Methods for Treating Autosomal Dominant Hypercholesterolemia Associated with PCSK9 Gain-Of-Function Mutations

• US 20190330371A1
• Filed: 03/28/2019
• Published: 10/31/2019
• Est. Priority Date: 05/30/2013
• Status: Abandoned Application

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: SWERGOLD, Gary, MELLIS, Scott, SASIELA, William J.
• Application Number:
  US16/367,795
• Publication Number:
  US 20190330371A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• 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: C12Q 1/68 involving nucleic acids
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

The present invention provides methods for treating autosomal dominant hypercholesterolemia (ADH). According to certain embodiments, the ADH is caused by or associated with a gain-of-function mutation (GOFm) in a gene encoding PCSK9. The present invention therefore includes methods comprising selecting a patient who carries a GOFm in one or both alleles of the PCSK9 gene, and administering to the patient 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.

Claims

1. A method of treating autosomal dominant hypercholesterolemia (ADH), wherein the method comprises selecting a patient who carries a gain-of-function mutation (GOFm) in one or both alleles of the PCSK9 gene, and administering to the patient a pharmaceutical composition comprising a PCSK9 inhibitor, wherein the GOFm is selected from the group consisting of:

V4I, E48K, P71L, R96C, and S465L, and wherein the PCSK9 inhibitor is an antibody or antigen binding fragment thereof that specifically binds PCSK9 and that 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 the patient is further selected on the basis of having a plasma LDL-C level greater than or equal to about 70 mg/dL prior to administration of the pharmaceutical composition comprising the PCSK9 inhibitor.

3. The method of claim 2, wherein the patient is on a background lipid lowering therapy at the time of and/or prior to administration of the pharmaceutical composition comprising the PCSK9 inhibitor.

4. The method of claim 3, wherein the background lipid lowering therapy is selected from the group consisting of statins, ezetimibe, fibrates, niacin, omega-3 fatty acids, and bile acid resins.

5. The method of claim 1, wherein the patient is further selected on the basis of having a body mass index (BMI) of greater than about 18.0 kg/m2 prior to administration of the pharmaceutical composition comprising the PCSK9 inhibitor.

6. The method of claim 1, wherein the pharmaceutical composition comprises 20 mg to 200 mg of the PCSK9 inhibitor.

7. The method of claim 6, wherein the pharmaceutical composition comprises 50 mg to 150 mg of the PCSK9 inhibitor.

8. The method of claim 7, wherein the pharmaceutical composition comprises 50 mg of the PCSK9 inhibitor.

9. The method of claim 7, wherein the pharmaceutical composition comprises 75 mg of the PCSK9 inhibitor.

10. The method of claim 7, wherein the pharmaceutical composition comprises 100 mg of the PCSK9 inhibitor.

11. The method of claim 7, wherein the pharmaceutical composition comprises 150 mg of the PCSK9 inhibitor.

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

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

13. The method of claim 12, wherein the antibody or antigen-binding fragment thereof 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.

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

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

15. The method of claim 14, wherein the antibody or antigen-binding fragment thereof 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.

16. The method of claim 1, wherein the antibody or antigen-binding fragment thereof binds to the same epitope on PCSK9 as an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs:

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

or SEQ ID NOs;

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

17. The method of claim 1, wherein the antibody or antigen-binding fragment thereof competes for binding to PCSK9 with an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs:

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

or SEQ ID NOs;

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

18. A method of treating autosomal dominant hypercholesterolemia (ADH), comprising selecting a patient who carries a gain-of-function mutation (GOFm) in one or both alleles of the PCSK9 gene, and administering to the patient a plurality of doses of a pharmaceutical composition comprising a PCSK9 inhibitor, wherein the doses are administered to the patient at a dosing frequency selected from the group consisting of:

once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks and once every twelve weeks, wherein the GOFm is selected from the group consisting of;

V4I, E48K, P71L, R96C, and S465L, and wherein the PCSK9 inhibitor is an antibody or antigen binding fragment thereof that specifically binds PCSK9 and that 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.

19. The method of claim 18, wherein the patient is further selected on the basis of having a plasma LDL-C level greater than or equal to about 70 mg/dL prior to administration of the pharmaceutical composition comprising the PCSK9 inhibitor.

20. The method of claim 18, wherein the patient is on a background lipid lowering therapy at the time of and/or prior to the first administration of the pharmaceutical composition comprising the PCSK9 inhibitor.

21. The method of claim 20, wherein the background lipid lowering therapy is selected from the group consisting of statins, ezetimibe, fibrates, niacin, omega-3 fatty acids, and bile acid resins.

22. The method of claim 18, wherein the patient is further selected on the basis of having a body mass index (BMI) of greater than about 18.0 kg/m2 prior to the first administration of the pharmaceutical composition comprising the PCSK9 inhibitor.

23. The method of claim 18, wherein the pharmaceutical composition comprises 20 mg to 200 mg of the PCSK9 inhibitor.

24. The method of claim 23, wherein the pharmaceutical composition comprises 50 mg to 150 mg of the PCSK9 inhibitor.

25. The method of claim 24, wherein the pharmaceutical composition comprises 50 mg of the PCSK9 inhibitor.

26. The method of claim 24, wherein the pharmaceutical composition comprises 75 mg of the PCSK9 inhibitor.

27. The method of claim 24, wherein the pharmaceutical composition comprises 100 mg of the PCSK9 inhibitor.

28. The method of claim 24, wherein the pharmaceutical composition comprises 150 mg of the PCSK9 inhibitor.

29. The method of claim 18, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:

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

30. The method of claim 29, wherein the antibody or antigen-binding fragment thereof 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.

31. The method of claim 18, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:

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

32. The method of claim 31, wherein the antibody or antigen-binding fragment thereof 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.

33. The method of claim 18, wherein the antibody or antigen-binding fragment thereof binds to the same epitope on PCSK9 as an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs:

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

or SEQ ID NOs;

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

34. The method of claim 18, wherein the antibody or antigen-binding fragment thereof competes for binding to PCSK9 with an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs:

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

or SEQ ID NOs;

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