Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/225—Polycarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

• the present invention relates to novel methods and novel uses in the treatment of heart failure in a patient, in particular in a patient with heart failure (HF) with a reduced ejection fraction (EF) (HFrEF), wherein treatment with sacubitril and valsartan is initiated shortly after an acute decompensation heart failure episode of said patient.
• HF heart failure
• EF reduced ejection fraction
• Heart failure is a global pandemic with an estimated worldwide prevalence of 38 million patients (Ambrosy AP, et al. J Am Coll Cardiol 2014;63: 1 123-33; Writing Group M, Mozaffarian D, et al. Circulation2016; 133:e38-360). In the United States alone, there are more than 1 million admissions for HF as a primary diagnosis per year, representing 1 %- 2% of all hospitalizations (Blecker S, et al. J Am Coll Cardiol 2013;61 : 1259-67;
• LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) being developed for the treatment of cardiovascular diseases such as hypertension and/or heart failure.
• ARNI angiotensin receptor neprilysin inhibitor
• Ingestion of LCZ696 results in systemic exposure to sacubitril (AHU377; (2R,4S)-5- biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, also named N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R- methylbutanoic acid ethyl ester), a neprilysin (neutral endopeptidase 24.11 , NEP) inhibitor (NEPi) prodrug, and valsartan providing inhibition of the angiotensin
• Sacubitril is further metabolized via esterases to the active NEPi, LBQ657 (N-(3-carboxy- 1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid).
• Neprilysin degrades biologically active natriuretic peptides (NPs), including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP).
• NEP atrial natriuretic peptide
• BNP B-type natriuretic peptide
• CNP C-type natriuretic peptide
• NPs acting through the second messenger cyclic guanosine monophosphate, have potent natriuretic and vasodilator properties, inhibit the activity of the renin-angiotensin- aldosterone system (RAAS), lower sympathetic drive and have anti-fibrotic and anti- hypertrophic effects.
• Angiotensin receptor blockade is specific and competitive at the angiotensin type 1 (AT1) receptor, which mediates the deleterious effects of angiotensin II on the cardiovascular system.
• AT1 angiotensin type 1
• LCZ696 through its dual mode of action, potentiates NPs via NEP inhibition while inhibiting the RAAS via AT 1 receptor blockade. Both of these mechanisms are considered to act in a complementary and additive manner to improve the morbidity and mortality of HF patients.
• HF still represents a major cause of cardiac mortality and morbidity with a clear need for better therapy.
• the present invention relates to a method of treating heart failure with reduced ejection fraction in a patient comprising administering to said patient in need thereof sacubitril and valsartan in a 1 :1 molar ratio, wherein treatment is initiated shortly after an acute decompensation heart failure (ADHF) episode of said patient.
• ADHF acute decompensation heart failure
• the present invention also relates to sacubitril and valsartan in a 1 :1 molar ratio for use in a method of treating heart failure with reduced ejection fraction in a patient, wherein treatment is initiated shortly after an acute decompensation heart failure (ADHF) episode of said patient.
• ADHF acute decompensation heart failure
• the present invention also relates to the use of sacubitril and valsartan in a 1 :1 molar ratio in the manufacture of a medicament for treating heart failure with reduced ejection fraction in a patient, wherein treatment is initiated shortly after an acute decompensation heart failure (ADHF) episode of said patient.
• ADHF acute decompensation heart failure
• the present invention also relates to the use of sacubitril and valsartan in a 1 :1 molar ratio for treating heart failure with reduced ejection fraction in a patient, wherein treatment is initiated shortly after an acute decompensation heart failure (ADHF) episode of said patient.
• ADHF acute decompensation heart failure
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising sacubitril and valsartan in a 1 :1 molar ratio, and one or more pharmaceutically acceptable carriers, for use in treating heart failure with reduced ejection fraction in a patient, wherein treatment is initiated shortly after an acute decompensation heart failure (ADHF) episode of said patient.
• ADHF acute decompensation heart failure
• treatment is understood the management and care of a patient for the purpose of combating the disease, condition or disorder.
• terapéuticaally effective amount refers to an amount of a pharmaceutical composition comprising sacubitril and valsartan in a 1 :1 molar ratio that will elicit the desired biological and/or medical response of a tissue, system or an animal (including man) that is being sought by a researcher or clinician.
• patient refers to a human.
• administration of and or “administering a” compound should be understood to mean providing a pharmaceutical composition comprising sacubitril and valsartan in a 1 :1 molar ratio to a subject in need of treatment.
• the administration of the pharmaceutical composition in order to practice the present invention is carried out by administering a therapeutically effective amount of the pharmaceutical composition to a subject in need of such treatment.
• the effective amount of the pharmaceutical composition is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration, other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
• pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
• the New York Heart Association (NYHA) classification grades the severity of heart failure symptoms as one of four functional classes.
• the NYHA classification is widely used in clinical practice and in research because it provides a standard description of severity that can be used to assess response to treatment and to guide management.
• the New York Heart Association functional classification based on severity of symptoms and physical activity:
• Class I No limitation of physical activity. Ordinary physical activity does not cause undue breathlessness, fatigue, or palpitations. Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue, or palpitations.
• Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in undue breathlessness, fatigue, or palpitations.
• Class IV Unable to carry on any physical activity without discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort is increased.
• the Child-Pugh score (or its associated Child-Pugh grade) is used as a means to give a description of the clinical state of patients with cirrhosis of the liver, and to indicate the severity of the condition.
• the Pugh-Child score is determined by scoring five clinical measures of liver disease. A score of 1 , 2, or 3 is given to each measure, with 3 being the most severe.
• the five clinical measures are:
• serum albumin blood protein produced in the liver
• prothrombin time prolongation(s) or INR: time for blood to clot
• a“medically stable” patient is also referred to as a patient“being stabilized” (after an acute decompensated heart failure episode).
• a patient characterize a patient as defined by at least one of the following characteristics (i) a systolic blood pressure 3100 mm Hg (preferably 3110 mm Hg) during 6 hours before initiation of treatment, (ii) no increase (i.e. , intensification) in intravenous (IV) diuretics or use of IV vasodilators during 6 hours before initiation of treatment, or (iii) no IV inotropes administered during 24 hours before initiation of treatment.
• a systolic blood pressure 3100 mm Hg preferably 3110 mm Hg
• a dose of 200mg LCZ696 b.i.d. means that the patient receives twice daily each a 200 mg unit dose of LCZ696, with 400 mg denoting the total daily dose.
• Acute decompensation heart failure (ADHF) episode refers to a period of medical stabilization after the occurrence of an acute heart failure event wherein the patient receives acute heart failure treatment. Such period is at least 24 hours.
• Figure 2 Comparison of treatments at baseline for the TRANSITION study, compared to the PARADIGM-HF and TITRATION studies
• Figure 3 Proportion of patients (safety set) meeting the primary and secondary endpoints of the TRANSITION study.
• Figure 4 Most common AEs (32 events in any treatment group) leading to permanent discontinuations (number of patients with at least one AE leading to permanent discontinuation) during the 10-week treatment period in the TRANSITION study.
• Figure 6 Proportion of de novo patients meeting the primary and secondary endpoints of the TRANSITION study.
• Figure 7 Proportion of Arb or ACE naive patients meeting the primary and secondary endpoints of the TRANSITION study.
• Figure 8 Trial flow diagram of the PIONEER-HF study.
• Figure 9 NT-proBNP by visit change from baseline of geometric mean values in the PIONEER-HF study.
• Figure 10 Percent change from baseline in NT-proBNP geometric mean in the PIONEER- HF study.
• Figure 11 Kaplan-Meier estimated cumulative incidence of the clinical composite of death from any cause, hospitalization for worsening HF, left ventricular assist device
• Figure 12 Subgroup analyses of change in NT-proBNP in evaluable patients by age, sex, race, prior HF and NYHA class, SBP, or NT-proBNP values, LVEF, eGFR, atrial fibrillation, hypertension, time from admission to randomization and prior ACEi and/or ARB use in the PIONEER-HF study.
• Figure 13 Subgroup analyses of clinical composite of death from any cause,
• HF left ventricular assist device implantation
• NT-proBNP values LVEF, eGFR, atrial fibrillation, hypertension, time from admission to randomization and prior ACEi and/or ARB use in the PIONEER-HF study.
• This invention is based on the clinical trials TRANSITION (NCT02661217) and PIONEER- HF (NCT02554890).
• NCT02661217 has compared Pre-discharge and Post discharge treatment initiation with LCZ696 therapy in heart failure patients with reduced ejection fraction (HFrEF) shortly after an acute decompensation heart failure (ADHF) episode. It has been shown that
• NCT02554890 The clinical trial PIONEER-HF (NCT02554890) was designed to assess the effect of in- hospital initiation of LCZ696 versus enalapril on the time-averaged proportional change in NT-proBNP levels from baseline to Weeks 4 and 8 in hemodynamically stable patients with HFrEF (LVEF £ 40%) following hospitalization for ADHF. It has been shown that
• LCZ696 was more effective than enalapril in a patient population of patients which identified semselves as black and for whom evidence of ARNi therapy from prior clinical studies was limited. Also in this patient population, it could be shown that there were no angioedema with LCZ696, whereas angioedema were observed with enalapril.
• the target dose of 200 mg LCZ696 b.i.d. is the dose studied in the PARADIGM-HF trial that demonstrated superiority over enalapril 10 mg b.i.d..
• a dose of 200 mg LCZ696 b.i.d. delivers similar exposures of valsartan (assessed by AUC) as valsartan 160 mg b.i.d., the maximal approved valsartan dose for HF and the dose recommended in international guidelines for the treatment of HF.
• biomarker analysis increase in levels of ANP and cGMP indicated that this dose delivers approximately 90% of its maximal neprilysin inhibition (Gu J, et al. J Clin Pharmacol 2010;50:401-14).
• the achievement of the target dose is indicative of a patient’s tolerability to the treatment, since the basis for up-titration towards the target dose was based on tolerability (i.e. , incidence of hypotension, renal or hepatic impairment and hyperkalemia) based on clinical evaluation and laboratory assessment of the patient.
• tolerability i.e. , incidence of hypotension, renal or hepatic impairment and hyperkalemia
• the high percentage of patients reaching the target dose of 200 mg LCZ696 b.i.d. in the TRANSITION study proves that early initiation of LCZ696 was feasible and overall well tolerated.
• the term“sacubitril and valsartan in a 1 : 1 molar ratio” refers to a combination of a 1 :1 molar ratio of
• said combination is provided in form of a complex or compound comprising valsartan and sacubitril and linking them together via non-covalent or covalent bonding, optionally via a linker.
• sacubitril and valsartan in a 1 :1 molar ratio is provided in the form of the compound of the formula (I)
• Ai is valsartan in the dianionic form
• a 2 is sacubitril in the anionic form
• Na + is a sodium ion
• x is 0.5 to 7.
• sacubitril and valsartan in a 1 : 1 molar ratio is provided in the form of the compound of the formula (I), wherein x is 0.5 to 3.5.
• sacubitril and valsartan in a 1 : 1 molar ratio is provided in the form of the compound of the formula (I), wherein x is 0.5 to 2.5.
• sacubitril and valsartan in a 1 : 1 molar ratio is provided in the form of the compound of the formula (I), wherein x is 2.5 to 3.5.
• the compound of formula (I) is in amorphous form.
• sacubitril and valsartan in a 1 : 1 molar ratio is provided in the form of the compound of the formula (I), wherein x is 2.5.
• the compound of formula (I) is in crystalline form.
• the compound of formula (I) is trisodium [3-((1 S,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.
• a “pharmaceutical composition for use” is a pharmaceutical composition comprising sacubitril and valsartan in a 1 :1 molar ratio, wherein sacubitril and valsartan in a 1 :1 molar ratio is as defined in the embodiments above.
• compositions and compounds containing sacubitril and valsartan, such as LCZ696, and their uses have for example been previously disclosed in W02003059345, W02007056546, W02009061713, WO2012027237, WO2014029848, W02015030711 , WO2015028941 , WO2016181284, WO2016193883, W02017006254 and
• compositions and compounds containing sacubitril and valsartan in a 1 : 1 molar ratio and their uses have also for example been previously disclosed in CN105037289A, WO2017096772, WO2016037552, WO2016049663, CN105461647A,
• WO2017009784 WO2017037591 , WO2017036420, WO2017037596, WO2017042700,
• Valsartan may be used in certain embodiments of the invention in its free acid form, as well as in any suitable salt form.
• esters or other derivatives of the carboxylic grouping may be employed as well as salts and derivatives of the tetrazole grouping.
• Sacubitril or N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R- methylbutanoic acid ethyl ester or a pharmaceutically acceptable salt thereof as well as (2R,4S)-5-biphenyl-4-yl-4(3-carboxy-propionyl amino)-2-methyl-pentanoic acid can be prepared by known methods such as described in U.S. Patent No. 5,217,996 which is herein incorporated by reference.
• the corresponding active ingredients or pharmaceutically acceptable salts thereof may also be used in the form of a hydrate or include other solvents used for crystallization.
• the compounds sacubitril or a salt thereof, valsartan or a salt thereof, compounds of formula (I), in particular LCZ696, are substantially pure or in a substantially pure form.
• substantially pure refers to at least about 90% purity, more preferably at least about 95% and most preferably at least about 98% purity.
• these compounds are solid or in a solid form or in solid state.
• the solid, solid form or solid state can be crystalline, partially crystalline, amorphous or poly- amorphous, preferably in the crystalline form.
• compositions can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.
• compositions contain, for example, from about 0.1% to about 100%, e.g. 80% or 90%, or from about 1% to about 60%, of the active ingredient.
• compositions for enteral or parenteral administration are, e.g., those in unit dose forms, such as sugar-coated tablets, tablets, capsules, bars, sachets, granules, syrups, aqueous or oily suspensions or suppositories and furthermore ampoules. These are prepared in a manner known per se, e.g. by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes.
• pharmaceutical compositions for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable excipients to give tablets or sugar-coated tablet cores.
• Tablets may be formed from the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch, lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tabletting the mixture by known methods.
• fillers for example calcium phosphate
• disintegrating agents for example maize starch, lubricating agents, for example magnesium stearate
• binders for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tabletting the mixture by known methods.
• capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound.
• dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing the active compounds in a suitable vegetable oil, for example arachis oil.
• a non-toxic suspending agent such as sodium carboxymethylcellulose
• oily suspensions containing the active compounds in a suitable vegetable oil for example arachis oil.
• the pharmaceutical compositions include active compounds that are formulated into granules with or without additional excipients.
• the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (e.g. water) before ingestion.
• a suitable liquid carrier e.g. water
• the granules may contain disintegrants, e.g. an effervescent pair formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
• the dosage of the active ingredients in the composition will vary with the nature of and the severity of the condition to be treated and with the particular active ingredient or active ingredients in the composition and its route of administration. It will also vary according to the age, weight and response of the individual patient.
• the combined unit dose of the therapeutic agents sacubitril and valsartan together in the pharmaceutical composition will be in the range from about 1 to about 1000 mg, such as 40 mg to 400 mg (e.g., 50 mg, 100 mg, 200 mg, 400 mg).
• compositions with lower doses may be prepared, for example combined unit doses of 0.5 to 100 mg; 0.5 to 50 mg; or 0.5 to 20 mg of sacubitril and valsartan.
• sacubitril and valsartan in a 1 :1 molar ratio are presented in the form of 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
• a unit dose of for example 100 mg LCZ696 delivers 100 mg of the two agents sacubitril and valsartan (i.e.
• a unit dose of 50 mg LCZ696 requires 56.6 mg
• a unit dose of 200 mg LCZ696 requires 226.2 mg
• a unit dose of 400 mg LCZ696 requires 452.4 mg of 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, respectively.
• compositions as used in the current invention can be administered any number of times per day, i.e. once a day (q.d.), twice (b.i.d.), three times, four time, etc. in an immediate release formation or less frequently as an extended or sustained release formation.
• the pharmaceutical composition is administered twice daily (b.i.d.).
• Corresponding doses may be taken, for example, in the morning, at mid-day or in the evening.
• the pharmaceutical composition is administered to deliver a daily overall dose of the combination of sacubitril and valsartan in a 1 : 1 molar ratio from about 50 mg to about 1000 mg, in particular to about 400 mg, or to about 200 mg.
• the pharmaceutical composition is administered to deliver the combination of sacubitril and valsartan in a 1 :1 molar ratio twice daily (b.i.d.) with a dose of 50 mg, 100 mg, or 200 mg.
• the combination of sacubitril and valsartan in a 1 :1 molar ratio is administered to the patient twice daily with an individual dose of 50 mg, 100 mg, or 200 mg, totaling to a daily dose of 100 mg, 200 mg or 400 mg, respectively.
• the 50 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to 24 mg sacubitril and 26 mg valsartan
• the 100 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to 49 mg sacubitril and 51 mg valsartan
• the 200 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to 97 mg sacubitril and 103 mg valsartan.
• the combination of sacubitril and valsartan in a 1 :1 molar ratio is delivered in the form of the compound 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, wherein
• the present invention relates to the following embodiments:
• Embodiment 1 is a diagrammatic representation of Embodiment 1 :
• a method of treating heart failure with reduced ejection fraction in a patient comprising administering to said patient in need thereof sacubitril and valsartan in a 1 :1 molar ratio, wherein treatment is initiated shortly after an acute decompensation heart failure episode of said patient, wherein the term shortly refers to a time period starting with medical stabilization after the end of acute heart failure treatment and up to and including 14 days after an acute decompensation heart failure episode.
• Embodiment 2 is a diagrammatic representation of Embodiment 1:
• a method according to Embodiment 1 wherein the treatment is initiated while the patient is still hospitalized due to the acute decompensation heart failure episode.
• Embodiment 3 is a diagrammatic representation of Embodiment 3
• Embodiment 4 is a diagrammatic representation of Embodiment 4:
• Embodiment 5 is a diagrammatic representation of Embodiment 5:
• Embodiment 6 is a diagrammatic representation of Embodiment 6
• Embodiment 7 is a diagrammatic representation of Embodiment 7:
• a method according to Embodiment 6, wherein the hemodynamically stable patient is characterized by (i) a systolic blood pressure 3100 mm Hg during 6 hours before initiation of treatment, (ii) no increase in IV diuretics or use of IV vasodilators during 6 hours before initiation of treatment, and (iii) no IV inotropes administered during 24 hours before initiation of treatment.
• Embodiment 8 is a diagrammatic representation of Embodiment 8
• an elevated plasma BNP or NT-proBNP level preferably a plasma BNP 3100 pg/mL or NT-proBNP 3400 pg/mL, more preferably a plasma BNP 3150 pg/mL or NT-proBNP 3600 pg/mL, even more preferably a plasma BNP 3450 pg/mL or NT-proBNP 31600 pg/mL, or
• LVEF left ventricular ejection fraction
• Embodiment 9 is a diagrammatic representation of Embodiment 9:
• a method according to Embodiment 8 wherein the patient suffers from heart failure with reduced ejection fraction classified as NYHA class II, III or IV and wherein the patient has a reduced left ventricular ejection fraction (LVEF) of £40%.
• LVEF left ventricular ejection fraction
• Embodiment 10 is a diagrammatic representation of Embodiment 10:
• Embodiment 1 A method according to any one of Embodiments 1 to 9, wherein the patient has been diagnosed as suffering from heart failure with reduced ejection fraction prior to said acute decompensation heart failure episode mentioned in Embodiment 1.
• Embodiment 11 is a diagrammatic representation of Embodiment 11 :
• Embodiment 12 is a diagrammatic representation of Embodiment 12
• Embodiment 1 A method according to any one of Embodiments 1 to 11 , wherein the patient has not received an ACEI or ARB or both for at least 4 weeks prior to said acute decompensation heart failure episode mentioned in Embodiment 1.
• Embodiment 13 is a diagrammatic representation of Embodiment 13:
• Embodiment 1 A method according to any one of Embodiments 1 to 11 , wherein the patient is an ACEI /ARB naive patient not having received an ACEI or ARB or both prior to said acute decompensation heart failure episode mentioned in Embodiment 1.
• Embodiment 14 A method according to any one of Embodiments 1 to 13, wherein the patient achieves a target dose of 200 mg of sacubitril and valsartan in a 1 :1 molar ratio b.i.d..
• Embodiment 15 is a diagrammatic representation of Embodiment 15:
• Embodiment 16 is a diagrammatic representation of Embodiment 16:
• Embodiment 17 is a diagrammatic representation of Embodiment 17:
• Embodiment 18 is a diagrammatic representation of Embodiment 18:
• Embodiment 19 is a diagrammatic representation of Embodiment 19:
• a method according to Embodiment 18, wherein the starting dose of 50 mg of sacubitril and valsartan in a 1 :1 molar ratio b.i.d. is used in a patient not taking an ACEI or ARB before initiation of treatment.
• Embodiment 20 is a diagrammatic representation of Embodiment 20.
• a method according to Embodiment 18, wherein the starting dose of 50 mg of sacubitril and valsartan in a 1 :1 molar ratio b.i.d. is used in a patient taking low doses of an ACEI or ARB before initiation of treatment.
• Embodiment 21 is a diagrammatic representation of Embodiment 21 :
• Embodiment 22 A method according to Embodiment 18, wherein the starting dose of 50 mg of sacubitril and valsartan in a 1 :1 molar ratio b.i.d. is used in a patient with moderate renal impairment (eGFR 30-60 ml/min/1.73 m 2 ) before initiation of treatment.
• moderate renal impairment eGFR 30-60 ml/min/1.73 m 2
• Embodiment 23 is a diagrammatic representation of Embodiment 23.
• Embodiment 24 is a diagrammatic representation of Embodiment 24.
• Embodiment 25 is a diagrammatic representation of Embodiment 25.
• Embodiment 26 is a diagrammatic representation of Embodiment 26.
• Embodiment 27 is a diagrammatic representation of Embodiment 27.
• a method according to any one of Embodiments 1 to 26, wherein sacubitril and valsartan in a 1 :1 molar ratio refers to a combination of a 1 :1 molar ratio of
• Embodiment 28 is a diagrammatic representation of Embodiment 28:
• Ai is valsartan in the dianionic form
• a 2 is sacubitril in the anionic form
• Na + is a sodium ion
• x is 0.5 to 7.
• Embodiment 29 A method according to Embodiment 27 or 28, wherein sacubitril and valsartan in a 1 :1 molar ratio is provided in the form of the compound of the formula (I), wherein x is 0.5 to
• Embodiment 30 is a diagrammatic representation of Embodiment 30.
• Embodiment 31
• a method according to any one of Embodiments 27 to 30, wherein sacubitril and valsartan in a 1 :1 molar ratio is provided in the form of the compound of the formula (I), which is 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.
• Embodiment 32 is a diagrammatic representation of Embodiment 32.
• a method according to any one of Embodiments 1 to 31 wherein the patient receives a base treatment with a stable dose of a beta-blocker, an aldosterone antagonists, and/ or a diuretic.
• Embodiment 33 is a diagrammatic representation of Embodiment 33.
• a method according to any one of Embodiments 1 to 31 wherein sacubitril and valsartan in a 1 :1 molar ratio has been shown to reduce the clinical composite endpoint of death, rehospitalization for HF, LVAD implantation, or listing for cardiac transplant.
• Embodiment 34 is a diagrammatic representation of Embodiment 34.
• Embodiment 35 is a diagrammatic representation of Embodiment 35.
• a method according to Embodiment 34 wherein sacubitril and valsartan in a 1 :1 molar ratio is at least 10%, preferably at least 15%, preferably at least 20%, more effective than a medicament comprising a therapeutically effective amount of enalapril in reducing the clinical composite endpoint of death, rehospitalization for HF, LVAD implantation, or listing for cardiac transplant.
• Embodiment 36 is a diagrammatic representation of Embodiment 36.
• Embodiment 37 is a diagrammatic representation of Embodiment 37.
• Embodiment 36 wherein the statistical superiority is expressed as a relative risk reduction rate of sacubitril and valsartan in a 1 :1 molar ratio compared with enalapril of at least 40%.
• Embodiment 38 is a diagrammatic representation of Embodiment 38.
• a method according to Embodiment 36 wherein the statistical superiority is expressed as an absolute risk reduction rate of sacubitril and valsartan in a 1 :1 molar ratio compared with enalapril of at least 5%, preferably at least 7%.
• Embodiment 1 b
• Sacubitril and valsartan in a 1 :1 molar ratio for use in a method of treating heart failure with reduced ejection fraction in a patient comprising, wherein treatment is initiated shortly after an acute decompensation heart failure episode of said patient, wherein the term shortly refers to a time period starting with medical stabilization after the end of acute heart failure treatment and up to and including 14 days after an acute decompensation heart failure episode.
• Embodiment 2b is a diagrammatic representation of Embodiment 2b.
• Embodiment 3b is a diagrammatic representation of Embodiment 3b.
• Embodiment 4b is a diagrammatic representation of Embodiment 4b.
• Embodiment 5b is a diagrammatic representation of Embodiment 5b.
• Embodiment 6b Sacubitril and valsartan in a 1 :1 molar ratio for use according to any one of Embodiments 1 b to 4b, wherein the patient is hemodynamically stable.
• Sacubitril and valsartan in a 1 :1 molar ratio for use according to Embodiment 5b wherein the hemodynamically stable patient is characterized by at least one of the following (i) a systolic blood pressure 3100 mm Hg during 6 hours before initiation of treatment, (ii) no increase in IV diuretics or use of IV vasodilators during 6 hours before initiation of treatment, or (iii) no IV inotropes administered during 24 hours before initiation of treatment.
• Embodiment 7b is a diagrammatic representation of Embodiment 7b.
• Sacubitril and valsartan in a 1 :1 molar ratio for use according to Embodiment 6b wherein the hemodynamically stable patient is characterized by (i) a systolic blood pressure 3100 mm Hg during 6 hours before initiation of treatment, (ii) no increase in IV diuretics or use of IV vasodilators during 6 hours before initiation of treatment, and (iii) no IV inotropes administered during 24 hours before initiation of treatment.
• Embodiment 8b is a diagrammatic representation of Embodiment 8b.
• an elevated plasma BNP or NT-proBNP level preferably a plasma BNP 3100 pg/mL or NT-proBNP 3400 pg/mL, more preferably a plasma BNP 3150 pg/mL or NT-proBNP 3600 pg/mL, even more preferably a plasma BNP 3450 pg/mL or NT-proBNP 31600 pg/mL, or
• LVEF left ventricular ejection fraction
• Embodiment 9b is a diagrammatic representation of Embodiment 9b.
• LVEF left ventricular ejection fraction
• Embodiment 10b is a diagrammatic representation of Embodiment 10b.
• Embodiment 11b Sacubitril and valsartan in a 1 :1 molar ratio for use according to any one of Embodiments 1 b to 9b, wherein the patient is a de novo patient not having been diagnosed as suffering from heart failure with reduced ejection fraction prior to said acute decompensation heart failure episode mentioned in Embodiment 1b.
• Embodiment 12b is a diagrammatic representation of Embodiment 12b.
• Embodiment 13b is a diagrammatic representation of Embodiment 13b.
• Embodiment 14b is a diagrammatic representation of Embodiment 14b.
• Embodiment 15b is a diagrammatic representation of Embodiment 15b.
• Embodiment 16b is a diagrammatic representation of Embodiment 16b.
• Embodiment 17b is a diagrammatic representation of Embodiment 17b.
• Embodiment 18b is a diagrammatic representation of Embodiment 18b.
• Embodiment 19b is a diagrammatic representation of Embodiment 19b.
• Embodiment 20b is a diagrammatic representation of Embodiment 20b.
• Embodiment 21b is a diagrammatic representation of Embodiment 21b.
• Sacubitril and valsartan in a 1 :1 molar ratio for use according to Embodiment 18b wherein the starting dose of 50 mg of sacubitril and valsartan in a 1 :1 molar ratio b.i.d. is used in a patient with moderate hepatic impairment (Child-Pugh grade B classification), or with AST/ALT values more than twice the upper limit of the normal range before initiation of treatment.
• Embodiment 22b is a diagrammatic representation of Embodiment 22b.
• Sacubitril and valsartan in a 1 :1 molar ratio for use according to Embodiment 18b wherein the starting dose of 50 mg of sacubitril and valsartan in a 1 :1 molar ratio b.i.d. is used in a patient with moderate renal impairment (eGFR 30-60 ml/min/1.73 m 2 ) before initiation of treatment.
• moderate renal impairment eGFR 30-60 ml/min/1.73 m 2
• Embodiment 23b is a diagrammatic representation of Embodiment 23b.
• Sacubitril and valsartan in a 1 :1 molar ratio for use according to Embodiment 14b wherein the target dose is reached after a titration from a starting dose of 100 mg of sacubitril and valsartan in a 1 :1 molar ratio b.i.d. increasing to the target dose during an up-titration period of from about 2 to about 10 weeks.
• Embodiment 24b is a diagrammatic representation of Embodiment 24b.
• Embodiment 25b is a diagrammatic representation of Embodiment 25b.
• Embodiment 26b Sacubitril and valsartan in a 1 :1 molar ratio for use according to Embodiment 25b, wherein the up-titration period is from about 2 to about 4 weeks.
• Embodiment 27b is a diagrammatic representation of Embodiment 27b.
• Embodiment 28b is a diagrammatic representation of Embodiment 28b.
• Ai is valsartan in the dianionic form
• a 2 is sacubitril in the anionic form
• Na + is a sodium ion
• x is 0.5 to 7.
• Embodiment 29b is a diagrammatic representation of Embodiment 29b.
• Embodiment 30b is a diagrammatic representation of Embodiment 30b.
• Embodiment 31b is a diagrammatic representation of Embodiment 31b.
• the compound of the formula (I) is trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3- ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)
• Embodiment 32b Sacubitril and valsartan in a 1 :1 molar ratio for use according to any one of Embodiments 1 b to 31b, wherein the patient receives a base treatment with a stable dose of a beta- blocker, an aldosterone antagonists, and/ or a diuretic.
• Embodiment 33b is a diagrammatic representation of Embodiment 33b.
• Embodiment 34b
• Embodiment 35b is a diagrammatic representation of Embodiment 35b.
• Sacubitril and valsartan in a 1 :1 molar ratio for use according to Embodiment 34b wherein sacubitril and valsartan in a 1 :1 molar ratio is at least 10%, preferably at least 15%, preferably at least 20%, more effective than a medicament comprising a therapeutically effective amount of enalapril in reducing the clinical composite endpoint of death, rehospitalization for HF, LVAD implantation, or listing for cardiac transplant.
• Embodiment 36b is a diagrammatic representation of Embodiment 36b.
• Embodiment 37b
• Embodiment 38b is a diagrammatic representation of Embodiment 38b.
• Sacubitril and valsartan in a 1 :1 molar ratio for use according to Embodiment 36b wherein the statistical superiority is expressed as an absolute risk reduction rate of sacubitril and valsartan in a 1 : 1 molar ratio compared with enalapril of at least 5%, preferably at least 7%.
• All the aforementioned enumerated embodiments relating to the methods of treatment or to sacubitril and valsartan in a 1 : 1 molar ratio for use in the treatment according to the present invention are equally applicable to
• a pharmaceutical composition comprising sacubitril and valsartan in a 1 : 1 molar ratio, and one or more pharmaceutically acceptable carriers, for use in the treatment according to the present invention.
• LCZ696 refers to the supramolecular complex 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.
• This compound and pharmaceutical compositions thereof have been previously disclosed in
• TRANSITION (NCT02661217) is a randomized, parallel, open-label study comparing pre- and post-discharge (1-14 days) initiation of LCZ696 in patients with HFrEF, New York Heart Association (NYHA) class 11— IV, left-ventricular ejection fraction (LVEF) £40% following hemodynamic stabilization after an episode of ADHF, including patients with newly diagnosed HF (Pascual Figal D, et al. ESC Heart Fail 2018;5(2):327-368).
• the study design comprises three Epochs (phases): the Screening Epoch; the Treatment Epoch defined as 10 weeks after Randomization; and 16-week Follow-up Epoch.
• Patients were stratified into three groups based on their pre-admission treatment status: (a) receiving an angiotensin-converting enzyme inhibitor (ACEI), (b) receiving an angiotensin receptor blocker (ARB), or (c) ACEI/ARB-naive patients. Patients were randomized 1 :1 within each stratum for initiation of LCZ696 treatment either pre- or post-discharge (see Figure 1).
• the study population consists of patients hospitalized for an episode of acute
• the TRANSITION study population represents a broad spectrum of HFrEF patients hospitalized due to an ADHF event who are stabilized and about to be discharged similar to the population in everyday clinical practice, including patients with new-onset (de novo) HFrEF and ACEI/ARB naive patients.
• the recommended starting dose of LCZ696 was 100 mg b.i.d..
• ACE angiotensin-converting enzyme
• ARB angiotensin II receptor blocker
• the dose of LCZ696 was doubled every 2-4 weeks to achieve the target dose of 200 mg twice daily, as tolerated by the patient.
• the basis for up-titration toward the target dose was taking into consideration tolerability (i.e. , incidence of hypotension, renal or hepatic impairment and hyperkalemia) based on clinical evaluation and laboratory assessment. In case of patients experiencing tolerability issues, (a) adjusting concomitant medications, or (b) temporary down-titration, or (c) temporary or permanent discontinuation of LCZ696 was considered.
• tolerability i.e. , incidence of hypotension, renal or hepatic impairment and hyperkalemia
• the primary endpoint is the proportion of patients achieving the target dose of 200 mg LCZ696 b.i.d. at 10 weeks’ post-randomization.
• the median time from admission to first dose of study drug was 7 days in the pre discharge group and 10 days in the post-discharge group. Median time from
• IQR 2-6 days in pre-discharge and post-discharge groups, respectively.
• the median time from discharge to the first dose was -1 day in the pre-discharge group (IQR -2 to -1 days) and 1 day in the post-discharge group (IQR 1-4 days).
• a lower 24/26 mg bid starting dose was chosen by the investigators in 436 (88.4%) patients in the pre-discharge, and in 413 (84.5%) patients in the post-discharge group.
• a multivariate logistic regression model was developed to identify baseline predictors of successful up-titration to LCZ696 200 mg b.i.d. target dose at the end of 10-week treatment. Odd ratios along with the 95% confidence intervals were constructed to identify those with high likelihood of achieving the target dose (see Figure 5).
• significant (P ⁇ 0.05) predictors of target-dose attainment within 10 weeks were age ⁇ 65 years, SBP 3120mmHg at baseline, history of hypertension, de novo HF, no atrial fibrillation at baseline, estimated glomerular filtration rate 360 ml_/min/1.73m2 at randomisation, and a sacubitril/valsartan starting dose of 49/51 mg bid.
• ACEI angiotensin converting-enzyme inhibitor
• ARB angiotensin receptor blocker
• PIONEER-HF NCT02554890 is a prospective, multicenter, double-blind, randomized, active-controlled trial, designed to assess the efficacy, safety and tolerability of LCZ696 in patients hospitalized for acute HFrEF.
• NT-proBNP N- terminal-pro b-type natriuretic peptide
• Acute coronary syndrome stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within one month prior to Visit 1.
• PCI percutaneous coronary intervention
• Pregnant or nursing (lactating) women where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
• Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods
• N-terminal pro-brain natriuretic peptide NT- proBNP
• the primary objective of this study is to assess the effect of in-hospital initiation of LCZ696 vs. enalapril on the time-averaged percentage change of NT-proBNP from baseline in patients who have been stabilized following hospitalization for ADHF and reduced ejection fraction (left ventricular ejection fraction [LVEF] £ 40%) between week 4 and 8.
• Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, including the genitalia and intestines.
• Patients were enrolled a median (25th, 75th) of 68 (48, 98) hours from initial presentation. HF signs and symptoms were highly prevalent at the time of randomization with 61.7% having peripheral edema and 32.9% with lung rales. Baseline characteristics, including demographics, clinical findings, medication history, and index hospitalization details were similar between the 2 treatment groups. Patients mean age was 61 ⁇ 14 years, 635 (72%) were male, and 316 (36%) self-identified as black. The index hospitalization was the first diagnosis of HF for 303 (34%) patients.
• the median SBP was 118 (110, 132) mm Hg and 23% patients had a SBP ⁇ 110 mm Hg.
• the baseline median LVEF was 0.25 (0.20, 0.30) and the median serum creatinine at baseline was 1.28 (1.06, 1.51) mg/dL.
• the screening local laboratory median NT-proBNP was 4812 (3050, 8745) pg/mL and median BNP was 1063 (718, 1743) pg/mL. At randomization, the majority of patients (85%) were treated with loop diuretic.
• index hospitalization During the index hospitalization and prior to randomization, 814 (93%) patients received intravenous furosemide therapy, 97 (11%) received care in an intensive care unit, and 68 (7.7%) required an intravenous inotrope. The median duration of the index hospitalization was 5.20 (4.09, 7.24) days.
• NT-proBNP levels declined in both treatment arms, with a significantly greater reduction in patients receiving LCZ696 compared with enalapril (LCZ696 vs. enalapril ratio of time- averaged change from baseline to the geometric mean of weeks 4 and 8: 0.71 , 95% Cl 0.63 to 0.81 ; p ⁇ .001) ( Figure 9 and 10, Table 8).
• the greater reduction in NT-proBNP concentration by LCZ696 treatment was apparent as early as week 1 (0.76, 95% Cl 0.69 to 0.85; p ⁇ .001) and at every subsequent visit.
• hsTn cardiac troponin
• sST2 soluble ST2
• HF heart failure
• Circulating hsTnT, sST2, and urinary cGMP at baseline, 1 , 2 (sST2, cGMP), 4, and 8 weeks (n 694 with all baseline biomarkers) were measured. Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril.
• the PIONEER-HF trial was performed to evaluate the use of a neprilysin inhibitor added to a renin-angiotensin system inhibitor, as compared with a renin-angiotensin system inhibitor alone, in the treatment of patients who were hospitalized for acute heart failure.
• the initiation of sacubitril-valsartan therapy after hemodynamic stabilization led to a greater reduction in the NT-proBNP concentration than enalapril therapy, a difference that was evident by the first week.
• results of the PIONEER-HF trial extend the evidence base regarding the use of sacubitril-valsartan to populations for which there had been limited or no data, including patients who are hospitalized for acute decompensated heart failure, patients who have new heart failure, patients who have not been exposed to high doses of guideline-directed medications for heart failure, and patients who are not receiving conventional renin- angiotensin system inhibitors.
• 35.9% of the patients in our trial identified as black, and there is limited evidence from previous clinical studies regarding the use of sacubitril-valsartan among black patients.
• the PIONEER-HF trial made use of the lowest starting dose of sacubitril-valsartan (24 mg of sacubitril with 26 mg of valsartan), with which there was less experience.
• PIONEER-HF trial set specific requirements for the in-hospital initiation of sacubitril- valsartan therapy.
• Patients were required to have had a systolic blood pressure of at least 100 mm Hg for the preceding 6 hours, with no increase in the dose of intravenous diuretics and no use of intravenous vasodilators during the preceding 6 hours and no use of intravenous inotropes during the preceding 24 hours.
• Sacubitril-valsartan therapy was initiated at a low dose among patients with lower systolic blood pressure, and the dose was adjusted according to a prespecified algorithm.
• a washout period of 36 hours was used to ensure that patients who had previously been taking an ACE inhibitor or ARB did not have any overlapping medication effects. Despite these precautions, approximately 20% of the patients in each treatment group had discontinued treatment by 8 weeks, in most cases because of an adverse event.
• sacubitril-valsartan therapy resulted in a significantly greater reduction in the NT-proBNP concentration than enalapril therapy.
• sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers (hsTnT, sST2, and urinary cGMP), with an onset that is apparent within 1-4 weeks.

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