# US 11,026,928 B2 · Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils

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- Number: US 11,026,928 B2
- Document ID: US11026928B2
- Status: Granted
- Kind: B2
- Application number: 15/923,650
- Filed: 2018-03-16
- Published: 2018-09-27
- Granted: 2021-06-08
- Earliest claimed: 2013-07-12
- Assignees: Knopp Biosciences LLC
- Applicants: Knopp Biosciences LLC
- Inventors: Michael E. Bozik; Gregory Hebrank; Wildon Farwell; Thomas Petzinger, Jr.; Steven Dworetzky
- Web page: https://patentgrep.com/patent/US11026928B2

## CPC

- A61K 31/428: condensed with carbocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/08: of the prostate
- A61P 17/00: Drugs for dermatological disorders
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 31/10: Antimycotics
- A61P 33/06: Antimalarials
- A61P 33/10: Anthelmintics
- A61P 35/02: specific for leukemia
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are methods of treating conditions, which may be associated with elevated levels of eosinophils and/or basophils, with a therapeutically effective amount of dexpramipexole or pharmaceutical acceptable salt thereof.

## Claims

### Claim 1

A method of treating a gastrointestinal disease associated with increased eosinophils comprising administering to a subject in need thereof a therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, wherein the gastrointestinal disease associated with increased eosinophils is selected from the group consisting of sclerosing cholangitis, irritable bowel disease, ulcerative colitis, eosinophilic esophagitis, eosinophilic gastroenteritis, inflammatory bowel disease, eosinophilic colitis, gluten sensitivity, Cronkhite-Canada syndrome, and any combination thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the pharmaceutically acceptable salt is (6R)-4, 5, 6, 7-tetrahydro-N6-propyl-2,6-benzothiazolediamine dihydrochloride monohydrate.

### Claim 3 (depends on 1)

The method of claim 1, further comprising measuring the level of eosinophils in the subject's peripheral blood, tissue, or a combination thereof.

### Claim 4 (depends on 3)

The method of claim 3, wherein the level of eosinophils is selected from the group consisting of at or above 100 cells per microliter, at or above 150 cells per microliter, at or above 200 cells per microliter, and at or above 300 cells per microliter.

### Claim 5 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is from about 50 milligrams to about 1,500 milligrams per day.

### Claim 6 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 milligrams per day.

### Claim 7 (depends on 1)

The method of claim 1, wherein the dexpramipexole or a pharmaceutically acceptable salt thereof is administered in a solid unit dose selected from a tablet or capsule.

### Claim 8 (depends on 1)

The method of claim 1, wherein administering comprises administering a fraction of the daily dose two or more times per day.

### Claim 9 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is administered as an initial dosing regimen followed by a maintenance dosing regimen.

### Claim 10 (depends on 9)

The method of claim 9, wherein the initial dosing regimen is administered for about 1 week to about 12 weeks.

### Claim 11 (depends on 9)

The method of claim 9, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the initial dosing regimen is from about 50 milligrams to about 1,500 milligrams per day.

### Claim 12 (depends on 9)

The method of claim 9, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the maintenance dosing regimen is from about 50 milligrams to about 300 milligrams per day.

### Claim 13 (depends on 1)

The method of claim 1, further comprising an induction step comprising administering a second therapeutic agent.

### Claim 14 (depends on 13)

The method of claim 13, wherein the second therapeutic agent is capable of decreasing eosinophil levels and is selected from the group consisting of a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a tyrosine kinase inhibitor, a fusion protein, a monoclonal antibody directed against one or more pro-inflammatory cytokines, a chemotherapeutic agent and a combination thereof.

### Claim 15 (depends on 13)

The method of claim 13, wherein said induction step comprises administering the second therapeutic agent from about 1 week to about 6 months.

### Claim 16 (depends on 1)

The method of claim 1, wherein therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is administered via a route of administration selected from the group consisting of orally, by inhalation, intranasally, via intravenous administration, topically, and any combination thereof.

### Claim 17 (depends on 1)

The method of claim 1, further comprising administering to the subject a therapeutically effective amount of one or more secondary agents.

### Claim 18 (depends on 17)

The method of claim 17, wherein the secondary agent is selected from the group consisting of a glucocorticoid, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a phenolic antioxidant, an anti-proliferative drug, a tyrosine kinase inhibitor, an anti-IL-5 or an anti-IL5 receptor monoclonal antibody, an anti-IL-13 or an anti-IL-13 receptor monoclonal antibody, an ant-IL-4 or an anti-IL-4 receptor monoclonal antibody, an anti-IgE monoclonal antibody, an anti-TSLP monoclonal antibody, a monoclonal antibody directed against one or more pro-inflammatory cytokines, a TNF-α inhibitor, a fusion protein, a chemotherapeutic agent, and a combination thereof.

### Claim 19 (depends on 1)

The method of claim 1, wherein the gastrointestinal disease is eosinophilic gastroenteritis.

### Claim 20 (depends on 19)

The method of claim 19, wherein the pharmaceutically acceptable salt is (6R)-4, 5, 6, 7-tetrahydro-N6-propyl-2,6-benzothiazolediamine dihydrochloride monohydrate.

### Claim 21 (depends on 19)

The method of claim 19, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is from about 50 milligrams to about 1,500 milligrams per day.

### Claim 22 (depends on 19)

The method of claim 19, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 milligrams per day.

### Claim 23 (depends on 21)

The method of claim 21, wherein administering comprises administering a fraction of the daily dose two or more times per day.

### Claim 24 (depends on 19)

The method of claim 19, wherein the dexpramipexole or a pharmaceutically acceptable salt thereof is administered in a solid unit dose selected from a tablet or capsule.

### Claim 25 (depends on 19)

The method of claim 19, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is administered as an initial dosing regimen followed by a maintenance dosing regimen.

### Claim 26 (depends on 25)

The method of claim 25, wherein the initial dosing regimen is administered for about 1 week to about 12 weeks.

### Claim 27 (depends on 25)

The method of claim 25, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the initial dosing regimen is from about 50 milligrams to about 1,500 milligrams per day.

### Claim 28 (depends on 25)

The method of claim 25, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the maintenance dosing regimen is from about 50 milligrams to about 300 milligrams per day.

### Claim 29 (depends on 19)

The method of claim 19, further comprising an induction step.

### Claim 30 (depends on 29)

The method of claim 29, wherein said induction step comprises administering a second therapeutic agent that is capable of decreasing eosinophil levels selected from the group consisting of a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a tyrosine kinase inhibitor, a fusion protein, a monoclonal antibody directed against one or more pro-inflammatory cytokines, a chemotherapeutic agent and a combination thereof.

### Claim 31 (depends on 29)

The method of claim 29, wherein said induction step is from about 1 week to about 6 months.

### Claim 32 (depends on 19)

The method of claim 19, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is administered via a route of administration selected from the group consisting of orally, by inhalation, intranasally, via intravenous administration, topically, and any combination thereof.

### Claim 33 (depends on 19)

The method of claim 19, further comprising administering to the subject a therapeutically effective amount of one or more secondary agents.

### Claim 34 (depends on 33)

The method of claim 33, wherein the secondary agent is selected from the group consisting of a glucocorticoid, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a phenolic antioxidant, an anti-proliferative drug, a tyrosine kinase inhibitor, an anti-IL-5 or an anti-IL5 receptor monoclonal antibody, an anti-IL-13 or an anti-IL-13 receptor monoclonal antibody, an anti-IL-4 or an anti-IL-4 receptor monoclonal antibody, an anti-IgE monoclonal antibody, an anti-TSLP monoclonal antibody, a monoclonal antibody directed against one or more pro-inflammatory cytokines, a TNF-α inhibitor, a fusion protein, a chemotherapeutic agent, and a combination thereof.

### Claim 35 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 milligrams per day.

### Claim 36 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 100 milligrams per day.

### Claim 37 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 milligrams per day.

### Claim 38 (depends on 19)

The method of claim 19, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 milligrams per day.

### Claim 39 (depends on 19)

The method of claim 19, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 100 milligrams per day.

### Claim 40 (depends on 19)

The method of claim 19, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 milligrams per day.