# US 10,441,595 B2 · Methods for treating fungal infections

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- Number: US 10,441,595 B2
- Document ID: US10441595B2
- Status: Granted
- Kind: B2
- Application number: 14/750,928
- Filed: 2015-06-25
- Published: 2015-12-31
- Granted: 2019-10-15
- Earliest claimed: 2014-06-26
- Assignees: Brigham Young University
- Applicants: Carl Genberg; Chad S. Beus; Paul B. Savage
- Inventors: Carl Genberg; Chad S. Beus; Paul B. Savage
- Web page: https://patentgrep.com/patent/US10441595B2

## CPC

- A61K 31/575: substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 31/10: Antimycotics
- A61P 31/18: for HIV
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- 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

Disclosed herein are methods of treating fungal infections in a patient, comprising identifying a patient in need of treatment and administering a therapeutically effective amount of at least one cationic steroid antimicrobial (CSA), or a pharmaceutically acceptable salt thereof. Kits comprising such compositions and instructions on such methods are also contemplated herein.

## Claims

### Claim 1

A method of treating a fungal infection, comprising:
identifying a patient in need of treatment for a fungal infection caused by one or more fungi selected from the group consisting of Trichophyton rubrum, Trichophyton mentagrophytes, terbinafine-resistant Trichophyton rubrum, Candida albicans, fluconazole-resistant Candida albicans, Candida krusei, fluconazole-resistant Candida krusei, fluconazole-resistant Candida glabrata, Candida parapsilosis, Trichophyton tonsurans, Microsporum canis, Aspergillus fumigatus, Aspergillus niger, Penicillium sp., and Cladosporium sp.,
administering a therapeutically effective amount of at least one cationic steroid antimicrobial (CSA) of Formula III, or a pharmaceutically acceptable salt thereof, to the patient in need thereof in order for the CSA to provide antifungal activity against the one or more fungi:
where,
R3, R7, and R12 are unsubstituted aminoalkyloxy; and
R18 is unsubstituted alkylaminoalkyl, and
the therapeutically effective amount of the at least one CSA, or a pharmaceutically acceptable salt thereof, treating the fungal infection by providing antifungal activity in the patient against the one or more fungi.

### Claim 2 (depends on 1)

The method of claim 1, wherein the patient is not immunocompromised.

### Claim 3 (depends on 1)

The method of claim 1 wherein the patient is immunocompromised.

### Claim 4 (depends on 1)

The method of claim 1, wherein the patient is infected with Human Immunodeficiency Virus.

### Claim 5 (depends on 1)

The method of claim 1, wherein the fungal infection is a skin infection.

### Claim 6 (depends on 5)

The method of claim 5, wherein the skin infection is Athlete's Foot.

### Claim 7 (depends on 5)

The method of claim 5, wherein the fungal infection is caused by one or more fungi from the group consisting of Trichophyton rubrum, and Trichophyton mentagrophytes.

### Claim 8 (depends on 5)

The method of claim 5, wherein the skin infection is ringworm.

### Claim 9 (depends on 8)

The method of claim 8, wherein the skin infection is ringworm caused by one or more fungi from the Microsporum or Trichophyton genera.

### Claim 10 (depends on 5)

The method of claim 5, wherein the skin infection is Tinea curis (jock itch).

### Claim 11 (depends on 5)

The method of claim 5, wherein the skin infection is caused by one or more fungi from the group consisting of Trichphyton rubrum, Candida albicans, and Trichophyton mentagrophytes.

### Claim 12 (depends on 1)

The method of claim 1, wherein the fungal infection is a lung infection.

### Claim 13 (depends on 12)

The method of claim 12, wherein the lung infection is pneumonia.

### Claim 14 (depends on 12)

The method of claim 12, wherein the patient has a chronic lung disease.

### Claim 15 (depends on 14)

The method of claim 14, wherein the chronic lung disease is cystic fibrosis.

### Claim 16 (depends on 12)

The method of claim 12, wherein the lung infection is caused by one or more fungi from the group consisting of Candida albicans and Aspergillus fumigatus.

### Claim 17 (depends on 1)

The method of claim 1, wherein the fungal infection is nail fungus (onychomycosis).

### Claim 18 (depends on 17)

The method of claim 17, wherein the nail fungus (onychomycosis) affects at least one of a toenail, a fingernail, or analogous structure in a non human animal.

### Claim 19 (depends on 17)

The method of claim 17, wherein the nail fungus is caused by a fungus or fungi selected from the group consisting of Candida albicans, fluconazole-resistant C. albicans, C. parapsilosis, fluconazole-resistant C. krusei, fluconazole-resistant C. galabrata, Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Aspergillus fumigates, and A. niger.

### Claim 20 (depends on 1)

The method of claim 1, wherein the infection is an eye infection.

### Claim 21 (depends on 1)

The method of claim 1, wherein R3, R7, and R12 are the same.

### Claim 22 (depends on 1)

The method of claim 1, wherein the CSA, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
and pharmaceutically acceptable salts of the foregoing.

### Claim 23 (depends on 1)

The method of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

### Claim 24 (depends on 23)

The method of claim 23, wherein the pharmaceutically acceptable salt is a mono-hydrochloride salt, a di-hydrochloride salt, a tri-hydrochloride salt, or a tetra-hydrochloride salt.

### Claim 25 (depends on 1)

The method of claim 1, wherein the CSA is selected by measuring a biomarker or subjecting a sample from the patient to a companion diagnostic device in the patient.

### Claim 26 (depends on 25)

The method of claim 25, wherein the biomarker is a cellular response to the CSA or the companion diagnostic device measures a cellular response to the CSA.

### Claim 27 (depends on 26)

The method of claim 26, wherein the cellular response is a change in mRNA levels associated with fungal infection.

### Claim 28 (depends on 1)

The method of claim 1, wherein the patient is a mammal.

### Claim 29 (depends on 28)

The method of claim 28, wherein the mammal is a human.

### Claim 30 (depends on 1)

The method of claim 1, wherein two or more CSAs are co-administered.

### Claim 31 (depends on 1)

The method of claim 1, wherein administration of the CSA is selected from the group consisting of inhalation, intravenous injection, subcutaneous injection, intraperitoneal injection, depot injection, intramuscular injection, transdermal patch, topical cream, ear drops, and eye drops.

### Claim 32 (depends on 1)

The method of claim 1, wherein one or more CSAs is administered in a pharmaceutically acceptable formulation.

### Claim 33

A method of treating a patient having fungal infection associated with Candida albicans or fluconazole-resistant Candida albicans, comprising:
identifying a patient in need of treatment for a fungal infection caused by Candida albicans or fluconazole-resistant C. albicans,
administering to the patient a therapeutically effective amount of at least one cationic steroid antimicrobial (CSA) comprising CSA-131, or a pharmaceutically acceptable salt thereof, and
the therapeutically effective amount of the at least one CSA comprising CSA-131, or a pharmaceutically acceptable salt thereof, treating the fungal infection by providing antifungal activity in the patient against the Candida albicans or fluconazole-resistant C. albicans.

### Claim 34

A method of treating a fungal infection, comprising:
identifying a patient in need of treatment for a fungal infection caused by one or more fungi selected from the group consisting of Trichophyton rubrum, Trichophyton mentagrophytes, terbinafine-resistant Trichophyton rubrum, Candida albicans, fluconazole-resistant Candida albicans, Candida krusei, fluconazole-resistant Candida krusei, fluconazole-resistant Candida glabrata, Candida parapsilosis, Trichophyton tonsurans, Microsporum canis, Aspergillus fumigatus, Aspergillus niger, Penicillium sp., and Cladosporium sp.,
administering a therapeutically effective amount of at least one cationic steroid antimicrobial (CSA), or a pharmaceutically acceptable salt thereof, to the patient in need thereof in order for the CSA to provide antifungal activity, and
the therapeutically effective amount of the at least one CSA, or a pharmaceutically acceptable salt thereof, treating the fungal infection by providing antifungal activity in the patient against the one or more fungi,
wherein the CSA, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
and pharmaceutically acceptable salts of the foregoing.

### Claim 35

A method of treating a fungal infection, comprising:
identifying a patient in need of treatment for a fungal infection caused at least in part by one or more of fluconazole-resistant Candida albicans, fluconazole-resistant Candida krusei, fluconazole-resistant Candida glabrata, or terbinafine-resistant Trichophyton rubrum,
selecting a cationic steroid antimicrobial (CSA) of Formula III, or a pharmaceutically acceptable salt thereof, to be administered to the patient:
where,
R3, R7, and R12 are unsubstituted aminoalkyloxy; and
R18 is unsubstituted alkylaminoalkyl,
wherein the CSA is selected by measuring a biomarker or subjecting a sample from the patient to a companion diagnostic device in the patient;
administering a therapeutically effective amount of the selected CSA to the patient in need thereof in order for the selected CSA to provide antifungal activity against one or more fungi causing the fungal infection; and
the therapeutically effective amount of the selected CSA treating the fungal infection by providing antifungal activity in the patient against one or more fungi causing the fungal infection.

### Claim 36 (depends on 1)

The method of claim 1, wherein the CSA is CSA-131 or a pharmaceutically acceptable salt thereof.

### Claim 37 (depends on 34)

The method of claim 34, wherein the CSA is CSA-131 or a pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 35)

The method of claim 35, wherein the biomarker is a cellular response to the CSA or the companion diagnostic device measures a cellular response to the CSA.

### Claim 39 (depends on 38)

The method of claim 38, wherein the cellular response is a change in mRNA levels associated with fungal infection.

### Claim 40 (depends on 1)

The method of claim 1, further comprising administering at least one non-CSA therapeutic agent with the at least one CSA or pharmaceutically acceptable salt thereof, the non-CSA therapeutic agent being selected from the group consisting of an antibacterial agent, a non-steroidal anti-inflammatory agent, an anti-viral agent, an anti-retroviral agent, an anti-pyretic, an anti-emetic, an immunomodulator, a chemotherapeutic agent, an anti-histamine, an opioid receptor agonist, an anti-cholinergic, and a beta2-adrenoreceptor agonist.

### Claim 41 (depends on 34)

The method of claim 34, further comprising administering at least one non-CSA therapeutic agent with the at least one CSA or pharmaceutically acceptable salt thereof, the non-CSA therapeutic agent being selected from the group consisting of an antifungal agent, a non-steroidal anti-inflammatory agent, an anti-viral agent, an anti-retroviral agent, an anti-pyretic, an anti-emetic, an immunomodulator, a chemotherapeutic agent, an anti-histamine, an opioid receptor agonist, an anti-cholinergic, and a beta2-adrenoreceptor agonist.