# US 11,439,648 B2 · Use of topical BRAF inhibitor compositions for treatment of radiation dermatitis

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- Number: US 11,439,648 B2
- Document ID: US11439648B2
- Status: Granted
- Kind: B2
- Application number: 17/384,221
- Filed: 2021-07-23
- Published: 2021-11-11
- Granted: 2022-09-13
- Earliest claimed: 2019-02-12
- Assignees: Lutris Pharma Ltd.
- Applicants: Lutris Pharma Ltd.
- Inventors: Noa Shelach; Noa Lowenton-Spier
- Web page: https://patentgrep.com/patent/US11439648B2

## CPC

- A61K 31/52: Purines, e.g. adenine
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61P 17/00: Drugs for dermatological disorders
- A61P 35/00: Antineoplastic agents
- 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 invention discloses methods of treatment, prevention and/or amelioration of radiation dermatitis caused by radiotherapy, by administration to a subject in need thereof of a topical composition comprising a therapeutically or prophylactically effective amount of at least one BRaf inhibitor of this invention, thus treating, preventing and/or ameliorating the effects of radiation dermatitis.

## Claims

### Claim 1

A method for treating, preventing or alleviating of radiation dermatitis, the method comprising:
administering topically to a subject in need thereof a composition comprising a therapeutically or prophylactically effective dose of at least one BRaf inhibitor or a combination thereof and a pharmaceutically acceptable carrier or excipient,
wherein the method reduces the severity or prevents the escalation of the radiation dermatitis.

### Claim 2 (depends on 1)

The method of claim 1, wherein the at least one BRaf inhibitor comprises BAY43-9006 (Sorafenib), LGX818 (encorafenib), PLX4032 (vemurafenib), GSK2118436 (dabrafenib), ARQ736, ARQ680, AZ628, C-1, C-15, C-19, C-A, CEP-32496, GDC-0879, NMS-P186, NMS-P349, NMS-P383, NMS-P396, NMS-P730, PLX3603 (R05212054), PLX4720 (Difluorophenyl-sulfonamine), PF-04880594, PLX4734, RAF265, R04987655, SB590885, ZM336372, BMS908662, WYE-130600, TAK632, MLN 2480, XL281,
a compound of formula (I):
wherein R is selected from the group consisting of p-chlorophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, 4-chloro-3-(trifluoromethyl)phenyl, 3-(1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl, 3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or 3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or a solvate thereof;
a compound of formula (II):
wherein R is NHR1, wherein R1 is 2-fluoro-4-iodophenyl, or a pharmaceutically acceptable salt or a solvate thereof;
a compound of formula (III):
wherein R is NHR1, wherein R1 is 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or 4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptable salt or a solvate thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein the at least one BRaf inhibitor is the compound of formula (I) and wherein R is 3-(trifluoromethoxy)phenyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein administration of the at least one BRaf inhibitor inhibits the activity of BRaf and increases cell proliferation.

### Claim 5 (depends on 1)

The method of claim 1, wherein the composition is in the form of a gel, a hydrogel, an ointment, a cream, a paste, a foam, a spray, a lotion, a liquid or a dermal patch.

### Claim 6 (depends on 1)

The method of claim 1, wherein the composition comprises the at least one BRaf inhibitor at a concentration of 1% w/w to 5% w/w of the total weight of the composition.

### Claim 7 (depends on 1)

The method of claim 1, wherein the composition comprises the at least one BRaf inhibitor at a concentration of 0.1% w/w to 10% w/w of the total weight of the composition.

### Claim 8 (depends on 1)

The method of claim 1, wherein the method reduces the severity of the cutaneous adverse reaction from grade 4 to grade 3, 2, 1, or 0 as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or according to the Radiation Therapy Oncology Group (RTOG) grading scale.

### Claim 9 (depends on 1)

The method of claim 1, wherein the method reduces the severity of the cutaneous adverse reaction from grade 3 to grade 2, 1, or 0, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades.

### Claim 10 (depends on 1)

The method of claim 1, wherein the method reduces the severity of the cutaneous adverse reaction from grade 2 to grade 1 or 0, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades.

### Claim 11 (depends on 1)

The method of claim 1, wherein the method reduces the severity of the cutaneous adverse reaction from grade 1 to grade 0, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades.

### Claim 12 (depends on 1)

The method of claim 1, wherein the method prevents the escalation of the cutaneous adverse reaction from grade 0 to grade 1, 2, 3, or 4, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades.

### Claim 13 (depends on 1)

The method of claim 1, wherein the method prevents the escalation of the cutaneous adverse reaction from grade 1 to grade 2, 3, or 4, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades.

### Claim 14 (depends on 1)

The method of claim 1, wherein the method prevents the escalation of the cutaneous adverse reaction from grade 2 to grade 3 or 4, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades.

### Claim 15 (depends on 1)

The method of claim 1, wherein the method prevents the escalation of the cutaneous adverse reaction from grade 3 to grade 4, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades.

### Claim 16 (depends on 3)

The method of claim 3, wherein topical administration of the compound of formula (I) wherein R is 3-(trifluoromethoxy)phenyl inhibits the activity of BRaf and increases cell proliferation.

### Claim 17 (depends on 3)

The method of claim 3, wherein the composition comprises the compound of formula (I) wherein R is 3-(trifluoromethoxy)phenyl at a concentration of 1% w/w to 5% w/w of the total weight of the composition.

### Claim 18 (depends on 3)

The method of claim 3, wherein the composition comprises the compound of formula (I) wherein R is 3-(trifluoromethoxy)phenyl at a concentration of 0.1% w/w to 10% w/w of the total weight of the composition.