# US 12,005,120 B2 · Galnac conjugated modified oligonucleotides as miR-122 inhibitor having HCV antiviral activity with reduced hyperbilirubinemia side-effect

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- Number: US 12,005,120 B2
- Document ID: US12005120B2
- Status: Granted
- Kind: B2
- Application number: 17/052,333
- Filed: 2019-05-07
- Published: 2021-06-10
- Granted: 2024-06-11
- Earliest claimed: 2018-05-08
- Assignees: Regulus Therapeutics Inc.
- Applicants: Regulus Therapeutics Inc.
- Inventors: Charles R. Allerson; Steven S. Neben; Timothy Wright
- Web page: https://patentgrep.com/patent/US12005120B2

## CPC

- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61P 31/14: for RNA viruses
- 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)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Described herein are compositions and methods for the inhibition of miR-122 activity. The compositions have certain nucleoside modifications that yield potent inhibitors of miR-122 activity and comprise moieties that facilitate delivery to the liver. The compositions may be administered to subjects infected with hepatitis C virus, as a treatment for hepatitis C virus and related conditions.

## Claims

### Claim 1

A compound of the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, which is a pharmaceutically acceptable salt of the structure.

### Claim 3 (depends on 2)

The compound of claim 2, which is a sodium salt of the structure.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable diluent is an aqueous solution.

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5, wherein the aqueous solution is a saline solution.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, which is a lyophilized composition.

### Claim 8 (depends on 1)

A pharmaceutical composition consisting essentially of a compound of claim 1 in a saline solution.

### Claim 9 (depends on 1)

A method of inhibiting the activity of miR-122 in a cell comprising contacting a cell with a compound of claim 1.

### Claim 10 (depends on 1)

A method of treating HCV infection comprising administering to an HCV-infected subject at least one dose of a compound of claim 1.

### Claim 11 (depends on 1)

A method of treating hepatitis C virus (HCV) infection comprising administering at least one dose of a compound of claim 1 and at least one direct-acting antiviral (DAA) to an HCV-infected subject during a treatment period, wherein the duration of the treatment period is 12 weeks or less, and wherein a start dose of the compound is administered at the start of the treatment period and an end dose of the compound is administered at the end of the treatment period, (ii) a start dose of the compound is administered at the start of the treatment period, and the start dose is the only dose of the compound administered during the treatment period, or (iii) an end dose of the compound is administered at the end of the treatment period, and the end dose is the only dose of the compound administered during the treatment period.

### Claim 12 (depends on 11)

The method of claim 11, wherein the duration of the treatment period is 2 to 10 weeks, 4 to 8 weeks, 2 to 6 weeks, or 1 to 4 weeks.

### Claim 13 (depends on 10)

The method of claim 10, where in the HCV-infected subject is infected with genotype 1, genotype 2, genotype 3, genotype 4, genotype 5, or genotype 6.

### Claim 14 (depends on 13)

The method of claim 13, wherein the HCV-infected subject is infected with genotype 1a or with genotype 1b.

### Claim 15 (depends on 10)

The method of claim 10, wherein the HCV-infected subject is determined to be infected with an HCV having one or more resistance-associated polymorphisms.

### Claim 16 (depends on 10)

The method of claim 10, wherein the HCV-infected subject is a treatment-naïve subject.

### Claim 17 (depends on 10)

The method of claim 10, wherein the HCV-infected subject has an HCV-associated disease, which is cirrhosis, liver fibrosis, steatohepatitis, steatosis, or hepatocellular carcinoma; and/or wherein the HCV-infected subject is an HCV-infected subject with renal impairment; and/or wherein the HCV-infected subject is an HCV/HIV co-infected subject.

### Claim 18 (depends on 10)

The method of claim 10, wherein the administering achieves a sustained viral response.

### Claim 19 (depends on 11)

The method of claim 11, wherein the DAA is administered daily.

### Claim 20 (depends on 11)

The method of claim 11, wherein the DAA is selected from a protease inhibitor, a nucleoside polymerase inhibitor, a nucleotide polymerase inhibitor, a non-nucleoside polymerase inhibitor, an NS3B inhibitor, an NS3/4A inhibitor, an NS4A inhibitor, an NS5A inhibitor, an NS5B inhibitor, and a cyclophilin inhibitor.

### Claim 21 (depends on 11)

The method of claim 11, wherein the DAA is selected from one or more of sofosbuvir, ledipasvir, ombitasvir, dasabuvir, glecaprevir, pibrentasvir, elbasvir, grazoprevir, ribavirin, ombitasvir, paritaprevir, ritonavir, boceprevir, vaniprevir, asunaprevir, daclatasvir, simeprevir, mericitabine, tegobuvir, danoprevir, sovaprevir, voxilaprevir, velpatasvir, and GSK2878175.

### Claim 22 (depends on 10)

The method of claim 10, wherein the dose of the compound is less than or equal to 4.0 mg/kg, less than or equal to 3.5 mg/kg, less than or equal to 3.0 mg/kg, less than or equal to 2.5 mg/kg, less than or equal to 2.0 mg/kg, less than or equal to 1.5 mg/kg, less than or equal to 1.0 mg/kg, or less than or equal to 0.5 mg/kg.