US2022133694A1PendingUtilityA1
Pharmaceutical use

Assignee: NOVARTIS AGPriority: May 11, 2015Filed: Jul 9, 2021Published: May 5, 2022
Est. expiryMay 11, 2035(~8.8 yrs left)· nominal 20-yr term from priority
Inventors:Adel Remond Rizkala Victor Chengwei Shi Fabian Chen
A61P 9/04A61K 31/225A61K 31/41A61K 2300/00
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References
Claims
Abstract

The present invention relates to novel methods and pharmaceutical compositions for the treatment of heart failure in a patient.
Claims

exact text as granted — not AI-modified
1 - 61 . (canceled) 
     
     
         62 . A regimen for treating chronic heart failure with reduced ejection fraction, which comprises providing to a human patient in need thereof a twice daily target dose of 200 mg of sacubitril or a pharmaceutically acceptable salt thereof together with valsartan or a pharmaceutically acceptable salt thereof;
 wherein the providing of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof to the human patient is administering to the human patient an amorphous solid form of a compound comprising anionic (S)-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine, anionic (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, and sodium cations in a 1:1:3 molar ratio;   wherein the twice daily target dose of 200 mg corresponds to 97 mg of sacubitril and 103 mg of valsartan;   wherein the twice daily target dose of 200 mg is reached after a titration with a twice daily starting dose of 50 mg of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof, for from about 3 weeks to about 4 weeks, wherein the twice daily starting dose of 50 mg corresponds to 24 mg of sacubitril and 26 mg of valsartan, followed by a twice daily dose of 100 mg of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof, for from about 3 weeks to about 4 weeks, wherein the twice daily dose of 100 mg corresponds to 49 mg of sacubitril and 51 mg of valsartan, followed by the twice daily target dose of 200 mg thereafter; and   wherein:
 (i) the twice daily starting dose of 50 mg is for use in a human patient neither taking an angiotensin-converting enzyme (ACE) inhibitor nor taking an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof, or 
 (ii) the twice daily starting dose of 50 mg is for use in a human patient taking a low dose of an angiotensin-converting enzyme (ACE) inhibitor or a low dose of an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof, wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to a dose of &lt;10 mg of enalapril per day. 
   
     
     
         63 . The regimen for treating chronic heart failure according to  claim 62 , wherein the twice daily target dose of 200 mg is reached after the titration with the twice daily starting dose of 50 mg for about 3 weeks, followed by the twice daily dose of 100 mg for about 3 weeks, followed by the twice daily target dose of 200 mg thereafter. 
     
     
         64 . The regimen for treating chronic heart failure according to  claim 62 , wherein the human patient has to stop taking the ARB or the ACE inhibitor at least 36 hours before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof. 
     
     
         65 . The regimen for treating chronic heart failure according to  claim 62 , wherein the human patient has an elevated plasma BNP of ≥100 pg/mL or NT-proBNP of ≥400 pg/mL. 
     
     
         66 . The regimen for treating chronic heart failure according to  claim 62 , wherein the human patient has an elevated plasma BNP of ≥150 pg/mL or NT-proBNP of ≥600 pg/mL. 
     
     
         67 . The regimen for treating chronic heart failure according to  claim 62 , wherein the human patient has a reduced left ventricular ejection fraction (LVEF) of ≤35%. 
     
     
         68 . The regimen for treating chronic heart failure according to  claim 62 , wherein the twice daily starting dose of 50 mg is for use in the human patient taking the low dose of the angiotensin-converting enzyme (ACE) inhibitor or the low dose of an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof 
     
     
         69 . The regimen for treating chronic heart failure according to  claim 68 , wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to the dose of &lt;10 mg of enalapril per day. 
     
     
         70 . A regimen for treating chronic heart failure with reduced ejection fraction, which comprises providing to a human patient in need thereof a twice daily target dose of 200 mg of sacubitril or a pharmaceutically acceptable salt thereof together with valsartan or a pharmaceutically acceptable salt thereof;
 wherein the providing of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof to the human patient is administering to the human patient an amorphous solid form of a compound consisting of anionic (S)-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl }-valine, anionic (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, and sodium cations in a 1:1:3 molar ratio;   wherein the twice daily target dose of 200 mg corresponds to 97 mg of sacubitril and 103 mg of valsartan;   wherein the twice daily target dose of 200 mg is reached after a titration with a twice daily starting dose of 50 mg of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof, for from about 3 weeks to about 4 weeks, wherein the twice daily starting dose of 50 mg corresponds to 24 mg of sacubitril and 26 mg of valsartan, followed by a twice daily dose of 100 mg of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof, for from about 3 weeks to about 4 weeks, wherein the twice daily dose of 100 mg corresponds to 49 mg of sacubitril and 51 mg of valsartan, followed by the twice daily target dose of 200 mg thereafter; and   wherein:
 (i) the twice daily starting dose of 50 mg is for use in a human patient neither taking an angiotensin-converting enzyme (ACE) inhibitor nor taking an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof, or 
 (ii) the twice daily starting dose of 50 mg is for use in a human patient taking a low dose of an angiotensin-converting enzyme (ACE) inhibitor or a low dose of an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof, wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to a dose of ≤10 mg of enalapril per day. 
   
     
     
         71 . The regimen for treating chronic heart failure according to  claim 70 , wherein the twice daily target dose of 200 mg is reached after the titration with the twice daily starting dose of 50 mg for about 3 weeks, followed by the twice daily dose of 100 mg for about 3 weeks, followed by the twice daily target dose of 200 mg thereafter. 
     
     
         72 . The regimen for treating chronic heart failure according to  claim 70 , wherein the human patient has to stop taking the ARB or the ACE inhibitor at least 36 hours before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof 
     
     
         73 . The regimen for treating chronic heart failure according to  claim 70 , wherein the human patient has an elevated plasma BNP of ≥100 pg/mL or NT-proBNP of ≥400 pg/mL. 
     
     
         74 . The regimen for treating chronic heart failure according to  claim 70 , wherein the human patient has an elevated plasma BNP of ≥150 pg/mL or NT-proBNP of ≥600 pg/mL. 
     
     
         75 . The regimen for treating chronic heart failure according to  claim 70 , wherein the human patient has a reduced left ventricular ejection fraction (LVEF) of ≤35%. 
     
     
         76 . The regimen for treating chronic heart failure according to  claim 70 , wherein the twice daily starting dose of 50 mg is for use in the human patient taking the low dose of the angiotensin-converting enzyme (ACE) inhibitor or the low dose of an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof 
     
     
         77 . The regimen for treating chronic heart failure according to  claim 76 , wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to the dose of &lt;10 mg of enalapril per day. 
     
     
         78 . A regimen for treating chronic heart failure with reduced ejection fraction, which comprises providing to a human patient in need thereof a twice daily target dose of 200 mg of sacubitril or a pharmaceutically acceptable salt thereof together with valsartan or a pharmaceutically acceptable salt thereof;
 wherein the providing of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof to the human patient is administering to the human patient an amorphous solid form of a compound comprising anionic (S)-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine, anionic (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, and sodium cations in a 1:1:3 molar ratio;   wherein the twice daily target dose of 200 mg is reached after a titration with a twice daily starting dose of 50 mg of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof, for from about 2 weeks to about 4 weeks, wherein the twice daily starting dose of 50 mg corresponds to 24 mg of sacubitril and 26 mg of valsartan, followed by a twice daily dose of 100 mg of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof, for from about 2 weeks to about 4 weeks, wherein the twice daily dose of 100 mg corresponds to 49 mg of sacubitril and 51 mg of valsartan, followed by the twice daily target dose of 200 mg thereafter, and wherein said titration to the target dose occurs over a period of at least about 6 weeks; and   wherein:
 (i) the twice daily starting dose of 50 mg is for use in a human patient neither taking an angiotensin-converting enzyme (ACE) inhibitor nor taking an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof, or 
 (ii) the twice daily starting dose of 50 mg is for use in a human patient taking a low dose of an angiotensin-converting enzyme (ACE) inhibitor or a low dose of an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof, wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to a dose of ≤10 mg of enalapril per day. 
   
     
     
         79 . The regimen for treating chronic heart failure according to  claim 78 , wherein the twice daily target dose is reached after the titration with the twice daily starting dose of 50 mg for about 3 weeks, followed by the twice daily dose of 100 mg for about 3 weeks, followed by the twice daily target dose of 200 mg thereafter. 
     
     
         80 . The regimen for treating chronic heart failure according to  claim 78 , wherein the human patient has an elevated plasma BNP of ≥100 pg/mL or NT-proBNP of ≥400 pg/mL. 
     
     
         81 . The regimen for treating chronic heart failure according to  claim 78 , wherein the human patient has an elevated plasma BNP of ≥150 pg/mL or NT-proBNP of ≥600 pg/mL. 
     
     
         82 . The regimen for treating chronic heart failure according to  claim 78 , wherein the human patient has a reduced left ventricular ejection fraction (LVEF) of ≤35%. 
     
     
         83 . The regimen for treating chronic heart failure according to  claim 78 , wherein the human patient has to stop taking the ARB or the ACE inhibitor at least 36 hours before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof. 
     
     
         84 . The regimen for treating chronic heart failure according to  claim 78 , wherein the twice daily starting dose of 50 mg is for use in the human patient taking the low dose of the ACE inhibitor or the low dose of the ARB before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof. 
     
     
         85 . The regimen for treating chronic heart failure according to  claim 78 , wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to the dose of &lt;10 mg of enalapril per day. 
     
     
         86 . The regimen for treating chronic heart failure according to  claim 78 , wherein a first week of the at least about 6 weeks is 5±2 days. 
     
     
         87 . A regimen for treating chronic heart failure with reduced ejection fraction, which comprises providing to a human patient in need thereof a twice daily target dose of 200 mg of sacubitril or a pharmaceutically acceptable salt thereof together with valsartan or a pharmaceutically acceptable salt thereof;
 wherein the providing of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof to the human patient is administering to the human patient an amorphous solid form of a compound consisting of anionic (S)-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine, anionic (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, and sodium cations in a 1:1:3 molar ratio wherein the twice daily target dose of 200 mg corresponds to 97 mg of sacubitril and 103 mg of valsartan;   wherein the twice daily target dose of 200 mg is reached after a titration with a twice daily starting dose of 50 mg of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof, for from about 2 weeks to about 4 weeks, wherein the twice daily starting dose of 50 mg corresponds to 24 mg of sacubitril and 26 mg of valsartan, followed by a twice daily dose of 100 mg of sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof, for from about 2 weeks to about 4 weeks, wherein the twice daily dose of 100 mg corresponds to 49 mg of sacubitril and 51 mg of valsartan, followed by the twice daily target dose of 200 mg thereafter, and wherein said titration to the target dose occurs over a period of at least about 6 weeks; and   wherein:
 (i) the twice daily starting dose of 50 mg is for use in a human patient neither taking an angiotensin-converting enzyme (ACE) inhibitor nor taking an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof, or 
 (ii) the twice daily starting dose of 50 mg is for use in a human patient taking a low dose of an angiotensin-converting enzyme (ACE) inhibitor or a low dose of an angiotensin II receptor blocker (ARB) before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof, wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to a dose of ≤10 mg of enalapril per day. 
   
     
     
         88 . The regimen for treating chronic heart failure according to  claim 87 , wherein the twice daily target dose is reached after the titration with the twice daily starting dose of 50 mg for about 3 weeks, followed by the twice daily dose of 100 mg for about 3 weeks, followed by the twice daily target dose of 200 mg thereafter. 
     
     
         89 . The regimen for treating chronic heart failure according to  claim 87 , wherein the human patient has an elevated plasma BNP of ≥100 pg/mL or NT-proBNP of ≥400 pg/mL. 
     
     
         90 . The regimen for treating chronic heart failure according to  claim 87 , wherein the human patient has an elevated plasma BNP of ≥150 pg/mL or NT-proBNP of ≥600 pg/mL. 
     
     
         91 . The regimen for treating chronic heart failure according to  claim 87 , wherein the human patient has a reduced left ventricular ejection fraction (LVEF) of ≤35%. 
     
     
         92 . The regimen for treating chronic heart failure according to  claim 87 , wherein the human patient has to stop taking the ARB or the ACE inhibitor at least 36 hours before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof. 
     
     
         93 . The regimen for treating chronic heart failure according to  claim 87 , wherein the twice daily starting dose of 50 mg is for use in the human patient taking the low dose of the ACE inhibitor or the low dose of the ARB before initiating the treatment with sacubitril or the pharmaceutically acceptable salt thereof and valsartan or the pharmaceutically acceptable salt thereof 
     
     
         94 . The regimen for treating chronic heart failure according to  claim 87 , wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to the dose of &lt;10 mg of enalapril per day. 
     
     
         95 . The regimen for treating chronic heart failure according to  claim 87 , wherein a first week of the at least about 6 weeks is 5±2 days.
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