Genome-Based Methods For Reducing Cardiovascular Risk

Patent metadata

Field	Value
Publication number	US-2021002724-A1
Application number	US-202016876030-A
Country	US
Kind code	A1
Filing date	May 16, 2020
Priority date	May 17, 2019
Publication date	Jan 7, 2021
Grant date	—

Abstract

The present disclosure provides methods of reducing cardiovascular risk by administration of a PCSK9 inhibitor to patients having a genetic profile associated with response to PCSK9 inhibitor therapy.

First claim

1 . A method of treating a patient at risk for a major adverse cardiovascular event (MACE), comprising:
determining the patient's coronary artery disease polygenic risk score (CAD-PRS), wherein the CAD-PRS comprises a weighted sum of a plurality of genetic variants associated with coronary artery disease; identifying a patient as at increased risk of a MACE if the patient has a CAD-PRS greater than a threshold CAD-PRS determined from a reference population; and when the patient is identified as at increased risk of a MACE, administering a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor to the patient.

2 . The method according to claim 1 , wherein the CAD-PRS threshold score is the top 30% within a reference population.

3 - 4 . (canceled)

5 . The method according to claim 1 , wherein the reference population comprises at least 100 patients.

6 - 13 . (canceled)

14 . The method according to claim 1 , wherein the plurality of genetic variants is determined by calculating genetic variant performance in the reference population and selecting the highest performing genetic variants.

15 . The method according to claim 14 , wherein genetic variant performance is calculated with respect to coronary artery disease risk based on statistical significance, strength of association, and/or a probability distribution.

16 . The method according to claim 15 , wherein the CAD-PRS is calculated using LDPred method.

17 . (canceled)

18 . The method according to claim 15 , wherein the CAD-PRS is calculated using pruning and thresholding method.

19 - 38 . (canceled)

39 . A method for lowering the level of serum LDL in a patient at increased risk of a major adverse cardiovascular event (MACE), comprising:
determining the patient's coronary artery disease polygenic risk score (CAD-PRS), wherein the CAD-PRS comprises a weighted sum of a plurality of genetic variants associated with coronary artery disease; identifying a patient as at increased risk of a MACE if the patient has a CAD-PRS greater than a threshold CAD-PRS determined from a reference population; and when the patient is identified as at increased risk of a MACE, administering a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor to the subject in an amount effective to lower the patient's level of serum LDL.

40 . The method according to claim 39 , wherein the CAD-PRS threshold score is the top 30% within a reference population.

41 - 42 . (canceled)

43 . The method according to claim 39 , wherein the reference population comprises at least 1,000 patients.

44 - 50 . (canceled)

51 . The method according to claim 39 , wherein the plurality of genetic variants is determined by calculating genetic variant performance in the reference population and selecting the highest performing genetic variants.

52 . The method according to claim 51 , wherein genetic variant performance is calculated with respect to coronary artery disease risk based on statistical significance, strength of association, and/or a probability distribution.

53 . The method according to claim 52 , wherein the CAD-PRS is calculated using LDPred method.

54 . (canceled)

55 . The method according to claim 52 , wherein the CAD-PRS is calculated using pruning and thresholding method.

56 - 75 . (canceled)

76 . A method for lowering the level of lipoprotein(a) (LPA or LP(a)) in a patient at increased risk of a major adverse cardiovascular event (MACE), comprising:
determining the patient's coronary artery disease polygenic risk score (CAD-PRS), wherein the CAD-PRS comprises a weighted sum of a plurality of genetic variants associated with coronary artery disease; identifying a patient as at increased risk of a MACE if the patient further has a CAD-PRS greater than a threshold CAD-PRS determined from a reference population; and when the patient is identified as at increased risk of a MACE, administering a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor to the subject in an amount effective to lower the patient's level of lipoprotein(a).

77 . The method according to claim 76 , wherein the CAD-PRS threshold score is the top 30% within a reference population.

78 - 79 . (canceled)

80 . The method according to claim 76 , wherein the reference population comprises at least 1,000 patients

81 - 87 . (canceled)

88 . The method according to claim 76 , wherein the plurality of genetic variants is determined by calculating genetic variant performance in the reference population and selecting the highest performing genetic variants.

89 . The method according to claim 88 , wherein genetic variant performance is calculated with respect to coronary artery disease risk based on statistical significance, strength of association, and/or a probability distribution.

90 . The method according to claim 89 , wherein the CAD-PRS is calculated using LDPred method.

91 . (canceled)

92 . The method according to claim 89 , wherein the CAD-PRS is calculated using pruning and thresholding method.

93 - 143 . (canceled)

Assignees

• Regeneron Pharma

Inventors

• Damask Amy
• Paulding Charles
• Baras Aris
• Abecasis Goncalo

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• G16B20/00

  ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations · CPC title

• G16B40/20

  Supervised data analysis · CPC title