Inhibitors for treating diseases characterized by atrial enlargement or remodeling

Patent metadata

Field	Value
Publication number	US-9517226-B2
Application number	US-201314422855-A
Country	US
Kind code	B2
Filing date	Aug 22, 2013
Priority date	Aug 24, 2012
Publication date	Dec 13, 2016
Grant date	Dec 13, 2016

Abstract

The present invention relates to the NEP inhibitor pro-drug N-(3-carboxy-1-oxopropyl)-(4S)-p -phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, or a pharmaceutically acceptable salt thereof; or the NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-p -phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid, or a pharmaceutically acceptable salt thereof, pro-drug for use in the treatment, prevention or delay of progression of a disease characterized by atrial enlargement and/or remodeling; a method for treatment, prevention or delay of progression of a disease characterized by atrial enlargement and/or remodeling comprising administration of a therapeutically effective amount, or a prophylactically effective amount, of the NEP inhibitor or the NEP inhibitor pro-drug, or a pharmaceutically acceptable salt pro-drug thereof, to a subject, e.g. a human subject, in need of such treatment. The present invention further relates to a pharmaceutical composition or a commercial package comprising the NEP inhibitor or the NEP inhibitor pro-drug, or a pharmaceutically acceptable salt thereof, pro-drug for use in the treatment, prevention or delay of progression of a disease characterized by atrial enlargement and/or remodeling.

First claim

The invention claimed is:

1. A method for the treatment or delay of progression of a disease characterized by atrial enlargement and/or remodeling in a human patient comprising administration of a therapeutically effective amount of the NEP inhibitor pro-drug N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, or a pharmaceutically acceptable salt thereof; or the NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid, or a pharmaceutically acceptable salt thereof, to the patient in need of such treatment, wherein the disease is heart failure with preserved ejection fraction (HF-PEF), and wherein the treatment or delay of progression is characterized by the reduction of the left atrial volume, the left atrial volume index (LAVI) and/or the left atrial dimension.

2. The method according to claim 1 , wherein the method is for the treatment of atrial fibrillation or for delaying the time until new onset of atrial fibrillation.

3. The method according to claim 1 , wherein the method is for the treatment of patients with no history of atrial fibrillation.

4. The method according to claim 1 , wherein the method is for the use of reducing the level of plasma NT-proBNP.

5. The method according to claim 1 , wherein the administration of the NEP inhibitor pro-drug or NEP inhibitor leads to a sustained reduction in plasma NT-proBNP concentration.

6. The method according to claim 1 , wherein the method is for the improvement, stabilization or delayed worsening in NYHA classification of patients suffering from heart failure.

7. The method according to claim 1 , wherein the NEP inhibitor or NEP inhibitor pro-drug is administered together, concomitantly or sequentially with the Angiotensin Receptor Blocker valsartan or a pharmaceutically acceptable salt thereof.

8. The method according to claim 7 , wherein the NEP inhibitor or NEP inhibitor pro-drug and the Angiotensin Receptor Blocker are administered in a 1:1 molar ratio.

9. The method according to claim 8 wherein the NEP inhibitor pro-drug delivered by administration of LCZ696 as 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.

10. The method according to claim 9 wherein LCZ696 is administered twice daily at a dose of 50 mg, 100 mg, 200 mg or 400 mg.

Assignees

• Schumacher Christoph
• Holbro Thomas
• Novartis Ag

Inventors

• Schumacher Christoph
• Holbro Thomas

Classifications

• 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

• A61K31/216 Primary

  of acids having aromatic rings, e.g. benactizyne, clofibrate · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61K31/194 Primary

  having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid · CPC title

• A61P9/06

  Antiarrhythmics · CPC title