Claims for Patent: 11,058,667

Summary for Patent: 11,058,667

Title:	Sacubitril-valsartan dosage regimen for treating heart failure
Abstract:	The present invention relates to sacubitril-valsartan dosage regimens for the treatment of heart failure in a patient.
Inventor(s):	Rizkala; Adel Remond (East Brunswick, NJ), Shi; Victor Chengwei (Mendham, NJ), Chen; Fabian (Englewood Cliffs, NJ)
Assignee:	Novartis AG (Basel, CH)
Application Number:	15/572,399
Patent Claims:	1. A regimen for treating chronic heart failure with reduced ejection fraction, which comprises administering to a human patient in need thereof a twice-daily target dose of 200 mg of sacubitril or a pharmaceutically acceptable salt thereof with valsartan or a pharmaceutically acceptable salt thereof, which are provided to the human patient in a 1:1 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 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, which are provided to the human patient in a 1:1 molar ratio, 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, which are provided to the human patient in a 1:1 molar ratio, 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 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 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. 2. The regimen for treating chronic heart failure according to claim 1, 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. 3. The regimen for treating chronic heart failure according to claim 1, 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. 4. The regimen for treating chronic heart failure according to claim 1, wherein the human patient has an elevated plasma BNP of .gtoreq.100 pg/mL or NT-proBNP of .gtoreq.400 pg/mL. 5. The regimen for treating chronic heart failure according to claim 1, wherein the human patient has an elevated plasma BNP of .gtoreq.150 pg/mL or NT-proBNP of .gtoreq.600 pg/mL. 6. The regimen for treating chronic heart failure according to claim 1, wherein the human patient has a reduced left ventricular ejection fraction (LVEF) of .ltoreq.35%. 7. A regimen for treating chronic heart failure with reduced ejection fraction, which comprises administering 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, which are provided to the human patient in a 1:1 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, which are provided to the human patient in a 1:1 molar ratio, 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, which are provided to the human patient in a 1:1 molar ratio, for from about 2 weeks to about 4 weeks, wherein the twice daily target 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 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 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. 8. The regimen for treating chronic heart failure according to claim 7, 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. 9. The regimen for treating chronic heart failure according to claim 7, wherein the human patient has an elevated plasma BNP of .gtoreq.100 pg/mL or NT-proBNP of .gtoreq.400 pg/mL. 10. The regimen for treating chronic heart failure according to claim 7, wherein the human patient has an elevated plasma BNP of .gtoreq.150 pg/mL or NT-proBNP of .gtoreq.600 pg/mL. 11. The regimen for treating chronic heart failure according to claim 7, wherein the human patient has a reduced left ventricular ejection fraction (LVEF) of .ltoreq.35%. 12. The regimen for treating chronic heart failure according to claim 7, 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. 13. The regimen for treating chronic heart failure according to claim 1, 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. 14. The regimen for treating chronic heart failure according to claim 13, wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to the dose of <10 mg of enalapril per day. 15. The regimen for treating chronic heart failure according to claim 7, 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. 16. The regimen for treating chronic heart failure according to claim 15, wherein the low dose of the ACE inhibitor or the low dose of the ARB is equivalent to the dose of <10 mg of enalapril per day. 17. The regimen for treating chronic heart failure according to claim 7, wherein a first week of the at least about 6 weeks is 5.+-.2 days. 18. The regimen for treating chronic heart failure according to claim 1, wherein sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof are provided to the human patient in a 1:1 molar ratio by administering to the human patient a compound trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propi- onate-(S)-3'-methyl-2'-(pentanoyl{2''-(tetrazol-5-ylate)biphenyl-4'- ylmethyl}amino)butyrate] hemipentahydrate (LCZ696). 19. The regimen for treating chronic heart failure according to claim 7, wherein sacubitril or the pharmaceutically acceptable salt thereof together with valsartan or the pharmaceutically acceptable salt thereof are provided to the human patient in a 1:1 molar ratio by administering to the human patient a compound trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propi- onate-(S)-3'-methyl-2'- (pentanoyl{2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate] hemipentahydrate (LCZ696).