Method for reducing the risk of a cardiovascular event with conjugated antisense compounds targeting apo(a)

Patent metadata

Field	Value
Publication number	US-2021395737-A1
Application number	US-201917292075-A
Country	US
Kind code	A1
Filing date	Nov 8, 2019
Priority date	Nov 9, 2018
Publication date	Dec 23, 2021
Grant date	—

Abstract

The present disclosure is directed to methods of reducing the risk of a cardiovascular event with conjugated antisense compounds targeting apo(a). Specifically, a method of reducing the risk of a cardiovascular event in a patient who has established cardiovascular disease with conjugated antisense compound ISIS 681257 or a salt thereof.

First claim

What is claimed is:

1 . A method of reducing the risk of a cardiovascular event in a patient who has established cardiovascular disease comprising, administering to said patient a unit dose comprising from about 75 mg to about 85 mg of the compound ISIS 681257 by subcutaneous injection once a month or once every four weeks, wherein said patient has a plasma Lp(a) concentration greater than or equal to 70 mg/dL prior to the time of the first administration of the compound.

2 . The method according to claim 1 , wherein the cardiovascular event is selected from a major adverse cardiovascular event (MACE), all cause death, coronary heart disease (CHD) death, acute myocardial infarction (AMI) death, heart failure (HF) death, death caused by the immediate complications of a cardiac procedure, and urgent lower limb re-vascularization or amputation for ischemia.

3 . The method according to claim 1 or 2 , wherein the major adverse cardiovascular event (MACE) is selected from cardiovascular (CV) death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary re-vascularization requiring hospitalization.

4 . The method according to any one of preceding claims, wherein the major adverse cardiovascular event (MACE) is cardiovascular death.

5 . The method according to any one of preceding claims, wherein the major adverse cardiovascular event (MACE) is non-fatal myocardial infarction.

6 . The method according to any one of preceding claims, wherein the major adverse cardiovascular event (MACE) is non-fatal stroke.

7 . The method according to any one of preceding claims, wherein the major adverse cardiovascular event (MACE) is urgent coronary re-vascularization.

8 . The method according to any one of preceding claims, wherein the cardiovascular event is selected from all cause death, coronary heart disease (CHD) death, acute myocardial infarction (AMI) death, heart failure (HF) death, death caused by the immediate complications of a cardiac procedure, and urgent lower limb re-vascularization or amputation for ischemia.

9 . The method according to any one of preceding claims, wherein the cardiovascular event is all cause death.

10 . The method according to any one of preceding claims, wherein the cardiovascular event is coronary heart disease (CHD) death.

11 . The method according to any one of preceding claims, wherein coronary heart disease (CHD) death comprises acute myocardial infarction (AMI) death, heart failure (HF) death, and death caused by the immediate complications of a cardiac procedure.

12 . The method according to any one of preceding claims, wherein the cardiovascular event is urgent lower limb re-vascularization or amputation for ischemia.

13 . The method according to any one of preceding claims, wherein the patient who has established cardiovascular disease is a patient having at least one of the following (i) a history of spontaneous myocardial infarction, (i) a history of ischemic stroke, and (iii) clinically significant symptomatic peripheral artery disease.

14 . The method according to any one of preceding claims, wherein the patient has a history of spontaneous myocardial infarction having occurred 3 months and 10 years prior to the time of the first administration of the compound.

15 . The method according to any one of preceding claims, wherein the patient has a history of ischemic stroke having occurred 3 months and 10 years prior to the time of the first administration of the compound.

16 . The method according to any one of preceding claims, wherein the ischemic stroke was an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue.

17 . The method according to any one of preceding claims, wherein the clinically significant symptomatic peripheral artery disease is evidenced by intermittent claudication with at least one of (i) ankle-brachial index ≤0.90; and (ii) lower limb amputation or re-vascularization due to lower limb ischemia.

18 . The method according to any one of preceding claims, wherein the patient has a plasma Lp(a) concentration ≥90 mg/dL prior to the time of the first administration of the compound.

19 . The method according to any one of preceding claims, wherein the unit dose comprises 75 mg to 85 mg of the compound.

20 . The method according to any one of preceding claims, wherein unit dose comprises about 80 mg of the compound.

21 . The method according to any one of preceding claims, wherein the unit dose comprises not more than 80 mg of the compound.

22 . The method according to any one of preceding claims, wherein the unit dose comprises 80 mg of the compound.

23 . The method according to any one of preceding claims, wherein the compound is formulated in a sterile liquid and wherein each unit dose of the compound does not comprise more than 1 mL of the sterile liquid.

24 . The method according to any one of preceding claims, wherein each unit dose of the compound does not comprise more than 0.8 mL of the sterile liquid.

25 . The method according to any one of preceding claims, wherein each unit dose of the compound does not comprise more than 0.5 mL of the sterile liquid.

26 . The method according to any one of preceding claims, wherein each unit dose of the compound does not comprise more than 0.4 mL of the sterile liquid.

27 . The method according to any one of preceding claims, wherein each unit dose of the compound does not comprise not more than 0.25 mL of the sterile liquid.

28 . The method according to any one of preceding claims, wherein each unit dose of the compound does not comprise not more than 0.2 mL of the sterile liquid.

29 . The method according to any one of preceding claims, wherein the sterile liquid is water.

30 . The method according to any one of preceding claims, wherein the sterile liquid is water with a sodium phosphate buffer.

31 . The method according to any one of preceding claims, wherein the sterile liquid is water with a sodium phosphate buffer and sodium chloride.

32 . The method according to any one of the preceding claims, wherein the mean/median plasma Lp(a) concentration in the patient is reduced by at least 50%, when the plasma Lp(a) concentration in the patient is measured at the start and the end of the period when the patient is dosed with the compound (dosing period).

33 . The method according to any one of the preceding claims, wherein the mean/median plasma Lp(a) concentration in the patient is reduced by at least 60%, when the plasma Lp(a) concentration in the patient is measured at the start and end of the dosing period

34 . The method according to any one of the preceding claims, wherein the mean/median plasma Lp(a) concentration in the patient is reduced by at least 70%, when the plasma Lp(a) concentration in the patient is measured at the start and end of the dosing period.

35 . The method according to any one of the preceding claims, wherein the mean/median plasma Lp(a) concentration in the patient is reduced by at least 75%, when the plasma Lp(a) concentration in the patient is measured at the start and end of the dosing period.

36 . The method according to any one of the preceding claims, wherein the overall risk of

Assignees

• Novartis Ag

Inventors

• Lesogor Anastasia
• Shao Qing
• Thuren Tom

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C12N2310/351

  Conjugate · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2320/30

  Special therapeutic applications · CPC title

• C12N2310/341

  Gapmers, i.e. of the type ===---=== · CPC title