pharmacokinetie s: Blood samples (6 l'l’lL per sample) were drawn and processed for plasma. The yield of plasma (~ 3 ml...) was subdivided into 2 samples (ml .5 mL each) {)ne of these samples was and the other was stored at _<_ —ZO°C at the CRU until completion of the study } Bioanalytlcal d for 'Flntieasone propionate quantita‘tion: Fluticasone propionate concentrations were measured using an LC/l‘viS/lVlS method validated in accordance with US regulatory guidelines. The method was developed starting from l mL of plasma collected from blood containing potassium oxalate/sodium fluoride as anticoagulant/preservative. The method is linear over the nominal concentration range of l.00 to 500 pg/mL. The limit of quantitation is l pg/mLZO. Samples from all sub} ects were analyzed.

Assessment Qf’Saféi}; } Safety assessments included the following: Adverse events, both ed and observed, regardless of severity or seriousness; Body weight; Vital sign measurements (lilood re, heart rate, temperature, respiration rate); ECG findings, Clinical laboratory tests and urinalysis, Physical examination findings. {@8695} Clinical Laboratory Tests: The clinical laboratories tests were as follows. l-lematology, hlood chemistry, coagulation, and urinalysis was performed at Screening, on Day 0 (CRU admission), at 12 hours postdose of each period, hefore CRU discharge of each period, and at the Follow—up Visit. {some} Hematology: Red blood cell (REC) count, hemoglobin, heniatocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration , white hlood cell (W’BC) count and differential, absolute neutrophil count (ANC), and, platelet count.

} Blood Chemistry/Coagulation: Alanine aininotransferase (ALT; SGPT) and Aspartate aininotransferase (AST; SGOT), total bilirubin, direct biliruhin, blood urea nitrogen (BUN), creatinine, ne phosphatase, sodium, potassium, calcium, chloride, glucose, and albumin {99698} Urine ncy test: Urine li~hCG test in women at screening, in for each period tie, Day 0, Day 7, Day 14) and Follow—up.

} Follicle Stimulating e (FSHV Luteinizing Hormone (LE) test: This test was performed in all menopausal women including surgical menopause.

T/Tlll} Urinalysis: Urinalysis included n'iacroscopic analysis and microscopic analysis only when indicated by dipstick Analyses included: Color, Turbidity, Specific Gravity, pl-l, Glucose, Protein, Ketones, Urohilinogen, hin, Blood, Nitrite, and Leukocyte Esterase. {llllVlll} Serology: l-llV Ag/Ah Combo, Hepatitis B (Ellis/lg (B) (hepatitis El) and Hepatitis C (HCV (CD (performed at Screening only), {@8792} Urine Drug Screen: Urine for a drug screening test was collected from all subjects during the screening period and on Day 0, Day 7, and Day l4. The sample was tested for the presence of cotinine, cocaine, tetrahy nahinol, barbiturates, amphetamines, henzodiazepmes, and opiates. Subj ects with positive urine drug screen test s for any of the ahove substances were excluded from this study. {@9793} Ethanol Breath Test: Alcohol consumption was not permitted within 3 days of first CRU ion through Follow—up. An ethanol breath test was performed at Screening and at CRU admission of each period (i.e., Day 0, Day 7 and Day l4). Sub_iects with positive l breath test results at ing were not enrolled in the study to avoid inadvertent enrollment of a sub} ect with chronic lisni. Subjects with positive ethanol breath test results on Day 0 {CRU admission) were also excluded from further participation in the study. {@9704} ADVERSE EVENTS {00705; A Serious Adverse Event (SAE) was defined as any untoward niedical occurrence that at any dose: Results in death; ls hreatening; Requires inpatient hospitalization or prolongation of existing hospitalization excepting hospital admissions due to administrative reasons leg, the suhject has no transportation home) or hospitalization for elective ent of a preexisting condition that did not worsen during the study unless a complication occurs during the alization; Results in permanent or significant disahility/incapacity; or Results in congenital anomaly/birth defect. {auras} nasunrs {00707} Figures 6 and ‘7 show the mean plasma concentrations of APTmlOll casone Propionate) administration in fasted, fed, and HS treatment regimens. Figures 8*10 show spaghetti plots of the plasma concentrations of APT-l 01 l, (Fluticasone Propionate) administration in fasted (Figure 8), fed (Figure 9), and HS (Figure 10) conditions. Surprisingly, HS administration to a patient laying down before sleep shows a sustained level of drug. Instead of a sharp, qui ck peak as observed in fed and fasted administration, HS stration in a prone position lead to a sustained tration of APT—1m l in the patient’s blood. This may be due to prolonged exposure to the distal esophagus. This long exposure in the distal esophagus has the added age of also reducing systemic exposure to APT-l0l l, which is expected to se adverse side effects. {00708} A total of 24 ipants enrolled and 22 (92%) completed the study, A summary of the Pl: parameters by test group is presented in Table l8. AM dosing was associated with a higher rate of ahsorption under fed compared to fasted conditions. Following a high fat nieal, there was a higher peal: concentration (Cain: ratio {9 % Cl] 120.65% [99.84%ul45.79%]), and a faster time to peak concentration, as compared to the fasted state (Tim: fed 5.00 h; fast 10.00 h).

However, lower total exposure in the fed compared to the fasted state (AUG-(1a: ratio [90% Cl} 76.97% [67.64941—87599/69 was observed. HS dosing was found to slow the rate of tion as compared to AM dosing conditions. Specifically, the time to peak concentration with l-lS (firm: l4 h) was longer than with AM dosing (Tm-m fast l0 h, fed 5 h). HS dosing was associated with higher overall exposure (AUCinr: ratio [90%CT] l22.36‘l/u [l0’7.02"/€nl39.88%l and lower Cmax ((:rnax: ratio {90%Cl} 67.79% {56.29%u8l64'3l/ial) as compared to the fed regimen. As compared to the fasted regimen, HS dosing yielded lower overall exposure (AUCmr: ratio {9092:1131} = 0 [7524934005 in} and lower Cm (can: lane [sot/tot} = 81.78% {asst/teamed).

Across all dosing regimens, the me of fluticasone with APT—1011 ranged from 597—200 pg/inL {W799} No AEs of special interest (AEST), no serious adverse events (SAE), and no deaths were reported for any of the ts enrolled in this study. No subiect was withdrawn by the investigator for safety reasons. {99719} A total of l2 treatment—emergent adverse events ) were reported by 7 (29%) of the 24 subjects who participated in this study. Of these events, 4 occurred after administration of Treatment A, l after administration of Treatment l3, and the other 7 after administration of Treatment C All TEAEs were deemed mild in severity Most TEAEs were considered possibly related (92%) to ent, } The TE/AEs reported in this study were experienced with a low nce, by l subject per treatment group (5% for Treatment A, 5% or Treatment 8, and 4% for Treatment C).

These ed: nausea, chest fort, upper respiratory tract infection, and headache for Treatment A, chest discomfort for Treatment El and pation, oral herpes, dizziness, vessel puncture site bruise, aspartate aminotransl‘erase increased, nasal tion, and hot flash for Treatment C. {(38712} The incidence of TEAEs was of 9% for Treatment A, 5% for Treatment B, and 22% for Treatment C. Drug—related T’EAEs were reported with a similar trend as the total TEAE incidence: 9% for Treatment A, 5% for Treatment B, and l7‘l/ii for Treatment C. {@9713} Generally, the abnormal clinical laboratory values were marginally higher or lower than their reference ranges and were mostly considered non—clinically significant by the investigator. However, one subject showed an abnormal aspartate transferase result at poststudy visit, which was considered clinically significant hy the investigator and reported as a mild TEAE (:increased aspartate ransferase). The last treatment administered to this subject was Treatment C. The event outcome was unknown at the end of the study; the sub} ect was lost to followuup. {98714} ()verall, the means of laboratory parameters, vital signs, and ECGs for the different treatments were comparable. ln addition, the mean for all subjects at screening and post—study of evaluated parameters were comparable. {(130715} Furthermore, there were no clinically significant alities in the vital signs and ECGs of the sub} ects in this study. {@9716} Overall, the most common answers in the palatahility assessments were “Like, a little”, and “Neither like not dislike”. } eoner'risron {W718} Oral APT—1011 was safe and, wellmtolerated when administered under AMI fasted, AM fed, or HS conditions to healthy subjects.

{W719} This phase 1 study demonstrated, that systemic re of Fl) is confirmed to be very low ing oral APT—l Gil l administration (total (lose 6 mg) under fast, fed and at bedtime . PK sampling allowed for accurate estimation of the elimination profile, Therefore, ison of extent of systemic exposure over 24 hours, 72 hours and infinity was performed {some} Peak values were comparable between inorning~fast and HS dosing, however maximal concentrations were reached more y when APTmlOI l was stered with a high fat meal. {99721} The interindividual variability (CV%) for Cum was the highest for the HS regimen followed by the morning—fast and fed regimens. Based on the ed low bioavailability of this formulation (expected minimum systemic exposure), this high level of variability observed was expected. {1949722} The food effect and time of day effect are ely proportional to the peak exposure of PP when compared to the nrorning~fast dosing. When compared to the morning-fast regimen, maximum peal; exposure was 20 % higher for the morning—fed n and lgll/ia lower for the HS administration. A lower rate of absorption is suggested when AlylllOll is given at bedtime, while a higher rate of absorption is observed when given in the morning with a high fat meal. {@8723} While there was faster absorption of ll under fed conditions and slower absorption at bedtime, overall absorption of fluticasone with this formulation is low (<20C) pg/inL).

Slower absorption with l-lS dosing suggests a potential for longer dwell times in the esophagus; WO 35393 the relationship of bedtime dosing with histological efficacy in both the proximal and distal portions of the esophagus will be explored in future studies ofAl?’l'—lOll in EoE {98724} ()verall, a food effect was observed as Cmax and AUC ratios and/or 90%(3l were not all within the predefined standard range of 80.00425.th %.

{W725} Also, complete ahsenee of time of day effect on ilability of El) could not he established as lower bounds of the 90%Cl for Cam and AUCmr were helow the pre—defined standard range of 8t‘t.00%. {99726} The overall extent of systemic exposure over 72 hours SQ was about 24% lower for the fed dosing as compared to a nonnstatistically significant decrease of 8% when given HS when compared to the niorningnfast stration.

{W727} 'l'he extrapolated extent of systemic exposure to infinity (AUCmr) was lower for both regimens (fed; decrease of 29%, and HS; decrease of 8%) when compared the morning—fast dosing. {@9728} Finally; HS n showed a higher decrease in exposure (33% decreases in Cmnx) when compared to the morningfed reginien than with the morning—fast regimen, Also, the extent of exposure over ‘72 hours and extrapolated to infinity was around 20% higher at e vs morning—fed suggesting that bedtime administration has a more sustained exposure with lower maximum peaks over time {@8729} Summaries of the pharmacokinetic ters for the Fast, Fed, and HS studies are provided in Tables lS—Zl.

Table 13 Summary of Plasma E? Pharmacokinetic Parameters Treatment A Treatment B Treatment. (7 g (Test Fast) (Test Fed) (”fest HS) FARAMETER szzbat N==2 18 Nflficr ________________________________________________________________________________________________________________________________________________________________________________________ Geometric ((gegmegrfig; Geometric etrif, Geometric (Geometric CW» 9/0)s ' v CV» 0/0) Cl“7 0/‘ Mean Mean Mean i0) cm (pg/m) sir (rose) 34.2 (102.3) 23s (lll.9) Tmaxlhours)“ moo (2.00-3000) 5‘00 (iris-ions) 14.00 (2.00-2000) AUClast (pg‘h/mL) 775.049 (94.6) 548933 (llll) 669.695 (98.3) AUCo-z4 (ng-h/rnl.) 366.607 (115.8) 361,277 (105.5) 3:59.541 (100.5) Treatmem A ’l‘matmmt B Treatmcnt C 1 (Fast Fast) (T001 10:11) (1011 1101 PARAMETER 214 11:20 N=23Caf 111111111(01011111101011111221250203};""""E;£07000?""EEEQEQQQF' Mean, CV ‘70} M10311 CoV. %) M03011 CV 9/0} AUCM(pg‘h/mL); 1044301; (90.11 0 (107.2) 720451 (1002) 4110111020, 7.13 (779) 5.112 (:11 .5) 4,91 (47,5) 21011111154) 0.0302 (32.5) 0.0370 (23.7) 0.0474 (21.2) 11,0 (hours) 19.14 (32.5) 111.72 (23.7) 14.01 (21.2) {EL/F (121101111 5745.43 (901) 10205.99 (107.21 3 (1002) VZ/ML) 151161112 (99.91 275013.92 (126.6) 174101133 (10111) Median and range are presented b 11===17 for AUCmf, , CL/E', VZ/F, 312:, and T112111 C 11:22] for AU (3101', AU :6“, CUP", VZ/E', 2&2, and T111111 d subjects 001, 002, 004—018, and 020—024 9 subjects 001, 003—007, 0094318, and 020—024 f subjects 001, 001024 T211110 19 Summary of thc Statist1cal Anaiysis 01" FF Food Effect 90% 00111111111111: GEOME'E‘REC LSMEANS“ 11111115 1%) 11111111— PARAMETER ESEUBJECT TreatmentB entA (3.171%) L091”ER {FIJPER c1111 37.1 37.7 31.3 120.65 99.34 1457 111101.11 23.1 102.404 307.351 109.51 97.12 123.55 1111131111 2419 1507.477 700234 715.97 07.154 87.59 111313111 211.9 15.50.1320 915302 71.10 151 .46 82.26 “0111ts are 110111113 1‘01” {:max and pg 11mL 101 AUCo24, ”1U1.1151 and AUC1111 “’11-"20101‘ 1UC1111 11:16 far ”1UC11f “Subjects 001, 7, 009—018, and 020_034 9 ts 001, 004—018, and; 020024 ’E‘abie 20 m Summary 0f the Statist1cal 11110137515 of FF ~ East vs HS Reg1r11e11 0% CONE“EDEN 1‘:E (11111311311111: 11131111211110 ‘3“. a r 11111115 (11/0) “3033471013“TER I T1eatmeat C Treatment A 3111; “20070509 ( V“ ( A); L (1001 HS) ("feast Fast) “‘QWER “WEEK (11=22)“"“ (11:21)” Cmax 37.1 25.6 313 $1.78 67.93 98.47 AUC0.24 23.1 389137 367351 105.93 94.14 119.19 AUCm 249 729.171 4 92.39 81.39 104.87 AUCM 24.9 796317 915302 87. 00 75.24 100. 59 “1111115 are 1321/1111. 1011 Cumx and 1.10 111111.011 AUC024 AUC1151; and AUCmf b11:20 fer AUCim C11:16 for AUC1n1 “ subjects 001,, 003018, and 020—024L “ ts 001, 0044318, and 020~024 Table 271 Summary of the Statistical Analysis of FF" Fed vs l-lS Regimen 90% ENCE GEOME'E‘REC LSMEANS“ LIB/11118 (0/0) 1 INTRA— parties/terns Treatment t: Treatment a 1 5531230?1. . ,0 Y ‘ (Test nsi (Test Fed} WWW WPER (Heme awaited Cm 37.1 25.6 37.7 57.79 56.29 81.64 AUCo-zi 23.1 389.137 402.404 96.70 35.93 108.83 AUC‘iast 249 729.171 607477 12003 105.72 136.28 AUCinf 24.9 7963.317 6511.820 122.36 107.02 139.88 units are pg/mL for {:max and pgh/inL for AUCou, AU :last and AUCita‘ b11:20 for AUCmr C subjects 001, 003—018, and 020024 d subjects 001, 004~007, 009—018, and 020024 Example 6 Scinagraphy study of anatomical contact of oral corticosteroid following oral administration to a lying down patient compared to an upright t. lllll73l‘t} The oral coiticosteroid (eg, thiticasorie propionate) will he radiolaheled by attaching radioisotopes, and the cortieosteroid will be formulated in a pharmaceutical eomposition, such as an orally disintegrating tahlet. The radiolabeled oral corticosteroid will be administered to the patient while the patient is lying down. Independently, radiolaheled oral corticosteroid will he administered to the patient while the patient is upright. {(39731} The radioisotopes ernit gamma radiation. al deteetors (gamma s) capture the gamma radiation ei'riitted from the radiolabeled osteroid as it traverses the esophagus wl'iich are coiwerted to images The location and ve amount of the corticosteroid in the distal and pl‘OXllTlal esophagus for the lying down patient versus the t patient can measured from said images } The results of the sciritigraphy study will indicate that similar amounts of the osteroid contact the proximal and distal esophagus when the oral corticosteroid is administered to a lying down patient, whereas an t t has a higher amount of corticosteroid in the proximal esophagus compared to the distal esophagus.

CLATMS l. A method of treating eosinophilic esophagitis (EoE) in a patient in need thereof, comprising administering an oral corticosteroid in an induction phase and a nance phase, wherein the induction phase results in an improvement in Peak eosinophiiic counts in at least one geal biopsy and the treating results in no worsening of patient mean weekly scores in a patient—reported outcome assessment which includes the assessment of dysphagia—free days. 2. The method of claim 1, wherein the induction phase comprises administration for at least about 6 weeks. 3. The method of claim 1, wherein the induction phase comprises administration for at least about 8 weeks. 4. The method of claim 1, wherein the induction phase comprises administration for at least about l0 weeks.

. The method of claim 1, wherein the induction phase ses stration for at least about l2 weeks. 6. The method of any one of claims 2 to 5, n the administration is at least twice daily. ’7. The method of claim l, wherein the corticosteroid is in an orally dissolving dosage form. 8. The method of claim ’7, wherein the osteroid is selected from the group consisting of hudesonide, fiuticasone, flunisolide, ciclesonide, niometasone, heclomethasone, tixocortoi and salts, esters, solvates, polymorphs, prodrugs, and mixtures thereof. 9. The method of claim l, wherein the patient has usiy been administered PP} l0. The method of claim 9, wherein the PPl therapy was not effective to substantially improve one or more symptoms ot‘EoE. ll. The method of claim l, wherein the patient does not relapse with active symptoms of l2. The method of claim l, wherein the induction phase results in a histological response in which Peak eosinophii counts per T—TPF are reduced to 6 or less. 13. The method of claim 1, wherein the induction phase results in no e of food impaction. 14. The method of claim 1, wherein the nance dose is substantially the same or less than the induction dose.

. The method of claim 1, wherein the maintenance dose is higher than the induction dose. 16. The method of claim 1, wherein the ent results in no worsening of patient inean weekly scores according to an EEsAl assessment. 17. The method of c1aini 7, n the oral dissolving dosage form is a tablet or wafer. 18. The method of claim 1, wherein the induction and maintenance doses are between about 1.5mg and about 3mg. 19. The method of claim 18, wherein the dose is administered twice daily.

, The method of claim 17, wherein the osteroid is deposited topically in the upper gastrointestinal tract. 41,A The method of claim 1, wherein the patient exhibits substantial improvement in esophageal function and morphology, including lessening of esophageal furrows, lessening of esophageal focal narrowing, increased esophageal diameter, increased esophageal compliance, increased esophageal body distensihility, increased ease swallowing, d edema, iniproved vascularity, reduction of rings, decrease or absence of exudate, and/or e of stricture. 22. A method of treating £013 in a t in need thereof, comprising administrating an oral corticosteroid in an induction phase and a maintenance phase, wherein the induction phase does not result in a substantial improvement in Peak eosinophilic counts in at least one esophageal biopsy, and treatment is continued resulting in an improvement in Peal: eosinophilic counts in at least one esophageal biopsy, and the treatment results in no worsening of patient mean weekly scores in a patient~reported e assessment which includes the assessment of dyspliagianfree days. 23. The method of claim 22, wherein the patient experiences at least one episode of food impaction in the induction phase. 24. The method of claim 22, wherein the induction phase comprises for at least about 6 weeks.

. The method of claim 22, n the induction phase comprises administration for at least about 8 weeks. 26. The method of claim 22, wherein the induction phase comprises administration for at least about l0 weeks. 27. The method of claim 22, n the induction phase comprises for at least about l2 weeks. 28. The method of any one of claims 24 to 27, wherein the administration is at least twice daily. 29. The method of claim 22, n the corticosteroid is in an orally dissolving dosage form.

. The method of claim 29, n the corticosteroid is selected from the group consisting of nide, fluticasone, llunisolide, ciclesonide, niometasone, beclomethasone, tixocortol and salts, or esters and mixtures thereof. 3l. The method of claim 22, wherein the patient has previously been administered PPl therapy. 32. The method or" claim 31, wherein the Pl’l therapy was not effective to substantially improve one or more oins ot‘EoE. 33. The method or" claim 22, wherein the patient exhibits active symptoms of EoE. 34. The method of claim 22, wherein the maintenance dose is substantially the same or less than the induction dose.

. The method of claim 22, wherein the maintenance dose is higher than the induction dose. 36. The method or" claim 29, wherein the oral dissolving dosage form is a tablet or wafer. 37. The method of claim 22, wherein the induction and maintenance doses are between about l.5mg and about 3mg. 38. The method of claim 37, wherein the dose is administered twice daily. 39. The method of claim 36, wherein the corticosteroid is deposited topically in the upper gastrointestinal tract. 40. The method of claim l, n the oral corticosteroid is administered before breakfast and/or at bedtime. 41. The method of claim l, wherein the treatment results in no significant systemic glucocorticoid or mineralocorticoid effect. 42. The method of claim l, wherein Peal: eosinophil counts are measured by esophageal biopsy during the maintenance phase. 43. The method of treating EoE according to any of claims l—42, wherein the patient prior to treatment (i) has a Peak eosinophil count per HP?" of greater than l5 and (ii) received prior treatment with a Pl’l over at least about 8 weeks which was not effective to substantially ye one or more symptoms of EoE. 44. A method of lly treating philic esophagitis (EoE) in patient in need thereof with an oral corticosteroid, comprising: a. administering the oral corticosteroid while the t is lying down or immediately prior to the patient lying down, wherein a therapeutically effective amount of the oral corticosteroid contacts the esophagus, thereby topically treating Eolil. 45. The method of claim 44, wherein the lying down is in a , prone, or laterally recumbent position. 46. The method of claim 44, wherein the oral corticosteroid is administered about 30 minutes or less before target sleep time. 47. The method of claim 44, wherein the oral corticosteroid is stered at least ahout 30 minutes after a meal. 48. The method of claim 44, wherein the patient does not eat or drink for at least about 30 s alter administration the oral corticosteroid. 49. The method of claim 44, wherein the oral corticosteroid is administered: (i) once daily; or (ii) twice daily, wherein the first daily dose is stered while the subject s upright. 50. The method of claim 44, wherein the oral corticosteroid has a systemic bioavailability of less than or equal to about 20% of its dose. 51. The method of claim 44, wherein the oral corticosteroid provides an average m blood plasma concentration (Cmax) of less than or equal to about 500 ; after oral administration of about Glfil mg to about 20 mg of the oral corticosteroid. 52. The method of claim 44, n the oral corticosteroid provides an average AUCoai of less than or equal to about 3,099 pg’i‘li/nili after oral administration of about 0.01 mg to about 2ft mg of the oral corticosteroid. 53. The method of claim 44, wherein the oral corticosteroid is budesonide, fluticasone, tlunisolide, ciolesonide, mometasone or beclomethasone, or a. pharmaceutically acceptable salt, solvent, ester, polymorpli or orodrug thereof. 54. The method of claim 44, wherein the oral corticosteroid is formulated: (i) as a liquid composition; (ii) as a solid composition; (iii) to form a solution or suspension prior to oral administration; or (iv) to form a. solution, suspension or gel after oral administration, wherein (i)~(iv) delivers a therapeutically effective amount of the oral corticosteroid to the esophagus. :3. The method of claim 54, wherein (i) the liquid composition is in the form ofa on, suspension or slurry; (ii) the solid composition is in the form ofa, gel, lozenge, lollipop, ellers'escent tablet, powder, granules or an orally disintegrating ition. :36. The method of claim 55, wherein the orally disintegrating composition is a tablet, wafer, film, or lyophilized matrix. 57. The method ct" claim 56, wherein the orally disintegrating composition is a tablet sing; a. the oral corticosteroid in an amount offrom about 1.5 mg to about 7.5 mg, b. a pharmaceutically acceptable carrier combined with the corticosteroid; and l”7‘5I . c. rapidly dispersing microgranules, wherein the orally disintegrating tablet disintegrates within 60 seconds when tested using the U SP <70l3> method for disintegration time. 58. The method or" claim 44, wherein the patient has a Cniax of the oral corticosteroid of less than or equal to about 200 pg/mL following oral administration 1.5 mg to about 7.5 mg of the oral corticosteroid. 59. The method of claim 44, n the oral corticosteroid is fluticasone nate, and the lying down patient has a CmaX within the range of about 80% to about l25% of about l5 pg/mL to about 45 pg/mL following oral administration of 6 mg fluticasone propionate or 3 mg of fluticasone propionate to a lying down patient. 60. The method of claim 59, wherein the (Smart of the corticosteroid for the laying down patient is lower than the CmaX of the oral corticosteroid for a fed patient that is upright and does not lay down immediately after administration of the oral osteroid. 61. The method of claim 60,, wherein the Cmax of the oral corticosteroid for the lying down patient is lowered by about l0% to about 30% compared to the CmaX of the oral corticosteroid for a fed patient that is t and does not lay down immediately after administration of the oral corticosteroid. 62. The method of claim 44,, wherein the average time to reach a maximum blood plasma concentration (Tmax) is in the range of about 80% to about l25% of about l2 h to about l5 he 63. The method of claim 62,, wherein the Tmax of the corticosteroid for the lying down patient is delayed compared to the Tmax of the oral corticosteroid for a patient that is upright and does not lay down immediately after administration of the oral osteroid. 64. The method of claim 63, wherein the Tmax of the corticosteroid for the lying down patient is delayed by at least about l hour compared to the average Tmax of the oral corticosteroid for a t that is upright and does not lay down immediately after administration of the oral corticosteroid, 65. The method of claim 64, wherein the Tmax of the osteroid for the lying down t is delayed by an amount of time in the range of about 4 h to about ‘9 h compared to the 'l‘max of the oral corticosteroid for a patient that is upright and does not lay down immediately after stration of the oral osteroid. 66. The method of claim 64, wherein after l2 weelrs of daily administration of the oral corticosteroid, esophageal inflammation is reduced as measured by a reduction in eosmophil count, an increase in dysphagia—t‘ree days, a reduction in episodes of dysphagia, improvement in EREFS score, EndoELlP documentation of improved esophageal compliance, evaluation of hiomarlzers, a decrease in es of food impaction, an improvement in EESAl scores (patient, physician, endoscopy, pathology scores), EoE-QOLnA, Visual Dysphagia Questionnaire (VDQ), Avoidance Modification and Slow Eating (AME-Z) scores, or histology. 67. The method of claim 66, n the patient’s eosinophil count is reduced by at least about 50%. 68. The method of claim 44, wherein the patient has a lactose allergy or starch allergy. \\\\\\\\\\\§\\\\\\\\\\\\\\\\\ mt “Hunk “\E‘kgximcxfi Emwfigwwm ....................................... VVVVVVVVVVVVVVVVVVVVVVVVV .......... a. 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"Ex“ pends)": 9-5.6: 13 am] Reine-Siva ELI-3:73 a. 2‘s. Hun: r-‘s-z‘; we 9 .. ------------------~\\\\\---------~e}~ Abbreviations: BID 2 twice daily; EGD : gogastroduodenoscopy; EREFS I Eosinophilic Esophagitis opic Reference Score; HS ; hora 50mm, (before sleep); PGI-C = Patient Globai Impression of Change; PGInS = Patieni Global Impression of Seventy; FRO = Patient Reported Outcomes; wk 2 Week Figure 5 PHi-KSE 2: Sgnifili-QQZ : \ : ‘ Screenin andéwk ‘ g g x 3 \ : STUBS’ and izatmn Izltlzifl \\ a X \ »»»»»»»»»»»»»»\\\\\\\\\\\\\\\\§\Q\\Q\\\\\\\\\\\\\\\\\ FHRSE 22 Primary endppin‘t. 29,52.) Erninogfiviisz‘HPF Sammie ’\.;\j¢\ XE Nan—Responders \ ‘« , \ A {based 993:1 new 95100;}: Abbreviations: BID 1 twice daily; EGD : esophagogastrodnodenoscopy; EREFS : Eosinophilic Esophagitis Endoscopic Reference Score; HS = hora somni e sleep“); PSI—C 2 Patient Global Impression of Change; PSI—S Patient Global impression of Seventy; PRO Patient Reported Outcomes; wk Week.

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