WO2017006254A1 - Combinaison de médicaments comprenant un antagoniste du récepteur de l'angiotensine ii, un inhibiteur d'endopeptidase neutre et un antagoniste du récepteur de minéralocorticoïdes - Google Patents

Combinaison de médicaments comprenant un antagoniste du récepteur de l'angiotensine ii, un inhibiteur d'endopeptidase neutre et un antagoniste du récepteur de minéralocorticoïdes Download PDF

Info

Publication number
WO2017006254A1
WO2017006254A1 PCT/IB2016/054039 IB2016054039W WO2017006254A1 WO 2017006254 A1 WO2017006254 A1 WO 2017006254A1 IB 2016054039 W IB2016054039 W IB 2016054039W WO 2017006254 A1 WO2017006254 A1 WO 2017006254A1
Authority
WO
WIPO (PCT)
Prior art keywords
combination
sacubitril
valsartan
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/IB2016/054039
Other languages
English (en)
Inventor
Markus ROHRWILD
Patrice Tinaye MATCHABA
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Publication of WO2017006254A1 publication Critical patent/WO2017006254A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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

Definitions

  • the invention relates to a combination of an Angiotensin II Receptor Antagonist (ARB), a 5 Neutral Endopeptidase inhibitor (NEP inhibitor) or prodrug thereof and of a
  • MR antagonist Mineralcorticoid Receptor antagonist
  • BB Beta Blocker
  • CHF Chronic heart failure
  • US United States
  • HF heart failure
  • US United States
  • HF heart failure
  • US United States
  • HF heart failure
  • HF heart failure
  • HF is responsible for more hospitalizations than all forms of cancer combined and is the leading cause of hospitalization in patients older than 65 years of age.
  • In-hospital mortality is excessive and readmission is distressingly common. Frequent hospitalizations, along with other direct and indirect costs, also place0 an enormous financial burden on healthcare systems.
  • HF left ventricular ejection fraction
  • LVEF left ventricular ejection fraction
  • therapies targeted at improving outcomes in HF with a low EF have been well studied over the past two decades, leading to an improvement in survival as5 well as a decrease in morbidity, mostly in the form of decrease in re-hospitalization for HF, with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), ⁇ -blockers and mineralocorticoid antagonists.
  • ACE angiotensin converting enzyme
  • ARBs angiotensin receptor blockers
  • ⁇ -blockers mineralocorticoid antagonists.
  • Valsartan Heart Failure Trial (Val-HeFT), a randomized, placebo-controlled, double-blind, parallel-group trial [N Engl J Med 2001 ; 345:1667-1675], showed the following: The primary outcomes0 were mortality and the combined end point of mortality and morbidity, defined as the
  • valsartan had a favorable effect in patients receiving neither or one of these types of drugs but an adverse effect in patients receiving both types of drugs.
  • ACE angiotensin-converting-enzyme
  • ARB Angiotensin II Receptor Antagonist
  • NEP inhibitor Neutral Endopeptidase inhibitor
  • MR antagonist Mineralcorticoid Receptor antagonist
  • BB Beta Blocker
  • Valsartan (CAS number 137862-53-4) is an Angiotensin II Receptor Antagonist (ARB) with the name N-(1 -oxopentyl)-N-[2'-(1 -tetrazol-5-yl)methyl]-valine. It has the formula:
  • Valsartan its manufacture, salts thereof and other properties are e.g. disclosed in
  • ARB useful in combinations according to the invention are losartan, irbesartan, telmisartan, eprosartan, candesartan, olmesartan, saprisartan, tasosartan, elisartan, or combinations of two or more of the ARB mentioned so far.
  • AHU377 (sacubitril; CAS number 149709-62-6) is a prodrug for an NEP inhibitor that is well known, it has the chemical name /V-(3-carboxyl-1 -oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester and the formula:
  • Sacubitril is a prodrug for the NEP inhibitor (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionyl amino)-2-methyl-pentanoic acid (also known as LBQ657 or sacubitrilate) that is formed from the prodrug in vivo.
  • NEP inhibitors or prodrugs thereof could also be potentially useful in combinations according to the invention. Also combinations of two or more NEP inhibitors could be potentially useful.
  • Finerenone (CAS number 1050477-31 -0; also known as BAY 94-8862) is an oral, non-steroidal Mineralcorticoid Receptor antagonist which is capable of blocking the deleterious effects of aldosterone, allowing to achieve decreased cardiovascular mortality especially in patients with heart failure.
  • the compound is currently in clinical development for the treatment of worsening chronic heart failure and diabetic nephropathy. It has the chemical name (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1 ,4-dihydro-1 ,6- naphthyridine-3-carboxamide; and the formula:
  • MR antagonists are eplerenone, or further prorenone, mexrenone, canrenone or spironolactone, which may also be combination partners according to the present invention, or combinations of two or more of the MR antagonists mentioned so far.
  • beta blockers such as acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nadolol, propranolol, sotalol and timolol might form a further component of the combination of the invention.
  • valsartan or a pharmaceutically acceptable salt thereof is preferably a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and finerenone, or a pharmaceutically acceptable salt thereof.
  • a special embodiment of the invention relates to a (based on the molar ratio of the free form of the respective compound) 1 :1 to 5:1 , especially a 1 :1 , combination of valsartan and sacubitril together with finerenone, which finerenone may for example be present in the combination in a molar amount of 0.05 to 10 mol per mol of valsartan, where any one or more of the three combination partners is present in free form or as a pharmaceutically acceptable salt thereof; in the case of sacubitril, the calcium or sodium salt are especially preferred.
  • Another special embodiment of the invention relates to a combination of (i) a compound (or salt complex) of the formula II ,
  • Ai is valsartan in the anionic form
  • a 2 is sacubitril in the anionic form
  • Na + is a sodium ion
  • y is 1 to 3;
  • x 0 to 3
  • said compound of the formula II is preferably 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 (also known as LCZ696; CAS number 936623-90-4; or trisodium sacubitril valsartan hemipentahydrate); and
  • the compound (salt complex or supramolecular complex) of the formula I I is, for example, disclosed in WO 2007/056546 A, together with the manufacture and use thereof.
  • a combination according to the invention can be shown to be of use in the treatment of a cardiovascular disorder or condition, especially to significantly prevent or delay time to first occurrence of mortality, in particular of cardiovascular mortality, and/or of cardiovascular hospitalizations, in particular hospitalizations for heart failure, in patients suffering from chronic systolic heart failure, for example in such patients with reduced ejection fraction .
  • Preferred is a therapeutically effective amount.
  • a combination according to the invention is useful in the prevention or delay or treatment of HF, especially as defined in the preceding paragraph .
  • prevention refers to prophylactic administration to a healthy subject to prevent the development of the conditions mentioned herein . Moreover, the term “prevention” means prophylactic administration to patients being in a pre-stage of the conditions to be treated.
  • treatment is understood the management and care of a patient for the purpose of combating the disease, condition or disorder.
  • therapeutically effective amount refers to an amount of a drug or a therapeutic agent 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 include, but are not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits and mice.
  • the preferred patients are humans.
  • prophylactically effective amount means the amount of the active compounds in the composition that will elicit the biological or medical response in a tissue, system, subject, or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, to prevent the onset of a disease characterized and / or manifested by atrial enlargement and/or remodeling.
  • 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.
  • Cardiovascular death and heart failure hospitalization both reflect disease-specific endpoints related to progressive worsening of the heart failure syndrome, and experienced by patients with systolic heart failure. These endpoints can be modified by treatments improving this condition, which has generally proved to be the case with drugs such as ACEIs, aldosterone antagonists, and ⁇ -blockers as well as devices for cardiac resynchronization therapy.
  • drugs such as ACEIs, aldosterone antagonists, and ⁇ -blockers as well as devices for cardiac resynchronization therapy.
  • 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 24.1 1 , NEP) inhibitor (NEPi) prodrug which is converted to the active form LBQ657 (2R,
  • Neprilysin (NEP) inhibition will expose subjects to enhanced levels of the physiologically active natriuretic peptides (NPs), including atrial natriuretic peptide (ANP).
  • NPs physiologically active natriuretic peptides
  • NPR- A natriuretic peptide receptor A
  • cGMP second messenger cyclic GMP
  • RAAS renin angiotensin aldosterone system
  • RAAS renin angiotensin aldosterone system
  • the angiotensin receptor blocker (ARB) blockade is specific and competitive at the angiotensin type 1 (AT1 ) receptor that mediates the deleterious effects of angiotensin II on the cardiovascular system.
  • LCZ696 provides concomitant NEP inhibition and AT1 blockade, which are considered to act complementary. Thus, LCZ696 may deliver clinical benefits to patients with cardiovascular disease, including heart failure and hypertension, in which vasoconstriction, volume expansion, and target organ damage play a key role in pathophysiology.
  • the compounds and pharmaceutical compositions disclosed herein include combinations of sacubitril and valsartan which compounds or pharmaceutical compositions thereof have been previously disclosed in WO 2003/059345, WO 2007/056546, WO 2009/061713, and WO2014029848, which are herein incorporated by reference.
  • the term "sacubitril and valsartan in a 1 :1 molar ratio” in particular refers to an Angiotensin Receptor Neprilysin inhibitor (ARNi) which is a combination comprising a therapeutically effective amount of a 1 :1 molar ratio of
  • the term "sacubitril and valsartan in a 1 :1 molar ratio” in particular refers to an Angiotensin Receptor Neprilysin inhibitor (ARNi) which 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 (LCZ696).
  • ARNi Angiotensin Receptor Neprilysin inhibitor
  • the invention encompasses a method for the treatment of chronic heart failure in patient with systolic dysfunction, comprising administering to said patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a combination of the inventtion as described hereinbefore and hereinafter.
  • the invention also encompasses a method for preventing or delaying time to first occurrence of mortality, in particular of cardiovascular mortality, cardiovascular
  • hospitalizations in particular hospitalizations for heart failure or the combination thereof in a patient suffering from chronic systolic heart failure, in particular heart failure with reduced ejection fraction, comprising administering to said patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a combination of the invention as described hereinbefore and hereinafter.
  • the invention encompasses a method for reducing the rate of cardiovascular death or heart failure hospitalization or a combination thereof in patients with chronic heart failure with systolic dysfunction, comprising administering to said patient in need thereof a therapeutically effective amount of a combination of the invention as described hereinbefore and hereinafter.
  • the patient suffering from chronic systolic heart failure in particular the patient with chronic systolic heart failure with reduced ejection fraction, has at least one of the following characteristics:
  • an elevated plasma BNP or NT-proBNP level preferably a plasma BNP >100 pg/mL (or NT-proBNP >400 pg/mL), more preferably a plasma BNP >150 pg/mL or NT-proBNP >600 pg/mL, and
  • LVEF left ventricular ejection fraction
  • the patient might be characterized by one or more of the following: iv) prior hospitalization for heart failure within the last 12 months,
  • the patient has heart failure classified as NYHA class II, III or IV and has systolic dysfunction. In another embodiment the patient has heart failure classified as NYHA class II. In a further embodiment, the patient has heart failure classified as NYHA class II with systolic dysfunction and has a reduced left ventricular ejection fraction (LVEF) of ⁇ 35%.
  • LVEF left ventricular ejection fraction
  • the present invention provides that the therapeutically effective amount the combination according to the invention is effective to prevent or delay time to first occurrence of cardiovascular hospitalization, preferably wherein the cardiovascular hospitalization is hospitalization for heart failure, non-fatal myocardial infarction, non-fatal stroke, or resuscitated sudden death, in particular hospitalization for heart failure, more particularly first hospitalization for worsening heart failure.
  • cardiovascular hospitalization is hospitalization for heart failure, non-fatal myocardial infarction, non-fatal stroke, or resuscitated sudden death, in particular hospitalization for heart failure, more particularly first hospitalization for worsening heart failure.
  • the present invention provides that the therapeutically effective amount of a combination according to the invention is effective to prevent or delay time to first occurrence of mortality, in particular cardiovascular mortality.
  • the mortality is a sudden death.
  • the therapeutically effective amount of a combination according to the invention has been shown to reduce the rate of cardiovascular death, or to reduce the rate of heart failure hospitalization or to reduce the rate of cardiovascular death and the rate of heart failure hospitalization.
  • the therapeutically effective amount of compound of a combination according to the invention has been shown to reduce the rate of
  • LVEF left ventricular ejection fraction
  • the therapeutically effective amount of a combination according to the invention has been shown to reduce the rate of all-cause mortality.
  • the patient receives a base treatment with a stable dose of a beta-blocker, an aldosterone antagonists, and/ or a diuretic. In one embodiment thereof, the patient receives base treatment with a stable dose of a beta-blocker.
  • the patient when the combo of the invention does not comprise a beta blocker, the patient receives base treatment with a stable dose of a beta-blocker.
  • the present invention also provides that the therapeutically effective amount of a combination according to the invention is also effective to prevent or delay time to first occurrence of new onset atrial fibrillation.
  • the present invention also provides that the therapeutically effective amount of compound of a combination according to the invention is also effective to prevent or slow decline in estimated glomerular filtration rate (eGFR).
  • eGFR estimated glomerular filtration rate
  • the present invention also provides that the therapeutically effective amount of compound of formula (I) or of the combination also reduces the blood pressure of the patient
  • the present invention also provides that the therapeutically effective amount of a combination according to the invention is more effective in preventing or delaying time to first occurrence of mortality, in particular cardiovascular mortality, and/or of cardiovascular hospitalizations, in particular hospitalization for heart failure, in patients suffering from chronic systolic heart failure, in particular heart failure with reduced ejection fraction, compared to a therapeutically effective amount of finerenone, valsartan or sacubitril, or a pharmaceutically acceptable salt thereof, respectively, or to a combination of only two of these drugs.
  • the combination according to the present invention can also be useful in the treatment of metabolic syndrome, adiposity and obesity.
  • Adiposity or obesity are conditions defined as abnormal or excessive fat accumulation that may impair health. It results from imbalances in the body's regulation of energy intake, expenditure and storage.
  • Obesity is a public health issue in the United States with more than one third of the adult population being identified as obese. Obesity in children is also on the rise. Obesity is also associated with an increased risk of a variety of co-morbid conditions such as diabetes, atherosclerosis and hypertension. Obesity also is one of the leading risk factors for metabolic syndrome. Metabolic syndrome is a group of five risk factors that increase an individual's risk for heart disease and other health problems such as diabetes and stroke. The five conditions or risk factors are high blood pressure, low HDL cholesterol levels in blood, large waistline, high triglyceride levels in blood, and high fasting blood sugar.
  • Metabolic syndrome also called syndrome X
  • Metabolic syndrome X is becoming an increasingly common diagnosis as the obesity rates rise in the United States. People with the metabolic syndrome are also at increased risk for cardiovascular disease and for increased mortality from both cardiovascular disease and all causes. Accordingly, health professionals predict that, sometime in the near future, metabolic syndrome may overtake smoking as the leading risk factor for heart disease.
  • Metabolic syndrome is a complex syndrome which can be associated with several of following criteria such as resistance to insulin-stimulated glucose uptake, glucose intolerance, hyperinsulinemia, increase LDL-cholesterol, increased VLDL triglycerides, decreased HDL cholesterol, hypertriglyceridemia, and others.
  • the compound of formula (II) 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 (LCZ696).
  • a daily overall dose of LCZ696 from 50 mg to 400 mg is administered in a combination according to the present invention, taken in one or more separate intakes.
  • LCZ696 is administered twice or once daily with a dose of 50 mg, 100 mg, or 200 mg and finerenone is administered once or twice daily with a dose of 1 mg, 1 .25 mg, 2.5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 50 mg, 75 mg or 100 mg.
  • the patient is orally administered the combination according to the present invention in one or more, e.g. one or two separate intakes (b.i.d.) per day, each intake comprising 103 mg or less, e.g. down to 1 mg, of an ARB, especially valsartan, or a pharmaceutically acceptable salt thereof, and 97 mg or less, e.g. down to 1 mg, of a NEP inhibitor, especially sacubitril, or a pharmaceutically acceptable salt thereof, and 100 mg or 50 mg or less, e.g. down to 1 mg, of a MR antagonist, especially or a pharmaceutically acceptable salt thereof, and per dosage unit.
  • each intake comprising 103 mg or less, e.g. down to 1 mg, of an ARB, especially valsartan, or a pharmaceutically acceptable salt thereof, and 97 mg or less, e.g. down to 1 mg, of a NEP inhibitor, especially sacubitril, or a pharmaceutically acceptable salt thereof, and 100 mg or 50 mg or less, e
  • 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 400 mg plus the respective dose of finerenone from about 10 mg to about 100 mg.
  • pharmaceutical composition is administered to deliver the combination of sacubitril and valsartan in a 1 :1 molar ratio twice daily with a dose of 50 mg, 100 mg, or 200 mg.
  • 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-((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 (LCZ696), wherein
  • the combination of sacubitril and valsartan is administered twice daily (BID), whereas finerenone is only administered once daily (QID).
  • BID twice daily
  • QID finerenone
  • A) a pharmaceutical composition comprising sacubitril and valsartan in a 1 :1 molar ratio (as defined herein), and
  • B) a pharmaceutical composition comprising sacubitril and valsartan in a 1 :1 molar ratio (as defined herein) and finerenone.
  • a combination can be a non-fixed combination for separate, combined or partially combined use, meaning that the combination partners can be administered at the same point in time, or two at one point in time, another at a separate point in time, or all of the combination partners can be administered at different points in time, preferably in such a manner that the combination partners are jointly effective, meaning especially that they show more effect than when the combination partners are administered separately from each other in such intervals that no improved, especially synergistic, effect is shown in the use.
  • a combination can also be in the form of a kit, in which each one or two of the combination partners is included in a pharmaceutical formulation, while the one or more (e.g. two) other partners are included in a further pharmaceutical combination, but all combination partners are included in said kit, e.g one package unit, preferably including also instructions for a combined use according to the present invention.
  • a combination product may be a kit as just mentioned, or a fixed combination product including all (e.g. all three) combination partners (combination partners wherever mentioned referring to the ARB, NEP inhibitors or prodrugs thereof and MR antagonists, or pharmaceutically acceptable salts thereof, respectively).
  • the combination partners in any invention embodiment are preferably formulated or used to be jointly (prophylactically or especially therapeutically) active.
  • beneficial effect e.g. a mutual enhancing of the effect of the combination partners, in particular a synergism, e.g. a more than additive effect, additional advantageous effects (e.g. a further therapeutic effect not found for any of the single com- pounds), less side effects, a combined therapeutic effect in a non-effective dosage of one or two or all (e.g
  • jointly (therapeutically) active may mean that the compounds may be given separately or sequentially (in a chronically staggered manner, especially a sequence-specific manner) in such time intervals that they preferably, in the warmblooded animal, especially human, to be treated, and still show a (preferably synergistic) interaction (joint therapeutic effect), or simultaneously, or in any combination of these ways o administration.
  • a joint therapeutic effect can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals, but this is not to exclude the case where the compounds are jointly active although they are not present in blood simultaneously.
  • the present invention thus pertains to a combination product for simultaneous, separate or sequential use, such as a combined preparation or a pharmaceutical fixed combination, or a combination of such preparation and combination.
  • fixed combination means that the active ingredients are administered to a patient simultaneously in the form of a single entity or dosage.
  • the active ingredients are present in one dosage form, e.g. in one tablet or in one capsule.
  • non-fixed combination means that the active ingredients are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • non-fixed combination thus defines especially a "kit of parts" in the sense that the combination partners as defined herein can be dosed independently of each other or by use of different fixed combinations with distinguished amounts of the combination partners, i.e.
  • the combination partners may also be used as entirely separate pharmaceutical dosage forms or pharmaceutical formulations that are also sold independently of each other and just instructions of the possibility of their combined use is or are provided in the package equipment, e.g. leaflet or the like, or in other information e.g. provided to physicians and medical staff.
  • the independent formulations or the parts of the kit of parts can then, e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the combination partners, thus being jointly active.
  • the ratio of the total amounts and the total amounts of the combination partners to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to age, sex, body weight, etc. of the patients.
  • the combinations according to the invention 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 at least one pharmacologically active combination partner alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.
  • enteral such as oral or rectal
  • parenteral administration to mammals (warm-blooded animals), including man
  • one or more of the active ingredients are administered orally.
  • carrier or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g. , antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the pharmaceutical combination product according to the invention (as fixed combination, or as pharmaceutical product or kit, e.g. as combination of a fixed combination and individual formulations for one or both combination partners or as kit of individual formulations of the combination partners) comprises the combination partners and optionally one or more further co-agents of the present invention and one or more pharmaceutically acceptable carrier materials (carriers, excipients).
  • the combination products or the combination partners constituting it can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the combination products of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • the combination products and/or their combination partners can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
  • the active ingredient(s) forming part of a combination product according to the present invention can be present each in a relative amount of 0.5 to 95 % of weight of the corresponding formulation (regarding the formulation as such, that is without packaging and leaflet), e.g. from 1 to 90, 5 to 95, 10 to 98 or 10 to 60 or 40 to 80 % by weight, respectively.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.
  • a physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the invention also relates to the embodiments in the claims, especially the dependent claims, which are incorporated into the present description by reference as part of the original document.
  • Example 1 Fixed combination of sacubitril, valsartan and finerenone
  • Sacubitril sodium salt, valsartan and finerenone are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
  • Sacubitril calcium salt, valsartan and finerenone are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
  • Sacubitril calcium salt, valsartan calcium and finerenone are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
  • LCZ696 trisodium sacubitril valsartan hemipentahydrate
  • finerenone are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
  • Example 2 Clinical trial
  • LCZ696 refers to the supramolecular complex 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.
  • This compound and pharmaceutical compositions thereof have been previously disclosed in
  • LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that comprises the molecular moieties of the NEP (neutral endopeptidase EC 3.4.24.1 1) inhibitor pro-drug sacubitril (INN, also known as AHU377 and N-(3-carboxy-1 -oxopropyl)-(4S)-p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester) and the angiotensin receptor blocker valsartan as a single compound.
  • NEP neutral endopeptidase EC 3.4.24.1 1
  • pro-drug sacubitril INN, also known as AHU377 and N-(3-carboxy-1 -oxopropyl)-(4S)-p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester
  • Sacubitril is metabolized by enzymatic cleavage to LBQ657 (N-(3-carboxy-1 -oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid), the active inhibitor of neutral endopeptidase, which is the major enzyme responsible for the breakdown of atrial natriuretic peptides.
  • the MR antagonist can be purchased from commercial sources or can be prepared according to known methods, e.g. as shown in the patent applications or patents mentioned above. Objective & Methods:
  • Patients with chronic HF, NYHA functional class ll-IV symptoms, an elevated plasma B- type natriuretic peptide (BNP) or NT-proBNP level and, initially, a left ventricular ejection fraction of ⁇ 40% (later amended to ⁇ 35%) are eligible.
  • the primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death with LCZ696, compared with finerenone.
  • Secondary outcome measures are change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score at 8 months, change in renal function, and time to all- cause mortality.
  • KCCQ Kansas City Cardiomyopathy Questionnaire
  • the study is a randomized, double-blind, parallel group, active-controlled, two-arm, event- driven trial comparing the long-term efficacy and safety of finerenone and LCZ696 in patients with chronic symptomatic heart failure and reduced ejection fraction (HF-REF).
  • the key exclusion criteria include:
  • MRAs MR antagonists
  • ARBs angiotensin receptor blockers
  • neprilysin inhibitors as well as known or suspected contraindications to the study drugs.
  • SBP systolic blood pressure
  • eGFR ⁇ 30 mL/min/1 .73m2 at Visit 1 (screening), Visit 3 (end of enalapril run-in), or Visit 5 (end of LCZ696 run-in and randomization) or > 35% decline in eGFR between Visit 1 and Visit 3 or between Visit 1 and Visit 5.
  • Coronary or carotid artery disease likely to require surgical or percutaneous
  • CRT cardiac resynchronization therapy device
  • the study consists of four phases: 1) screening, 2) single-blind finerenone run-in, 3) and single-blind LCZ696 run-in, and 4) randomized double-blind treatment.
  • Eligibility BNP and NT-proBNP
  • serum potassium and estimated glomerular filtration rate (eGFR) are measured in a central laboratory.
  • Patients who can no longer tolerate the target dose of study drug can be down-titrated to the lower dose at the investigator's discretion (after considering whether any other relevant non disease-modifying therapy can be discontinued, e.g. a calcium channel or alpha-adrenoceptor blocker in a hypotensive patient).
  • the dose of background disease modifying drugs, such as ⁇ -blockers, should not be reduced to facilitate maintenance of study drug. Every attempt should be made to re-challenge the patients so as to maintain as many patients as possible on the target dose of study drug.
  • the purpose of this study is to evaluate the effect of LCZ696 compared with finerenone, in addition to conventional heart failure treatment, in delaying time to first occurrence of either cardiovascular death or heart failure hospitalization.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une combinaison spécifique d'un ARB, tel que le valsartan, un inhibiteur de NEP ou un promédicament de celui-ci, tel que le sacubitril, et un antagoniste de MR, tel que la finérénone; ainsi que des modes de réalisation associés de l'invention.
PCT/IB2016/054039 2015-07-08 2016-07-06 Combinaison de médicaments comprenant un antagoniste du récepteur de l'angiotensine ii, un inhibiteur d'endopeptidase neutre et un antagoniste du récepteur de minéralocorticoïdes WO2017006254A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562189939P 2015-07-08 2015-07-08
US62/189,939 2015-07-08

Publications (1)

Publication Number Publication Date
WO2017006254A1 true WO2017006254A1 (fr) 2017-01-12

Family

ID=56373095

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/054039 WO2017006254A1 (fr) 2015-07-08 2016-07-06 Combinaison de médicaments comprenant un antagoniste du récepteur de l'angiotensine ii, un inhibiteur d'endopeptidase neutre et un antagoniste du récepteur de minéralocorticoïdes

Country Status (1)

Country Link
WO (1) WO2017006254A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107602410A (zh) * 2017-09-13 2018-01-19 浙江三门恒康制药有限公司 沙库比曲钠盐的晶型ii及其制备方法
WO2020039394A1 (fr) 2018-08-24 2020-02-27 Novartis Ag Nouvelles combinaisons de médicaments
WO2020039386A1 (fr) 2018-08-23 2020-02-27 Novartis Ag Nouvelle utilisation pharmaceutique pour le traitement d'une insuffisance cardiaque
WO2022120442A1 (fr) * 2020-12-10 2022-06-16 Aché Laboratórios Farmacêuticos S.A. Co-médicaments d'antagonistes du récepteur de type 1 de l'angiotensine ii et inhibiteurs de néprilysine
EP4032532A4 (fr) * 2019-09-20 2023-10-04 Shenzhen Salubris Pharmaceuticals Co. Ltd Utilisations d'un complexe constitué d'un métabolite antagoniste du récepteur de l'angiotensine ii et d'un inhibiteur de la nep dans le traitement de l'insuffisance cardiaque

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0443983A1 (fr) 1990-02-19 1991-08-28 Ciba-Geigy Ag Composés acylés
US5217996A (en) 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
WO2003059345A1 (fr) 2002-01-17 2003-07-24 Novartis Ag Compositions pharmaceutiques a base de valsartan et d'inhibiteurs nep
US20040192584A1 (en) * 2003-03-18 2004-09-30 Pharmacia Corporation Combination of an aldosterone receptor antagonist and a neutral endopeptidase inhibitor
WO2007056546A1 (fr) 2005-11-09 2007-05-18 Novartis Ag Combinaison pharmaceutiques d'un antagoniste de recepteur d'angiotensine et d'un inhibiteur de nep
WO2008083967A2 (fr) 2007-01-12 2008-07-17 Novartis Ag Nouveau procédé
WO2008104306A2 (fr) 2007-02-27 2008-09-04 Bayer Schering Pharma Aktiengesellschaft Amides de 4-aryl-1,4-dihydro-1,6-naphthyridine substitués et utilisation de ceux-ci
WO2009061713A1 (fr) 2007-11-06 2009-05-14 Novartis Ag Compositions pharmaceutiques
WO2014029848A1 (fr) 2012-08-24 2014-02-27 Novartis Ag Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0443983A1 (fr) 1990-02-19 1991-08-28 Ciba-Geigy Ag Composés acylés
US5399578A (en) 1990-02-19 1995-03-21 Ciba-Geigy Corp Acyl compounds
US5217996A (en) 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
WO2003059345A1 (fr) 2002-01-17 2003-07-24 Novartis Ag Compositions pharmaceutiques a base de valsartan et d'inhibiteurs nep
US20040192584A1 (en) * 2003-03-18 2004-09-30 Pharmacia Corporation Combination of an aldosterone receptor antagonist and a neutral endopeptidase inhibitor
WO2007056546A1 (fr) 2005-11-09 2007-05-18 Novartis Ag Combinaison pharmaceutiques d'un antagoniste de recepteur d'angiotensine et d'un inhibiteur de nep
WO2008083967A2 (fr) 2007-01-12 2008-07-17 Novartis Ag Nouveau procédé
WO2008104306A2 (fr) 2007-02-27 2008-09-04 Bayer Schering Pharma Aktiengesellschaft Amides de 4-aryl-1,4-dihydro-1,6-naphthyridine substitués et utilisation de ceux-ci
US8436180B2 (en) 2007-02-27 2013-05-07 Bayer Intellectual Property Gmbh Substituted-4-aryl-1,4-dihydro-1,6-naphthyridinamides and use thereof
EP2132206B1 (fr) 2007-02-27 2015-04-01 Bayer Intellectual Property GmbH Amides de 4-aryl-1,4-dihydro-1,6-naphthyridine substitués et utilisation de ceux-ci
US9051316B2 (en) 2007-02-27 2015-06-09 Bayer Intellectual Property Gmbh Substituted 4-aryl-1,4-dihydro-1,6-naphthyridine amides and their use
WO2009061713A1 (fr) 2007-11-06 2009-05-14 Novartis Ag Compositions pharmaceutiques
WO2014029848A1 (fr) 2012-08-24 2014-02-27 Novartis Ag Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329
JOHN J.V. MCMURRAY ET AL: "Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure", NEW ENGLAND JOURNAL OF MEDICINE, vol. 371, no. 11, 11 September 2014 (2014-09-11), pages 993 - 1004, XP055175908, ISSN: 0028-4793, DOI: 10.1056/NEJMoa1409077 *
N ENGL J MED, vol. 345, 2001, pages 1667 - 1675

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107602410A (zh) * 2017-09-13 2018-01-19 浙江三门恒康制药有限公司 沙库比曲钠盐的晶型ii及其制备方法
WO2020039386A1 (fr) 2018-08-23 2020-02-27 Novartis Ag Nouvelle utilisation pharmaceutique pour le traitement d'une insuffisance cardiaque
WO2020039394A1 (fr) 2018-08-24 2020-02-27 Novartis Ag Nouvelles combinaisons de médicaments
EP4032532A4 (fr) * 2019-09-20 2023-10-04 Shenzhen Salubris Pharmaceuticals Co. Ltd Utilisations d'un complexe constitué d'un métabolite antagoniste du récepteur de l'angiotensine ii et d'un inhibiteur de la nep dans le traitement de l'insuffisance cardiaque
WO2022120442A1 (fr) * 2020-12-10 2022-06-16 Aché Laboratórios Farmacêuticos S.A. Co-médicaments d'antagonistes du récepteur de type 1 de l'angiotensine ii et inhibiteurs de néprilysine

Similar Documents

Publication Publication Date Title
EP3038654B1 (fr) Nouvelle utilisation
US9937143B2 (en) Inhibitors for treating diseases characterized by atrial enlargement or remodeling
US20220133694A1 (en) Pharmaceutical use
WO2017006254A1 (fr) Combinaison de médicaments comprenant un antagoniste du récepteur de l'angiotensine ii, un inhibiteur d'endopeptidase neutre et un antagoniste du récepteur de minéralocorticoïdes
EP3038653A1 (fr) Nouvelle utilisation
US9320727B2 (en) Combinations of SGLT 2 inhibitors and antihypertensive drugs
EP3411021A1 (fr) Nouvelle utilisation d'une combinaison de sacubitril et de valsartan
EP2035009A1 (fr) Amélioration prolongée d'une fonction rénale comprenant une administration peu fréquente d'un aa1ra
US10016397B2 (en) Selective AT2 receptor agonists for use in treatment of cachexia
JP2006515877A (ja) 心臓血管、心肺、肺又は腎疾患の予防又は治療のための医薬併用剤
JP2008044871A (ja) 心血管疾患予防・治療剤
EP2568982B1 (fr) Association d'inhibiteurs de la xanthine oxydase et d'antagonistes du récepteur de l'angiotensine ii et son utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16736631

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16736631

Country of ref document: EP

Kind code of ref document: A1