Methods for treating hypercholesterolemia and reducing LDL-C using antibodies to PCSK9

• US 9,724,411 B2
• Filed: 12/09/2013
• Issued: 08/08/2017
• Est. Priority Date: 12/15/2008
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Sleeman, Mark W., Huang, Tammy T., MacDonald, Douglas, Pordy, Robert C., Swergold, Gary, Sasiela, William J., Martin, Joel H.
• Primary Examiner(s): STANFIELD, CHERIE MICHELLE
• Application Number:
  US14/100,992
• Publication Number:
  US 20140099312A1
• Time in Patent Office: 1,338 Days
• 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 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention provides methods for treating hypercholesterolemia and reducing LDL-C. The methods of the present invention comprise administering to a subject in need thereof a therapeutic composition comprising an anti-PCSK9 antibody or antigen-binding fragment thereof.

Claims

1. A method for treating hypercholesterolemia in a patient, the method comprising administering to the patient a first dose of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds hPCSK9, wherein the amount of the antibody in the first dose is 75 mg (“

the 75 mg dose”

);

and administering to the patient a second dose of a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof that specifically binds hPCSK9, wherein the amount of antibody in the second dose is 150 mg (“

the 150 mg dose”

);

wherein the 150 mg dose is administered to the patient two weeks after the 75 mg dose;

wherein the antibody or antigen-binding fragment that specifically binds hPCSK9 comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs;

90/92 and 218/226.

2. The method of claim 1, wherein, after receiving the 75 mg dose, but before receiving the 150 mg dose, the patient has not achieved a reduction in LDL-C level of at least 50% from the patient'"'"'s baseline LDL-C level.

3. The method of claim 1, wherein, after receiving the 75 mg dose, but before receiving the 150 mg dose, the patient has not achieved an LDL-C blood concentration of less than or equal to 100 milligrams per deciliter (mg/dL).

4. The method of claim 3, wherein, after receiving the 75 mg dose, but before receiving the 150 mg dose, the patient has not achieved an LDL-C blood concentration of less than or equal to 70 mg/dL.

5. The method of claim 1, wherein the antibody or antigen-binding fragment that specifically binds hPCSK9 comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:

220, 222, 224, 228, 230 and 232.

6. The method of claim 5, wherein the antibody or antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO:

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

226.

7. The method of claim 1, wherein the antibody or antigen-binding fragment that specifically binds hPCSK9 comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:

76, 78, 80, 84, 86 and 88.

8. The method of claim 7, wherein the antibody or antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO:

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

92.

9. The method of claim 1, wherein the patient is on a therapeutic statin regimen at the time of or just prior to administration of the 75 mg dose.

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

11. The method of claim 10, wherein the statin is atorvastatin.

12. The method of claim 1, wherein the patient is on another lipid lowering agent prior to or concurrent with administration of the antibody or antigen-binding fragment thereof.

13. The method of claim 12, wherein the lipid lowering agent is selected from the group consisting of ezetimibe, a bile acid resin, niacin, and an omega-3 fatty acid.

14. The method of claim 1, wherein the pharmaceutical composition is administered to the patient subcutaneously.

15. The method of claim 1, wherein the patient has heterozygous Familial Hypercholesterolemia (heFH).

16. The method of claim 1, wherein the patient has a form of hypercholesterolemia that is not Familial Hypercholesterolemia (nonFH).

17. A method for reducing LDL-C in a patient in need thereof, the method comprising administering to the patient a first dose of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds hPCSK9, wherein the amount of the antibody in the first dose is 75 mg (“

the 75 mg dose”

);

and administering to the patient a second dose of a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof that specifically binds hPCSK9, wherein the amount of antibody in the second dose is 150 mg (“

the 150 mg dose-”

);

wherein the 150 mg dose is administered to the patient two weeks after the 75 mg dose;

wherein the antibody or antigen-binding fragment that specifically binds hPCSK9 comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs;

90/92 and 218/226.

18. The method of claim 17, wherein, after receiving the 75 mg dose, but before receiving the 150 mg dose, the patient has not achieved a reduction in LDL-C level of at least 50% from the patient'"'"'s baseline LDL-C level.

19. The method of claim 17, wherein, after receiving the 75 mg dose, but before receiving the 150 mg dose, the patient has not achieved an LDL-C blood concentration of less than or equal to 100 milligrams per deciliter (mg/dL).

20. The method of claim 19, wherein, after receiving the 75 mg dose, but before receiving the 150 mg dose, the patient has not achieved an LDL-C blood concentration of less than or equal to 70 mg/dL.

21. The method of claim 17, wherein the antibody or antigen-binding fragment that specifically binds hPCSK9 comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:

220, 222, 224, 228, 230 and 232.

22. The method of claim 21, wherein the antibody or antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO:

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

226.

23. The method of claim 17, wherein the antibody or antigen-binding fragment that specifically binds hPCSK9 comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:

76, 78, 80, 84, 86 and 88.

24. The method of claim 23, wherein the antibody or antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO:

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

92.

25. The method of claim 17, wherein the patient is on a therapeutic statin regimen at the time of or just prior to administration of the 75 mg dose.

26. The method of claim 25, wherein the therapeutic statin regimen comprises a statin selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin and pravastatin.

27. The method of claim 26, wherein the statin is atorvastatin.

28. The method of claim 17, wherein the patient is on another lipid lowering agent prior to or concurrent with administration of the antibody or antigen-binding fragment thereof.

29. The method of claim 28, wherein the lipid lowering agent is selected from the group consisting of ezetimibe, a bile acid resin, niacin, and an omega-3 fatty acid.

30. The method of claim 17, wherein the pharmaceutical composition is administered to the patient subcutaneously.

31. The method of claim 17, wherein the patient has heterozygous Familial Hypercholesterolemia (heFH).

32. The method of claim 17, wherein the patient has a form of hypercholesterolemia that is not Familial Hypercholesterolemia (nonFH).