Combination therapy of cardiac myosin activator and sinus node if current inhibitor

Abstract

Disclosed herein are combination therapies for the treatment of heart failure using a cardiac myosin activator, such as omecamtiv mecarbil, and a sinus node If current inhibitor, such as ivabradine. Also disclosed herein are compositions comprising a cardiac myosin activator and a sinus node If current inhibitor.

What is claimed: 
     
         1 . A method of treating a subject suffering from heart failure comprising administering to the subject a cardiac myosin activator and a sinus node If current inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the cardiac myosin activator is omecamtiv mecarbil, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         3 . The method of  claim 1  or  2 , wherein the sinus node If current inhibitor is ivabradine, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         4 . The method of  claim 3 , wherein the omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof and ivabradine or pharmaceutically acceptable salt or hydrate thereof are administered sequentially. 
     
     
         5 . The method of  claim 4 , wherein the omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof administration is before the ivabradine or pharmaceutically acceptable salt or hydrate thereof administration. 
     
     
         6 . The method of  claim 4 , wherein the omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof administration is after the ivabradine or pharmaceutically acceptable salt or hydrate thereof administration. 
     
     
         7 . The method of  claim 3 , wherein the omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof and ivabradine or pharmaceutically acceptable salt or hydrate thereof are administered simultaneously. 
     
     
         8 . The method of  claim 7 , wherein the omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof and ivabradine or pharmaceutically acceptable salt or hydrate thereof are co-formulated. 
     
     
         9 . The method of any one of  claims 3 - 8 , wherein the omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof, ivabradine or pharmaceutically acceptable salt or hydrate thereof, or both are administered orally, intravenously, subcutaneously, intramuscularly, intrathecally, or via inhalational. 
     
     
         10 . The method of any one of  claims 2 - 9 , wherein the omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof is administered orally. 
     
     
         11 . The method of any one of  claims 3 - 9 , wherein the ivabradine or pharmaceutically acceptable salt or hydrate thereof is administered orally. 
     
     
         12 . The method of any one of  claims 2 - 11 , wherein the omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof is administered in a total daily amount of 10 mg to 200 mg. 
     
     
         13 . The method of  claims 12 , wherein the omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof is administered in a total daily amount of 12.5 mg to 75 mg. 
     
     
         14 . The method of any one of  claims 3 - 13 , wherein the ivabradine or pharmaceutically acceptable salt or hydrate thereof is administered in a total daily amount of 2.5 mg to 20 mg. 
     
     
         15 . The method of any one of  claims 1 - 14 , wherein the subject suffers from congestive heart failure. 
     
     
         16 . The method of any one of  claims 1 - 15 , wherein the subject suffers from systolic heart failure. 
     
     
         17 . The method of any one of  claims 1 - 16 , wherein the subject suffers from heart failure with reduced left ventricular ejection fraction. 
     
     
         18 . The method of any one of  claims 3 - 17 , wherein the administration of omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof and ivabradine or pharmaceutically acceptable salt or hydrate thereof results in a decrease in ischemic events, compared to administration of omecamtiv mecarbil alone. 
     
     
         19 . The method of any one of  claims 3 - 18 , wherein the administration of omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof and ivabradine or pharmaceutically acceptable salt or hydrate thereof results in a decrease in systolic to diastolic ratio, compared to administration of omecamtiv mecarbil alone. 
     
     
         20 . The method of any one of  claims 3 - 19 , wherein the administration of omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof and ivabradine or pharmaceutically acceptable salt or hydrate thereof results in a decrease in troponin levels, compared to administration of omecamtiv mecarbil alone. 
     
     
         21 . The method of any one of  claims 3 - 18 , wherein the administration of omecamtiv mecarbil or pharmaceutically acceptable salt or hydrate thereof and ivabradine or pharmaceutically acceptable salt or hydrate thereof results in an increase in cardiac contractility, compared to administration of ivabradine alone. 
     
     
         22 . A pharmaceutical composition comprising a cardiac myosin activator and a sinus node If current inhibitor. 
     
     
         23 . The composition of  claim 22 , wherein the sinus node If current inhibitor is ivabradine, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         24 . The composition of  claim 23 , wherein the ivabradine is present as ivabradine hydrochloride. 
     
     
         25 . The composition of any one of  claims 22 - 24 , wherein the cardiac myosin activator is omecamtiv mecarbil, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         26 . The composition of  claim 25 , wherein the omecamtiv mecarbil is present as omecamtiv mecarbil dihydrochloride hydrate. 
     
     
         27 . The composition of any one of  claims 22 - 26 , in the form of a tablet. 
     
     
         28 . The composition of  claim 27 , further comprising a control release agent; a pH modifying agent; a filler; and a lubricant. 
     
     
         29 . The composition of  claim 28 , wherein the control release agent comprises methylcellulose, hydroxypropyl methylcellulose, or a combination thereof. 
     
     
         30 . The composition of  claim 28  or  29 , wherein the pH modifying agent comprises fumaric acid. 
     
     
         31 . The composition of any one of  claims 28 - 30 , wherein the filler comprises microcrystalline cellulose, lactose monohydrate, or a combination thereof. 
     
     
         32 . The composition of any one of  claims 28 - 31 , wherein the lubricant comprises magnesium stearate. 
     
     
         33 . Omecamtiv mecarbil, or a pharmaceutically acceptable salt or hydrate thereof, for use in combination with ivabradine, or a pharmaceutically acceptable salt or hydrate thereof, for treating heart failure. 
     
     
         34 . Ivabradine, or a pharmaceutically acceptable salt or hydrate thereof, for use in combination with omecamtiv mecarbil, or a pharmaceutically acceptable salt or hydrate thereof, for treating heart failure. 
     
     
         35 . A combination therapeutic comprising ivabradine, or a pharmaceutically acceptable salt or hydrate thereof, and omecamtiv mecarbil, or a pharmaceutically acceptable salt or hydrate thereof, as separate entities for oral administration. 
     
     
         36 . Use of the combination therapeutic of  claim 35  in the treatment of heart failure.