Methods and pharmaceutical compositions for reducing arterial stiffness with a combination of a therapeutic agent blocking the angiotensin receptor and a therapeutic agent inhibiting the NEP enzyme

Patent metadata

Field	Value
Publication number	US-10596151-B2
Application number	US-201615755733-A
Country	US
Kind code	B2
Filing date	Aug 24, 2016
Priority date	Aug 28, 2015
Publication date	Mar 24, 2020
Grant date	Mar 24, 2020

Abstract

The present invention relates to methods and pharmaceutical compositions for reducing arterial stiffness in a human patient showing at least one symptom selected from increased pulse wave velocity (PWV) and increased pulse pressure (PP) comprising administration to said patient of a therapeutically effective amount or a prophylactically effective amount of a combination of a therapeutic agent blocking the angiotensin receptor and a therapeutic agent inhibiting the NEP enzyme, in particular of a combination of sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof in a 1:1 molar ratio.

First claim

The invention claimed is:

1. A method of reducing arterial stiffness in a human patient showing increased pulse wave velocity (PWV) of more than 12 msec and increased pulse pressure (PP) defined as a wide brachial pulse pressure of more than 60 mm Hg comprising administering to said patient a therapeutically effective amount or a prophylactically effective amount of a combination of sacubitril and valsartan in a 1:1 molar ratio, wherein said patient is aged 60 years or older.

2. The method according to claim 1 , wherein the method is for treating, preventing or reducing the risk of experiencing a disorder or disease selected from cognitive impairment, a cardiovascular event, a cerebrovascular event and combinations thereof.

3. The method according to claim 2 , wherein said cognitive impairment is selected from the group consisting of mild cognitive impairment, age related cognitive function decline, and Alzheimer's disease.

4. The method according to claim 2 , wherein said cardiovascular event is selected from the group consisting of cardiovascular death, myocardial infarction (MI), atrial fibrillation, hospitalization for unstable angina, acute coronary syndrome, other non-coronary ischemic event (transient ischemic attack or limb ischemia), any revascularization procedure (coronary and non-coronary), hospitalization or prolongation of hospitalization for heart failure, and coronary revascularization procedures.

5. The method according to claim 2 , wherein said cerebrovascular event is stroke.

6. The method according to claim 1 , wherein increased pulse pressure (PP) is defined as a wide brachial pulse pressure of more than 65 mm Hg.

7. The method according to claim 1 , wherein increased pulse pressure (PP) is defined as a wide brachial pulse pressure of more than 70 mg Hg.

8. The method according to claim 1 , wherein said patient also has an increased central aortic pulse pressure (CPP) defined as a CPP of more than 50 mg Hg.

9. The method according to claim 8 , wherein increased central aortic pulse pressure (CPP) is defined as a CPP of more than 55 mg Hg.

10. The method according to claim 8 , wherein increased central aortic pulse pressure (CPP) is defined as a CPP of more than 60 mg Hg.

11. The method according claim 1 , wherein said patient has a diagnosis of essential hypertension.

12. The method according claim 11 , wherein said patient has a mean sitting systolic blood pressure (msSBP) of ≥150 and <180 mm Hg.

13. The method according claim 1 , wherein the therapeutically effective amount or the prophylactically effective amount of a combination of sacubitril and valsartan in a 1:1 molar ratio comprises a daily overall dose of the combination of sacubitril and valsartan in a 1:1 molar ratio from about 50 mg to about 1000 mg.

14. The method according to claim 13 , wherein the combination of sacubitril and valsartan in a 1:1 molar ratio is administered to the patient once or twice daily with an individual dose of 50 mg, 100 mg, or 200 mg.

15. The method according to claim 14 , wherein
a) the 50 mg dose of sacubitril and valsartan in a 1:1 molar ratio corresponds to 24 mg sacubitril and 26 mg valsartan,
b) the 100 mg dose of sacubitril and valsartan in a 1:1 molar ratio corresponds to 49 mg sacubitril and 51 mg valsartan, and
c) the 200 mg dose of sacubitril and valsartan in a 1:1 molar ratio corresponds to 97 mg sacubitril and 103 mg valsartan.

16. The method according to claim 1 , wherein the combination of sacubitril and valsartan in a 1:1 molar ratio is delivered in the form of the compound trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate (LCZ696).

17. The method according to claim 16 , wherein sacubitril and valsartan in a 1:1 molar ratio are delivered in the form of the compound trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)buty rate] hemipentahydrate (LCZ696), and wherein
a) the 50 mg dose of sacubitril and valsartan in a 1:1 molar ratio corresponds to around 56.6 mg LCZ696,
b) the 100 mg dose of sacubitril and valsartan in a 1:1 molar ratio corresponds to around 113.1 mg LCZ696, and
c) the 200 mg dose of sacubitril and valsartan in a 1:1 molar ratio corresponds to around 226.2 mg LCZ696.

18. The method according to claim 1 , wherein said patient is concomitantly receiving standard of care treatment for preventing or reducing risk of experiencing recurrent cardiovascular events.

19. The method according to claim 18 , wherein said standard of care treatment comprises treatment with a stable dose of a beta-blocker, an aldosterone antagonist, and/or a diuretic.

20. The method according to claim 18 , wherein said standard of care treatment comprises treatment with a stable dose of a beta-blocker and optionally an aldosterone antagonist.

Assignees

• Godtfredsen Sven Erik
• Zappe Dion Hubert
• Guo Weinong
• Zhang Jack Ziyu
• Novartis Ag

Inventors

• Godtfredsen Sven Erik
• Zappe Dion Hubert
• Guo Weinong
• Zhang Jack Ziyu

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K31/225

  Polycarboxylic acids · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61K31/41 Primary

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title