USE OF SGLT-2 INHIBITORS FOR THE PREVENTION AND/OR TREAT-MENT OF CARDIAC DISEASES IN FELINES

Abstract

The present invention is directed to the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the prophylaxis and/or treatment of one or more cardiac diseases in feline animals

Claims

1. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use in a method of prevention and/or treatment of one or more cardiac diseases in feline animals

2. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the use according to claim 1, wherein the one or more cardiac diseases are selected from the group consisting of: heart failure, heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), heart failure due to restrictive cardiomyopathy (RCM), heart failure due to dilated cardiomyopathy (DCM), heart failure due to unclassified cardiomyopathy (UCM), heart failure due to arrythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), dilated cardiomyopathy (DCM), unclassified cardiomyopathy (UCM), and/or anythmogenic right ventricular cardiomyopathy (ARVC); preferably selected from the group consisting of: heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), hypertrophic cardiomyopathy (HCM).

3. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the use according to claim 2, wherein the one or more cardiac diseases are selected from the group consisting of: heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), heart failure due to restrictive cardiomyopathy (RCM), heart failure due to dilated cardiomyopathy (DCM), heart failure due to unclassified cardiomyopathy (UCM), heart failure due to arrythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), dilated cardiomyopathy (DCM), unclassified cardiomyopathy (UCM), and/or arrythmogenic right ventricular cardiomyopathy (ARVC).

4. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the use according to claim 3, wherein the one or more cardiac diseases are selected from the group consisting of: heart failure due to hypertrophic cardiomyopathy (HCM), hypertrophic cardiomyopathy (HCM).

5. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 4, wherein the one or more SGLT-2 inhibitors are glucopyranosyl-substituted benzene derivatives.

6. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 5, wherein the one or more SGLT-2 inhibitors are selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1) ##STR00044## wherein R.sup.1 denotes cyano, Cl or methyl (most preferably cyano); R.sup.2 denotes H, methyl, methoxy or hydroxy (most preferably H) and R.sup.3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxylethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano; wherein R.sup.3 is preferably selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and most preferably R.sup.3 is cyclopropyl, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2): ##STR00045## (3) Dapagliflozin, represented by formula (3): ##STR00046## (4) Canagliflozin, represented by formula (4): ##STR00047## (5) Empagliflozin, represented by formula (5): ##STR00048## (6) Luseogliflozin, represented by formula (6): ##STR00049## (7) Tofogliflozin, represented by formula (7): ##STR00050## (8) Ipragliflozin, represented by formula (8): ##STR00051## (9) Ertugliflozin, represented by formula (9): ##STR00052## (10) Atigliflozin, represented by formula (10): ##STR00053## (11) Remogliflozin, represented by formula (11): ##STR00054## (11A) Remogliflozin etabonate, represented by formula (11A): ##STR00055## (12) a thiophene derivative of the formula (12) ##STR00056## wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13); ##STR00057## (14) a spiroketal derivative of the formula (14): ##STR00058## wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl; (15) a pyrazole-O-glucoside derivative of the formula (15) ##STR00059## wherein R.sup.1 denotes C.sub.1-3-alkoxy, L.sup.1, L.sup.2 independently of each other denote H or F, R.sup.6 denotes H, (C.sub.1-3-alkyl)carbonyl, (C.sub.1-6-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Sotagliflozin, represented by formula (16): ##STR00060## (17) Sergliflozin, represented by formula (17): ##STR00061## (18) a compound represented by formula (18): ##STR00062## wherein R.sup.3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, and wherein R.sup.3 is preferably selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and R.sup.3 most preferably is cyclopropyl, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19): ##STR00063## (20) Janagliflozin, represented by formula (20): ##STR00064## (21) Rongliflozin, (22) Wanpagliflozin.

7. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 6, wherein the pharmaceutically acceptable form thereof is a crystalline complex between the one or more SGLT2 inhibitors and one or more amino acids, preferably proline, more preferably L-proline; and most preferably is co-crystal of the one or more SGLT2 inhibitors, L-proline and crystalline water.

8. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 7, wherein the feline animal is a feline patient in need of such prevention and/or treatment; and preferably is a cat in need of such prevention and/or treatment, more preferably a non-diabetic cat in need of such prevention and/or treatment.

9. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 8, wherein the one or more SGLT-2 inhibitors are administered orally, parenterally intravenously, subcutaneously or intramuscularly, preferably orally.

10. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 9, wherein the one or more SGLT-2 inhibitors are to be administered at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight, preferably at a dose of 0.01 mg/kg bodyweight to 5 mg/kg bodyweight, more preferably at a dose of 0.01 mg/kg bodyweight to 4 mg/kg bodyweight, even more preferably at a dose of 0.01 mg/kg bodyweight to 3 mg/kg bodyweight, even more preferably at a dose of 0.01 mg/kg bodyweight to 2 mg/kg bodyweight, even more preferably at a dose of 0.01 mg/kg bodyweight to 1 mg/kg bodyweight, even more preferably at a dose of 0.1 mg/kg bodyweight to 1 mg/kg bodyweight, most preferably at a dose of 0.5 mg/kg bodyweight to 1 mg/kg bodyweight.

11. The one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 10, wherein such one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof is to be administered only once per day or twice per day.

12. The one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 11, wherein the one or more SGLT-2 inhibitors is velagliflozin and velagliflozin is to be administered as single SGLT-2 inhibitor, preferably orally, more preferably once or twice per day at a dose of 0.1 mg/kg bodyweight to 1 mg/kg bodyweight, even more preferably at a dose of 0.5 mg/kg bodyweight to 1 mg/kg bodyweight.

13. The one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 12, wherein the one or more SGLT-2 inhibitors are to be administered before, after or concomitantly with administering one or more other active pharmaceutical ingredients, preferably diuretics, such as furosemide, torasemide or spironolactone; beta-blockers, such as atenolol or propranolol; calcium-channel blockers, such as amlodipine and diltiazem; ACE inhibitors, such as benazepril, ramipril or enalapril; angiotensin receptors blockers, such as telmisartan; antiarrhythmic agents, such as flecainide; platelet agglutination inhibitors, such as clopidogrel; nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin; anticoagulants, such as Coumarins (vitamin K antagonists), (low molecular weight) heparin, synthetic pentasaccharide inhibitors of factor Xa, as well as direct factor Xa inhibitors and/or direct thrombin inhibitors; and/or calcium-channel sensitizers and/or positive inotropes, such as pimobendan and/or or digitalis alkaloids.

14. The one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for the use according to any one of claims 1 to 13, wherein the preventive and/or therapeutic effect is characterized by one or more of the following clinical and/or biochemical parameters: improved cardiometabolic efficiency, characterized by an increased ratio of cardiac output/metabolic substrate consumed and/or characterized by an increased ratio of cardiac output/oxygen consumed; increase of the production of ketone bodies in the liver, characterized by increased plasma levels of 3-hydroxybutyric acid and/or the corresponding acylcarnitines i.e. hydroxybutylylcarnitine and increased plasma levels of one or more of the branched-chain amino acids valine, leucine and/or isoleucine; improved cardiac function by achieved reduced pre- and/or afterload, improved arterial wall structure function; improved echocardiographic parameters, such as decreased LA (Left atrium dimension measured as right parasternal short-axis), LA/Ao (left atrium to aorta ratio; Ao=Aortic root diameter), IVSd (interventricular septal end diastolic dimension, i.e. the thickness of the interventricular septum), and/or LAD (Left atrium measured as right parasternal long-axis), and improved cardiac biomarkers, such as decreased NT-proBNP (N-terminal prohormone of brain natriuretic peptide) and/or decreased cTnI (cardiac Troponin I), as well as improved heart murmur; delayed onset of different phenotypes of cardiomyopathies, preferably at least by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more months, or even stopped progression of different phenotypes of cardiomyopathies; longer time of survival, preferably at least by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more months, and/or delay of next episode of heart failure, preferably at least by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more months, and/or lower level of cardiac mortality and/or morbidity; higher quality of life.

15. A pharmaceutical composition comprising one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof according to any one of claims 1 to 14 for use according to any one of claims 1 to 14.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0201] FIG. 1: FIG. 1 shows plasma non-esterified fatty acids (NEFA), cholesterol and beta-hydroxybutyrat (BHB)—individual data in cats prior to start of treatment (pre) with velagliflozin or control and at the end of the four week treatment period (post). A significant treatment effect, an increase in blood lipids (NEFA, cholesterol) and plasma concentrations of BHB is noted.

EXAMPLES

[0202] The following examples serve to further illustrate the present invention; but the same should not be construed as a limitation of the scope of the invention disclosed herein.

Example 1

Clinical Field Study

[0203] Client-owned cat patients (older than 1 year) with every possible phenotype of cardiomyopathy (HCM, RCM, UCM, DCM and ARVC) with or without clinical symptoms (e.g. congestive heart failure) are treated orally and once daily with a velagliflozin dosage of 1 mg/kg bodyweight.

[0204] During the study period the body weight, body condition score, blood pressure and the cardiovascular system (including heart rates, rhythm, presence of gallop sound or murmur and intensity) are examined on a regular basis during the visits at the site by the investigator. Additionally, thoracic radiographs (in the right lateral and dorso ventral view), echocardiography (including LV septal & free wall thickness, LVIDD, LVIDS (FS %), LA/Ao, LAD, ejection fraction) and electrocardiography are performed. In order to obtain an overview as complete as possible regular blood tests include a complete hematology (white blood cells (WBC), WBC differential, red blood cells, hemoglobin, hematocrit, Heinz bodies, platelet count), a biochemistry panel (total protein, Albumin, Globulin, Alkaline phosphatase (ALP), Alanine transaminase (ALT), Aspartate transaminase (AST), Total bilirubin, Creatinine, Blood urea nitrogen or urea (BUN), Calcium, Sodium, Potassium, Chloride, Phosphorus, Glucose, Cholesterol, Triglycerides, Fructosamine), the measurement of total T4, ketone bodies and cardiac biomarkers (Plasma NT-pro BNP, Cardiac troponin I, ST2).

[0205] Variables of interest are the number of events defined as cardiac death, cardiac related euthanasia and (re-) occurrence of congestive heart failure and the time to event (survival time of the cat patients).

[0206] The results of the clinical field trial show a significant and clinically relevant prolongation of survival time and the time to event (event was defined as cardiac death/euthanasia and (re-)occurrence of congestive heart failure) compared to placebo on top of standard of care (SoC). Additionally, clinical parameters (e.g. appetite, activity level and breathing) compared to placebo on top of SoC improve significantly.

Example 2

Exploratory Clinical Field Study

[0207] Introduction, Materials and Methods:

[0208] In an exploratory clinical field study (prospective, baseline controlled, open label and multi-site) under real world conditions, four cats were screened for eligibility for compassionate use of velagliflozin to treat cardiomyopathies and heart failure in cats. Two cats with hypertrophic cardiomyopathy (HCM) and recent heart failure were found to meet the inclusion criteria and were treated orally with the SGLT-2-Inhibitor velagliflozin at a dosage of 1 mg/kg bodyweight once per day. Due to non-compliance to treatment regime of one pet owner only one cat remained in the study over the complete planned time period of 90 days. Clinical symptoms (evaluated in a physical examination according to Good Veterinary Practice), echocardiographic parameters (always done by the same person at each visit and according to the ACVIM consensus statement guidelines for the classification, diagnosis, and management of cardiomyopathies in cats), blood parameters (evaluated by IDEXX Bioresearch Laboratories, Germany), number of events (re-occurrence of heart failure, cardiac related death or euthanasia) and time to event in days were documented at each visit on the respective Case Report Form.

[0209] Results:

[0210] Case 101 was a 10 years old, female spayed Maine Coon cat, diagnosed with hypertrophic cardiomyopathy (HCM) and previous congestive heart failure. At day 0 (study start) the cat was clinically stable, under owner care and did not receive any additional medication. During the treatment period (Day 1 until Day 90) the cat experienced no adverse event and no heart failure or pulmonary oedema re-occurred. The cat terminated the study in good general health.

TABLE-US-00001 TABLE 1 Clinical symptoms at Screening visit at day −7 and the following two study visits at day 45 and day 90 Screening Visit Visit 2 Visit 3 Cardiological examination (D −7) (D 45) (D 90) BPM (mmHG) 128 136 124 Resting respiratory rate  28  34  34 Heart rate 140 180 176 Presence of gallop sound no no no Presence of arrythmia no no no Presence of murmur yes yes yes Timing of murmur systolic systolic systolic Grade of murmur  4  3  2 Point of maximum intensity left apical left apical left apical

TABLE-US-00002 TABLE 2 Echocardiographic parameters at Screening visit at day −7 and the following two study visits at day 45 and day 90 Echocardiographic Screening Visit Visit 2 Visit 3 parameters (D −7) (D 45) (D 90) LA (mm) 1.55 1.44 1.19 LA/Ao 1.63 1.36 1.07 IVSd (mm) 0.76 0.5 0.43 LAD max (mm) 16.3 13.8 12.6

[0211] LA (Left atrium dimension measured as right parasternal short-axis); Ao (Aortic root diameter); LA/Ao, left atrium to aorta ratio; IVSd (interventricular septal end diastolic dimension, i.e. the thickness of the interventricular septum); LAD (Left atrium measured as right parasternal long-axis)

TABLE-US-00003 TABLE 3 Cardiac biomarker at Screening visit at day −7 and the following two study visits at day 45 and day 90 Screening Visit 2 Visit 3 Cardiac biomarker visit(D −7) (D 45) (D 90) NT-proBNP (pmol/l) 177 104 39 NT-proBNP (N-terminal prohormone of brain natriuretic peptide)

[0212] Conclusion:

[0213] At the Screening visit (before treatment) the pathophysiological characteristics of cat 101 exhibited a hypertrophic cardiomyopathy (HCM). HCM phenotype is characterized by increased left ventricular wall thickness (LVWT) in the absence of abnormal loading conditions capable of producing a similar degree of ventricular thickening as well as thickening of the interventricular septum (IVSd). A further characteristic of the disease is an increased left atrium (LA) as has been shown also in cat 101 at screening.

[0214] The cardiac biomarker N-terminal prohormone of brain natriuretic peptide (NT-pro BNP) exhibited a stressed myocardium at screening.

[0215] All echocardiographic parameters in Table 2 and the cardiac biomarker depicted in Table 3 as well as the abnormal heart murmur improved continuously during the treatment period and thus clearly demonstrate that a treatment with velagliflozin has a beneficial therapeutic effect on heart failure due to hypertrophic cardiomyopathy (HCM) and/or hypertrophic cardiomyopathy (HCM) in cats.

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