# US 10,478,433 B2 · Unit dose of an aryl sulfonamide that is effective for treating eye disease and averting potential vision loss

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- Number: US 10,478,433 B2
- Document ID: US10478433B2
- Status: Granted
- Kind: B2
- Application number: 16/007,880
- Filed: 2018-06-13
- Published: 2018-10-25
- Granted: 2019-11-19
- Earliest claimed: 2014-01-28
- Assignees: Unity Biotechnology, Inc.; Buck Institute for Research on Aging; Mayo Foundation for Medical Education and Research
- Applicants: Unity Biotechnology, Inc.; Buck Institute for Research on Aging; Mayo Foundation for Medical Education and Research
- Inventors: Remi-Martin Laberge; Judith Campisi; Marco Demaria; Nathaniel David; Darren J. Baker; James L. Kirkland; Tamar Tchkonia; Yi Zhu; Jan M. A. van Deursen; Alain Philippe Vasserot; Bennett G. Childs
- Web page: https://patentgrep.com/patent/US10478433B2

## CPC

- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0073: {Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M)}
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/728: Hyaluronic acid
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 47/6807: {the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense}
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- C12N 5/0081: {Purging biological preparations of unwanted cells}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 2320/30: Special therapeutic applications
- C12N 2501/999: Small molecules not provided for elsewhere
- C12N 2503/02: Drug screening
- C12Q 1/485: {involving kinase}
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

## Claims

### Claim 1

A unit dose of a pharmaceutical composition formulated for treating of an ophthalmic disease or disorder in an eye of a subject;
wherein the unit dose contains a formulation of an effective amount of the compound (R)—N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl)piperazin-1-yl)phenyl)-4-((4-(4-hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (BM-1197) or a salt thereof, compounded in a defined volume;
wherein the formulation, the amount of the compound, and the defined volume configure the unit dose to be safe and effective for treating the ophthalmic disease or disorder when administered intraocularly into the eye of the subject.

### Claim 2 (depends on 1)

The unit dose according to claim 1, wherein the ophthalmic disease or disorder is a back-of-the-eye disease.

### Claim 3 (depends on 2)

The unit dose according to claim 2, wherein the ophthalmic disease or disorder is age-related macular degeneration (AMD).

### Claim 4 (depends on 1)

The unit dose according to claim 1, wherein the ophthalmic disease or disorder is glaucoma.

### Claim 5 (depends on 1)

The unit dose according to claim 1, wherein the ophthalmic disease or disorder is not a cancer.

### Claim 6 (depends on 1)

The unit dose according to claim 1, wherein the formulation of the composition, the amount of the compound, and the defined volume configure the unit dose to be safe and effective for preventing or delaying vision loss.

### Claim 7 (depends on 1)

The unit dose according to claim 1, wherein the unit dose is formulated for intravitreal injection.

### Claim 8 (depends on 1)

The unit dose according to claim 1, wherein the formulation of the composition, the amount of the compound, and the defined volume configure the unit dose to be safe and effective when administered to the eye by intravitreal injection.

### Claim 9 (depends on 1)

The unit dose according to claim 1, wherein the formulation of the composition, the amount of the compound, and the defined volume configure the unit dose to be effective in removing from the eye p16-positive senescent cells that are causing one or more symptoms of the ophthalmic disease or disorder.

### Claim 10 (depends on 1)

The unit dose according to claim 1, wherein the amount of the compound configures the unit dose to be effective in treating the ophthalmic condition when administered as a single dose.

### Claim 11 (depends on 1)

The unit dose according to claim 1, wherein the amount of the compound configures the unit dose to be effective in at least partially relieving symptoms of the ophthalmic conditions for at least one month following administration.

### Claim 12 (depends on 1)

The unit dose according to claim 1, wherein the amount of the compound configures the unit dose to be effective in delaying progression of the ophthalmic conditions for at least one month following administration.

### Claim 13 (depends on 1)

The unit dose according to claim 1, packaged in a kit containing a plurality of such doses.

### Claim 14 (depends on 1)

A product that comprises a unit dose according to claim 1 and a package insert that describes the use and attendant benefits of the unit dose in treating a back-of-the-eye disease.

### Claim 15 (depends on 14)

The product of claim 14, wherein the back-of-the-eye disease is age-related macular degeneration (AMD).

### Claim 16 (depends on 1)

A product that comprises a unit dose according to claim 1 in an appliance or device that is configured for dispensing the unit dose intraocularly into the eye of the subject.

### Claim 17

A unit dose containing an effective amount of a compound having the following formula, or a pharmaceutically effective salt thereof;
wherein the unit dose is formulated as a pharmaceutical composition in an excipient in a volume suitable for intraocular administration into an eye of a subject in need thereof;
wherein the amount of the compound in the unit dose renders the unit dose effective for treating an ophthalmic disease or disorder in the eye that is not a cancer.

### Claim 18

A unit dose of a pharmaceutical composition in a formulation for intravitreal administration into an eye of a subject in need thereof;
wherein the pharmaceutical composition contains the compound (R)—N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl)piperazin-1-yl)phenyl)-4-((4-(4-hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof,
wherein the formulation of the composition, an amount of the compound, and a volume of the unit dose configure the unit dose to be safe and effective for removing p16-positive senescent cells that are not cancer cells from the eye of the subject.

### Claim 19 (depends on 18)

The unit dose according to claim 18, wherein the p16-positive senescent cells are causing or mediating one or more symptoms of an ophthalmic disease or disorder in the eye.

### Claim 20 (depends on 18)

The unit dose according to claim 18, wherein the formulation of the composition, the amount of the compound, and the volume of the unit dose configure the unit dose to be effective in reducing the number of the senescent cells in the eye of the subject for at least two weeks following a single administration of the unit dose.