# US 2014/0194492 A1 · Methods for treating hypercholesterolemia

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- Number: US 2014/0194492 A1
- Document ID: US20140194492A1
- Status: Published application
- Kind: A1
- Application number: 14/152,825
- Filed: 2014-01-10
- Published: 2014-07-10
- Earliest claimed: 2006-11-27
- Assignees: Isis Pharmaceuticals, Inc.
- Applicants: Isis Pharmaceuticals, Inc.
- Inventors: Susan M. Freier; Rosanne M. Crooke; Mark J. Graham; Kristina M. Lemonidis; Sanjay Bhanot; Diane Tribble; Andrew T. Watt
- Web page: https://patentgrep.com/patent/US20140194492A1

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- C12N 2310/11: Antisense
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/351: Conjugate
- C12N 2320/30: Special therapeutic applications
- 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

## Abstract

Disclosed herein are antisense compounds and methods for decreasing LDL-C in an individual having elevated LDL-C. Additionally disclosed are antisense compounds and methods for treating, preventing, or ameliorating hypercholesterolemia and/or atherosclerosis. Further disclosed are antisense compounds and methods for decreasing coronary heart disease risk. Such methods include administering to an individual in need of treatment an antisense compound targeted to a PCSK9 nucleic acid. The antisense compounds administered include gapmer antisense oligonucleotides.

## Claims

### Claim 1

A modified oligomeric compound comprising an oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the oligonucleotide is at least 90% complementary to an equal-length portion of 1077-1117 of SEQ ID NO: 1, wherein the oligonucleotide has at least one modification.

### Claim 2 (depends on 1)

The oligomeric compound of claim 1, wherein the oligonucleotide consists of 20-25 linked nucleosides.

### Claim 3 (depends on 1)

The oligomeric compound of claim 1, wherein the oligonucleotide consists of 19-22 linked nucleosides.

### Claim 4 (depends on 3)

The oligomeric compound of claim 3, wherein the nucleobase sequence of the oligonucleotide is at least 95% complementary to an equal-length portion of 1077-1117 of SEQ ID NO: 1.

### Claim 5 (depends on 3)

The oligomeric compound of claim 3, wherein the nucleobase sequence of the oligonucleotide is fully complementary to an equal-length portion of 1077-1117 of SEQ ID NO: 1.

### Claim at position 6

6-9. (canceled)

### Claim 10 (depends on 1)

A composition comprising the oligomeric compound of claim 1, or a salt thereof and a pharmaceutically acceptable carrier or diluent.

### Claim 11

A method comprising administering to a human with hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, acute coronary syndrome, early onset coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, hypertriglyceridemia, hyperfattyacidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, or elevated non-HDL cholesterol, a therapeutically effective amount of a composition comprising an oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the oligonucleotide is at least 90% complementary to an equal-length portion of 1077-1117 of SEQ ID NO: 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein the elevated LDL-cholesterol level is above a target level of at least about 100 mg/dL, 130 mg/dL, 160 mg/dL, or 190 mg/dL.

### Claim 13 (depends on 11)

The method of claim 11, wherein administering the composition results in an LDL-cholesterol level below a target level of at least about 190 mg/dL, 160 mg/dL, 130 mg/dL, 100 mg/dL, 70 mg/dL, or 50 mg/dL.

### Claim 14 (depends on 11)

The method of claim 11, wherein administering said composition results in a reduction of ApoB, LDL-cholesterol, VLDL-cholesterol, Lp(a), small LDL-particle, small VLDL-particle, non-HDL-cholesterol, liver triglyceride level, serum triglycerides, serum phospholipids, or any combination thereof.

### Claim 15 (depends on 14)

The method of claim 14, wherein at least one of the ApoB reduction, the LDL-cholesterol reduction, the, VLDL-cholesterol reduction, the Lp(a) reduction, the small LDL-particle reduction, the small VLDL-particle reduction, the non-HDL-cholesterol reduction, the liver triglyceride level reduction, the serum triglycerides reduction, or serum phospholipids reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

### Claim 16 (depends on 3)

The oligomeric compound of claim 3, wherein the oligonucleotide consists of 19 linked nucleosides

### Claim 17 (depends on 1)

The oligomeric compound of claim 1, wherein the oligonucleotide comprises a modified nucleobase.