# US 11,026,887 B2 · Methods of treating eosinophilic esophagitis

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- Number: US 11,026,887 B2
- Document ID: US11026887B2
- Status: Granted
- Kind: B2
- Application number: 16/131,812
- Filed: 2018-09-14
- Published: 2019-01-10
- Granted: 2021-06-08
- Earliest claimed: 2016-08-18
- Assignees: Ellodi Pharmaceuticals, L.P.
- Applicants: Ellodi Pharmaceuticals, L.P.
- Inventors: Brian A. Meltzer; Gail M. Comer
- Web page: https://patentgrep.com/patent/US11026887B2

## CPC

- A61K 9/006: {Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays}
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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 embodiments, the methods include treating EoE by administering the oral corticosteroid at nighttime and/or while the patient is lying down.

## Claims

### Claim 1

A method of topically treating eosinophilic esophagitis (EoE) in a patient in need thereof with an oral corticosteroid, comprising:
a. administering the oral corticosteroid while the patient 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 EoE.

### Claim 2 (depends on 1)

The method of claim 1, wherein the lying down is in a supine, prone, or laterally recumbent position.

### Claim 3 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is administered about 30 minutes or less before target sleep time.

### Claim 4 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is administered at least about 30 minutes after a meal.

### Claim 5 (depends on 1)

The method of claim 1, wherein the patient does not eat or drink for at least about 30 minutes after administering the oral corticosteroid.

### Claim 6 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is administered:
(i) once daily; or
(ii) twice daily, wherein the first daily dose is administered while the subject remains upright.

### Claim 7 (depends on 1)

The method of claim 1, wherein the oral corticosteroid has a systemic bioavailability of less than or equal to about 20% of its dose.

### Claim 8 (depends on 1)

The method of claim 1, wherein 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 0.01 mg to about 20 mg of the oral corticosteroid.

### Claim 9 (depends on 1)

The method of claim 1, wherein the oral corticosteroid provides an average AUC0-24 of less than or equal to about 3,000 pg*h/mL after oral administration of about 0.01 mg to about 20 mg of the oral corticosteroid.

### Claim 10 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is budesonide, fluticasone, flunisolide, ciclesonide, mometasone or beclomethasone, or a pharmaceutically acceptable salt, solvent, ester, polymorph or prodrug thereof.

### Claim 11 (depends on 1)

The method of claim 1, 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.

### Claim 12 (depends on 11)

The method of claim 11, wherein
(i) the liquid composition is in the form of a solution, suspension or slurry;
(ii) the solid composition is in the form of a gel, lozenge, lollipop, effervescent tablet, powder, granules or an orally disintegrating composition.

### Claim 13 (depends on 12)

The method of claim 12, wherein the orally disintegrating composition is a tablet, wafer, film, or lyophilized matrix.

### Claim 14 (depends on 13)

The method of claim 13, wherein the orally disintegrating composition is a tablet comprising:
a. the oral corticosteroid in an amount of from about 1.5 mg to about 7.5 mg;
b. a pharmaceutically acceptable carrier combined with the corticosteroid; and
c. rapidly dispersing microgranules,
wherein the orally disintegrating tablet disintegrates within 60 seconds when tested using the USP <701> method for disintegration time.

### Claim 15 (depends on 1)

The method of claim 1, wherein the patient has a Cmax of the oral corticosteroid of less than or equal to about 200 pg/mL following oral administration of about 1.5 mg to about 7.5 mg of the oral corticosteroid.

### Claim 16 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is fluticasone propionate, and the patient has a Cmax within the range of about 80% to about 125% of about 15 pg/mL to about 45 pg/mL following oral administration of 6 mg fluticasone propionate or 3 mg of fluticasone propionate.

### Claim 17 (depends on 1)

The method of claim 1, wherein the Cmax of the corticosteroid for the 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 corticosteroid.

### Claim 18 (depends on 16)

The method of claim 16, wherein the Cmax of the oral corticosteroid for the patient is lowered by about 10% 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.

### Claim 19 (depends on 1)

The method of claim 1, wherein the average time to reach a maximum blood plasma concentration (Tmax) is in the range of about 80% to about 125% of about 12 h to about 15 h.

### Claim 20 (depends on 1)

The method of claim 1, wherein the Tmax of the corticosteroid for the 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 corticosteroid.

### Claim 21 (depends on 20)

The method of claim 20, wherein the Tmax of the corticosteroid for the patient is delayed by at least about 1 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 corticosteroid.

### Claim 22 (depends on 21)

The method of claim 21, wherein the Tmax of the corticosteroid for the patient is delayed by an amount of time in the range of about 4 h to about 9 h 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 corticosteroid.

### Claim 23 (depends on 1)

The method of claim 1, wherein after 12 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, improvement in EREFS score, EndoFLIP documentation of improved esophageal compliance, evaluation of biomarkers, a decrease in episodes of food impaction, an improvement in EEsAI scores (patient, physician, endoscopy, pathology scores), EoE-QOL-A, Visual Dysphagia Questionnaire (VDQ), Avoidance Modification and Slow Eating (AMS) scores, or histology.

### Claim 24 (depends on 23)

The method of claim 23, wherein the patient's eosinophil count is reduced by at least about 50%.

### Claim 25 (depends on 1)

The method of claim 1, wherein the patient has a lactose allergy or a starch allergy.

### Claim 26 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is administered within about 5 minutes prior to the patient lying down.

### Claim 27 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is administered within about 4 minutes prior to the patient lying down.

### Claim 28 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is administered within about 3 minutes prior to the patient lying down.

### Claim 29 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is administered within about 2 minutes prior to the patient lying down.

### Claim 30 (depends on 1)

The method of claim 1, wherein the oral corticosteroid is administered within about 1 minute prior to the patient lying down.