Methods for inhibiting atherosclerosis by administering an inhibitor of PCSK9

• US 10,494,442 B2
• Filed: 06/06/2014
• Issued: 12/03/2019
• Est. Priority Date: 06/07/2013
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated, Sanofi Biotechnology
• Original Assignee: Sanofi Biotechnology
• Inventors: Sasiela, William J., Gusarova, Viktoria, Peyman, Anusch, Schafer, Hans Ludwig, Schwahn, Uwe
• Primary Examiner(s): Howard, Zachary C
• Application Number:
  US14/896,196
• Publication Number:
  US 20160115246A1
• Time in Patent Office: 2,006 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/4703 Inhibitors; Suppressors
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides methods and compositions for inhibiting atherosclerotic plaque formation in a subject. In certain embodiments, the methods of the present invention comprise selecting a subject who has, or is at risk of developing, atherosclerosis, and administering to the subject a pharmaceutical composition comprising a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. In certain embodiments, the PCSK9 inhibitor is an anti-PCSK9 antibody, or antigen binding protein.

Claims

1. A method of inhibiting atherosclerotic plaque formation, the method comprising:

(a) selecting a subject who has atherosclerosis; and

(b) administering to the subject a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs;

2, 3, 4, 7, 8, and 10, such that the administration of the antibody or antigen-binding fragment thereof inhibits an increase in the number, total area, severity, or instability of atherosclerotic plaques in the subject.

2. The method of claim 1, wherein the subject has suffered a stroke or myocardial infarction.

3. The method of claim 1, wherein the subject has one or more of the following conditions:

a) a disease or disorder selected from the group consisting of type I diabetes mellitus, type II diabetes mellitus, Kawasaki disease, chronic inflammatory disease, and hypertension;

b) heterozygous Familial Hypercholesterolemia (heFH); and

c) a form of hypercholesterolemia that is not Familial Hypercholesterolemia (nonFH).

4. The method of claim 1, wherein the subject has an elevated level of an inflammatory marker.

5. The method of claim 4, wherein the inflammatory marker is C-reactive protein or an inflammatory cytokine.

6. The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO:

1 and an LCVR having the amino acid sequence of SEQ ID NO;

6.

7. The method of claim 1, wherein the antibody or antigen-binding fragment thereof inhibits the increase of the number, total area, severity, or instability of atherosclerotic plaques in the subject by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

8. The method of claim 1, wherein the subject is on another lipid-modifying agent before and/or during administration of the antibody or antigen-binding fragment thereof.

9. The method of claim 8, wherein the therapeutic lipid-modifying agent is selected from the group consisting of a statin, ezetimibe, a fibrate, niacin, an omega-3 fatty acid, and a bile acid resin.

10. The method of claim 9, wherein the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin and pravastatin.

11. The method of claim 1, wherein the subject is not on another lipid-modifying agent before and/or during administration of the antibody or antigen-binding fragment thereof.

12. The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

13. The method of claim 1, wherein the antibody or antigen-binding fragment thereof inhibits an increase in the number of atherosclerotic plaques.

14. The method of claim 1, wherein the antibody or antigen-binding fragment thereof inhibits an increase in the total area of atherosclerotic plaques.

15. The method of claim 1, wherein the antibody or antigen-binding fragment thereof inhibits an increase in the severity of atherosclerotic plaques.

16. The method of claim 1, wherein the antibody or antigen-binding fragment thereof inhibits an increase in the instability of atherosclerotic plaques.

17. The method of claim 1, wherein the antibody or antigen-binding fragment thereof inhibits an increase in the number, total area, severity, and instability of atherosclerotic plaques.

18. A method of inhibiting atherosclerotic plaque formation, the method comprising:

(a) selecting a subject who has atherosclerosis and hypercholesterolemia; and

(b) administering to the subject a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to PCSK9, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs;

2, 3, 4, 7, 8, and 10, such that the administration of the antibody or antigen-binding fragment thereof inhibits an increase in the number, total area, severity, or instability of atherosclerotic plaques in the subject.

19. The method of claim 18, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO:

1 and an LCVR having the amino acid sequence of SEQ ID NO;

6.

20. A method of inhibiting atherosclerotic plaque formation, the method comprising:

(a) selecting a subject who has atherosclerosis and hypercholesterolemia; and

(b) administering to the subject subcutaneously a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to PCSK9, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO;

1 and an LCVR having the amino acid sequence of SEQ ID NO;

6, such that the administration of the antibody or antigen-binding fragment thereof inhibits an increase in the number, total area, severity, or instability of atherosclerotic plaques in the subject.