# US 10,308,943 B2 · Compositions with improved intravitreal half-life and uses thereof

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- Number: US 10,308,943 B2
- Document ID: US10308943B2
- Status: Granted
- Kind: B2
- Application number: 15/990,542
- Filed: 2018-05-25
- Published: 2018-11-29
- Granted: 2019-06-04
- Earliest claimed: 2016-02-08
- Assignees: Vitrisa Therapeutics, Inc.
- Applicants: Vitrisa Therapeutics, Inc.
- Inventors: Carl Erickson; Christopher P. Rusconi; Kevin G. McLure; Renta Hutabarat
- Web page: https://patentgrep.com/patent/US10308943B2

## CPC

- C12N 15/115: Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith {; Nucleic acids binding to non-nucleic acids, e.g. aptamers}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/711: Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61P 27/02: Ophthalmic agents
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C12N 2310/16: Aptamers
- C12N 2310/317: with an inverted bond, e.g. a cap structure
- C12N 2310/351: Conjugate
- C12N 2310/3519: Fusion with another nucleic acid
- C12N 2320/51: modulating the chemical stability, e.g. nuclease-resistance
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Provided herein are compositions and methods for the treatment of retinal diseases. The compositions and methods include a therapeutic agent conjugated to a vitreous component binding moiety. The vitreous component binding moiety may be an aptamer or a small molecule that binds to a structural component of the vitreous humor (e.g., hyaluronic acid, collagen or vitronectin).

## Claims

### Claim 1

A composition comprising a therapeutic aptamer conjugated to a vitreous component binding moiety, wherein said vitreous component binding moiety comprises an aptamer that selectively binds to hyaluronan.

### Claim 2 (depends on 1)

The composition of claim 1, wherein said aptamer that selectively binds to hyaluronan is an RNA aptamer or a modified RNA aptamer.

### Claim 3 (depends on 1)

The composition of claim 1, wherein said aptamer that selectively binds to hyaluronan is a DNA aptamer or a modified DNA aptamer.

### Claim 4 (depends on 1)

The composition of claim 1, wherein said aptamer selectively binds to hyaluronan with a Kd of less than 1 mM.

### Claim 5 (depends on 1)

The composition of claim 1, wherein said composition has an intravitreal half-life of at least 6 days in a human, an intravitreal half-life of at least 2 days in a rabbit, an intravitreal half-life of at least 3 days in a non-human primate, or any combination thereof.

### Claim 6 (depends on 1)

The composition of claim 1, wherein said therapeutic aptamer is a therapeutic aptamer for treatment of a retinal disease.

### Claim 7 (depends on 6)

The composition of claim 6, wherein said retinal disease is selected from the group consisting of: macular degeneration, geographic atrophy, diabetic macular edema, diabetic retinopathy, retinal vein occlusion, Stargardt disease, retinal neovascularization, and uveitis.

### Claim 8 (depends on 1)

The composition of claim 1, wherein said therapeutic aptamer is an inhibitor of hypoxia-inducible factor-1α, vascular endothelial growth factor, platelet-derived growth factor, angiopoietin-2, interleukin-6, interleukin-2, interleukin-8, complement Factor D, complement Factor P, complement component 5, complement component 3, integrin, or any combination thereof.

### Claim 9 (depends on 1)

The composition of claim 1, wherein: (i) said vitreous component binding moiety comprises an aptamer that selectively binds to hyaluronan with a Kd of less than 1 mM; (ii) said composition has an intravitreal half-life of at least 6 days in a human, an intravitreal half-life of at least 2 days in a rabbit, an intravitreal half-life of at least 3 days in a non-human primate, or any combination thereof; and (iii) said therapeutic aptamer is a therapeutic aptamer for treatment of macular degeneration.

### Claim 10 (depends on 1)

The composition of claim 1, wherein said composition does not comprise a polyethylene glycol polymer of molecular weight greater than 30 kDa.

### Claim 11 (depends on 1)

The composition of claim 1, wherein said therapeutic aptamer is capable of dissociating from said vitreous component binding moiety over a period of time.

### Claim 12 (depends on 1)

The composition of claim 1, wherein said composition has a molecular weight of less than 40 kDa and an intravitreal retention time comparable to that of a composition comprising a 40 kDa polyethylene glycol polymer.

### Claim 13 (depends on 12)

The composition of claim 12, wherein said composition has a viscosity that is no more than half of a viscosity of a composition comprising a 40 kDa polyethylene glycol polymer, when said compositions are each formulated in a liquid formulation suitable for intravitreal administration.

### Claim 14 (depends on 1)

The composition of claim 1, wherein said composition is formulated in a liquid formulation.

### Claim 15 (depends on 14)

The composition of claim 14, wherein said composition is present in said liquid formulation at a concentration of at least 40 mg/ml when said liquid formulation is formulated for intravitreal administration.

### Claim 16 (depends on 15)

The composition of claim 15, wherein said liquid formulation has a dynamic viscosity of less than 970,800 centipoise when formulated in a 50 μL volume and administered with a ½ inch 27-gauge needle.

### Claim 17 (depends on 15)

The composition of claim 15, wherein said liquid formulation has a dynamic viscosity of less than 325,000 centipoise when formulated in a 50 μL volume and administered with a ½ inch 30-gauge needle.

### Claim 18 (depends on 15)

The composition of claim 15, wherein said liquid formulation has a dynamic viscosity of less than 75,000 centipoise when formulated in a 50 μL volume and administered with a ½ inch 33-gauge needle.

### Claim 19 (depends on 1)

A method of treating a retinal disease in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of a composition of claim 1, thereby treating said retinal disease.

### Claim 20 (depends on 19)

The method of claim 19, wherein said administering comprises administering said composition to said subject by intravitreal administration.

### Claim 21 (depends on 19)

The method of claim 19, wherein said administering comprises administering said composition at least once every 8 weeks.

### Claim 22 (depends on 19)

The method of claim 19, wherein said administering said composition comprises administering said composition using a needle with a gauge within a range of 27 gauge to 33 gauge.

### Claim 23 (depends on 22)

The method of claim 22, wherein said needle within a range of 27 gauge to 33 gauge has a length of ½-inch or less.

### Claim 24 (depends on 19)

The method of claim 19, wherein said administering comprises administering a dose of said composition of at least 2 mg to said subject in a single intravitreal administration.

### Claim 25 (depends on 19)

The method of claim 19, wherein said therapeutically effective amount is from 0.1 mg to 50 mg in 15 μl to 100 μl per eye.

### Claim 26 (depends on 1)

The composition of claim 1, wherein said therapeutic aptamer is an RNA aptamer or a modified RNA aptamer.

### Claim 27 (depends on 1)

The composition of claim 1, wherein said therapeutic aptamer is a DNA aptamer or a modified DNA aptamer.

### Claim 28 (depends on 19)

The method of claim 19, wherein said retinal disease is selected from the group consisting of: macular degeneration, geographic atrophy, diabetic macular edema, diabetic retinopathy, retinal vein occlusion, Stargardt disease, retinal neovascularization, and uveitis.