# US 2014/0154262 A1 · Human antibodies to pcsk9 for use in methods of treating particular groups of subjects

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- Number: US 2014/0154262 A1
- Document ID: US20140154262A1
- Status: Published application
- Kind: A1
- Application number: 13/982,373
- Filed: 2012-01-27
- Published: 2014-06-05
- Earliest claimed: 2011-01-28
- Assignees: Sanofi
- Inventors: Corinne Hanotin; Laurence Bessac; Umesh Chaudhari
- Web page: https://patentgrep.com/patent/US20140154262A1

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 5/00: Drugs for disorders of the endocrine system
- 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
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/40: against enzymes
- A61J 1/05: for collecting, storing or administering blood, plasma or medical fluids {(multiple bags systems for separating or storing blood components A61M1/0209); Infusion or perfusion containers}
- A61K 31/215: of carboxylic acids
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2039/505: {comprising antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 14/4703: {Inhibitors; Suppressors}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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)
- A61J: CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE

## Abstract

The present invention relates to methods for treating diseases or conditions in which proprotein convertase subtilisin/kexin type 9 (PCSK9) expression or activity causes an impact by administration of PCSK9-specific antibodies or antigen-binding fragments thereof and preferably by additional administration of an inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase). The present invention further relates to PCSK9-specific antibodies or antigen-binding fragments thereof for use in the treatment of diseases or conditions in which PCSK9 expression or activity causes an impact. The present invention also relates to articles of manufacture comprising packaging material, PCSK9-specific antibodies or antigen-binding fragments thereof, and a label or packaging insert indicating which groups of patients can be treated with said antibodies or fragments, which groups of patients must not be treated with said antibodies or fragments, and which dosage regimen should be used. The present invention further relates to methods of testing the efficacy of PCSK9-specific antibodies or antigen-binding fragments thereof for the treatment of certain diseases or conditions and for the treatment of specific sub-groups of patients.

## Claims

### Claim 1

A method for treating a disease or condition in which proprotein convertase subtilisin/kexin type 9 (PCSK9) expression or activity causes an impact, comprising:
(a) administering a therapeutic amount of an antibody or an antigen-binding fragment thereof which specifically binds PCSK9 to a subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered in a dosage amount ranging from about 40 mg to 500 mg, and
(b) administering a therapeutic amount of an HMG-CoA reductase inhibitor to said subject, wherein the HMG-CoA reductase inhibitor is preferably administered in a dosage amount ranging from 0.05 mg to 100 mg.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The method of claim 1, wherein the disease or condition in which PCSK9 expression or activity causes an impact is selected from the group consisting of: elevated total cholesterol levels, elevated low-density lipoprotein cholesterol (LDL-C) levels, hyperlipidemia, dyslipidemia, atherosclerosis, cardiovascular disease, hypercholesterolemia, primary hypercholesterolemia, familial hypercholesterolemia, and hypercholesteremia which is uncontrolled by statins.

### Claim 4 (depends on 1)

The method of claim 1, wherein the HMG-CoA reductase inhibitor is administered three times per day, twice per day, once per day, every other day, every third day, every fourth day, every fifth day, or every sixth day, every week, every other week, every third week, or every fourth week or every month.

### Claim 5 (depends on 1)

The method of claim 1, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of cerivastatin simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin.

### Claim 6 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered to the subject every other week or every 4 weeks.

### Claim 7 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered in a dosage selected from the group consisting of 50 mg, 100 mg, 150 mg, 200 mg, and 300 mg.

### Claim 8 (depends on 1)

The method of claim 1, wherein the antibody or the antigen-binding fragment thereof is characterized by one or more of the following:
(i) capable of reducing serum total cholesterol at least about 25 to about 35% and sustaining the reduction over at least a 24 day period relative to a predose level;
(ii) capable of reducing serum LDL cholesterol at least about 65-80% and sustaining the reduction over at least a 24 day period relative to a predose level;
(iii) capable of reducing serum triglyceride at least about 25-40% relative to predose level;
(iv) achieves one or more of (i)-(iii) without reducing serum HDL cholesterol or reducing serum HDL cholesterol no more than 5% relative to predose level; and
(v) achieves one or more of (i)-(iii) with little or no measurable effect on liver function, as determined by ALT and AST measurements.

### Claim 9 (depends on 1)

The method of claim 1, wherein the antibody or the antigen-binding fragment thereof comprises heavy and light chain CDR sequences from the HCVR and LCVR amino acid sequence pair having SEQ ID NOs: 90/92.

### Claim 10

An article of manufacture comprising
(a) a packaging material;
(b) an antibody or an antigen-binding fragment thereof which specifically binds PCSK9; and
(c) a label or packaging insert contained within the packaging material indicating the treatment of patients with said antibody or antigen-binding fragment thereof together with the administration of a statin.

### Claim 11

A method for treating a disease or condition in which PCSK9 expression or activity causes an impact comprising administering a therapeutic amount of an antibody or an antigen-binding fragment thereof which specifically binds PCSK9 to a subject in need thereof, wherein the subject in need thereof falls into one or more of the following groups of subjects:
(i) subjects having a serum LDL cholesterol (LDL-C) level of at least 100 mg/dL,
(ii) subjects having a serum HDL-C level of less than 40 mg/dL;
(iii) subjects having a serum cholesterol level of at least 200 mg/dL;
(iv) subjects having a serum triacylglycerol level of at least 150 mg/dL, wherein said triacylglycerol level is determined after fasting for at least 8 hours;
(v) subjects being at least 35 years old;
(vi) subjects younger than 75 years old;
(vii) subjects having a BMI of 25 or more;
(vii) subjects in which the administration of said antibody or antigen-binding fragment thereof leads to a reduction in the serum LDL-C level by at least 30 mg/dL relative to predose level; and
(viii) subjects in which the administration of said antibody or antigen-binding fragment thereof leads to a reduction in the serum LDL-C level by at least 20% relative to predose level.

### Claim 12

(canceled)

### Claim 13 (depends on 11)

The method of claim 11, wherein the disease or condition in which PCSK9 expression or activity causes an impact is selected from the group consisting of: elevated total cholesterol levels, elevated low-density lipoprotein cholesterol (LDL-C) levels, hyperlipidemia, dyslipidemia, atherosclerosis, cardiovascular disease, hypercholesterolemia, primary hypercholesterolemia, familial hypercholesterolemia, and hypercholesteremia which is uncontrolled by statins.

### Claim 14 (depends on 11)

The method of claim 11, wherein the HMG-CoA reductase inhibitor is administered three times per day, twice per day, once per day, every other day, every third day, every fourth day, every fifth day, or every sixth day, every week, every other week, every third week, or every fourth week or every month.

### Claim 15 (depends on 11)

The method of claim 11, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of cerivastatin simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin.

### Claim 16 (depends on 11)

The method f claim 11, wherein the antibody or antigen-binding fragment thereof is administered to the subject every other week or every 4 weeks.

### Claim 17 (depends on 11)

The method of claim 11, wherein the antibody or antigen-binding fragment thereof is administered in a dosage selected from the group consisting of 50 mg, 100 mg, 150 mg, 200 mg, and 300 mg.

### Claim 18 (depends on 11)

The method of claim 11, wherein the antibody or the antigen-binding fragment thereof is characterized by one or more of the following:
(i) capable of reducing serum total cholesterol at least about 25 to about 35% and sustaining the reduction over at least a 24 day period relative to a predose level;
(ii) capable of reducing serum LDL cholesterol at least about 65-80% and sustaining the reduction over at least a 24 day period relative to a predose level;
(iii) capable of reducing serum triglyceride at least about 25-40% relative to predose level;
(iv) achieves one or more of (i)-(iii) without reducing serum HDL cholesterol or reducing serum HDL cholesterol no more than 5% relative to predose level; and
(v) achieves one or more of (i)-(iii) with little or no measurable effect on liver function, as determined by ALT and AST measurements.

### Claim 19 (depends on 11)

The method of claim 11, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from the HCVR and LCVR amino acid sequence pair having SEQ ID NOs: 90/92.

### Claim 20

An article of manufacture comprising
(a) a packaging material;
(b) an antibody or an antigen-binding fragment thereof which specifically binds PCSK9; and
(c) a label or packaging insert contained within the packaging material indicating that patients receiving treatment with said antibody or antigen-binding fragment can be treated for a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases, and further indicating that the patients fall into one or more of the following groups of subjects:
(i) subjects having a serum LDL cholesterol (LDL-C) level of at least 100 mg/d L,
(ii) subjects having a serum HDL-C level of less than 40 mg/dL;
(iii) subjects having a serum cholesterol level of at least 200 mg/dL;
(iv) subjects having a serum triacylglycerol level of at least 150 mg/dL, wherein said triacylglycerol level is determined after fasting for at least 8 hours;
(v) subjects being at least 35 years old;
(vi) subjects younger than 75 years old;
(vii) subjects having a BMI of 25 or more;
(vii) subjects in which the administration of said antibody or antigen-binding fragment thereof leads to a reduction in the serum LDL-C level by at least 30 mg/dL relative to predose level; and
(viii) subjects in which the administration of said antibody or antigen-binding fragment thereof leads to a reduction in the serum LDL-C level by at least 20% relative to predose level.

### Claim at position 21

21-29. (canceled)