# US 9,517,226 B2 · Inhibitors for treating diseases characterized by atrial enlargement or remodeling > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,517,226 B2 - Document ID: US9517226B2 - Status: Granted - Kind: B2 - Application number: 14/422,855 - Filed: 2013-08-22 - Published: 2015-07-09 - Granted: 2016-12-13 - Earliest claimed: 2012-08-24 - Assignees: Novartis AG - Applicants: Christoph Schumacher; Thomas Holbro - Inventors: Christoph Schumacher; Thomas Holbro - Web page: https://patentgrep.com/patent/US9517226B2 ## CPC - A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate - A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid - A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205) - A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole - A61K 31/4192: 1,2,3-Triazoles - A61P 7/00: Drugs for disorders of the blood or the extracellular fluid - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - A61P 9/06: Antiarrhythmics - A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis - A61P 9/12: Antihypertensives - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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. ## Claims ### Claim 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. ### Claim 2 (depends on 1) 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. ### Claim 3 (depends on 1) The method according to claim 1, wherein the method is for the treatment of patients with no history of atrial fibrillation. ### Claim 4 (depends on 1) The method according to claim 1, wherein the method is for the use of reducing the level of plasma NT-proBNP. ### Claim 5 (depends on 1) 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. ### Claim 6 (depends on 1) 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. ### Claim 7 (depends on 1) 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. ### Claim 8 (depends on 7) 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. ### Claim 9 (depends on 8) 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. ### Claim 10 (depends on 9) 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.