WO2020039394A1 - New drug combinations - Google Patents

New drug combinations Download PDF

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Publication number
WO2020039394A1
WO2020039394A1 PCT/IB2019/057103 IB2019057103W WO2020039394A1 WO 2020039394 A1 WO2020039394 A1 WO 2020039394A1 IB 2019057103 W IB2019057103 W IB 2019057103W WO 2020039394 A1 WO2020039394 A1 WO 2020039394A1
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WIPO (PCT)
Prior art keywords
combination
sacubitril
valsartan
patient
inhibitor
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PCT/IB2019/057103
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French (fr)
Inventor
Sven Godtfredsen
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Novartis Ag
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Publication of WO2020039394A1 publication Critical patent/WO2020039394A1/en

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    • 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
    • A61P9/12—Antihypertensives
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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 invention relates to a pharmaceutical combination of an Angiotensin II Receptor Antagonist (ARB), a Neutral Endopeptidase inhibitor (NEP inhibitor) or prodrug thereof and of a Sodium-D-glucose co-transporter (SGLT) inhibitor, optionally in the presence of a pharmaceutically acceptable excipient and pharmaceutical compositions comprising them. Furthermore, the invention is directed to said pharmaceutical combination for use in the prevention, delay or treatment of cardiovascular disorders, as well as compositions, methods for treating cardiovascular disorders, uses and regimens involving such combinations.
  • ARB Angiotensin II Receptor Antagonist
  • NEP inhibitor Neutral Endopeptidase inhibitor
  • SGLT Sodium-D-glucose co-transporter
  • Heart failure is a clinical syndrome caused by the inability of the heart to provide adequate blood supply or by sustaining adequate blood supply at the expense of elevated left ventricular (LV) filling pressure.
  • Patients with Heart Failure face a poor diagnosis, and about 50% of patients die from HF within 5 years. About 66% of patients with HF are non-diabetic patients. Total prevalence of HF worldwide was 26 million in 2013. In the United States (US) alone, approximately 5 million patients have heart failure (HF) and there are over half a million newly diagnosed cases annually. In Europe, the prevalence of HF is between 2 and 3%, and that in the elderly is estimated between 10 to 20%.
  • HF is often classified according to ejection fraction and then termed as HF with reduced (HFrEF), HF with preserved (HFpEF) and more recently also as HF with mid-range (HFmEF) Ejection Fraction. All are associated with high morbidity and mortality.
  • Current treatment options for HFrEF are mainly based on administration of beta-blockers, ACEi, ARBs, ARNi, MRAs and diuretics. Despite these options, outcomes remain suboptimal. In particular, there are at present no effective treatments indicated for FIFpEF or FIFmEF, with treatment focused on symptom management and on comorbidities.
  • 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) is a neprilysin (neutral endopeptidase 24.1 1 , NEP) inhibitor (NEPi) prodrug which is converted to the active form LBQ657 (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionyl amino)-2-methyl-pentanoic acid).
  • 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
  • Valsartan is a well-known angiotensin II type 1 (AT1 ) receptor blocker (ARB).
  • AZA angiotensin receptor blocker
  • 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
  • LCZ696 comprises the anionic forms of sacubitril and valsartan, sodium cations and water molecules in the molar ratio of 1 :1 :3:2.5, respectively (ratio of 6:6:18:15 in the asymmetric unit cell of the solid state crystal), and which is schematically present in the following formula:
  • the left molecule depicts the NEP inhibitor prodrug sacubitril, whereas the right molecule valsartan, a known angiotensin receptor blocker (ARB).
  • ARB angiotensin receptor blocker
  • LCZ696 Ingestion of LCZ696 results in systemic exposure to sacubitril and valsartan. LCZ696 provides concomitant NEP inhibition and AT1 blockade, which are considered to act complementary. Thus, LCZ696 delivers 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.
  • LCZ696 and formulations thereof have been previously disclosed in WO 2007/056546 and WO 2009/061713, which are herein incorporated by reference.
  • Sodium-D-glucose co-transporter belongs to the sodium/glucose co-transporter (SGLT) family SLCA5.
  • SGLT sodium/glucose co-transporter
  • SGLT-1 transports glucose as well as galactose, and is expressed both in the kidney and in the intestine, while SGLT-2 is found exclusively in the S1 and S2 segments of the renal proximal tubule.
  • SGLT-2 inhibitors are proposed as inducers of urinary sugar excretion and as
  • SGLT-2 inhibitors have been developed for the treatment or improvement of glycemic control in patients with type 2 diabetes. More recently, SGLT-2 inhibitors have also shown to reduce hospitalizations in patients with heart failure.
  • SGLT-2 inhibitors are glucopyranosyl-substituted benzene derivatives, for example as described in WO 01/16147, WO 01/27128, WO 02/36602, WO 02/053573, WO 02/68439, WO 02/88157, WO 03/099836, WO 2004/007517, WO 2004/0131 18,
  • the present invention relates to a combination comprising (a therapeutically effective amount of)
  • each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt.
  • Such combination is useful in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a cardiovascular disease in a patient in need thereof.
  • Such combination is also useful in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a renal disease in a patient in need thereof.
  • Such combination is also useful in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a metabolic disease in a patient in need thereof.
  • the present invention also relates to a combination comprising (a therapeutically effective amount of)
  • each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt, wherein the combination is in the form of a fixed dose combination of the combination partners, further including at least one pharmaceutically acceptable excipient.
  • the present invention relates to the use of such a combination in the preparation of a medicament.
  • Another aspect of the present invention relates to the use of such a combination in the preparation of a medicament for treatment, amelioration, prevention, delay of progression or delay of the occurrence of a cardiovascular disease, renal disease and/or metabolic disease.
  • the present invention also relates to a combination comprising (a therapeutically effective amount of)
  • each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt, for use in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a cardiovascular disease, renal disease and/or metabolic disease.
  • the present invention relates to a combination comprising (a therapeutically effective amount of)
  • each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt, wherein the combination is in the form of a fixed dose combination of the combination partners, further including at least one pharmaceutically acceptable excipient, for use for use in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a cardiovascular disease, renal disease and/or metabolic disease.
  • the present invention provides for a method for the prevention, delay or treatment of a cardiovascular disease, a renal disease and/or a metabolic disease, comprising administering a combination comprising (a therapeutically effective amount of)
  • each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt, and to a patient in need of such treatment.
  • Cardiovascular diseases include chronic heart failure, such as heart failure with reduced ejection fraction or heart failure with preserved ejection fraction, and acute heart failure.
  • Metabolic diseases include pre-diabetes, type 1 diabetes mellitus, type 2 diabetes mellitus adiposity, obesity or metabolic syndrome, or a combination of two or more of these conditions.
  • Renal diseases include chronic kidney disease.
  • active ingredient of a combination or pharmaceutical composition according to the present invention means a pharmaceutically active substance as defined herein.
  • active ingredient refers to valsartan, sacubitril or an SGLT-2 inhibitor.
  • An “active ingredient” is also sometimes referred to herein as an “active substance”.
  • treatment is understood the management and care of a patient for the purpose of combating the disease, condition or disorder.
  • treatment and treating comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form.
  • Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease.
  • compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy.
  • treatment is understood to comprise amelioration of the disease and/or disease symptoms as well as the delay of progression of the disease or disease symptoms.
  • 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. Moreover, the term “prevention” comprises the delay of occurrence of the disease and/or disease symptoms.
  • prophylactically treating means preventing a condition in which patients are at risk to develop a condition mentioned hereinbefore, thus reducing said risk.
  • terapéuticaally effective amount refers to an amount of an active ingredient 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 patient.
  • administration of and or “administering a” compound should be understood to mean providing the combination or pharmaceutical composition of the invention to a subject in need of treatment.
  • the administration of the combination or pharmaceutical composition of the present invention in order to practice the present methods of therapy is carried out by administering a therapeutically effective amount of the active ingredients in the combination or pharmaceutical composition to a subject in need of such treatment or prophylaxis.
  • the need for a prophylactic administration according to the methods of the present invention is determined via the use of well-known risk factors.
  • the therapeutcially effective amount of an individual compound 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.
  • the term “about” refers to +/- 20%, +/- 10%, or +/- 5% of a value.
  • 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.
  • 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.
  • CHF cardiac heart failure
  • CHF congestive heart failure
  • the extent of heart failure may be classified according to the New York Fleart Association (NYFIA) Functional Classification and encompasses the NYFIA classes I, II, III and IV.
  • NYFIA New York Fleart Association
  • the New York Fleart Association (NYFIA) classification grades the severity of heart failure symptoms as one of four functional classes.
  • the NYFIA 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 Fleart 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.
  • Chronic heart failure may be distinguished according to the ability of the left ventricle to contract is affected (heart failure with reduced ejection fraction) or the heart's abiility to relax is affected (heart failure with preserved ejection fraction).
  • FIFpEF refers to heart failure with preserved ejection fraction.
  • FIFrEF refers to heart failure with reduced ejection fraction.
  • LVEF refers to the left ventricular ejection fraction
  • the ejection fraction may be obtained by echocardiography, radionuclide ventriculography and angiography, preferably by echocardiography.
  • BNP refers to the brain natriuretic peptide, also called B-type natriuretic peptide. BNP is used for screening and diagnosis for chronic heart failure. The BNP value is determined in the blood plasma or serum.
  • NT-proBNP refers to the N-terminal of the prohormone brain natriuretic peptide. NT-proBNP is used for screening and diagnosis for chronic heart failure. The NT- proBNP value is determined in the blood plasma or serum.
  • 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 b-blockers as well as devices for cardiac resynchronization therapy.
  • drugs such as ACEIs, aldosterone antagonists, and b-blockers as well as devices for cardiac resynchronization therapy.
  • KCCQ refers to Kansas City Cardiomyopathy Questionnaire.
  • the health related quality of life may be measured according to KCCQ or KCCQ-12.
  • KCCQ-12 is a validated short version of the original 23-item KCCQ (Kansas City Cardiomyopathy Questionnaire). This self-administered questionnaire is designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, self- efficacy, and quality of life in patients with HF.
  • MLHFQ Minnesota Living With Heart Failure Questionnaire.
  • the quality of life including for example its physical, emotional, social and mental dimensions, may be measured according to MLHFQ.
  • hypertension is defined as follows: According to a commonly used definition, hypertension is diagnosed if the systolic blood pressure (SBP) exceeds a value of 140 mm Hg and diastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patient is suffering from manifest diabetes it is currently recommended that the systolic blood pressure be reduced to a level below 130 mm Hg and the diastolic blood pressure be lowered to below 80 mm Hg.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • body mass index or "BMI” of a human patient is defined as the weight in kilograms divided by the square of the height in meters, such that BMI has units of kg/m 2 .
  • overweight is defined as the condition wherein the individual has a BMI greater than or 25 kg/m 2 and less than 30 kg/m 2 .
  • overweight and “pre-obese” are used interchangeably.
  • the terms “obesity” or “being obese” and the like are defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m 2 .
  • the term obesity may be categorized as follows: the term “class I obesity” is the condition wherein the BMI is equal to or greater than 30 kg/m 2 but lower than 35 kg/m 2 ; the term “class II obesity” is the condition wherein the BMI is equal to or greater than 35 kg/m 2 but lower than 40 kg/m 2 ; the term “class III obesity” is the condition wherein the BMI is equal to or greater than 40 kg/m 2 .
  • the indication obesity includes in particular exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity, visceral obesity, abdominal obesity.
  • visceral obesity is defined as the condition wherein a waist-to-hip ratio of greater than or equal to 1 .0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.
  • abdominal obesity is usually defined as the condition wherein the waist circumference is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women.
  • abdominal obesity may be defined as waist circumferences 85 cm in men and3 90 cm in women (see e.g.
  • euglycemia is defined as the condition in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg/dl_ (3.89 mmol/L) and less than 100 mg/dl_ (5.6 mmol/L).
  • fasting has the usual meaning as a medical term.
  • hypoglycemia is defined as the condition in which a subject has a fasting blood glucose concentration above the normal range, greater than 100 mg/dL (5.6 mmol/L).
  • fasting has the usual meaning as a medical term.
  • hypoglycemia is defined as the condition in which a subject has a blood glucose concentration below the normal range, in particular below 70 mg/dL (3.89 mmol/L).
  • postprandial hyperglycemia is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 200 mg/dl_ (1 1 .1 1 mmol/L).
  • IGF paired fasting blood glucose
  • a subject with "normal fasting glucose” has a fasting glucose concentration smaller than 100 mg/dl, i.e. smaller than 5.6 mmol/l.
  • ITT paired glucose tolerance
  • the abnormal glucose tolerance i.e. the 2 hour postprandial blood glucose or serum glucose
  • concentration can be measured as the blood sugar level in mg of glucose per dl_ of plasma 2 hours after taking 75 g of glucose after a fast.
  • a subject with "normal glucose tolerance” has a 2 hour postprandial blood glucose or serum glucose concentration smaller than 140 mg/dl (7.78 mmol/L).
  • hyperinsulinemia is defined as the condition in which a subject with insulin resistance, with or without euglycemia, has fasting or postprandial serum or plasma insulin concentration elevated above that of normal, lean individuals without insulin resistance, having a waist-to-hip ratio ⁇ 1 .0 (for men) or ⁇ 0.8 (for women).
  • insulin resistance is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to maintain the euglycemic state (Ford ES, et al. JAMA. (2002) 287:356-9).
  • a method of determining insulin resistance is the euglycaemic-hyperinsulinaemic clamp test. The ratio of insulin to glucose is determined within the scope of a combined insulin-glucose infusion technique. There is found to be insulin resistance if the glucose absorption is below the 25th percentile of the background population investigated (WFIO definition).
  • insulin resistance the response of a patient with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia may be quantified by assessing the "homeostasis model assessment to insulin resistance (HOMA-IR)" score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001 ; 24: 362-5). Further reference is made to methods for the determination of the HOMA-index for insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl.1 ): A459) and to an euglycemic clamp study.
  • HOMA-IR homeostasis model assessment to insulin resistance
  • FIOMA homeostasis assessment model
  • HOMA-IR [fasting serum insulin (mu/mL)] x [fasting plasma glucose(mmol/L)/22.5].
  • Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score.
  • insulin resistance is defined as the clinical condition in which an individual has a HOMA-IR score > 4.0 or a HOMA-IR score above the upper limit of normal as defined for the laboratory performing the glucose and insulin assays.
  • the patient's triglyceride concentration is used, for example, as increased triglyceride levels correlate significantly with the presence of insulin resistance.
  • Individuals likely to have insulin resistance are those who have two or more of the following attributes: 1 ) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1 st degree relative with a diagnosis of IGT or IFG or type 2 diabetes.
  • Patients with a predisposition for the development of IGT or IFG or type 2 diabetes are those having euglycemia with hyperinsulinemia and are by definition, insulin resistant.
  • a typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of pre-diabetes. Thus, it may be that in order to maintain glucose homoeostasis a person needs 2-3 times as much insulin as a healthy person, without this resulting in any clinical symptoms.
  • Pre-diabetes is a general term that refers to an intermediate stage between normal glucose tolerance (NGT) and overt type 2 diabetes mellitus (T2DM), also referred to as intermediate hyperglycaemia. Therefore in one aspect of the present invention "pre diabetes” is diagnosed in an individual if HbA1 c is more or equal to 5.7% and less than 6.5%.
  • pre-diabetes represents 3 groups of individuals, those with impaired glucose tolerance (IGT) alone, those with impaired fasting glucose (IFG) alone or those with both IGT and IFG.
  • IGT and IFG usually have distinct pathophysiologic etiologies, however also a mixed condition with features of both can exist in patients. Therefore in another aspect of the present invention a patient being diagnosed of having "pre-diabetes” is an individual with diagnosed IGT or diagnosed IFG or diagnosed with both IGT and IFG.
  • ADA American Diabetes Association
  • FPG fasting plasma glucose
  • PG 2-hour plasma glucose
  • IGT IGT
  • FPG fasting plasma glucose
  • PG 2-hour plasma glucose
  • FPG fasting plasma glucose
  • PG 2-hour plasma glucose
  • Pre-diabetes are individuals being pre-disposed to the development of type 2 diabetes. Pre-diabetes extends the definition of IGT to include individuals with a fasting blood glucose within the high normal ranges 100 mg/dl_ (J. B. Meigs, et al. Diabetes 2003; 52:1475-1484). The scientific and medical basis for identifying pre-diabetes as a serious health threat is laid out in a Position Statement entitled "The Prevention or Delay of Type 2 Diabetes” issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749).
  • pancreatic beta-cells pancreatic beta-cells
  • An improvement of beta-cell function can be measured for example by determining a HOMA- index (homeostasis model assessment) for beta-cell function, HOMA-B, (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al.,
  • Diabetes 2003, 52(Suppl.1 ): A459) first and second phase insulin secretion after an oral glucose tolerance test or a meal tolerance test (Stumvoll et al., Diabetes care 2000, 23: 295-301 ), the insulin/C-peptide secretion after an oral glucose tolerance test or a meal tolerance test, or by employing a hyperglycemic clamp study and/or minimal modeling after a frequently sampled intravenous glucose tolerance test (Stumvoll et al., Eur J Clin Invest 2001 , 31 : 380-81 ).
  • type 1 diabetes is defined as the condition in which a subject has, in the presence of autoimmunity towards the pancreatic beta-cell or insulin, a fasting blood glucose or serum glucose concentration greater than 125 mg/dl_ (6.94 mmol/L). If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dl_ (1 1 .1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach, in the presence of autoimmunity towards the pancreatic beta cell or insulin.
  • a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it.
  • the presence of autoimmunity towards the pancreatic beta-cell may be observed by detection of circulating islet cell autoantibodies ["type 1 A diabetes mellitus"], i.e., at least one of: GAD65
  • a genetic predisposition is present (e.g. HLA, INS VNTR and PTPN22), but this is not always the case.
  • type 2 diabetes mellitus or "T2DM” is defined as the condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg/dl_ (6.94 mmol/L).
  • the measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dl_ (1 1 .1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it.
  • the blood sugar level before taking the glucose will be between 60 and 1 10 mg per dl_ of plasma, less than 200 mg per dl_ 1 hour after taking the glucose and less than 140 mg per dl_ after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is regarded as abnormal glucose tolerance.
  • latent autoimmune diabetes of adults refers to patients that have a clinical diagnosis of type 2 diabetes, but who are being detected to have autoimmunity towards the pancreatic beta cell.
  • Latent autoimmune diabetes of adults is also known as slowly progressive type 1 diabetes mellitus (T1 DM), "mild” T1 DM, non-insulin dependent type 1 DM, type 1 1 ⁇ 2 DM, double diabetes or antibody positive type 2 DM (T2DM).
  • T1 DM slowly progressive type 1 diabetes mellitus
  • T2DM double diabetes or antibody positive type 2 DM
  • HbA1 c refers to the product of a non-enzymatic glycation of the haemoglobin B chain. Its determination is well known to one skilled in the art. In monitoring the treatment of diabetes mellitus the HbA1 c value is of exceptional importance. As its production depends essentially on the blood sugar level and the life of the erythrocytes, the HbA1 c in the sense of a "blood sugar memory” reflects the average blood sugar levels of the preceding 4-6 weeks. Diabetic patients whose HbA1 c value is consistently well adjusted by intensive diabetes treatment (i.e. ⁇ 6.5 % of the total haemoglobin in the sample), are significantly better protected against diabetic microangiopathy.
  • metformin on its own achieves an average improvement in the HbA1 c value in the diabetic of the order of 1 .0 - 1 .5 %.
  • This reduction of the HbA1 C value is not sufficient in all diabetics to achieve the desired target range of ⁇ 7% or ⁇ 6.5 % and preferably ⁇ 6 % HbA1 c.
  • insufficient glycemic control or "inadequate glycemic control” in the scope of the present invention means a condition wherein patients show HbA1 c values above 6.5 %, in particular above 7.0 %, even more preferably above 7.5 %, especially above 8 %.
  • the “metabolic syndrome”, also called “syndrome X” (when used in the context of a metabolic disorder), also called the “dysmetabolic syndrome” is a syndrome complex with the cardinal feature being insulin resistance (Laaksonen DE, et al. Am J Epidemiol 2002;156:1070-7).
  • ATP lll/NCEP guidelines Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
  • diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present:
  • Abdominal obesity defined as waist circumference > 40 inches or 102 cm in men, and > 35 inches or 94 cm in women; or with regard to a Japanese ethnicity or Japanese patients defined as waist circumferences 85 cm in men and3 90 cm in women;
  • Triglycerides 3 150 mg/dl_
  • NCEP definitions have been validated (Laaksonen DE, et al. Am J Epidemiol. (2002)
  • T riglycerides and HDL cholesterol in the blood can also be determined by standard methods in medical analysis and are described for example in Thomas L
  • albuminuria is defined as a condition wherein more than the normal amount of albumin is present in the urine.
  • Albuminuria can be determined by the albumin excretion rate (AER) and/or the albumin-to-creatine ratio (ACR) in the urine (also refered to as UACR).
  • AER albumin excretion rate
  • ACR albumin-to-creatine ratio
  • Albuminuria categories in CKD are defined as follows:
  • Category A1 reflects no albuminuria
  • category A2 reflects microalbuminuria
  • category A3 reflects macroalbuminuria. The progression of category A1 usually leads to
  • microalbuminuria (A2) but may also directly result in macroalbuminuria (A3). Progression of microalbuminuria (A2) results in macroalbuminuria (A3).
  • the term "eGFR” refers to estimated glomerular filtration rate.
  • the GFR describes the flow rate of filtered fluid through the kidney.
  • the estimated GFR may be calculated based on serum creatinine values e.g. using the Chronic Kidney Disease Epidemiology
  • eGFR is calculated by the Modification in Diet in Renal Disease (MDRD) formula, which is the one recommended by NICE and The Renal Association (UK), and which is based on the equation described in Levey AS,
  • the estimated glomerular filtration rate can be derived from serum creatinine values, age sex and race based on the CKD-EPI equation:
  • GFR 141 x min (S cr /K, 1 ) Q * max(S cr /K, 1 ) "1 209 * 0.993 A9e * 1 .018 [if female] * 1 .159 [if black]
  • Scr is serum creatinine in mg/dl_
  • K is 0.7 for females and 0.9 for males
  • a is -0.329 for females and -0.41 1 for males
  • max indicates the maximum of S cr /K or 1.
  • the degree of renal impairment in a patient is defined by the following estimated glomerular filtration rate (eGFR):
  • Moderate renal impairment (CKD stage 3): eGFR330 to ⁇ 60 mL/min/1 .73 m 2
  • Severe renal impairment (CKD stage 4): eGFR315 to ⁇ 30 mL/min/1.73 m 2
  • moderate renal impairment can be further divided into two sub-stages:
  • Moderate A renal impairment CKD 3A
  • Moderate B renal impairment CKD 3B
  • CKD 3A eGFR345 to ⁇ 60 mL/min/1.73 m 2
  • CKD 3B Moderate B renal impairment
  • Valsartan (CAS number 137862-53-4) is an Angiotensin II Receptor Antagonist (ARB) and is the INN for the compound name N-(1 -oxopentyl)-N-[2’-(1 -tetrazol-5-yl)methyl]-valine (also termed S-N-valeryl-N- ⁇ [2’-(1 FI-tetrazole-5-yl)-biphenyl-4-yl]-methyl ⁇ -valine). It has the formula:
  • Valsartan can be purchased from commercial sources or can be prepared according to known methods, such as described in U.S. Patent No. 5,399,578 and EP 0443983, whose preparative teachings are incorporated by reference herein. Valsartan may be used in certain embodiments of the invention in its free acid form, as well as in any suitable salt form. Depending upon the circumstance, esters or other derivatives of the carboxylic grouping may be employed as well as salts and derivatives of the tetrazole grouping.
  • Sacubitril (CAS number 149709-62-6; also known as AHU377) is a prodrug for an NEP inhibitor is the INN for a compound with the chemical name A/-(3-carboxyl-1 -oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2/ : ?)-methyl butanoic acid ethyl ester. Sacubitril has 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 sacubitrilat) that is formed from the prodrug in vivo. Sacubitril and Valsartan in a 1 :1 molar ratio
  • the term“sacubitril and valsartan in a 1 :1 molar ratio” refers to a 1 :1 molar ratio of valsartan or a pharmaceutically acceptable salt thereof; and sacubitril or a pharmaceutically acceptable salt thereof.
  • said sacubitril and valsartan in a 1 :1 molar ratio 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.
  • SGLT-2 inhibitors have been developed for the treatment or improvement of glycemic control in patients with type 2 diabetes. More recently, SGLT-2 inhibitors have also shown to reduce hospitalizations in patients with heart failure.
  • Suitable SGLT-2 inhibitors which have already been approved or are in clinical development include dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, tofogliflozin, remogliflozin (or remogliflozin etabonate), luseogliflozin, ipragliflozin, atigliflozin, bexagliflozin, and henagliflozin.
  • SGLT-2 inhibitor are for example:
  • Crystalline forms thereof are described for example in WO 2008/002824 and WO 2008/1 16179.
  • empagliflozin also comprises its hydrates, solvates and polymorphic forms thereof, and prodrugs thereof.
  • An advantageous crystalline form of empagliflozin is described in WO 2006/1 17359 and WO 201 1 /039107, which hereby are incorporated herein in their entirety.
  • This crystalline form possesses good solubility properties which enables a good bioavailability of the SGLT2 inhibitor.
  • the crystalline form is physico-chemically stable and thus provides a good shelf-life stability of the pharmaceutical composition.
  • Preferred pharmaceutical compositions, such as solid formulations for oral administration, for example tablets, are described in WO
  • sotagliflozin (US patent No. 7,781 ,577), having the following structural formula:
  • ipragliflozin having the following structural formula:
  • 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 a more than additive 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 valsartan, the NEP inhibitor prodrug sacubitril and an SGLT-2 inhibitor, or pharmaceutically acceptable salts thereof, respectively).
  • 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 administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration still provides therapeutically effective levels of the two compounds in the body of the patient.
  • the term“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. simultaneously or at different time points, where 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.
  • 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.
  • a combination comprising the Angiotensin II Receptor Antagonist (ARB) valsartan, the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril and a Sodium-D-glucose co-transporter (SGLT) inhibitor can lead to an improved, preferably more than additive, especially synergistic, effect in the treatment of cardiovascular diseases.
  • ARB Angiotensin II Receptor Antagonist
  • NEP inhibitor Neutral Endopeptidase inhibitor
  • SGLT Sodium-D-glucose co-transporter
  • the present invention is directed to a combination comprising
  • each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt.
  • the combination of the invention comprises an SGLT-2 inhibitor selected from the group consisting of dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, tofogliflozin, remogliflozin (or remogliflozin etabonate), luseogliflozin, ipragliflozin, atigliflozin, bexagliflozin, and henagliflozin, wherein the DGLT-2 inhibitor may be present in free form or in the form of a pharmaceutically acceptable salt.
  • the SGLT-2 inhibitor is dapagliflozin.
  • the SGLT-2 inhibitor is empagliflozin.
  • the SGLT-2 inhibitor is canagliflozin.
  • the SGLT-2 inhibitor is ertugliflozin.
  • the SGLT-2 inhibitor is sotagliflozin.
  • the SGLT-2 inhibitor is tofogliflozin.
  • the SGLT-2 inhibitor is remogliflozin (or remogliflozin etabonate).
  • the SGLT-2 inhibitor is luseogliflozin.
  • the SGLT-2 inhibitor is ipragliflozin.
  • the SGLT-2 inhibitor is atigliflozin.
  • the SGLT-2 inhibitor is bexagliflozin.
  • the SGLT-2 inhibitor is henagliflozin.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and empagliflozin, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and canagliflozin, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and ertugliflozin, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and sotagliflozin, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and tofogliflozin, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and remogliflozin, or a pharmaceutically acceptable salt thereof, or remogliflozin etabonate.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and luseogliflozin, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and ipragliflozin, or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and atigliflozin, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and bexagliflozin, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and henagliflozin, or a pharmaceutically acceptable salt thereof.
  • the combination comprises (based on the molar ratio of the free form of the respective compound) a 1 :1 molar ratio of valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof.
  • said 1 :1 sacubitril/valsartan part of the combination 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.
  • 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 in crystalline form is also referred to as LCZ696.
  • compositions and compounds containing sacubitril and valsartan for example in the form of LCZ696, and their uses have for example been previously disclosed in W02003059345, W02007056546, W02009061713, WO2012027237,
  • compositions and compounds containing sacubitril and valsartan in a 1 :1 molar ratio and their uses have also for example been previously disclosed in
  • 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 active ingredients sacubitril or a salt thereof, valsartan or a salt thereof, compounds of formula (I), in particular LCZ696, and the SGLT-2 inhibitors are sacubitril or a salt thereof, valsartan or a salt thereof, compounds of formula (I), in particular LCZ696, and the SGLT-2 inhibitors.
  • substantially pure or in a substantially pure form refers to at least about 90% purity, more preferably at least about 95% and most preferably at least about 98% purity. Also preferred is that 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 excipients, 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.
  • compositions for oral use can be obtained by combining the active ingredient with solid excipients, 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.
  • the pharmaceutical compositions include active ingrediens 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 excipient or carrier (e.g. water) before ingestion.
  • 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.
  • 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-((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, 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-((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, wherein
  • one embodiment of the invention relates to a combination comprising (based on the molar ratio of the free form of the respective compound) a 1 :1 molar ratio of valsartan and sacubitril in any of the forms as described in the various embodiments above in combination with any of the SGLT-2 inhibitors or a pharmaceutically acceptable salt thereof listed above.
  • the SGLT-2 inhibitor may for example be present in a molar amount of 0.01 to 100 mol per mol of valsartan/sacubitril.
  • the combination according to invention comprises the SGLT-2 inhibitor 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, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg or 1000 mg.
  • the combination is delivered twice delay to the patient.
  • 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 comprises 103 mg or less, e.g. down to 1 mg, of valsartan, or a pharmaceutically acceptable salt thereof, and 97 mg or less, e.g. down to 1 mg, of sacubitril, or a pharmaceutically acceptable salt thereof, and 1000 mg or 500 mg or less, e.g. down to 1 mg, of a SGLT-2 inhibitor, or a pharmaceutically acceptable salt thereof, and per dosage unit.
  • the combination of sacubitril and valsartan is administered twice daily (b.i.d.), whereas and the SGLT-2 inhibitor is only administered once daily (QID).
  • QID administered once daily
  • 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 and the SGLT-2 inhibitor (as defined herein).
  • the cardiovascular disease is heart failure with reduced ejection fraction or heart failure with preserved ejection fraction or acute heart failure.
  • the metabolic disease is pre-diabetes, type 1 diabetes mellitus, type 2 diabetes mellitus adiposity, obesity or metabolic syndrome, or a combination of two or more of these conditions.
  • methods of treatment, amelioration, prevention, delay of progression or delay of occurrence of a cardiovascular disease, renal disease and/or metabolic disease include
  • ADHF decompensated heart failure
  • the methods of treatment, amelioration, prevention, delay of progression or delay of occurrence of a cardiovascular disease, renal disease and/or metabolic disease include
  • the methods of treatment, amelioration, prevention, delay of progression or delay of occurrence of a cardiovascular disease, renal disease and/or metabolic disease include methods for preventing, slowing or reversing the progression to macroalbuminuria in the patient.
  • the patient is a patient with heart failure with reduced ejection fraction or heart failure with preserved ejection fraction.
  • the patient has heart failure with reduced ejection fraction.
  • the patient has heart failure with preserved ejection fraction.
  • the present invention provides a method of treatment comprising: a) identifying a patient in need of treatment for chronic heart failure ; and b) administering the combination of the invention to said patient.
  • the present invention provides a method of treating chronic heart failure in a patient comprising:
  • a determining the symptoms according to the NYHA classification of the patient; b. identifying that the patient has chronic heart failure according to NYHA class II, III or IV;
  • the present invention provides a method of treating chronic heart failure in a patient comprising:
  • the present invention provides a method of treating chronic heart failure in a patient comprising:
  • a determining the symptoms according to the NYHA classification of the patient; b. determining the ejection fraction of the patient;
  • the present invention provides a method of treating chronic heart failure in a patient comprising:
  • a determining the symptoms according to the NYHA classification of the patient; b. determining the ejection fraction of the patient;
  • the present invention provides a method of treating chronic heart failure in a patient comprising: a. determining the symptoms according to the NYHA classification of the patient; b. determining the ejection fraction of the patient;
  • III or IV has an ejection fraction equal or smaller than 40%, in particular greater than 50%, and has an elevated BNP or NT-proBNP value;
  • an elevated BNP or NT-proBNP value is particularly a BNP value equal to or greater than 150 pg/mL or a NT-proBNP value equal to or greater than 600 pg/mL
  • an elevated BNP or NT-proBNP value is particularly a BNP value equal to or greater than 100 pg/mL or a NT-proBNP value equal to or greater than 400 pg/mL if the patient was hospitalized for heart failure within the last 9 months.
  • the patient suffering from chronic systolic heart failure in particular the patient with 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 3100 pg/mL (or NT-proBNP 3400 pg/mL), more preferably a plasma BNP 3150 pg/mL or NT-proBNP 3600 pg/mL, and
  • LVEF left ventricular ejection fraction
  • the patient might be characterized by one or more of the following:
  • 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 £5%.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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 the SGLT-2 inhibitor, 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) is becoming an increasingly common diag nosis 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 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 the SGLT-2 inhibitor luseoaliflozin
  • Sacubitril sodium salt, valsartan and luseogliflozin are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
  • Sacubitril calcium salt, valsartan and luseogliflozin are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
  • Sacubitril calcium salt, valsartan calcium and luseogliflozin are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
  • LCZ696 trisodium sacubitril valsartan hemipentahydrate
  • luseogliflozin are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
  • Example 2 Animal models to assess the effectiveness of the combinations of the invention
  • DIO diet induced obesity
  • rat model Glucose control
  • DIO diet induced obesity
  • Example 2A A preclinical study design for Heart Failure:
  • BP/HR change from baseline
  • 24 hr diuresis/natriuresis day -3, 1 , 7, 14, 21 and 28, referenced to d-3 baseline
  • Plasma HF markers NproBNP, sST2
  • Example 2B A preclinical study design for Heart Failure:
  • Study design Assessment of glucose tolerance, insulin sensitivity, body weight, heart weight, fat mass and liver steatosis in DIO mouse model in 18 week-old male DIO mice on high fat diet from 6 weeks of age following 4 weeks of therapy.
  • Plasma HF markers (NT-proBNP, sST2), heart weight (and other organs - liver, fat, kidney) at day 28, histology, body weight and food intake, body composition, liver steatosis
  • 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-S-ylatejbiphenyl- ⁇ -ylmethylJaminojbutyratejhemipentahydrate.
  • This compound and pharmaceutical compositions thereof have been previously disclosed in
  • LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that comprises the mole cular 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 ethy
  • 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 SGLT-2 inhibitor luseogliflozin (US patent No 7,910,619, and EP1845095B1 ) has the following structural formula: and 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.
  • 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% are eligible. Patients enter a single blind luseogliflozin run-in period which, depending on tolerability, is followed by an LCZ696 run-in period. Then, patients tolerating both drugs at the target dose, are randomized 1 :1 to either luseogliflozin or LCZ696.
  • the primary outcome is the composite of cardiovascular death or HF hospitaliza tion, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death with LCZ696, compared with luseogliflozin.
  • 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 luseogliflozin and LCZ696 in patients with chronic symptomatic heart failure and reduced ejection fraction (HF-REF).
  • the key exclusion criteria include:
  • SGLT-2 inhibitors SGLT-2 inhibitors
  • ARBs angiotensin receptor blockers
  • neprilysin inhibitors as well as known or suspected contraindications to the study drugs.
  • SBP systolic blood pressure
  • 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 luseogliflozin run-in, 3) and single-blind LCZ696 run-in, and 4) randomized double-blind treatment.
  • Patients tolerating both luseogliflozin and LCZ696 are randomized in a 1 :1 ratio to double blind treatment with either luseogliflozin or LCZ696. Study visits occur every 2 to 8 weeks during the first 4 months of the double-blind period and every 4 months thereafter (with additional unscheduled visits, at the discretion of the investigator).
  • 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 b-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 luseogliflozin, in addition to conventional heart failure treatment, in delaying time to first occurrence of either cardiovascular death or heart failure hospitalization.
  • trial designs such as described in WO2017157816 for empagliflozin for the treatment of heart failure, which is incorporated by reference, can also be used be adding an additional treatment arm using for example 200 mg LCZ696.

Abstract

A specific combination of an ARB, such as valsartan, a NEP inhibitor or prodrug thereof, such as sacubitril, and an SGLT-2 inhibitor; and related invention embodiments.

Description

NEW DRUG COMBINATIONS
FIELD OF THE INVENTION
The invention relates to a pharmaceutical combination of an Angiotensin II Receptor Antagonist (ARB), a Neutral Endopeptidase inhibitor (NEP inhibitor) or prodrug thereof and of a Sodium-D-glucose co-transporter (SGLT) inhibitor, optionally in the presence of a pharmaceutically acceptable excipient and pharmaceutical compositions comprising them. Furthermore, the invention is directed to said pharmaceutical combination for use in the prevention, delay or treatment of cardiovascular disorders, as well as compositions, methods for treating cardiovascular disorders, uses and regimens involving such combinations.
BACKGROUND OF THE INVENTION
Heart failure (HF)
Heart failure (HF) is a clinical syndrome caused by the inability of the heart to provide adequate blood supply or by sustaining adequate blood supply at the expense of elevated left ventricular (LV) filling pressure. Patients with Heart Failure (HF) face a poor diagnosis, and about 50% of patients die from HF within 5 years. About 66% of patients with HF are non-diabetic patients. Total prevalence of HF worldwide was 26 million in 2013. In the United States (US) alone, approximately 5 million patients have heart failure (HF) and there are over half a million newly diagnosed cases annually. In Europe, the prevalence of HF is between 2 and 3%, and that in the elderly is estimated between 10 to 20%.
In the US, more than 1 million HF hospitalizations occur every year. 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 place an enormous financial burden on healthcare systems.
Accordingly, there is a considerable unmet need in HF. The overall goal for the treatment of HF is to prevent hospitalization and mortality, control symptoms, and improve quality of life.
HF is often classified according to ejection fraction and then termed as HF with reduced (HFrEF), HF with preserved (HFpEF) and more recently also as HF with mid-range (HFmEF) Ejection Fraction. All are associated with high morbidity and mortality. Current treatment options for HFrEF are mainly based on administration of beta-blockers, ACEi, ARBs, ARNi, MRAs and diuretics. Despite these options, outcomes remain suboptimal. In particular, there are at present no effective treatments indicated for FIFpEF or FIFmEF, with treatment focused on symptom management and on comorbidities.
Therefore, there is an unmet medical need for methods for treating heart failure with a good efficacy, with regard to disease-modifying properties and with regard to reduction of risk of mortality or hospitalization while at the same time showing a good safety profile.
Sacubitril and Valsartan
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) is a neprilysin (neutral endopeptidase 24.1 1 , NEP) inhibitor (NEPi) prodrug which is converted to the active form LBQ657 (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionyl amino)-2-methyl-pentanoic acid).
Neprilysin (NEP) inhibition will expose subjects to enhanced levels of the physiologically active natriuretic peptides (NPs), including atrial natriuretic peptide (ANP). NPs mediate their cardiovascular effects through activation of the natriuretic peptide receptor A (NPR- A) and their second messenger cyclic GMP (cGMP) resulting in potent vasodilation, natriuresis and diuresis, inhibition of the renin angiotensin aldosterone system (RAAS) by reducing renin and aldosterone release, reduced sympathetic drive, and anti-proliferative and antihypertrophic effects on vascular endothelium and smooth muscle cells.
Valsartan is a well-known angiotensin II type 1 (AT1 ) receptor blocker (ARB). 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.
Combinations of sacubitril and valsartan have been previously disclosed in
WO 03/059345 which is herein incorporated by reference.
LCZ696 (Sacubitril and valsartan)
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.
LCZ696 comprises the anionic forms of sacubitril and valsartan, sodium cations and water molecules in the molar ratio of 1 :1 :3:2.5, respectively (ratio of 6:6:18:15 in the asymmetric unit cell of the solid state crystal), and which is schematically present in the following formula:
Figure imgf000004_0001
The left molecule depicts the NEP inhibitor prodrug sacubitril, whereas the right molecule valsartan, a known angiotensin receptor blocker (ARB).
Ingestion of LCZ696 results in systemic exposure to sacubitril and valsartan. LCZ696 provides concomitant NEP inhibition and AT1 blockade, which are considered to act complementary. Thus, LCZ696 delivers 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.
LCZ696 and formulations thereof have been previously disclosed in WO 2007/056546 and WO 2009/061713, which are herein incorporated by reference.
SGLT inhibitors
Sodium-D-glucose co-transporter belongs to the sodium/glucose co-transporter (SGLT) family SLCA5. Two different SGLT isoforms, SGLT-1 and SGLT-2, have been identified to mediate renal tubular glucose reabsorption in humans. Both of them are characterized by their different substrate affinity. Although both of them show 59% homology in their amino acid sequence, they are functionally different. SGLT-1 transports glucose as well as galactose, and is expressed both in the kidney and in the intestine, while SGLT-2 is found exclusively in the S1 and S2 segments of the renal proximal tubule.
SGLT-2 inhibitors are proposed as inducers of urinary sugar excretion and as
medicaments in the treatment of diabetes, in particular SGLT-2 inhibitors have been developed for the treatment or improvement of glycemic control in patients with type 2 diabetes. More recently, SGLT-2 inhibitors have also shown to reduce hospitalizations in patients with heart failure.
Examples of SGLT-2 inhibitors are glucopyranosyl-substituted benzene derivatives, for example as described in WO 01/16147, WO 01/27128, WO 02/36602, WO 02/053573, WO 02/68439, WO 02/88157, WO 03/099836, WO 2004/007517, WO 2004/0131 18,
WO 2004/080990, WO 2005/012326, WO 2005/021566, WO 2005/092877,
WO 2006/034489, WO 2006/064033, WO 2006/080421 , WO 2006/1 17359,
WO 2006/1 17360, WO 2007/025943, WO 2007/028814, WO 2007/031548,
WO 2007/093610, WO 2007/128749, WO 2007/140191 , WO 2008/013280,
WO 2008/049923, WO 2008/055870, and WO 2008/055940.
There exists a need for novel and better treatments of cardiovascular disorders or conditions, including drugs and drug combinations, for the treatment of heart failure.
It has now been surprisingly found that a combination comprising the Angiotensin II Receptor Antagonist (ARB) valsartan, the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril and an Sodium-D-glucose co-transporter (SGLT) inhibitor, and especially as presented in more detail below and in the claims, leads to an improved, preferably more than additive, especially synergistic, effect in the treatment of
cardiovascular diseases.
SUMMARY OF THE INVENTION
The present invention relates to a combination comprising (a therapeutically effective amount of)
(i) the Angiotensin II Receptor Antagonist (ARB) valsartan;
(ii) the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril; and
(iii) an SGLT-2 inhibitor,
wherein each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt.
Such combination is useful in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a cardiovascular disease in a patient in need thereof.
Such combination is also useful in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a renal disease in a patient in need thereof. Such combination is also useful in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a metabolic disease in a patient in need thereof.
In one aspect, the present invention also relates to a combination comprising (a therapeutically effective amount of)
(i) the Angiotensin II Receptor Antagonist (ARB) valsartan;
(ii) the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril; and
(iii) an SGLT-2 inhibitor,
wherein each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt, wherein the combination is in the form of a fixed dose combination of the combination partners, further including at least one pharmaceutically acceptable excipient.
In another aspect, the present invention relates to the use of such a combination in the preparation of a medicament.
Another aspect of the present invention relates to the use of such a combination in the preparation of a medicament for treatment, amelioration, prevention, delay of progression or delay of the occurrence of a cardiovascular disease, renal disease and/or metabolic disease.
The present invention also relates to a combination comprising (a therapeutically effective amount of)
(i) the Angiotensin II Receptor Antagonist (ARB) valsartan;
(ii) the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril; and
(iii) an SGLT-2 inhibitor,
wherein each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt, for use in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a cardiovascular disease, renal disease and/or metabolic disease.
In one aspect, the present invention relates to a combination comprising (a therapeutically effective amount of)
(i) the Angiotensin II Receptor Antagonist (ARB) valsartan;
(ii) the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril; and
(iii) an SGLT-2 inhibitor, wherein each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt, wherein the combination is in the form of a fixed dose combination of the combination partners, further including at least one pharmaceutically acceptable excipient, for use for use in the treatment, amelioration, prevention, delay of progression or delay of the occurrence of a cardiovascular disease, renal disease and/or metabolic disease.
In another aspect, the present invention provides for a method for the prevention, delay or treatment of a cardiovascular disease, a renal disease and/or a metabolic disease, comprising administering a combination comprising (a therapeutically effective amount of)
(i) the Angiotensin II Receptor Antagonist (ARB) valsartan;
(ii) the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril; and
(iii) an SGLT-2 inhibitor,
wherein each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt, and to a patient in need of such treatment.
Cardiovascular diseases include chronic heart failure, such as heart failure with reduced ejection fraction or heart failure with preserved ejection fraction, and acute heart failure.
Metabolic diseases include pre-diabetes, type 1 diabetes mellitus, type 2 diabetes mellitus adiposity, obesity or metabolic syndrome, or a combination of two or more of these conditions.
Renal diseases include chronic kidney disease.
Definitions
Throughout this specification and in the claims that follow, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term "active ingredient" of a combination or pharmaceutical composition according to the present invention means a pharmaceutically active substance as defined herein. In the context of the invention“active ingredient” refers to valsartan, sacubitril or an SGLT-2 inhibitor. An "active ingredient" is also sometimes referred to herein as an "active substance".
The term "treatment" is understood the management and care of a patient for the purpose of combating the disease, condition or disorder. The terms "treatment" and "treating" comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy.
The term“treatment” is understood to comprise amelioration of the disease and/or disease symptoms as well as the delay of progression of the disease or disease symptoms.
The term "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. Moreover, the term "prevention" comprises the delay of occurrence of the disease and/or disease symptoms.
Accordingly, the terms "prophylactically treating", "preventively treating" and "preventing" are used interchangeably and comprise a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.
The term "therapeutically effective amount" refers to an amount of an active ingredient 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.
The terms "patient" refers to a human patient.
The terms "administration of" and or "administering a" compound should be understood to mean providing the combination or pharmaceutical composition of the invention to a subject in need of treatment. The administration of the combination or pharmaceutical composition of the present invention in order to practice the present methods of therapy is carried out by administering a therapeutically effective amount of the active ingredients in the combination or pharmaceutical composition to a subject in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well-known risk factors. The therapeutcially effective amount of an individual compound 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.
As used herein, the term "about" refers to +/- 20%, +/- 10%, or +/- 5% of a value. The term "pharmaceutically acceptable", as used herein, 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 term“b.i.d.” as used herein, means twice daily. For example, 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.
In the context of the present invention, the term "chronic heart failure" or "CHF" is considered a synonym of the term“congestive heart failure (CCF)”. The extent of heart failure may be classified according to the New York Fleart Association (NYFIA) Functional Classification and encompasses the NYFIA classes I, II, III and IV.
The New York Fleart Association (NYFIA) classification grades the severity of heart failure symptoms as one of four functional classes. The NYFIA 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 Fleart 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.
Chronic heart failure may be distinguished according to the ability of the left ventricle to contract is affected (heart failure with reduced ejection fraction) or the heart's abiility to relax is affected (heart failure with preserved ejection fraction).
The term "FIFpEF" refers to heart failure with preserved ejection fraction. FIFpEF is
sometimes also referred to as "Diastolic Fleart Failure".
The term "FIFrEF" refers to heart failure with reduced ejection fraction. FIFrEF is
sometimes also referred to as "Systolic Fleart Failure". The term "LVEF" refers to the left ventricular ejection fraction.
The ejection fraction may be obtained by echocardiography, radionuclide ventriculography and angiography, preferably by echocardiography.
The term "BNP" refers to the brain natriuretic peptide, also called B-type natriuretic peptide. BNP is used for screening and diagnosis for chronic heart failure. The BNP value is determined in the blood plasma or serum.
The term "NT-proBNP" refers to the N-terminal of the prohormone brain natriuretic peptide. NT-proBNP is used for screening and diagnosis for chronic heart failure. The NT- proBNP value is determined in the blood plasma or serum.
Choice of endpoints: 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 b-blockers as well as devices for cardiac resynchronization therapy.
The term "KCCQ" refers to Kansas City Cardiomyopathy Questionnaire. The health related quality of life may be measured according to KCCQ or KCCQ-12. KCCQ-12 is a validated short version of the original 23-item KCCQ (Kansas City Cardiomyopathy Questionnaire). This self-administered questionnaire is designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, self- efficacy, and quality of life in patients with HF.
The term "MLHFQ" refers to Minnesota Living With Heart Failure Questionnaire. The quality of life, including for example its physical, emotional, social and mental dimensions, may be measured according to MLHFQ.
The term“hypertension” is defined as follows: According to a commonly used definition, hypertension is diagnosed if the systolic blood pressure (SBP) exceeds a value of 140 mm Hg and diastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patient is suffering from manifest diabetes it is currently recommended that the systolic blood pressure be reduced to a level below 130 mm Hg and the diastolic blood pressure be lowered to below 80 mm Hg.
The term "body mass index" or "BMI" of a human patient is defined as the weight in kilograms divided by the square of the height in meters, such that BMI has units of kg/m2. The term "overweight" is defined as the condition wherein the individual has a BMI greater than or 25 kg/m2 and less than 30 kg/m2. The terms "overweight" and "pre-obese" are used interchangeably.
The terms "obesity" or "being obese" and the like are defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m2. According to a WHO definition the term obesity may be categorized as follows: the term "class I obesity" is the condition wherein the BMI is equal to or greater than 30 kg/m2 but lower than 35 kg/m2; the term "class II obesity" is the condition wherein the BMI is equal to or greater than 35 kg/m2 but lower than 40 kg/m2; the term "class III obesity" is the condition wherein the BMI is equal to or greater than 40 kg/m2.
The indication obesity includes in particular exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity, visceral obesity, abdominal obesity.
The term "visceral obesity" is defined as the condition wherein a waist-to-hip ratio of greater than or equal to 1 .0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.
The term "abdominal obesity" is usually defined as the condition wherein the waist circumference is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women. With regard to a Japanese ethnicity or Japanese patients abdominal obesity may be defined as waist circumferences 85 cm in men and³ 90 cm in women (see e.g.
investigating committee for the diagnosis of metabolic syndrome in Japan).
The term "euglycemia" is defined as the condition in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg/dl_ (3.89 mmol/L) and less than 100 mg/dl_ (5.6 mmol/L). The word "fasting" has the usual meaning as a medical term.
The term "hyperglycemia" is defined as the condition in which a subject has a fasting blood glucose concentration above the normal range, greater than 100 mg/dL (5.6 mmol/L). The word "fasting" has the usual meaning as a medical term.
The term "hypoglycemia" is defined as the condition in which a subject has a blood glucose concentration below the normal range, in particular below 70 mg/dL (3.89 mmol/L). The term "postprandial hyperglycemia" is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 200 mg/dl_ (1 1 .1 1 mmol/L).
The term "impaired fasting blood glucose" or "IFG" is defined as the condition in which a subject has a fasting blood glucose concentration or fasting serum glucose concentration in a range from 100 to 125 mg/dl (i.e. from 5.6 to 6.9 mmol/l), in particular greater than 1 10 mg/dl_ and less than 126 mg/dl (7.00 mmol/L). A subject with "normal fasting glucose" has a fasting glucose concentration smaller than 100 mg/dl, i.e. smaller than 5.6 mmol/l.
The term "impaired glucose tolerance" or "IGT" is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 140 mg/dl (7.78 mmol/L) and less than 200 mg/dl_ (1 1 .1 1 mmol/L). The abnormal glucose tolerance, i.e. the 2 hour postprandial blood glucose or serum glucose
concentration can be measured as the blood sugar level in mg of glucose per dl_ of plasma 2 hours after taking 75 g of glucose after a fast. A subject with "normal glucose tolerance" has a 2 hour postprandial blood glucose or serum glucose concentration smaller than 140 mg/dl (7.78 mmol/L).
The term "hyperinsulinemia" is defined as the condition in which a subject with insulin resistance, with or without euglycemia, has fasting or postprandial serum or plasma insulin concentration elevated above that of normal, lean individuals without insulin resistance, having a waist-to-hip ratio < 1 .0 (for men) or < 0.8 (for women).
The terms "insulin-sensitizing", "insulin resistance-improving" or "insulin resistance lowering" are synonymous and used interchangeably.
The term "insulin resistance" is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to maintain the euglycemic state (Ford ES, et al. JAMA. (2002) 287:356-9). A method of determining insulin resistance is the euglycaemic-hyperinsulinaemic clamp test. The ratio of insulin to glucose is determined within the scope of a combined insulin-glucose infusion technique. There is found to be insulin resistance if the glucose absorption is below the 25th percentile of the background population investigated (WFIO definition). Rather less laborious than the clamp test are so called minimal models in which, during an intravenous glucose tolerance test, the insulin and glucose concentrations in the blood are measured at fixed time intervals and from these the insulin resistance is calculated. With this method, it is not possible to distinguish between hepatic and peripheral insulin resistance.
Furthermore, insulin resistance, the response of a patient with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia may be quantified by assessing the "homeostasis model assessment to insulin resistance (HOMA-IR)" score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001 ; 24: 362-5). Further reference is made to methods for the determination of the HOMA-index for insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl.1 ): A459) and to an euglycemic clamp study. In addition, plasma adiponectin levels can be monitored as a potential surrogate of insulin sensitivity. The estimate of insulin resistance by the homeostasis assessment model (FIOMA)-IR score is calculated with the formula (Galvin P, et al. Diabet Med 1992;9:921 -8):
HOMA-IR = [fasting serum insulin (mu/mL)] x [fasting plasma glucose(mmol/L)/22.5].
Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score. For the purpose of this invention, insulin resistance is defined as the clinical condition in which an individual has a HOMA-IR score > 4.0 or a HOMA-IR score above the upper limit of normal as defined for the laboratory performing the glucose and insulin assays.
As a rule, other parameters are used in everyday clinical practice to assess insulin resistance. Preferably, the patient's triglyceride concentration is used, for example, as increased triglyceride levels correlate significantly with the presence of insulin resistance.
Individuals likely to have insulin resistance are those who have two or more of the following attributes: 1 ) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1st degree relative with a diagnosis of IGT or IFG or type 2 diabetes.
Patients with a predisposition for the development of IGT or IFG or type 2 diabetes are those having euglycemia with hyperinsulinemia and are by definition, insulin resistant. A typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of pre-diabetes. Thus, it may be that in order to maintain glucose homoeostasis a person needs 2-3 times as much insulin as a healthy person, without this resulting in any clinical symptoms.
"Pre-diabetes" is a general term that refers to an intermediate stage between normal glucose tolerance (NGT) and overt type 2 diabetes mellitus (T2DM), also referred to as intermediate hyperglycaemia. Therefore in one aspect of the present invention "pre diabetes" is diagnosed in an individual if HbA1 c is more or equal to 5.7% and less than 6.5%.
According to another aspect of this invention "pre-diabetes" represents 3 groups of individuals, those with impaired glucose tolerance (IGT) alone, those with impaired fasting glucose (IFG) alone or those with both IGT and IFG. IGT and IFG usually have distinct pathophysiologic etiologies, however also a mixed condition with features of both can exist in patients. Therefore in another aspect of the present invention a patient being diagnosed of having "pre-diabetes" is an individual with diagnosed IGT or diagnosed IFG or diagnosed with both IGT and IFG. Following the definition according to the American Diabetes Association (ADA) and in the context an aspect of the present invention a patient being diagnosed of having "pre-diabetes" is an individual with:
a) a fasting plasma glucose (FPG) concentration <100 mg/dl_ [1 mg/dl_ = 0.05555 mmol/L] and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT), ranging between >140 mg/dl_ and <200 mg/dl_
(i.e., IGT); or
b) a fasting plasma glucose (FPG) concentration between >100 mg/dl_ and <126 mg/dl_ and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT) of <140 mg/dl_ (i.e., IFG); or
c) a fasting plasma glucose (FPG) concentration between >100 mg/dl_ and <126 mg/dl_ and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT), ranging between³140 mg/dl_ and <200 mg/dl_ (i.e., both IGT and IFG).
Patients with "pre-diabetes" are individuals being pre-disposed to the development of type 2 diabetes. Pre-diabetes extends the definition of IGT to include individuals with a fasting blood glucose within the high normal ranges 100 mg/dl_ (J. B. Meigs, et al. Diabetes 2003; 52:1475-1484). The scientific and medical basis for identifying pre-diabetes as a serious health threat is laid out in a Position Statement entitled "The Prevention or Delay of Type 2 Diabetes" issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749).
The methods to investigate the function of pancreatic beta-cells are similar to the above methods with regard to insulin sensitivity, hyperinsulinemia or insulin resistance: An improvement of beta-cell function can be measured for example by determining a HOMA- index (homeostasis model assessment) for beta-cell function, HOMA-B, (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al.,
Diabetes 2003, 52(Suppl.1 ): A459), first and second phase insulin secretion after an oral glucose tolerance test or a meal tolerance test (Stumvoll et al., Diabetes care 2000, 23: 295-301 ), the insulin/C-peptide secretion after an oral glucose tolerance test or a meal tolerance test, or by employing a hyperglycemic clamp study and/or minimal modeling after a frequently sampled intravenous glucose tolerance test (Stumvoll et al., Eur J Clin Invest 2001 , 31 : 380-81 ).
The term "type 1 diabetes" is defined as the condition in which a subject has, in the presence of autoimmunity towards the pancreatic beta-cell or insulin, a fasting blood glucose or serum glucose concentration greater than 125 mg/dl_ (6.94 mmol/L). If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dl_ (1 1 .1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach, in the presence of autoimmunity towards the pancreatic beta cell or insulin. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it. The presence of autoimmunity towards the pancreatic beta-cell may be observed by detection of circulating islet cell autoantibodies ["type 1 A diabetes mellitus"], i.e., at least one of: GAD65
[glutamic acid decarboxylase-65], ICA [islet-cell cytoplasm], IA-2 [intracytoplasmatic domain of the tyrosine phosphatase-like protein IA-2], ZnT8 [zinc-transporter-8] or anti insulin; or other signs of autoimmunity without the presence of typical circulating autoantibodies [type 1 B diabetes], i.e. as detected through pancreatic biopsy or imaging). Typically a genetic predisposition is present (e.g. HLA, INS VNTR and PTPN22), but this is not always the case.
The term "type 2 diabetes mellitus" or "T2DM" is defined as the condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg/dl_ (6.94 mmol/L). The measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dl_ (1 1 .1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it. In a healthy subject, the blood sugar level before taking the glucose will be between 60 and 1 10 mg per dl_ of plasma, less than 200 mg per dl_ 1 hour after taking the glucose and less than 140 mg per dl_ after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is regarded as abnormal glucose tolerance.
The term "late stage type 2 diabetes mellitus" includes patients with a secondary drug failure, indication for insulin therapy and progression to micro- and macrovascular complications e.g. diabetic nephropathy, or coronary heart disease (CHD). The term "LADA" ("latent autoimmune diabetes of adults") refers to patients that have a clinical diagnosis of type 2 diabetes, but who are being detected to have autoimmunity towards the pancreatic beta cell. Latent autoimmune diabetes of adults (LADA) is also known as slowly progressive type 1 diabetes mellitus (T1 DM), "mild" T1 DM, non-insulin dependent type 1 DM, type 1 ½ DM, double diabetes or antibody positive type 2 DM (T2DM). LADA is often not clearly defined and, opposed to T1 DM, seldom or never presents with significant weight loss and ketoacidosis due to rapidly progressive b-cell failure.
The term "HbA1 c" refers to the product of a non-enzymatic glycation of the haemoglobin B chain. Its determination is well known to one skilled in the art. In monitoring the treatment of diabetes mellitus the HbA1 c value is of exceptional importance. As its production depends essentially on the blood sugar level and the life of the erythrocytes, the HbA1 c in the sense of a "blood sugar memory" reflects the average blood sugar levels of the preceding 4-6 weeks. Diabetic patients whose HbA1 c value is consistently well adjusted by intensive diabetes treatment (i.e. < 6.5 % of the total haemoglobin in the sample), are significantly better protected against diabetic microangiopathy. For example, metformin on its own achieves an average improvement in the HbA1 c value in the diabetic of the order of 1 .0 - 1 .5 %. This reduction of the HbA1 C value is not sufficient in all diabetics to achieve the desired target range of <7% or < 6.5 % and preferably < 6 % HbA1 c.
The term "insufficient glycemic control" or "inadequate glycemic control" in the scope of the present invention means a condition wherein patients show HbA1 c values above 6.5 %, in particular above 7.0 %, even more preferably above 7.5 %, especially above 8 %.
The "metabolic syndrome", also called "syndrome X" (when used in the context of a metabolic disorder), also called the "dysmetabolic syndrome" is a syndrome complex with the cardinal feature being insulin resistance (Laaksonen DE, et al. Am J Epidemiol 2002;156:1070-7). According to the ATP lll/NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III) JAMA: Journal of the American Medical Association (2001 )
285:2486-2497), diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present:
1 . Abdominal obesity, defined as waist circumference > 40 inches or 102 cm in men, and > 35 inches or 94 cm in women; or with regard to a Japanese ethnicity or Japanese patients defined as waist circumferences 85 cm in men and³ 90 cm in women;
2. Triglycerides:³ 150 mg/dl_
3. HDL-cholesterol < 40 mg/dl_ in men
4. Blood pressures 130/85 mm Hg (SBPs 130 or DBPs 85)
5. Fasting blood glucoses 100 mg/dl_
The NCEP definitions have been validated (Laaksonen DE, et al. Am J Epidemiol. (2002)
156:1070-7). T riglycerides and HDL cholesterol in the blood can also be determined by standard methods in medical analysis and are described for example in Thomas L
(Editor): "Labor und Diagnose", TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.
The term "albuminuria" is defined as a condition wherein more than the normal amount of albumin is present in the urine. Albuminuria can be determined by the albumin excretion rate (AER) and/or the albumin-to-creatine ratio (ACR) in the urine (also refered to as UACR). Albuminuria categories in CKD are defined as follows:
Figure imgf000017_0001
Category A1 reflects no albuminuria, category A2 reflects microalbuminuria, category A3 reflects macroalbuminuria. The progression of category A1 usually leads to
microalbuminuria (A2) but may also directly result in macroalbuminuria (A3). Progression of microalbuminuria (A2) results in macroalbuminuria (A3).
The term "eGFR" refers to estimated glomerular filtration rate. The GFR describes the flow rate of filtered fluid through the kidney. The estimated GFR may be calculated based on serum creatinine values e.g. using the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) equation, the Cockcroft-Gault formula or the Modification of Diet in Renal Disease (MDRD) formula, which are all known in the art.
Within the context of the present invention the eGFR is calculated by the Modification in Diet in Renal Disease (MDRD) formula, which is the one recommended by NICE and The Renal Association (UK), and which is based on the equation described in Levey AS,
Bosch JP, Lewis JB, et al;“A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.” Ann Intern Med. 1999 Mar 16;130(6):461 -70.
Alternatively, the estimated glomerular filtration rate (eGFR) can be derived from serum creatinine values, age sex and race based on the CKD-EPI equation:
GFR = 141 x min (Scr /K, 1 )Q * max(Scr /K, 1 )"1 209 * 0.993A9e * 1 .018 [if female] * 1 .159 [if black]
wherein:
Scr is serum creatinine in mg/dl_,
K is 0.7 for females and 0.9 for males,
a is -0.329 for females and -0.41 1 for males,
min indicates the minimum of Scr /K or 1 , and
max indicates the maximum of Scr /K or 1.
For the purpose of the present invention, the degree of renal impairment in a patient is defined by the following estimated glomerular filtration rate (eGFR):
Normal renal function (CKD stage 1 ): eGFR³ 90 mL/min/1.73 m2
Mild renal impairment (CKD stage 2): eGFR³60 to <90 ml_/min/1.73 m2
Moderate renal impairment (CKD stage 3): eGFR³30 to <60 mL/min/1 .73 m2
Severe renal impairment (CKD stage 4): eGFR³15 to <30 mL/min/1.73 m2
Kidney failure (CKD stage 5): eGFR <15 mL/min/1 .73 m2
According to the present invention moderate renal impairment can be further divided into two sub-stages:
Moderate A renal impairment (CKD 3A): eGFR³45 to <60 mL/min/1.73 m2 Moderate B renal impairment (CKD 3B): eGFR³30 to <45 mL/min/1.73 m2
Valsartan
Valsartan (CAS number 137862-53-4) is an Angiotensin II Receptor Antagonist (ARB) and is the INN for the compound name N-(1 -oxopentyl)-N-[2’-(1 -tetrazol-5-yl)methyl]-valine (also termed S-N-valeryl-N-{[2’-(1 FI-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine). It has the formula:
Figure imgf000019_0001
Valsartan can be purchased from commercial sources or can be prepared according to known methods, such as described in U.S. Patent No. 5,399,578 and EP 0443983, whose preparative teachings are incorporated by reference herein. Valsartan may be used in certain embodiments of the invention in its free acid form, as well as in any suitable salt form. Depending upon the circumstance, esters or other derivatives of the carboxylic grouping may be employed as well as salts and derivatives of the tetrazole grouping.
Sacubitril
Sacubitril (CAS number 149709-62-6; also known as AHU377) is a prodrug for an NEP inhibitor is the INN for a compound with the chemical name A/-(3-carboxyl-1 -oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2/:?)-methyl butanoic acid ethyl ester. Sacubitril has the formula:
Figure imgf000019_0002
The synthesis, salts and many properties of that compound are, for example, described in US 5,217,996, WO 2008/083967 and others. These, especially with regard to the features just mentioned, are incorporated here by reference. 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 sacubitrilat) that is formed from the prodrug in vivo. Sacubitril and Valsartan in a 1 :1 molar ratio
In the context of the present invention, the term“sacubitril and valsartan in a 1 :1 molar ratio” refers to a 1 :1 molar ratio of valsartan or a pharmaceutically acceptable salt thereof; and sacubitril or a pharmaceutically acceptable salt thereof.
In one embodiment, said sacubitril and valsartan in a 1 :1 molar ratio 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.
In one embodiment, sacubitril and valsartan in a 1 :1 molar ratio is provided in the form of the compound of the formula (I)
[(Ai)(A2)](Na+)3 - x H20 (I)
wherein
Ai is valsartan in the dianionic form;
A2 is sacubitril in the anionic form;
Na+ is a sodium ion; and
x is 0.5 to 7.
SGLT-2 inhibitors
SGLT-2 inhibitors have been developed for the treatment or improvement of glycemic control in patients with type 2 diabetes. More recently, SGLT-2 inhibitors have also shown to reduce hospitalizations in patients with heart failure.
Suitable SGLT-2 inhibitors which have already been approved or are in clinical development include dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, tofogliflozin, remogliflozin (or remogliflozin etabonate), luseogliflozin, ipragliflozin, atigliflozin, bexagliflozin, and henagliflozin.
Known SGLT-2 inhibitor are for example:
- dapagliflozin (US patent No 6,414,126 and WO 03/099836), having the following
structural formula:
Figure imgf000020_0001
Crystalline forms thereof are described for example in WO 2008/002824 and WO 2008/1 16179.
empagliflozin (US patent No 7,579,449 and WO 2005/092877) (1 -chloro-4-(3-D- glucopyranos-1 -yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene), having the following structural formula:
Figure imgf000021_0001
Methods of synthesis are described in the literature, for example WO 2006/120208 and WO 201 1 /039108. According to this invention, it is to be understood that the definition of empagliflozin also comprises its hydrates, solvates and polymorphic forms thereof, and prodrugs thereof. An advantageous crystalline form of empagliflozin is described in WO 2006/1 17359 and WO 201 1 /039107, which hereby are incorporated herein in their entirety. This crystalline form possesses good solubility properties which enables a good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline form is physico-chemically stable and thus provides a good shelf-life stability of the pharmaceutical composition. Preferred pharmaceutical compositions, such as solid formulations for oral administration, for example tablets, are described in WO
2010/092126, which hereby is incorporated herein in its entirety.
- canagliflozin (US patent No. 7,943,788 or WO 2005/012326 and WO 2009/035969), having the following structural formula:
Figure imgf000021_0002
Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327 for example ertugliflozin (US patent No. 8,080,580), having the following structural formula:
Figure imgf000022_0001
sotagliflozin (US patent No. 7,781 ,577), having the following structural formula:
Figure imgf000022_0002
- tofogliflozin (US patent No. 7,767,651 or WO 2007/140191 ), having the following structural formula:
Figure imgf000022_0003
remogliflozin (EP 1354888 A1 ), having the following structural formula
Figure imgf000023_0001
in particular remogliflozin etabonate
Figure imgf000023_0002
luseogliflozin (US patent No 7,910,619, and EP1845095B1 ) having the following structural formula:
Figure imgf000023_0003
ipragliflozin (WO 2004/080990), having the following structural formula:
Figure imgf000024_0001
atigliflozin (WO 2004/007517), having the following structural formula:
Figure imgf000024_0002
bexagliflozin (US patent No. 7,838,499), having the following structural formula
Figure imgf000024_0003
Henagliflozin (US patent No. 8,609,622 and EP patent No. EP2604612B1 ), having the following structural formula:
Figure imgf000025_0001
Another known SGLT inhibitor ((2S,3R,4R,5S,6R)-2-(3-((2,3-dihydrobenzo[b][1 ,4]dioxin-6- yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound C)) having the following structural formula
Figure imgf000025_0002
is disclosed in WO 201 1/0481 12, incorporated by reference herein, which shows inhibition of both SGLT-1 and SGLT-2. Dual inhibition of SGLT-1 and SGLT-2 results in glucose excretion through the kidneys (SGLT-2 and SGLT-1 ) in an insulin independent manner, decreased intestinal glucose absorption (SGLT-1 ), as well as an increased release of incretin hormones (SGLT-1 ).
The terms of the different compounds named and displayed above, as employed herein, always refers to the respective compound, including hydrates and solvates thereof, and crystalline forms thereof, and - if applicable - pharmaceutically acceptable salts as well as their hydrates, solvates and crystalline forms.
Combination
The term“combination” as used herein 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 a more than additive 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 valsartan, the NEP inhibitor prodrug sacubitril and an SGLT-2 inhibitor, or pharmaceutically acceptable salts thereof, respectively).
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.
The term“fixed combination” means that the active ingredients are administered to a patient simultaneously in the form of a single entity or dosage. In other terms: the active ingredients are present in one dosage form, e.g. in one tablet or in one capsule.
The term“non-fixed combination” means that the active ingredients are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration still provides therapeutically effective levels of the two compounds in the body of the patient. The term“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. simultaneously or at different time points, where 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. Very preferably, 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. Detailed Description
As indicated above, it has now been surprisingly found that a combination comprising the Angiotensin II Receptor Antagonist (ARB) valsartan, the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril and a Sodium-D-glucose co-transporter (SGLT) inhibitor can lead to an improved, preferably more than additive, especially synergistic, effect in the treatment of cardiovascular diseases.
Accordingly, the present invention is directed to a combination comprising
(i) the Angiotensin II Receptor Antagonist (ARB) valsartan;
(ii) the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril; and
(iii) an SGLT-2 inhibitor,
wherein each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt.
In one embodiment the combination of the invention comprises an SGLT-2 inhibitor selected from the group consisting of dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, tofogliflozin, remogliflozin (or remogliflozin etabonate), luseogliflozin, ipragliflozin, atigliflozin, bexagliflozin, and henagliflozin, wherein the DGLT-2 inhibitor may be present in free form or in the form of a pharmaceutically acceptable salt.
In one embodiment, the SGLT-2 inhibitor is dapagliflozin.
In one embodiment, the SGLT-2 inhibitor is empagliflozin.
In one embodiment, the SGLT-2 inhibitor is canagliflozin.
In one embodiment, the SGLT-2 inhibitor is ertugliflozin.
In one embodiment, the SGLT-2 inhibitor is sotagliflozin.
In one embodiment, the SGLT-2 inhibitor is tofogliflozin.
In one embodiment, the SGLT-2 inhibitor is remogliflozin (or remogliflozin etabonate).
In one embodiment, the SGLT-2 inhibitor is luseogliflozin.
In one embodiment, the SGLT-2 inhibitor is ipragliflozin.
In one embodiment, the SGLT-2 inhibitor is atigliflozin.
In one embodiment, the SGLT-2 inhibitor is bexagliflozin.
In one embodiment, the SGLT-2 inhibitor is henagliflozin. Any of the ARB, NEP inhibitor or prodrug thereof, and SGLT-2 inhibitor mentioned so far herein can, in the combinations according to the invention, be present in free (= non-salt) form, in the form of a pharmaceutically acceptable salt, a solvent form of the free form or pharmaceutically acceptable salt, or as a mixture of two or more of these forms.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and empagliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and canagliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and ertugliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and sotagliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and tofogliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and remogliflozin, or a pharmaceutically acceptable salt thereof, or remogliflozin etabonate.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and luseogliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and ipragliflozin, or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and atigliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and bexagliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a combination of valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and henagliflozin, or a pharmaceutically acceptable salt thereof.
In one embodiment of the invention the combination comprises (based on the molar ratio of the free form of the respective compound) a 1 :1 molar ratio of valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof.
In one embodiment, said 1 :1 sacubitril/valsartan part of the combination is provided in the form of the compound of the formula (I)
[(Ai)(A2)](Na+)y * x H20 (l)
wherein
Ai is valsartan in the dianionic form;
A2 is sacubitril in the anionic form;
Na+ is a sodium ion; and
x is 0.5 to 7.
In one embodiment thereof, 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.
In one embodiment thereof, 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.
In one embodiment thereof, 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.
In one embodiment thereof, the compound of formula (I) is in amorphous form.
In one embodiment thereof, 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.
In one embodiment thereof, the compound of formula (I) is in crystalline form. In one embodiment thereof, 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.
In one embodiment thereof, 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 is present in crystalline form.
In one embodiment, 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 in crystalline form is also referred to as LCZ696.
Pharmaceutical compositions and compounds containing sacubitril and valsartan, for example in the form of LCZ696, and their uses have for example been previously disclosed in W02003059345, W02007056546, W02009061713, WO2012027237,
WO2014029848, WO201503071 1 , WO2015028941 , WO2016181284, WO2016193883, WO2017006254 and WO2017037577, which are herein incorporated by reference.
Pharmaceutical 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, WO2016051393, CN105503760A, CN105669581 A, WO2016125123, CN105929031 A, WO2016151525, CN106032361 A, WO2016201238, CN106316973A, W02017012917, WO2017009784, WO2017037591 , WO2017036420, WO2017037596, WO2017042700, CN106518709A, WO2017085573, IN03835DE2015, WO2017097085, IN04304DE2015, CN107033094A, WO2017154017, WO2017191619, IN201641010897A,
IN201641022870A, CN107674038A, TW201806936A, WO2018069833, WO2018069937, and WO2018078592, which are 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.
Preferably, the active ingredients sacubitril or a salt thereof, valsartan or a salt thereof, compounds of formula (I), in particular LCZ696, and the SGLT-2 inhibitors are
substantially pure or in a substantially pure form. As used herein,“substantially pure” refers to at least about 90% purity, more preferably at least about 95% and most preferably at least about 98% purity. Also preferred is that 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.
The pharmaceutical 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 excipients, especially suitable for enteral or parenteral application.
The pharmaceutical 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. The term “about” or“approximately”, as used herein in each instance, shall have the meaning of within 10%, more preferably within 5%, of a given value or range.
Pharmaceutical 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. Thus, pharmaceutical compositions for oral use can be obtained by combining the active ingredient with solid excipients, 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. Similarly, 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.
Other 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. The pharmaceutical compositions include active ingrediens 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 excipient or carrier (e.g. water) before ingestion. 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.
In one embodiment, 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).
Alternatively, pharmaceutical 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.
In embodiments, where sacubitril and valsartan in a 1 :1 molar ratio are presented in the form of 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 unit dose of for example 100 mg LCZ696 delivers 100 mg of the two agents sacubitril and valsartan (i.e. 49 mg sacubitril and 51 mg valsartan) and amounts to 1 13.1 mg of 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. Correspondingly, a unit dose of 50 mg LCZ696 requires 56.6 mg, a unit dose of 200 mg LCZ696 requires 226.2 mg, and a unit dose of 400 mg LCZ696 requires 452.4 mg of 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, respectively.
Pharmaceutical 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. Preferably 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.
In one embodiment of the present invention, 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.
In one embodiment thereof, 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. in other words, 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.
In one embodiment thereof,
a) the 50 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to 24 mg sacubitril and 26 mg valsartan,
b) the 100 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to 49 mg sacubitril and 51 mg valsartan, and
c) the 200 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to 97 mg sacubitril and 103 mg valsartan.
In a particular embodiment of the pharmaceutical composition, 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, wherein
a) the 50 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to around
56.6 mg 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,
b) the 100 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to around
1 13.1 mg 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, and
c) the 200 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to around
226.2 mg 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. Accordingly, one embodiment of the invention relates to a combination comprising (based on the molar ratio of the free form of the respective compound) a 1 :1 molar ratio of valsartan and sacubitril in any of the forms as described in the various embodiments above in combination with any of the SGLT-2 inhibitors or a pharmaceutically acceptable salt thereof listed above. In such combination, the SGLT-2 inhibitor may for example be present in a molar amount of 0.01 to 100 mol per mol of valsartan/sacubitril.
In one embodiment, the combination according to invention comprises the SGLT-2 inhibitor 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, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg or 1000 mg.
In one embodiment of the invention, the combination is delivered twice delay to the patient.
In another embodiment of the invention, 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.
In one embodiment, each intake comprises 103 mg or less, e.g. down to 1 mg, of valsartan, or a pharmaceutically acceptable salt thereof, and 97 mg or less, e.g. down to 1 mg, of sacubitril, or a pharmaceutically acceptable salt thereof, and 1000 mg or 500 mg or less, e.g. down to 1 mg, of a SGLT-2 inhibitor, or a pharmaceutically acceptable salt thereof, and per dosage unit.
In one aspect of the present invention, the combination of sacubitril and valsartan is administered twice daily (b.i.d.), whereas and the SGLT-2 inhibitor is only administered once daily (QID). In one embodiment, this is realized by a kit comprising
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 and the SGLT-2 inhibitor (as defined herein).
In one embodiment of the invention the cardiovascular disease is heart failure with reduced ejection fraction or heart failure with preserved ejection fraction or acute heart failure.
In another embodiment of the invention the metabolic disease is pre-diabetes, type 1 diabetes mellitus, type 2 diabetes mellitus adiposity, obesity or metabolic syndrome, or a combination of two or more of these conditions. In the context of the present invention, methods of treatment, amelioration, prevention, delay of progression or delay of occurrence of a cardiovascular disease, renal disease and/or metabolic disease include
- methods for reducing the risk of cardiovascular death in the patient.
- methods for reducing the risk of (first and recurrent) hospitalization for an acute
decompensated heart failure (ADHF) episode in the patient.
- methods for treating, preventing, protecting against, reducing the risk of or delaying the occurrence of acute heart failure, including acute decompensated heart failure.
- methods for reducing all-cause mortality in the patient.
- methods for reducing the risk of all-cause hospitalization in the patient
methods for reducing the risk of new onset of atrial fibrillation in the patient
- methods for improving the health related quality of life and/or the functional capacity in the patient.
In another embodiment, the methods of treatment, amelioration, prevention, delay of progression or delay of occurrence of a cardiovascular disease, renal disease and/or metabolic disease include
methods for improving the renal function in the patient.
- methods for reducing the risk of, delaying the occurrence of and/or delaying the
progression of chronic kidney disease in the patient.
In another embodiment, the methods of treatment, amelioration, prevention, delay of progression or delay of occurrence of a cardiovascular disease, renal disease and/or metabolic disease include methods for preventing, slowing or reversing the progression to macroalbuminuria in the patient.
In one embodiment of these embodiments, the patient is a patient with heart failure with reduced ejection fraction or heart failure with preserved ejection fraction.
In one embodiment of these embodiments, the patient has heart failure with reduced ejection fraction.
In an alternative embodiment of these embodiments, the patient has heart failure with preserved ejection fraction.
In one embodiment, the present invention provides a method of treatment comprising: a) identifying a patient in need of treatment for chronic heart failure ; and b) administering the combination of the invention to said patient.
In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising:
a. determining the symptoms according to the NYHA classification of the patient; b. identifying that the patient has chronic heart failure according to NYHA class II, III or IV;
c. administering the combination of the invention to the patient.
In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising:
a. determining the ejection fraction of the patient;
b. identifying that the patient has an ejection fraction equal or smaller than 40%; c. administering the combination of the invention to the patient.
In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising:
a. determining the symptoms according to the NYHA classification of the patient; b. determining the ejection fraction of the patient;
c. identifying that the patient has chronic heart failure according to NYHA class II, III or IV and has an ejection fraction equal or smaller than 40%;
d. administering the combination of the invention to the patient.
In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising:
a. determining the symptoms according to the NYHA classification of the patient; b. determining the ejection fraction of the patient;
c. identifying that the patient has chronic heart failure according to NYHA class II, III, or IV and has an ejection fraction greater than 40%, in particular greater than 50%;
d. administering the combination of the invention to the patient.
In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising: a. determining the symptoms according to the NYHA classification of the patient; b. determining the ejection fraction of the patient;
c. determining the BNP or NT-proBNP value of the patient;
d. identifying that the patient has chronic heart failure according to NYHA class II,
III or IV and has an ejection fraction equal or smaller than 40%, in particular greater than 50%, and has an elevated BNP or NT-proBNP value;
e. administering the combination of the invention to the patient.
According to this embodiment an elevated BNP or NT-proBNP value is particularly a BNP value equal to or greater than 150 pg/mL or a NT-proBNP value equal to or greater than 600 pg/mL Furthermore according to this embodiment an elevated BNP or NT-proBNP value is particularly a BNP value equal to or greater than 100 pg/mL or a NT-proBNP value equal to or greater than 400 pg/mL if the patient was hospitalized for heart failure within the last 9 months.
In one embodiment, the patient suffering from chronic systolic heart failure, in particular the patient with heart failure with reduced ejection fraction, has at least one of the following characteristics:
i) heart failure of NYHA class II, III or IV,
ii) 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, and
iii) a reduced left ventricular ejection fraction (LVEF) of £40%.
In addition, the patient might be characterized by one or more of the following:
iv) prior hospitalization for heart failure within the last 12 months,
vi) systolic blood pressure ³ 95 mm Hg,
vii) eGFR ³ 30 ml/min/1.73 m2 and
viii) serum K £ 5.4 mEq/L.
In one embodiment, 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%. In one embodiment, 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.
In another embodiment, 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.
In another embodiment the mortality is a sudden death.
In a further embodiment, 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.
In another embodiment, the therapeutically effective amount of compound of a
combination according to the invention has been shown to reduce the rate of
cardiovascular death and heart failure hospitalization in patients with chronic heart failure classified as NYHA class II, III or IV with systolic dysfunction, preferably wherein the patient also has a reduced left ventricular ejection fraction (LVEF) of £40%.
In one embodiment, the therapeutically effective amount of a combination according to the invention has been shown to reduce the rate of all-cause mortality.
In a further embodiment, 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.
In one embodiment, 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.
In a further embodiment, 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). 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 the SGLT-2 inhibitor, 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.
Individuals with three or more of these conditions are diagnosed with metabolic syndrome.
Metabolic syndrome (also called syndrome X) is becoming an increasingly common diag nosis 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. It is known that one of the diseases that commonly develops in patients with metabolic syndrome is type II diabetes; in turn, the number one cause of death of patients with type II diabetes is atherosclerosis, a disease that causes plaques to build up in the arteries and eventually lead to heart attacks and stroke.
All the aforementioned embodiments for the methods of protection and treatment according to the present invention are equally applicable to
the use of a combination according to the invention as defined herein for the manufacture of a combination, especially free combination or combination product or medicament for use according to the present invention,
- the use of a combination, especially a free combination or combination product or medicament according to the invention as defined herein according to the present invention,
- a combination according to the invention as defined herein for use according to the present invention,
a free combination, combination product or medicament in the form of one or more pharmaceutical compositions comprising a combination according to the present invention as defined herein for the use according to the present invention, the use of a free combination, combination product or medicament in the form of one or more pharmaceutical compositions comprising a combination accoding to the invention as defined herein according to the present invention and
the use of the free combination, combination product or medicament in the form of one or more pharmaceutical compositions comprising a combination according to the invention as defined herein for the manufacture of a free combination, combination product or medicament for use according to the present invention.
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.
The following Examples illustrate the invention without limiting its scope:
Example 1 : Fixed combination of sacubitril, valsartan and the SGLT-2 inhibitor luseoaliflozin
A) Sacubitril sodium salt, valsartan and luseogliflozin are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
B)
Sacubitril calcium salt, valsartan and luseogliflozin are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
B)
Sacubitril calcium salt, valsartan calcium and luseogliflozin are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
C)
LCZ696 (trisodium sacubitril valsartan hemipentahydrate) and luseogliflozin are combined in a single tablet formulation using a binder, a diluent and a disintegrant.
Example 2: Animal models to assess the effectiveness of the combinations of the invention
The effectiveness of the combination of the invention can be investigated in the following models:
1 . DIO (diet induced obesity) rat model: Glucose control
2. DIO (diet induced obesity) rat model: Insulin resistance
3. DSS (Dale salt sensitive) rat model: BP control
4. DSS (Dale salt sensitive) rat model: 24 hr diuresis/natriuresis
5. DSS (Dale salt sensitive) rat model: NTproBNP (HF)
6. DSS (Dale salt sensitive) rat model: heart/kidney weight (28 d)
Example 2A: A preclinical study design for Heart Failure:
Goal: Demonstrate that an ARB / NEPi / SGLT2-i combination will provide a more than additive, preferably synergistic pharmacodynamic response for mechanisms contributing to HF pathophysiology - blood pressure (BP), diuresis, and natriuresis.
Study design: Assessment of BP response, natriuresis, and diuresis response to single agent and combined agent in Dahl Salt-sensitive (DSS) hypertensive rats following 4 weeks of therapy. : 5 groups (n=6) of telemetry implanted DSS rats
- Normal salt diet
High salt diet (HSD) + vehicle (4 weeks treatment)
HSD + ARB + NEPi (4 weeks treatment)
HSD + SGLT2i (4 weeks treatment)
HSD + ARB + NEPi + SGLT2i (4 weeks treatment)
Read-outs
Primary: BP/HR (change from baseline); 24 hr diuresis/natriuresis (day -3, 1 , 7, 14, 21 and 28, referenced to d-3 baseline)
- Secondary/Exploratory: Plasma HF markers (NTproBNP, sST2), heart
weight/kidney weight at day 28, histology
Total n = 30 rats and 6 weeks + study with 1 dedicated person (PK studies not included).
Interpretation: Evidence of an increased response in the primary readouts for the combined therapy arm over the additive effects of the‘monotherapy’ arms will support the claim of a more than additive, preferably a synergistic effect relevant to HF.
Example 2B: A preclinical study design for Heart Failure:
Goal: Demonstrate an an ARB / NEPi / SGLT2-i combination will provide a more than additive, preferably synergistic pharmacodynamic response for mechanisms contributing to HF pathophysiology via impact on metabolic MOA - glucose tolerance, insulin sensitivity, and heart weight, in DIO diet induced obesity mouse model
Study design: Assessment of glucose tolerance, insulin sensitivity, body weight, heart weight, fat mass and liver steatosis in DIO mouse model in 18 week-old male DIO mice on high fat diet from 6 weeks of age following 4 weeks of therapy.
4 groups (n=6) of DIO mice:
Vehicle (PBS, 4 weeks treatment)
ARB + NEPi (4 weeks treatment)
- SGLT2i (4 weeks treatment)
ARB + NEPi + SGLT2i (4 weeks treatment)
Read-outs - Primary: Blood glucose (fasting), insulin and lipids (TG and FFA, fasting), insulin tolerance test (ITT) and oral glucose tolerance testing
- Secondary/Exploratory: Plasma HF markers (NT-proBNP, sST2), heart weight (and other organs - liver, fat, kidney) at day 28, histology, body weight and food intake, body composition, liver steatosis
Interpretation: Evidence of an increased response in the primary or exploratory readouts for the combined therapy arm over the additive effects of the‘monotherapy’ arms will support the claim of an improved effect, preferably a more than additive, especially a synergistic effect relevant to HF.
Example 3: Clinical trial
A randomized, double-blind, parallel group, active-controlled, two-arm, event-driven trial comparing the long-term efficacy and safety of luseogliflozin and LCZ696 on morbidity and mortality in patients with chronic symptomatic heart failure and reduced ejection fraction (HF-.
LCZ696:
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-S-ylatejbiphenyl-^-ylmethylJaminojbutyratejhemipentahydrate. This compound and pharmaceutical compositions thereof have been previously disclosed in
W02007/056546 and WO 2009/061713, whose preparative teachings are incorporated herein by reference.
LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that comprises the mole cular 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. 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.
Luseogliflozin
The SGLT-2 inhibitor luseogliflozin (US patent No 7,910,619, and EP1845095B1 ) has the following structural formula:
Figure imgf000044_0001
and 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% are eligible. Patients enter a single blind luseogliflozin run-in period which, depending on tolerability, is followed by an LCZ696 run-in period. Then, patients tolerating both drugs at the target dose, are randomized 1 :1 to either luseogliflozin or LCZ696. The primary outcome is the composite of cardiovascular death or HF hospitaliza tion, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death with LCZ696, compared with luseogliflozin. 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.
Detailed Study Design and Procedures
TRIAL DESIGN AND METHODS
The study is a randomized, double-blind, parallel group, active-controlled, two-arm, event- driven trial comparing the long-term efficacy and safety of luseogliflozin and LCZ696 in patients with chronic symptomatic heart failure and reduced ejection fraction (HF-REF). Patients
Entry criteria: 1 ) age 18 years or older and able to give written informed consent 2) New York Heart Association (NYHA) functional class ll - IV, 3) left ventricular ejection fraction (LVEF) £ 35% (initially this was £ 40% but changed in a protocol amendment dated December 15, 2010), 4) plasma B-type natriuretic peptide (BNP) ³ 150 pg/ml (or N- terminal [NT]-proBNP ³ 600 pg/ml) at the screening visit or a BNP ³ 100 pg/mL (or NT- proBNP ³ 400 pg/ml) and a hospitalization for HF within the last 12 months, 5) treatment with a stable dose of an ACE inhibitor or an ARB equivalent to enalapril 10 mg/d for at least 4 weeks before the screening visit, 6) treatment with stable dose of a b-blocker for at least 4 weeks prior to Visit 1 , unless contraindicated or not tolerated. Although not required, the protocol specified that an aldosterone antagonist should also be considered in all patients, taking account of renal function, serum potassium and tolerability. If given, the dose of aldosterone antagonist should be stable for at least 4 weeks prior to the screening visit.
The key exclusion criteria include:
1 . History of hypersensitivity or allergy to any of the study drugs, drugs of similar
chemical classes, SGLT-2 inhibitors, angiotensin receptor blockers (ARBs) or neprilysin inhibitors as well as known or suspected contraindications to the study drugs.
2. Previous history of intolerance to recommended target doses of SGLT-2 inhibitors or ARBs.
3. Current acute decompensated heart failure (exacerbation of chronic heart failure
manifested by signs and symptoms that may require intravenous therapy).
4. Symptomatic hypotension and/or a systolic blood pressure (SBP) < 100 mmHg at Visit 1 (screening) or < 95 mmHg at Visit 3 or at Visit 5 (randomization).
5. Estimated GFR (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.
6. Serum potassium > 5.2 mmol/L at Visit 1 (screening) or > 5.4 mmol/L at Visit 3 or Visit 5 (randomization).
7. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention or carotid angioplasty within the 3 months prior to Visit 1 .
8. Coronary or carotid artery disease likely to require surgical or percutaneous
intervention within the 6 months after Visit 1 .
9. Implantation of a cardiac resynchronization therapy device (CRT) within 3 months prior Visit 1 or intent to implant a CRT. 10. History of heart transplant or on a transplant list or with left ventricular assistance device.
1 1. History of severe pulmonary disease.
12. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12
months prior to Visit 1.
13. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1.
14. Symptomatic bradycardia or second or third degree atrio-ventricular block without a pacemaker.
15. Presence of haemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation.
16. Presence of other haemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis.
17. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of study drugs, including but not limited to any of the following:
• History of active inflammatory bowel disease during the 12 months before Visit 1.
• Active duodenal or gastric ulcers during the 3 months prior to Visit 1 .
• Evidence of hepatic disease as determined by any one of the following: aspartate aminotransferase or alanine aminotransferase values exceeding 2 x upper limit of normal at Visit 1 , history of hepatic encephalopathy, history of oesophageal varices, or history of porto-caval shunt.
• Current treatment with cholestyramine or colestipol resins.
18. Presence of any other disease with a life expectancy of < 5 years.
STUDY DESIGN
The study consists of four phases: 1 ) screening, 2) single-blind luseogliflozin run-in, 3) and single-blind LCZ696 run-in, and 4) randomized double-blind treatment.
Screening (Visit 1 )
At the screening visit, patient eligibility are assessed according to the inclusion/exclusion criteria. Any local measurement of LVEF £35%, made within the past 6 months, is acceptable provided there is no subsequent LVEF measurement above 35%. Eligibility BNP (and NT-proBNP), serum potassium and estimated glomerular filtration rate (eGFR) are measured in a central laboratory.
Luseogliflozin Active Run-in Period (Visit 2)
At Visit 2, most eligible patients started two weeks of single-blind treatment with luseogliflozin.
LCZ696 Active Run-in Period (Visits 3 and 4)
At visit 3, patients started single-blind treatment with LCZ696.
Randomization to double-blind treatment (Visit 5)
Patients tolerating both luseogliflozin and LCZ696 are randomized in a 1 :1 ratio to double blind treatment with either luseogliflozin or LCZ696. Study visits occur every 2 to 8 weeks during the first 4 months of the double-blind period and every 4 months thereafter (with additional unscheduled visits, at the discretion of the investigator).
Monitoring of safety and tolerability during double blind period
Patients are assessed at each study visit for hyperkalaemia, symptomatic hypotension, increase in serum creatinine, angioedema and other AEs and serious AEs (SAEs).
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 b-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.
STUDY OBJECTIVES
Primary objectives
The purpose of this study is to evaluate the effect of LCZ696 compared with luseogliflozin, in addition to conventional heart failure treatment, in delaying time to first occurrence of either cardiovascular death or heart failure hospitalization.
In order to analyze the effects of the combination, trial designs such as described in WO2017157816 for empagliflozin for the treatment of heart failure, which is incorporated by reference, can also be used be adding an additional treatment arm using for example 200 mg LCZ696.

Claims

CLAIMS:
1 . A combination comprising
(iv) the Angiotensin II Receptor Antagonist (ARB) valsartan;
(v) the Neutral Endopeptidase inhibitor (NEP inhibitor) prodrug sacubitril; and
(vi) an SGLT-2 inhibitor,
wherein each of the combination partners may be present in free form or in the form of a pharmaceutically acceptable salt.
2. The combination according to claim 1 , wherein the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, tofogliflozin, remogliflozin (or remogliflozin etabonate), luseogliflozin, ipragliflozin, atigliflozin, bexagliflozin, and henagliflozin.
3. The combination according to claim 2, wherein the SGLT-2 inhibitor is luseogliflozin.
4. The combination according to anyone of claims 1 to 3, wherein the combination comprises - based on the molar ratio of the free form of the respective compound - a 1 :1 molar ratio of valsartan and sacubitril in combination with the SGLT-2 inhibitor, which is present in a molar amount of 0.01 to 100 mol per mol of valsartan/sacubitril.
5. The combination according to claim 4, wherein the combination comprises sacubitril and valsartan in a 1 :1 molar ratio with an overall dose of 50 mg, 100 mg, or 200 mg, wherein
a) the 50 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to 24 mg sacubitril and 26 mg valsartan,
b) the 100 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to 49 mg sacubitril and 51 mg valsartan, and
c) the 200 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to 97 mg sacubitril and 103 mg valsartan.
6. The combination according to any one of claims 1 to 5, wherein sacubitril and
valsartan are present in the form of a compound of the formula (I),
[(Ai)(A2)](Na+)3 · x H20 (I
wherein
Ai is valsartan in the anionic form;
A2 is sacubitril in the anionic form; Na+ is a sodium ion; and
x is 0.5 to 7.
7. The combination according to claim 6, wherein said 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}ami- no)butyrate] hemipentahydrate.
8. The combination according to claim 6, wherein
a) the 50 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to around 56.6 mg of the compound of formula (I) with x=2.5,
b) the 100 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to around 1 13.1 mg of the compound of formula (I) with x=2.5, and
c) the 200 mg dose of sacubitril and valsartan in a 1 :1 molar ratio corresponds to around 226.2 mg of the compound of formula (I) with x=2.5.
9. The combination according to any one of claims 1 to 8, wherein the combination comprises the SGLT-2 inhibitor in a form to be delivered 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, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg or 1000 mg.
10. The combination according to any one of claims 1 to 9 in the form of a fixed dose combination of the combination partners, further including at least one
pharmaceutically acceptable excipient.
1 1. The use of a combination according to any one of claims 1 to 10 in the preparation of a medicament for the treatment or prevention of a cardiovascular disease, a renal disease and/or metabolic disease in a patient.
12. The combination according to any one of claims 1 to 10 for use in the treatment or prevention of a cardiovascular disease and/or metabolic disease in a patient.
13. A method for the treatment or prevention of a cardiovascular disease and/or a
metabolic disease, comprising administering a combination according to any one of claims 1 to 10 in a therapeutically effective amount to a patient in need of such treatment.
14. The use according to claim 1 1 , the combination for use according to claim 12, or the method according to claim 13, wherein the combination is delivered twice delay to the patient.
15. The use according to claim 1 1 , the combination for use according to claim 12, or the method according to claim 13, wherein the cardiovascular disease is heart failure with reduced ejection fraction or heart failure with preserved ejection fraction or acute heart failure.
16. The use according to claim 1 1 , the combination for use according to claim 12, or the method according to claim 13, wherein the metabolic disease is pre-diabetes, type 1 diabetes mellitus, type 2 diabetes mellitus adiposity, obesity or metabolic syndrome, or a combination of two or more of these conditions.
17. The use according to any one of claims 1 1 and 14 - 16, the combination for use according to any one of claims 12 and 14 - 16, or the method according to any one of claims 13 and 14 - 16, wherein the treatment or prevention of a cardiovascular disease and/or metabolic disease is characterized by at least one of the following
(i) reducing the risk of cardiovascular death in the patient,
(ii) reducing the risk of hospitalization for an acute decompensated heart failure episode in the patient,
(iii) reducing all-cause mortality in the patient,
(iv) reducing the risk of all-cause hospitalization in the patient,
(v) reducing the risk of new onset of atrial fibrillation in the patient,
(vi) reducing the risk of, delaying the occurrence of and/or delaying the progression of chronic kidney disease in the patient,
(vii) improving the health related quality of life and/or the functional capacity in the patient.
18. The use according to claim 17, the combination for use according to claim 17, or the method according to claim 17, wherein the patient has heart failure with reduced ejection fraction according at least one of the following characteristics
(i) heart failure of NYHA class II, III or IV,
(ii) 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, or
(iii) a reduced left ventricular ejection fraction (LVEF) of £40%.
19. The use according to any one of claims 1 1 , 14 -18, the combination for use
according to any one of claims 12, 14 - 18, or the method according to any one of claims 13 - 18, wherein the patient is a non-diabetic patient.
20. The use according to any one of claims 1 1 , 14 -19, the combination for use
according to any one of claims 12, 14 - 19, or the method according to any one of claims 13-19, wherein the patient has an eGFR equal to or greater than 20 ml_/min/173m2 or eGFR equal to or greater than 30 ml_/min/173m2 or eGFR equal to or greater than 45 mL/min/173m2 or eGFR equal to or greater than 60 mL/min/1.73m2.
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WO2022036506A1 (en) * 2020-08-17 2022-02-24 天津睿创康泰生物技术有限公司 Composition and use of sglt-2 inhibitor and angiotensin receptor blockers
KR20220105505A (en) * 2021-01-20 2022-07-27 주식회사 대웅제약 A pharmaceutical composition comprising NEP inhibitor and ARB, and method for preparing the same
WO2023075461A1 (en) * 2021-10-27 2023-05-04 지용하 Composite composition containing angiotensin receptor blocker and sglt2 inhibitor

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