# US 11,304,947 B2 · Compositions and methods for treating lung injuries associated with SARS-COV-2 infections

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- Number: US 11,304,947 B2
- Document ID: US11304947B2
- Status: Granted
- Kind: B2
- Application number: 17/325,968
- Filed: 2021-05-20
- Published: 2021-11-25
- Granted: 2022-04-19
- Earliest claimed: 2020-05-22
- Assignees: Qx Therapeutics Inc.; Yale University
- Applicants: Qx Therapeutics Inc.
- Inventors: Dianqing Wu; Ho Yin Lo
- Web page: https://patentgrep.com/patent/US11304947B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 31/14: for RNA viruses
- 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

The present invention provides methods and compositions for treating and preventing lung injuries due to or associated with coronavirus infections that cause Severe Acute Respiratory Syndrome, including COVID-19. More specifically the present invention provides methods for treating or preventing the lung injuries associated with SARS-CoV-2 infections, such as acute lung injury (ALI), lung fibrosis, and acute respiratory distress syndrome (ARDS). The methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising a protein kinase inhibitor compound having MAP3K2/MAP3K3 inhibition activity, such as pazopanib or nintedanib, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a patient in need thereof. The present invention also provides devices for administering the compositions.

## Claims

### Claim 1

A method for treating or reducing the severity of a lung injury associated with a coronavirus infection comprising administering to a human subject in need thereof a therapeutically effective amount of nintedanib, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

The method of claim 1 wherein the coronavirus infection is caused by the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2).

### Claim 3 (depends on 1)

The method of claim 1 wherein the pharmaceutically acceptable salt is selected from a salt of a mineral acid selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, or a salt selected from mesylate, esylate, besylate, tosylate, and combinations thereof.

### Claim 4 (depends on 3)

The method of claim 3 wherein the pharmaceutically acceptable salt is the esylate salt.

### Claim 5 (depends on 1)

The method of claim 1 wherein the nintedanib, or a pharmaceutically acceptable salt or solvate thereof is administered using an administration route selected from the group consisting of oral, intra venous, parenteral, nasal, inhalation, intratracheal, intrapulmonary, and intrabronchial.

### Claim 6 (depends on 5)

The method of claim 5 wherein the administration route is selected from the group consisting of oral, parenteral, nasal, inhalation, intratracheal, intrapulmonary, and intrabronchial, and the administration is performed using a spray device or nebulizer.

### Claim 7 (depends on 1)

The method of claim 1 wherein the lung injury is lung fibrosis.

### Claim 8 (depends on 1)

The method of claim 1 wherein the lung injury is selected from the group consisting of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

### Claim 9 (depends on 8)

The method of claim 8 wherein the lung injury is acute lung injury (ALI).

### Claim 10 (depends on 8)

The method of claim 8 wherein the lung injury is acute respiratory distress syndrome (ARDS).

### Claim 11 (depends on 1)

The method of claim 1 wherein the lung injury involves pulmonary edema, and wherein the pulmonary edema is reduced after treatment.

### Claim 12 (depends on 1)

The method of claim 1 wherein the patient experiences one or more improvements of condition after treatment selected from the group consisting of: reduced time on ventilator, improved blood oxygen levels, an increase in rheumatoid factor (RF) production from neutrophils, an increase in reactive oxygen species (ROS), reduced recovery time, reduced pulmonary permeability, improved pulmonary barrier function, increased pulmonary barrier cell survival.

### Claim 13 (depends on 1)

The method of claim 1 wherein the nintedanib, or a pharmaceutically acceptable salt or solvate thereof is administered according to a regimen selected from the group consisting of about four times per day, about three times per day, about two times per day, about one time per day, about one time every other day, about two times per week, and about one time per week.

### Claim 14 (depends on 13)

The method of claim 13 wherein the nintedanib, or a pharmaceutically acceptable salt or solvate thereof is administered for a period selected from the group consisting of about 1 day to about 30 days, about 1 day to about one month, about 1 day to about 14 days, about 1 day to about 10 days, about 1 day to about 1 week (7 days), about 1 day to about 5 days, about 1 day to about 3 days, and until the infection is treated.

### Claim 15 (depends on 14)

The method of claim 14 wherein at least one of the following pharmacokinetic parameters is achieved in the patient selected from the group consisting of an AUC of about 1,037 mcg*h/mL or a Cmax of about 58.1 mcg/mL, equivalent to about 132 μM.

### Claim 16

A method for treating or reducing the severity of a lung injury associated with a coronavirus infection comprising administering to a human subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:
nintedanib or a pharmaceutically acceptable salt or solvate thereof.

### Claim 17 (depends on 16)

The method of claim 16 wherein the coronavirus infection is caused by the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2).

### Claim 18 (depends on 16)

The method of claim 16 wherein the pharmaceutical composition further comprises an anti-viral agent.

### Claim 19 (depends on 16)

The method of claim 16 wherein the lung injury is selected from the group consisting of acute lung injury (ALI), lung fibrosis, and acute respiratory distress syndrome (ARDS).

### Claim 20

A pharmaceutical composition for treating or reducing the severity of a lung injury associated with a SARS-CoV-2 infection, comprising:
(a) a therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt or solvate thereof, and
(b) a pharmaceutically acceptable carrier.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20 further comprising an anti-viral agent.

### Claim 22 (depends on 21)

The pharmaceutical composition of claim 21 wherein the anti-viral agent is remdesivir, or a pharmaceutically acceptable salt, ester, or solvate thereof.

### Claim 23 (depends on 16)

The method of claim 16 wherein the pharmaceutical composition comprises from about 1 to about 1000 mg per unit dosage of nintedanib, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 24 (depends on 16)

The method of claim 16 wherein the pharmaceutical composition comprises about 100 mg, or about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg or about 600 mg, or about 700 mg, or about 800 mg per unit dosage of nintedanib, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 25 (depends on 16)

The method of claim 16 wherein the pharmaceutical composition comprises about 100 mg, or about 150 mg, or about 200 mg, or about 250 mg, or about 300 mg of nintedanib, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 26 (depends on 16)

The method of claim 16 wherein the pharmaceutical composition comprises about 150 mg of nintedanib, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 27 (depends on 16)

The method of claim 16 wherein the pharmaceutical composition is administered according to a regimen selected from the group consisting of about four times per day, about three times per day, about two times per day, about one time per day, about one time every other day, about two times per week, and about one time per week.

### Claim 28 (depends on 16)

The method of claim 16 wherein the pharmaceutical composition is administered about two times per day.

### Claim 29 (depends on 26)

The method of claim 26 wherein the pharmaceutical composition is administered about two times per day.

### Claim 30 (depends on 13)

The method of claim 13 wherein the pharmaceutical composition is administered for a period selected from the group consisting of about 1 day to about 30 days, about 1 day to about one month, about 1 day to about 14 days, about 1 day to about 10 days, about 1 day to about 1 week (7 days), about 1 day to about 5 days, about 1 day to about 3 days, and until the infection is treated.

### Claim 31 (depends on 1)

The method of claim 1 wherein the nintedanib, or a pharmaceutically acceptable salt or solvate thereof is administered at about 100 mg, or about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg or about 600 mg, or about 700 mg, or about 800 mg per unit dosage.

### Claim 32 (depends on 1)

The method of claim 1 wherein the nintedanib, or a pharmaceutically acceptable salt or solvate thereof is administered at about 100 mg, or about 150 mg, or about 200 mg, or about 250 mg, or about 300 mg per unit dosage.

### Claim 33 (depends on 1)

The method of claim 1 wherein the nintedanib, or a pharmaceutically acceptable salt or solvate thereof is administered at about 150 mg per unit dosage.

### Claim 34 (depends on 1)

The method of claim 1 wherein the nintedanib, or a pharmaceutically acceptable salt or solvate thereof is administered about two times per day.

### Claim 35 (depends on 33)

The method of claim 33 wherein the nintedanib, or a pharmaceutically acceptable salt or solvate thereof is administered about two times per day.

### Claim 36 (depends on 18)

The method of claim 18 wherein the anti-viral agent is remdesivir, or a pharmaceutically acceptable salt, ester, or solvate thereof.