Methods for treating patients with heterozygous familial hypercholesterolemia (heFH) with an anti-PCSK9 antibody

• US 10,544,232 B2
• Filed: 07/16/2015
• Issued: 01/28/2020
• Est. Priority Date: 07/16/2014
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated, Sanofi Biotechnology SAS (Sanofi )
• Original Assignee: Sanofi Biotechnology SAS (Sanofi )
• Inventors: Baccara-Dinet, Marie, Hanotin, Corinne, Bessac, Laurence, Chaudhari, Umesh, Pordy, Robert C., Sasiela, William J., Schwemmer Gipe, Daniel A.
• Primary Examiner(s): Howard, Zachary C
• Application Number:
  US14/801,384
• Publication Number:
  US 20160137745A1
• Time in Patent Office: 1,657 Days
• Field of Search: None
• 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 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: 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 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 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• 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

Abstract

The present invention provides methods for treating hypercholesterolemia. The methods of the present invention comprise administering to patients with heterozygous familial hypercholesterolemia a pharmaceutical composition comprising a PCSK9 inhibitor. In certain embodiments, the PCSK9 inhibitor is an anti-PCSK9 antibody such as the exemplary antibody referred to herein as mAb316P. The methods of the present invention are useful for treating patients with heterozygous familial hypercholesterolemia who are not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy.

Claims

1. A method for treating hypercholesterolemia, the method comprising:

(a) selecting a patient with heterozygous familial hypercholesterolemia (heFH) not adequately controlled by a maximally tolerated statin therapy; and

(b) administering to the patient one or more doses of a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds human 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, thereby treating hypercholesterolemia in the patient.

2. The method of claim 1, wherein the patient has a low-density lipoprotein cholesterol (LDL-C) level higher than or equal to 160 mg/dL.

3. The method of claim 1, wherein the diagnosis of heFH is made either by genotyping or clinical criteria.

4. The method of claim 3, wherein the clinical criteria is either the Simon Broome Register Diagnostic Criteria for Heterozygous Familial Hypercholesterolemia, or the WHO/Dutch Lipid Network criteria with a score >

8.

5. The method of claim 1, wherein the patient has type 2 diabetes mellitus.

6. The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence set forth in SEQ ID NO:

1 and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID NO;

6.

7. The method of claim 1, wherein the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is administered to the patient at a dose of about 75 mg at a frequency of once every two weeks.

8. The method of claim 1, wherein administering one or more doses of the antibody or antigen-binding fragment thereof to the patient comprises:

(i) administering to the patient two or more initial doses of 75 mg of the antibody or antigen-binding fragment thereof about every two weeks; and

(ii) administering to the subject one or more further doses of 75 mg of the antibody or antigen-binding fragment thereof about every two weeks if the LDL-C level in the patient after step (i) is lower than a threshold level, or administering to the subject one or more doses of 150 mg of the antibody or antigen-binding fragment thereof about every two weeks if the LDL-C level in the patient after step (i) is greater than or equal to the threshold level.

9. The method of claim 8, wherein the threshold level is 70 mg/dL.

10. The method of claim 1, wherein the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is administered to the patient at a dose of about 150 mg at a frequency of once every two weeks.

11. The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered to the patient in combination with the maximally tolerated statin therapy.

12. The method of claim 11, wherein the antibody or antigen-binding fragment thereof is administered to the patient in further combination with at least one other lipid lowering therapy.

13. The method of claim 1, wherein the maximally tolerated statin therapy comprises a daily dose of about 40 mg to about 80 mg of atorvastatin.

14. The method of claim 1, wherein the maximally tolerated statin therapy comprises a daily dose of about 20 mg to about 40 mg of rosuvastatin.

15. The method of claim 1, wherein the maximally tolerated statin therapy comprises a daily dose of about 80 mg of simvastatin.

16. The method of claim 1, wherein the method improves at least one hypercholesterolemia-associated parameter selected from the group consisting of:

(a) reduction of the patient'"'"'s low density lipoprotein cholesterol (LDL-C) by at least 40%;

(b) reduction of the patient'"'"'s apolipoprotein B (ApoB) by at least 30%;

(c) reduction of the patient'"'"'s non-high density lipoproprotein cholesterol (non-HDL-C) by at least 35%;

(d) reduction of the patient'"'"'s total cholesterol by at least 20%;

(e) increase of the patient'"'"'s high density lipoprotein cholesterol (HDL-C) by at least 3%;

(f) reduction of the patient'"'"'s triglycerides by at least 5%;

(g) reduction of the patient'"'"'s lipoprotein a (Lp(a)) by at least 10%; and

(h) increase of the patient'"'"'s apolipoprotein A-1 by at least 1%.