Method of reducing cholesterol levels using a human anti-PCSK9 antibody

• US 9,561,155 B2
• Filed: 01/27/2012
• Issued: 02/07/2017
• Est. Priority Date: 01/28/2011
• Status: Active Grant

• Current Assignee: Sanofi Biotechnology
• Original Assignee: Sanofi Biotechnology
• Inventors: Hanotin, Corinne, Bessac, Laurence, Chaudhari, Umesh
• Primary Examiner(s): HOWARD, ZACHARY C
• Application Number:
  US13/982,373
• Publication Number:
  US 20140154262A1
• Time in Patent Office: 1,838 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: 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
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding

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

1. A method for treating a disease or condition in which proprotein convertase subtilisin/kexin type 9 (PCSK9) expression or activity causes an impact, the method comprising:

administering to a subject in need thereof a pharmaceutical composition comprising a fixed dose of 75, 150, or 300 mg of an antibody or an antigen-binding fragment thereof which specifically binds human proprotein convertase subtilisin/kexin type 9 (hPCSK9) together with a pharmaceutically acceptable excipient or carrier, wherein the pharmaceutical composition is administered about every two or four weeks, and wherein the antibody or antigen-binding fragment thereof

comprises the three heavy chain CDRs set forth in SEQ ID NOs;

76, 78, and 80 and the three light chain CDRs set forth in SEQ ID NOs;

84, 86, and 88.

2. The method of claim 1, wherein the antibody or antigen-binding fragment thereof

comprises the heavy chain variable region (HCVR) amino acid sequence and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID NOs:

90 and 92, respectively.

3. 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 non-high-density lipoprotein (HDL) cholesterol levels, elevated low-density lipoprotein (LDL-C) levels, elevated apolipoprotein B100 (ApoB100) levels, hyperlipidemia, dyslipidemia, atherosclerosis, cardiovascular diseases, coronary heart disease (CHD), hypercholesterolemia, primary hypercholesterolemia, familial hypercholesterolemia, non-familial hypercholesterolemia, heterozygous familial hypercholesterolemia (heFH), hypercholesteremia that is uncontrolled by statins, and hypercholesterolemia that is resistant to statins.

4. The method of claim 1, wherein the antibody or antigen-binding fragment thereof is for administration to a subject falling into at least one 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; and

(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.

5. The method of claim 1, wherein the pharmaceutical composition comprises a fixed dose of 75 mg of the antibody or antigen-binding fragment thereof, and wherein the pharmaceutical composition is administered about every two weeks.

6. The method of claim 1, wherein the pharmaceutical composition comprises a fixed dose of 150 mg of the antibody or antigen-binding fragment thereof, and wherein the pharmaceutical composition is administered about every two weeks.

7. The method of claim 1, wherein the pharmaceutical composition comprises a fixed dose of 150 mg of the antibody or antigen-binding fragment thereof, and wherein the pharmaceutical composition is administered about every four weeks.

8. The method of claim 1, wherein the pharmaceutical composition comprises a fixed dose of 300 mg of the antibody or antigen-binding fragment thereof, wherein the pharmaceutical composition is administered about every four weeks.

9. The method of claim 1, wherein the pharmaceutical composition is a lml injection solution comprising a fixed dose of 75 mg, 150 mg, or 300 mg of the antibody or antigen-binding fragment thereof.

10. The method of claim 9, wherein the injection solution comprises a fixed dose of 75 mg of the antibody or antigen-binding fragment thereof and wherein the pharmaceutical composition is administered about every two weeks.

11. The method of claim 9, wherein the injection solution comprises a fixed dose of 150 mg of the antibody or antigen-binding fragment thereof and wherein the pharmaceutical composition is administered about every two weeks.

12. The method of claim 9, wherein the injection solution comprises a fixed dose of 150 mg of the antibody or antigen-binding fragment thereof and wherein the pharmaceutical composition is administered about every four weeks.

13. The method of claim 9, wherein the injection solution comprises a fixed dose of 300 mg of the antibody or antigen-binding fragment thereof and wherein the pharmaceutical composition is administered about every four weeks.

14. The method of claim 1, wherein the pharmaceutical composition is comprised in a unit dosage form, and wherein the unit dosage form comprises a fixed dose of, 75 mg, 150 mg or 300 mg of the antibody or antigen-binding fragment thereof.

15. The method of claim 14, wherein the unit dosage form comprises a fixed dose of 75 mg of the antibody or antigen-binding fragment thereof and wherein the pharmaceutical composition is administered about every two weeks.

16. The method of claim 14, wherein the unit dosage form comprises a fixed dose of 150 mg of the antibody or antigen-binding fragment thereof and wherein the pharmaceutical composition is administered about every two weeks.

17. The method of claim 14, wherein the unit dosage form comprises a fixed dose of 150 mg of the antibody or antigen-binding fragment thereof and wherein the pharmaceutical composition is administered about every four weeks.

18. The method of claim 14, wherein the unit dosage form comprises a fixed dose of 300 mg of the antibody or antigen-binding fragment thereof and wherein the pharmaceutical composition is administered about every four weeks.

19. The method of claim 1, wherein the pharmaceutical composition is in a hermetically sealed container selected from the group consisting of a vial, a sachette, a pre-filled syringe, a pre-filled autoinjector, a cartridge for a reusable syringe, and an applicator.

20. The method of claim 1, wherein the pharmaceutical composition is administered by subcutaneous injection.

21. The method of claim 1, wherein the antibody or antigen-binding fragment thereof binds an epitope comprising one or more of amino acid residues at positions 153, 159, 238, and 343 of hPCSK9 (SEQ ID NO:

755).

22. The method of claim 1, wherein the antibody or antigen-binding fragment thereof achieves one or more of the following when administered to a subject:

(a) reduction of LDL-C of at least −

60% to at least −

75% relative to a predose level with a sustained reduction over at least a 14 day-period upon administering to a subject a dose of 150 mg every two weeks;

(b) reduction of LDL-C of at least −

50% to −

75% relative to a predose level with a sustained reduction over at least a 28 day-period upon administering to a subject a dose of 300 mg every four weeks;

(c) increase of serum HDL cholesterol levels of at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5% or at least 5.5% relative to a predose level upon administering to a subject a dose of 150 mg every two weeks; and

(d) reduction of one or more of;

total-cholesterol levels, ApoB levels, non HDL-C levels, and ApoB/ApoA-1 ratio.

23. A method for treating a disease or condition in which PCSK9 expression or activity causes an impact, the method comprising:

administering to a subject in need thereof a pharmaceutical composition comprising a fixed dose of 75 mg of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID NOs;

90 and 92, respectively, wherein the pharmaceutical composition is administered about every two weeks in a 1 ml injection solution.

24. A method for treating a disease or condition in which PCSK9 expression or activity causes an impact, the method comprising:

administering to a subject in need thereof a pharmaceutical composition comprising a fixed dose of 150 mg of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID NOs;

90 and 92, respectively, wherein the pharmaceutical composition is administered about every two weeks or every four weeks in a 1 ml injection solution.

25. A method for treating a disease or condition in which PCSK9 expression or activity causes an impact, the method comprising:

administering to a subject in need thereof a pharmaceutical composition comprising a fixed dose of 300 mg of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9,

wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID NOs;

90 and 92, respectively, wherein the pharmaceutical composition is administered about every four weeks in a 1 ml injection solution.