WO2025128432A1 - Istaroxime et dérivés métabolites associés pour réduire le risque d'arythmie myocardique aiguë - Google Patents

Istaroxime et dérivés métabolites associés pour réduire le risque d'arythmie myocardique aiguë Download PDF

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WO2025128432A1
WO2025128432A1 PCT/US2024/058923 US2024058923W WO2025128432A1 WO 2025128432 A1 WO2025128432 A1 WO 2025128432A1 US 2024058923 W US2024058923 W US 2024058923W WO 2025128432 A1 WO2025128432 A1 WO 2025128432A1
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acute myocardial
hydroxy
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6alpha
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Steven Simonson
Shih-Che Hsu
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Windtree Therapeutics Inc
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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
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to the field of pharmaceuticals, in particular to formulations of istaroxime or metabolite derivatives thereof, such as Formula II and Formula IV, for reducing the risk of or preventing myocardial arrhythmias in individuals having early cardiac shock, or heart failure with acute myocardial ischemia and/or an acute myocardial infarction and/or during the treatment of these conditions.
  • HF heart failure
  • myocardial arrhythmias heart rhythm disturbances referred to as myocardial (or cardiac) arrhythmias, which can lead to severe complications that increase the mortality in these individuals.
  • atrial fibrillation AF which is caused by extremely rapid and irregular electrical impulses in the atria of the heart, can result in stroke and/or worsening heart failure if left untreated [January et al., 2019, Circulation 140(2)].
  • VF ventricular fibrillation
  • Other types of myocardial arrhythmias include ventricular tachycardia (VT), supraventricular tachycardia (SVT), atrial flutter, and others.
  • CHF chronic heart failure
  • AHF acute heart failure
  • ADHF acute decompensated heart failure
  • Clinical symptoms in HF are caused by a cardiac double pathological feature that consists in an inotropic abnormality, resulting in diminished systolic emptying (systolic dysfunction) and a compliance abnormality in which the ability of the ventricles to suck blood from the venous system is impaired (diastolic dysfunction), thus reducing the amount of blood available for systolic contraction, which is an impairment of left ventricle (LV) filling.
  • SR sarcoplasmic reticulum
  • Cardiogenic shock Another serious AHF condition is cardiogenic shock, which occurs when the heart fails to pump sufficient blood to the brain and other organs.
  • Cardiogenic shock is commonly caused by acute myocardial infarction (AMI), when blood flow to the heart is significantly decreased or stopped and is associated with high rates of morbidity and mortality, posing a therapeutic challenge for clinicians [van Diepen el al., 2017, Circulation 136:e232-e268; Hunziker el al., Circ. Cardiovasc. Interv. 12(4):e007293; Berg et al., 2019, Circ. Outcomes 12:e005618].
  • AMLinduced cardiogenic shock is the revascularization of culprit coronary vessels.
  • AHF and other cardiovascular diseases such as cardiogenic shock or early cardiogenic shock
  • myocardial ischemia which is characterized by reduced or blocked blood flow to the heart.
  • a common intervention in these patients is to reestablish cardiac blood flow.
  • Increasing blood flow to the heart, or reperfusion can be performed using various techniques known in the art, including, anticoagulants, thrombolysis, embolectomy, and surgical revascularization.
  • reperfusion after myocardial ischemia has been shown to increase the risk of adverse cardiovascular outcomes, including myocardial arrhythmias.
  • Istaroxime is disclosed in EP0825197 and in De Munari et al., [2003, J. Med. Chem. 64:3644-3654] and is the compound (3Z,5a)-3-[(2-aminoethoxy)imino]androstane-6, 17-dione. Istaroxime may have potential to overcome may of the issues with prior or existing therapies being used to treat patients with these disorders.
  • WO 2020/180356 A9 discloses another clinical study that examined prolonged istaroxime infusion in 120 patients with ADHF [see also Carabelli et al., 2020, Euro. J. Heart Failure 22:1684-1693].
  • This study involved two doses of istaroxime (0.5 pg/kg/min and 1.0 pg/kg/min) infused for up to 24 hours.
  • the primary endpoint of this study was E/Ea ratio and revealed an improvement in both treatment groups compared to the placebo groups.
  • prolonged infusion with Istaroxime showed significant improvements for most of the diastolic function parameters measured after 6 hours of infusion.
  • patients with cardiogenic shock, acute myocardial infarctions, acute myocardial ischemia, and/or significant myocardial arrhythmias were excluded.
  • the SEISMiC study examined the effects of istaroxime in patients with AHF-related pre- cardiogenic shock [Metra et al., 2022, Euro. J. Heart Failure 24:1967-1977].
  • the primary endpoint of this study was SBP AUC through 6 hours and revealed patients administered istaroxime had improved blood pressure. Again, patients with overt cardiogenic shock, acute myocardial infarctions, acute myocardial ischemia, and/or significant myocardial arrhythmias were excluded.
  • istaroxime has been studied extensively in AHF patients, it has not been shown to be effective in significantly protecting against the risk of serious myocardial arrhythmias, especially in patients presenting with acute myocardial ischemia and/or acute myocardial infarction.
  • the exclusion of these subjects was due, in part, to the concern that istaroximc’s ability to inhibit Na + /K + -ATPase activity would increase the risk of patient susceptibility to myocardial arrythmias and other deleterious side effects. Accordingly, conventional wisdom dictated that the risk could be even more elevated in patients already presenting with acute myocardial ischemia and/or acute myocardial infarction, especially when reperfusion is accomplished.
  • compositions containing istaroxime, or a derivative thereof, formulated for administration to a subject for use in a treatment method for AHF with acute myocardial ischemia and/or an acute myocardial infarction are administered by intravenous infusion, whereby the E wave, E wave deceleration time, A wave, E/A ratio, e’, E/e’ ratio, stroke volume, heart rate, cardiac index, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure, and/or other parameters of heart function in the individual are improved.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • compositions and methods herein include dual mechanism compounds and pure SERCA2a activators derived from istaroxime or its metabolites. This surprising result enables the use of this life-saving medication to be administered to a broader spectrum of AHF patients, including those exhibiting pre-cardiogenic shock or cardiogenic shock who are at risk for arrythmias from having clinical ischemia-reperfusion to the myocardium.
  • One aspect of the invention features a method of treating acute heart failure in a human subject, which includes the steps of treating the human subject suffering from early cardiogenic shock with myocardial ischemia and/or an acute myocardial infarction, via intravenous infusion a pharmaceutical composition comprising istaroxime, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, at a dose of about 0.1 mcg/kg/min to about 2.5 mcg/kg/min, for an infusion period of at least about 3 hours.
  • the administering of the istaroxime or derivative thereof results in a measurable improvement in heart function and an absence or reduction of acute myocardial arrhythmias.
  • the absence of acute myocardial arrhythmias continues for at least 3 hours following initiation of infusion.
  • a reduction of acute myocardial arrhythmias can compared be to the average number of acute myocardial arrhythmias or the average duration of acute myocardial arrhythmias in a cohort of individuals not administered istaroxime or derivative thereof.
  • the infusion period can be at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, or at least about 60 hours.
  • the acute heart failure comprises pre-cardiogenic shock or cardiogenic shock.
  • istaroxime is administered at a dose of about 0.5 mcg/kg/min to about 1.5 mcg/kg/min and istraroxime or derivatives thereof are infused for about 60 hours.
  • the acute myocardial ischemia is detected by: (i) ECG monitoring, echocardiogram, stress test, coronary angiogram, nuclear perfusion imaging, positron emission tomography, cardiovascular- magnetic resonance, a chest X-ray, or a heart MRI; and/or (ii) laboratory blood tests for proteins and enzymes.
  • the acute myocardial ischemia may be detected by ECG monitoring.
  • reperfusion is performed/induced following diagnoses of the acute myocardial ischemia. For instance, reperfusion may be initiated within 3 hours of the diagnosis of the acute myocardial ischemia.
  • the reperfusion comprises administration of recombinant tissue plasminogen activator (rTPA), reteplase, anistreplase, desmoteplase, nattokinase, lumbrokinase, serrapeptase, papain, DNAse, bromelain, honiol, tenecteplase,reteplase, urokinase, streptokinase, anticoagulation with heparin, calcium channel blockers, ranolazine, beta blockers, nitrates, aspirin, or cholesterol-lowering compounds.
  • the reperfusion comprises balloon angioplasty, stent placement, coronary artery bypass graft, or enhanced external counterpuls ation .
  • the absence or reduction of acute myocardial arrhythmias is measured by electrocardiogram.
  • the acute myocardial arrhythmias can be a ventricular tachycardia, ventricular fibrillation, or a combination thereof.
  • the absence or reduction of acute myocardial arrhythmias comprises a reduction in the duration of the acute myocardial arrhythmias.
  • the improvement in heart function is diastolic heart function measured by echocardiography, such as, but not limited to decreased E wave, increased E wave deceleration time, increased A wave, decreased E/A ratio, increased e’, or decreased E/e’ ratio.
  • Another aspect of the invention features a method of treating acute heart failure in a human subject having acute heart failure associated with acute myocardial ischemia and/or an acute myocardial infarction, and administering to the human subject by intravenous infusion a pharmaceutical composition comprising a dual mechanism compound at a dose of about 0.1 mcg/kg/min to about 2.5 mcg/kg/min, for an infusion period of at least about 3 hours.
  • administration of the dual mechanism compound results in a measurable improvement in heart function and an absence or reduction of acute myocardial arrhythmias, such as (i) the absence of acute myocardial arrhythmias continues for at least 3 hours following initiation of infusion; or (ii) the reduction of acute myocardial arrhythmias is compared to the average number of acute myocardial arrhythmias or the average duration of acute myocardial arrhythmias in a cohort of individuals not administered the dual mechanism compound.
  • the dual mechanism compound has a structure formula (II) wherein X, Y, Z are annular atoms comprised in a five-membered carbocyclic or heterocyclic ring, selected from the group consisting of CH, NH, N, O, S; and wherein n is 0 or 1 and said heterocyclic ring selected from the group consisting of imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, and the corresponding dihydro- and tetrahydro derivatives;
  • the dual mechanism compound may be 3-beta-hydroxy-5-beta-10- beta-methyl-13-beta-methyl-14-beta-hydroxy-17-beta-(imidazol-4-yl)androstane; 3-beta- hydroxy-5-beta-10-beta-methyl-13-beta-methyl-14-beta-hydroxy-17-beta-(2-guanidino-thiazol- 4-yl)androstane; 3-beta-hydroxy-5-beta-10-beta-methyl-13-beta-methyl-14-beta-hydroxy-17- beta-(pyrazol-3-yl)androstane; 3-beta-hydroxy-5-beta-10-beta-methyl-12-beta-hydroxy-13-beta- methyl- 14-beta-hy droxy- 17 -beta-(imidazol-4-y l)andro stane; 3-beta-hydroxy-5-beta- 10-
  • Another aspect of the invention features a method of treating acute heart failure in a human subject having acute myocardial ischemia and/or an acute myocardial infarction comprises administering to the human subject by intravenous infusion a pharmaceutical composition comprising a pure SERCA2a activator at a dose of about 0.1 mcg/kg/min to about 2.5 mcg/kg/min, for an infusion period of at least about 3 hours.
  • Y at C6 is a hydroxyl (OH) in the alpha- or beta-configuration or a hydroxymethyl (CH2OH) in the alpha-configuration;
  • FIGS 2A -2B Triggered activity incidence in left ventricular papillary muscles isolated from various group hearts.
  • Fig. 2A Representative tracings of action potential driven at 2, 3.3, and 5 Hz in preparations isolated from various group hearts exposed to high calcium (5.4 mmol/L) + isoproterenol (1 pM).
  • Triggered activity (spontaneous action potentials; red double arrow line) could be induced in a preparation from DM+Veh group heart following 1 -minute stimulation at all frequencies.
  • Fig. 2B Incidence of triggered activity in preparations isolated from various group hearts at driven frequencies of 2, 3.3, and 5 Hz. Results are shown as the percentage of preparations (n) inducible into triggered activity/total of preparations. *P ⁇ 0.05 vs Ctr group by Fisher exact test. DM indicates STZ injection; Ista, Istaroxime; and Veh, vehicle.
  • FIG. 4A Effect of 10 pM Istaroxime and CVie216 infusion on reperfusion-induced arrhythmias in the isolated, perfused Diabetic rats’ hearts following 10 min regional ischemia.
  • Fig. 4A Raw ECG recordings for ventricular tachycardia/fibrillation (VT/VF) in DM rats isolated heart under ER.
  • Fig. 4B Mean data for incidence of Reperfusion induced VT/VF which significant decreased in lOpM CVie216 group, compared with the Veh group.
  • Fig. 4C Arrhythmias score in different experimental groups.
  • individuals with AHF and acute myocardial ischemia are administered istaroxime and exhibit an improvement in one or more parameters of heart function with decreased incidence of (or reduced duration of) serious acute myocardial arryth ias, such as VF or VT.
  • individuals presenting with AHF-related pre-cardiogenic shock or cardiogenic shock resulting from an acute myocardial infarction or patients exhibiting decreased cardiac blood flow resulting in ischemia are administered istaroxime and exhibit an improvement in one or more parameters of heart function with decreased incidence of (or reduced duration of) serious acute myocardial arrythmias.
  • istaroxime or istaroxime derivative may reduce the occurrence of ventricular arrythmias in a larger percentage of individuals as compared to placebo and/or control groups.
  • individuals with heart failure and acute myocardial ischemia and/or acute myocardial infarction are administered a derivative of istaroxime, such as Formula II or Formula IV, and exhibit an improvement in one or more parameters of heart function with no incidence of (or reduced duration of) serious acute myocardial arrythmias.
  • a derivative of istaroxime such as Formula II or Formula IV
  • compositions and methods disclosed herein will be described in more detail below.
  • the term “about” refers to the variation in the numerical value of a measurement, e.g., volume, time, pressure, concentration, etc., due to typical error rates of the device used to obtain that measure. In one embodiment, the term “about” means within 5% of the reported numerical value, preferably, the term “about” means within 3% of the reported numerical value.
  • cardiogenic shock refers to a condition in an individual, such as a human patient, where the heart cannot pump enough blood and oxygen to the brain, kidneys, and other vital organs leading to end-organ hypoperfusion.
  • Overt “cardiogenic shock” or SCAI Stage C “cardiogenic shock” is defined by a systolic blood pressure of less than about 90 mmHg (hypotension), a cardiac index of less than about 2.2 L/min/m 2 , pulmonary capillary wedge pressure of greater than 15 mmHg, and evidence of end-organ hypoperfusion.
  • Pre-cardiogenic shock SCAI Stage B “pre-cardiogenic shock”, or “early cardiogenic shock” refer to a condition where the individual has not yet developed overt “cardiogenic shock” and is defined by a systolic blood pressure of less than about 90 mmHg without evidence of end-organ hypoperfusion.
  • heart failure refers to a clinical syndrome characterized by typical symptoms (e.g., breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure, pulmonary crackles and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.
  • typical symptoms e.g., breathlessness, ankle swelling and fatigue
  • signs e.g., elevated jugular venous pressure, pulmonary crackles and peripheral edema
  • AHF acute heart failure
  • the terms “acute heart failure” or “AHF” are used interchangeably herein and refer generally to a rapid onset or worsening of symptoms and/or signs of HF requiring immediate treatment and hospitalization.
  • the current definition of “acute heart failure” is rather nonspecific and may include a broad spectrum of conditions with several phenotypes characterized by different clinical presentation, etiology, precipitating factors, therapeutic approach, and prognosis.
  • a large proportion of human patients have a subacute course of the disease with a progressive worsening of signs and symptoms of HF which could develop days before hospital admission.
  • acute coronary syndrome refers to a sudden reduction or blockage of blood flow to the heart.
  • a common example of “acute coronary syndrome” is a myocardial infarction (heart attack).
  • arrhythmia cardiac arrhythmia
  • myocardial arrhythmia refers to an irregular- heartbeat.
  • a resting heart rate that is too fast e.g., greater than about 100 beats per minute in an adult human
  • tachycardia a resting heart rate that is too slow
  • atrial fibrillation or “AF” is a cardiac arrhythmia characterized by rapid and irregular beating in the atrial chambers of the heart.
  • chronic heart failure or “CHF” are used interchangeably herein and refer to the current clinical classification of chronic HF based on the presence of signs and symptoms of HF and left ventricular ejection fraction (LVEF) in an individual, such as a human patient, recognizing three categories: “heart failure with reduced ejection fraction” or “HFrEF,” which is characterized by an LVEF of less than about 40%; “heart failure with mid-range ejection fraction” or “HFmEF” or “HFmrEF,” which is characterized by an LVEF from about 40% to about 49%; and “heart failure with preserved ejection fraction” or “HFpEF,” which is characterized by an LVEF of equal to or greater than about 50%.
  • HFrEF left ventricular ejection fraction
  • HFmrEF and “HFpEF” include two additional criteria, namely increased natriuretic peptides levels (BNP >35 pg/ml and/or NT-proBNP >125 pg/mL) associated with the evidence of structural and/or functional heart disease (left ventricular hypertrophy and/or left atrium enlargement and/or evidence of diastolic dysfunction).
  • hypotension as used herein is defined as systolic blood pressure (SBP) that is less than 90 mmHg or mean arterial blood pressure (MAP) less than about 60 mmHg or greater than 30 mmHg drop from baseline.
  • SBP systolic blood pressure
  • MAP mean arterial blood pressure
  • treating refers to any indicia of success in the treatment or amelioration of the disease or condition in an individual. Treating can include, for example, reducing or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by an individual, such as a human patient.
  • preventing refers to the prevention of the disease or condition, e.g., pre- myocardial arrhythmia, in an individual, such as a human patient. For example, if an individual at risk of developing a serious acute myocardial arrhythmia is treated with the methods of the present invention and does not later develop a serious acute myocardial arrhythmia, then the disease has been prevented in that individual.
  • the disease or condition e.g., pre- myocardial arrhythmia
  • treat or prevent is sometimes used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition and contemplates a range of results directed to that end, including but not restricted to prevention of the condition entirely.
  • pharmaceutically acceptable salt, solvate, hydrate, or ester means a salt, solvate, hydrate, or ester form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.
  • the term “pharmaceutically acceptable carrier” means a chemical composition with which an istaroxime compound or a derivative or metabolite of the istaroxime compound may be combined and which, following the combination, can be used to administer the compound to a mammal.
  • intravenous infusion refers to the administration or delivery of liquid substances directly into a vein of a mammal. Some “infusions” use only the pressure supplied by gravity, whereas other “infusions” use an infusion pump or other device to control the rate of administration and/or the dose of liquid substances into the vein of the mammal.
  • heart function means any heart function that is observable or measurable using suitable measuring techniques available in the art.
  • a non-limiting list of exemplary “parameters” of heart function include heart rate (HR), blood pressure (BP), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP), systolic blood pressure (SBP), systolic blood pressure area under the curve (SBP AUC), creatine clearance, deceleration slope, mitral inflow velocity, mean arterial pressure, brain natriuretic peptide levels (BNP), NT-pro-BNP levels, troponin levels, venous lactate levels, echocardiographic measurements, left ventricle end diastolic diameter (EDD), left ventricle end systolic diameter (ESD), left ventricle end diastolic volume (EDV), left ventricle end systolic volume (ESV), left atrium
  • HR heart rate
  • BP blood pressure
  • measuring one or more “parameters” of heart function can be used to detect heart dysfunction as compared to the average normal parameters and can also be used to determine whether heart function has improved following or during treatment.
  • the terms “therapeutically active” or “active” ingredient or compound refer to a substance that provides a beneficial effect to the individual to whom the substance is administered.
  • a “therapeutically effective amount” or “therapeutically effective dose” is the amount of a composition or active ingredient sufficient to provide a beneficial effect to the individual to whom the composition or active ingredient is administered.
  • VF ventricular fibrillation
  • VT ventricular tachycardia
  • VT cardiac arrhythmia is characterized by 3 or more heartbeats in a row at a heart rate of greater than 100 beats per minute originating in the ventricle as opposed to the normal cardiac electrical conduction system in the heart.
  • the present invention is directed to administration of istaroxime, or derivatives thereof, to individuals, such as human patients, to treat AHF with acute myocardial ischemia and/or acute myocardial infarction.
  • individuals such as human patients
  • the Na + /K + -ATPase inhibitory function of istaroxime could increase the risk of myocardial arrythmias
  • the data presented herein shows that istaroxime can reduce the risk of serious myocardial arrythmias in individuals with AHF, even if that individual is exhibiting acute myocardial ischemia and even after reperfusion of the heart.
  • istaroxime can be used to treat AHF and improve heart function while reducing the risk of serious myocardial arrhythmias.
  • This finding has profound implications in the treatment of cardiovascular disorders since the number of individuals with AHF that can be treated with istaroxime is substantially increased.
  • previous clinical trials with istaroxime expressly excluded individuals presenting with acute myocardial ischemia and/or myocardial infarction [see, e.g., Gheorghiade et al., 2008, JACC 51(2):2276-2285; Carabelli et al., 2020, Euro. J. Heart Failure. 22(9):1684-1693; Metra et al., 2022, Euro. J. Heart Failure 24:1967-1977; WO 2020/180356 A9; the entire content of each of which is incorporated by reference herein].
  • istaroxime (or derivative thereof), is administered to the individual by intravenous infusion.
  • the istaroxime is administered within 24 hours of the onset of symptoms of acute myocardial ischemia, or within 12 hours of the onset of symptoms of acute myocardial ischemia, or within 6 hours of the onset of symptoms of acute myocardial ischemia, or within 3 hours, or within 2 hours, or within 1 hour, or within 30 minutes of the onset of symptoms of acute myocardial ischemia.
  • infusion is for at least about 6 hours, or at least about 12 hours, or at least about 24 hours, or at least about 48 hours, or at least about 60 hours. It being understood that treatment with istaroximc (or derivative thereof) not only improves heart function in the individual, but additional prevents or reduces the risk/severity of acute myocardial arrhythmias.
  • Istaroxime is an inotropic compound having the following structural Formula (I):
  • Istaroxime has two known mechanisms of action: 1) the inhibition of the Na + /K + -ATPase activity; and 2) the activation of the sarcoplasmic reticulum calcium ATPase isoform (SERCA2a).
  • istaroxime and other istaroxime metabolites or derivatives with the dual mechanism of action are sometimes referred to herein as “dual mechanism compounds.” It is an object of the present invention to utilize istaroximc, or its pharmaceutically acceptable salt or ester, hydrate, solvate, or polymorphic form in a medicament to treat or prevent AHF (or AHF-related pre- or overt cardiogenic shock) in an individual while reducing or eliminating the risk of developing acute myocardial arrhythmias.
  • AHF or AHF-related pre- or overt cardiogenic shock
  • dual mechanism compounds derived from istaroxime are suitable for use in the pharmaceutical compositions and methods provided herein. It is an object of the present invention to utilize these dual mechanism compounds, or their pharmaceutically acceptable salts or esters, hydrates, solvates, or polymorphic forms in a medicament to treat or prevent AHF (or AHF-related pre- or overt cardiogenic shock) in an individual while reducing or eliminating the risk of developing acute myocardial arrhythmias.
  • a dual mechanism compound is administered to an individual for the treatment of AHF (or AHF-related pre- or overt cardiogenic shock) with or without acute myocardial ischemia and/or acute myocardial infarction to improve heart functioning while reducing or eliminating the risk of developing acute myocardial arrhythmias.
  • AHF or AHF-related pre- or overt cardiogenic shock
  • PST 3093 or its pharmaceutically acceptable salt or ester, hydrate, solvate, or polymorphic form in a medicament to treat or prevent AHF (or AHF-related pre- or overt cardiogenic shock) in an individual while reducing or eliminating the risk of developing acute myocardial arrhythmias.
  • PST 3093 is administered directly or via administration of istaroxime to an individual for the treatment of AHF (or AHF-related pre- or overt cardiogenic shock) with or without acute myocardial ischemia and/or acute myocardial infarction to improve heart functioning while reducing or eliminating the risk of developing acute myocardial arrhythmias.
  • other pure SERCA2a activators are used in the medicaments, pharmaceutical compositions and methods provided herein. These pure SERCA2a activators have the general formula (IV):
  • Y at C6 is a hydroxyl (OH) in the alpha- or beta-configuration or a hydroxymethyl (CH2OH) in the alpha-configuration;
  • Ethyl 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) caproate (CVie218): 6-(6bcta-hydroxy-17-oxoandrostanc-3-yl) caproic acid (CVie219):
  • these agents are administered to an individual for the treatment of AHF or AHF-related pre- or overt cardiogenic shock with or without acute myocardial ischemia and/or acute myocardial infarction to improve heart functioning while reducing or eliminating the risk of developing acute myocardial arrhythmias.
  • compositions comprising istaroxime or one of the dual mechanism compounds or pure SERCA2a activators described above in an admixture with at least one pharmaceutically acceptable vehicle and/or excipient.
  • the pharmaceutical composition is formulated for administering to an individual by infusion, preferably, it is by intravenous infusion.
  • art-standard equipment e.g., echocardiogram, pulmonary artery catheter, transpulmonary thermodilution, sphygmomanometer, EKG, and others
  • cardiac output e.g., cardiac index, stroke volume, stroke volume index, E/A ratio, e’, E/e’ ratio, Sa, S, left ventricle ejection fraction (LVEF), Aa, Ea, and the like.
  • LVEF left ventricle ejection fraction
  • echocardiography can be performed on individuals according to international standards [see, for example, Lang et al., 2005, J. Am. Soc. Echocardiogr. 18(12); 1440-1463; Negueh el al., 2009, Eur. J. Echocardiogr. 10(2): 165- 193; Evangelista el al., 2008, Eur. J. Echocardiogr. 9(4):438-448] . Echocardiography is within the purview of skilled physicians or sonographers. For instance, echocardiography can be performed during screening of potential clinical study participants or upon admission of an individual to a health care facility.
  • echocardiography is done prior to treatment and/or at baseline and then 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h, 25 h, 26 h, 27 h, 28 h, 29 h, 30 h, 31 h, 32 h, 33 h, 34 h, 35 h, 36 h, 37 h, 38 h, 39 h, 40 h, 41 h, 42 h, 43 h, 44 h, 45 h, 46 h, 47 h, 48 h, 72 h, 96, h, 5 days, 6 days, 7 days,
  • echocardiography is monitored prior to, during , and immediately following the initiation of infusion, and values are recorded. Echocardiographic values may continue to be monitored and recorded at 24 and 30 hours postinfusion. In other embodiments, echocardiographic values are recorded prior to, during, immediately following infusion, and 12, 24, 48, 72, and 96 hours post-infusion. Table 1 summarizes exemplary echocardiographic and other heart function parameters.
  • an individual presenting with AHF with acute myocardial ischemia and/or an acute myocardial infarction is administered istaroxime (or one of the dual mechanism compounds or pure SERCA2a activators described above), whereby the heart rate is decreased by about 3 to about 9 beats per minute, e.g., 3, 4, 5, 6, 7, 8, or 9, beats per minute.
  • individuals with AHF and acute myocardial ischemia and/or an acute myocardial infarction who are administered istaroxime will exhibit an improvement in one or more additional parameters of cardiac function, including, but not limited to, increased cardiac index (CI), decreased left atrial area, increased stroke volume, decreased left ventricular end- systolic volume, decreased pulmonary capillary wedge pressure, increased cardiac output, increased diastolic blood pressure, and decreased left ventricular end-diastolic volume.
  • istaroxime administration improved CI by increasing the stroke volume, but not by increasing the heart rate.
  • istaroxime increases cardiac output in these individuals without additional strain of increased heart rate on the heart.
  • blood is drawn from the individual, e.g., during prescreening, at baseline and/or at various timepoints post-infusion, e.g., 12, 24, 48, 72, 96 hours, 5 days, 10 days, 30 days after the start of istaroxime, dual mechanism compound, or pure SERCA2a activator administration.
  • This blood can be used for various laboratory testing to assess the individual’s body chemistry, hematology, heart protein levels, and the pharmacokinetics of the istaroxime infusion.
  • Exemplary chemistry includes, but is not limited to, electrolytes, liver function tests, lipids, creatinine (and estimated glomerular filtration rate (eGFR)), urea, blood urea nitrogen (BUN), glucose, albumin, and protein.
  • Exemplary hematology includes, but is not limited to, complete blood count with differential.
  • Suitable heart proteins include cardiac troponin I (cTNI), cardiac troponin T (cTNT), N-terminal pro b-type natriuretic peptide (NT- proBNP), and brain natriuretic peptide (BNP).
  • cTNI cardiac troponin I
  • cTNT cardiac troponin T
  • NT- proBNP N-terminal pro b-type natriuretic peptide
  • BNP brain natriuretic peptide
  • the levels of most of these proteins provide information to the practitioner about heart function and the measurement and/or interpretation of these levels is well within the purview of the skilled artisan.
  • the level of NT-proBNP is decreased as compared to baseline within about 6 hour of infusion, or within about 24 hours of administration.
  • the levels of some of parameters are not a direct measure of heart function, but rather are used to assess kidney function.
  • heart function parameters of heart function include chest congestion, which can be measured by use of a chest x-ray, lung ultrasound, or other art-standard equipment, wherein an improvement in the level of chest congestion following istaroxime infusion or infusion of one of the dual mechanism compound or SERCA2a activators described above indicates treatment or prevention of AHF.
  • heart rate mean arterial pressure (MAP), dyspnea or labored breathing, need for administration of intravenous vasopressors, other inotropes, and/or mechanical cardiac or renal support, symptoms of worsening heart failure, incident of adverse events (AEs) or serious adverse events (SAEs), need for admission to intensive care unit, discharge from the intensive care unit, and death.
  • MAP is increased as compared to baseline within about 24 hours of infusion.
  • Ischemia or decreased cardiac blood flow, in heart failure subjects can be detected using a variety of techniques, such as, but not limited to, with ECG monitoring, echocardiogram, stress test, coronary angiogram, nuclear perfusion imaging, positron emission tomography, cardiovascular magnetic resonance, a chest X-ray, or a heart MRI.
  • ECG monitoring ECG monitoring
  • echocardiogram stress test
  • coronary angiogram nuclear perfusion imaging
  • positron emission tomography positron emission tomography
  • cardiovascular magnetic resonance a chest X-ray
  • a chest X-ray or a heart MRI.
  • the most common ECG sign of acute myocardial ischemia is flat or down sloping ST-segment depression of 1.0 mm or greater followed by elevation of the ST segment as ischemia progresses to infarction.
  • Treatment for acute myocardial ischemia may include reperfusion, which is the reintroduction of blood flow to the heart.
  • Reperfusion can be performed medically and/or mechanically.
  • drug-induced reperfusion may include the administration of certain drugs that initiate the breakdown of blood clots (also referred to as thrombolytic therapy), such as, but not limited to recombinant tissue plasminogen activator (rTPA), reteplase, anistreplase, desmoteplase, nattokinase, lumbrokinase, serrapeptase, papain, DNAse, bromelain, honiol, tenecteplase,reteplase, urokinase, and streptokinase.
  • rTPA tissue plasminogen activator
  • reteplase anistreplase
  • desmoteplase desmoteplase
  • nattokinase lumbro
  • Additional anticoagulation with heparin may also be employed.
  • Other compounds for medically induced reperfusion include calcium channel blockers, ranolazinc, beta blockers, nitrates, aspirin, and cholesterol-lowering compounds.
  • Thrombolytic/fibrinolytic therapy is typically began within 12 hours of the onset of ischemia symptoms; preferably, within 6 hours of the onset of symptoms; more preferably, within the first 2 hours or even 90 minutes of the onset of ischemia symptoms.
  • Mechanical reperfusion includes, but is not limited to, balloon angioplasty, stent placement, coronary artery bypass graft, enhanced external counterpulsation, and the like.
  • mechanical reperfusion therapy is typically began within 12 hours of the onset of ischemia symptoms; preferably, within 6 hours of the onset of symptoms; more preferably, within the first 2 hours or even 90 minutes of the onset of ischemia symptoms.
  • tachycardia refers to a resting heart rate that is elevated relative to normal (greater than about 100 beats per minute)
  • bradycardia refers to a resting heart rate that is lower relative to normal (less than about 60 beats per minute)
  • fibrillation refers to a form of electrical chaos resulting in the absence of definable P waves or QRS complexes (the first negative deviation Q wave followed by an upward positive deviation R wave, and a negative deflection after the R portion referred to as the S wave)
  • flutter refers to a highly organized reentrant rhythm.
  • the duration of the episode is also recorded to measure the severity of the arrythmia.
  • AHF patients have increased risk for arrythmias.
  • the more severe the heart failure the higher the risk for arrythmias from the disease and/or from medications given to treat the disease.
  • high risk individuals can be identified as having a family history of arrythmias and heart failure, physical examination, and laboratory assessments, including blood tests for elevated brain natriuretic peptide (BNP) N- tcrminal-pro brain natriuretic peptide (NT-proBNP).
  • BNP brain natriuretic peptide
  • NT-proBNP N- tcrminal-pro brain natriuretic peptide
  • art-standard medical assessments can be used to identify subjects or cohorts of subjects that present with HF (including AHF and pre/overt cardiogenic shock) with ischemia, HF with ischemia-reperfusion injury, and HF with elevated risk of myocardial arrythmias.
  • HF including AHF and pre/overt cardiogenic shock
  • istaroxime and its metabolites and derivatives can be used to treat AHF and AHF-related disorders (such as pre- cardiogenic shock and cardiogenic shock) while protecting against acute myocardial arrhythmias, including arrhythmias due to reperfusion injury.
  • AHF and AHF-related disorders such as pre- cardiogenic shock and cardiogenic shock
  • the latter has important implications for the treatment of patients who exhibit sudden ischemia or myocardial infarction and need immediate reperfusion.
  • istaroxime and its progeny can be used to treat a much wider range of AHF patients without significantly increasing the risk of arrythmias.
  • compositions and formulations for intravenous infusion comprising istaroxime, CVie 216, or one of the other dual mechanism compounds or pure SERCA2a activators described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof in an admixture with at least one conventional pharmaceutically acceptable carrier and/or vehicle and/or excipient are commonly known in the art.
  • compositions and formulations for intravenous infusion can be formulated in any way and can be administered in a variety of unit dosage forms depending upon the condition or disease and the degree of illness, the general medical condition of each patient, the resulting preferred method of administration and the like. Details on techniques for formulation and administration arc well described in the scientific and patent literature [see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA (“Remington’s”)].
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier or vehicle material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration.
  • the amount of active ingredient that can be combined with a earner material to produce a single dosage form will generally be the amount of the compound which produces a therapeutic effect.
  • compositions as provided herein can be prepared according to any method known to the art for the manufacture of pharmaceuticals. Such formulations can contain additional agents, such as preserving or stabilizing agents.
  • a formulation can be admixtured with nontoxic pharmaceutically acceptable carriers or excipients which are suitable for manufacture. Formulations may comprise one or more diluents, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, lyophilized powders, etc.
  • Aqueous suspensions can contain an active agent (e.g., a composition used to practice the uses and methods as provided herein) in an admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents, such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., poly
  • IV intravenous
  • formulations can comprise a solution of active agent dissolved in a pharmaceutically acceptable carrier.
  • Acceptable vehicles and solvents that can be employed arc water, dextrose in water, and Ringer's solution, an isotonic sodium chloride. These solutions are sterile and generally free of undesirable matter.
  • formulations may be sterilized by conventional, well known sterilization techniques.
  • the formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • the concentration of active agent in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs.
  • the administration is by bolus or continuous infusion (e.g., substantially uninterrupted introduction into a blood vessel for a specified period of time).
  • the compounds as provided herein can be lyophilized.
  • a stable lyophilized formulation comprising a composition as provided herein, which can be made by lyophilizing a solution comprising a pharmaceutical as provided herein and a bulking agent, e.g., mannitol, trehalose, raffinose, lactose, and sucrose or mixtures thereof.
  • a bulking agent e.g., mannitol, trehalose, raffinose, lactose, and sucrose or mixtures thereof.
  • a bulking agent e.g., mannitol, trehalose, raffinose, lactose, and sucrose or mixtures thereof.
  • a bulking agent e.g., mannitol, trehalose, raffinose, lactose, and sucrose or mixtures thereof.
  • lactose is the most common.
  • Formulations of a pharmaceutical composition suitable for oral administration comprise at least one of the compounds described herein combined with a pharmaceutically acceptable carrier, in a variety of dosage forms, including but not limited to pills, tablets, granules, powders, capsules, dispersions, suspensions, solutions, emulsions, microemulsions, gels and films, to name a few.
  • dosage forms typically include carriers, excipients, and or permeation enhancers to facilitate formulation and delivery of the active ingredients.
  • the pharmaceutically acceptable carriers for oral formulations are selected from proteins, carbohydrates, lipids, organic and inorganic molecules, and combinations thereof.
  • the active ingredients can be combined with the carrier in an appropriate diluent to form a solution or a suspension.
  • Such liquid formulations can be viscous or non-viscous depending on the amount and the carrier used.
  • the liquid formulations can be used directly or can be further formulated into an appropriate capsule, gel capsule or solid by methods know to those skilled in the art.
  • solid formulations can be made by combining solid components.
  • Such solid formulations can be used as a powder or formulated into granules, capsules, tablets or films any one of which can be made as a time release formulation.
  • Suitable proteins for use as carriers in oral dosage forms include milk proteins such as casein, sodium caseinate, whey, reduced lactose whey, whey protein concentrate, gelatin, soy protein (isolated), brown algae protein, red algae protein, baker’s yeast extract and albumins.
  • Suitable carbohydrates include celluloses such as methylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate and ethyl cellulose, starches such as cornstarch, potato starch, tapioca starch, wheat starch, acid modified starch, pregelatinized starch and unmodified starch, alginates such as ammonium alginate, sodium alginate, and calcium alginate, glutens such as corn gluten and wheat gluten, gums such as acacia (gum Arabic), gum ghatti, guar gum, karaya gum (sterculia gum) and gum (tragacanth), insoluble glucose isomerase enzyme preparations, sugars such as com sugar, invert sugar, com syrup, high fructose corn syrup, and sodium gluconate.
  • starches such as cornstarch, potato starch, tapioca starch, wheat starch, acid modified starch, pregelatinized starch and unmodified star
  • Suitable lipids include tocopherols such as a-tocopherol acetate, short-, medium- and long-chain fatty acids and esters thereof, fatty alcohols and ethers thereof, oils such as coconut oil (refined), soybean oil (hydrogenated) and rapeseed oil, aluminum palmitate, dilauryl thiodipropionate, enzyme-modified lecithin, calcium stearate, enzyme-modified fats, glyceryl palmitostereate, lecithin, mono- and diglycerides, glycerin and waxes such as beeswax (yellow and white), candelilla wax and carnauba wax and vegetable oil.
  • tocopherols such as a-tocopherol acetate, short-, medium- and long-chain fatty acids and esters thereof, fatty alcohols and ethers thereof, oils such as coconut oil (refined), soybean oil (hydrogenated) and rapeseed oil, aluminum palm
  • Suitable organic and inorganic substances include methyl and vinyl pyrrolidones such as polyvinylpyrrolidone, methylsulfonyl methane, dimethylsulfoxide and related compounds, hydroxy and polyhydroxy acids such as poly lactic acid, among many others.
  • compositions are administered to a subject already suffering from a condition, or disease in an amount sufficient to treat, prevent, cure, alleviate or partially arrest the clinical manifestations of the condition, or disease and its complications (z.e., a “therapeutically effective amount”).
  • pharmaceutical compositions as provided herein are administered in an amount sufficient to treat, prevent or ameliorate in an individual in need thereof.
  • the amount of pharmaceutical composition adequate to accomplish this is defined as a “therapeutically effective dose.”
  • the dosage schedule and amounts effective for this use, i.e., the “dosing regimen,” will depend upon a variety of factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient's health, the patient’s physical status, age and the like. In calculating the dosage regimen for a patient, the mode of administration also is taken into consideration.
  • the dosage regimen also takes into consideration pharmacokinetics parameters well known in the art, i.e., the active agents’ bioavailability, metabolism, clearance, and the like [see, e.g., Hidalgo- Aragones, 1996, Steroid Biochem. Mol. Biol. 58:611-617; Groning, 1996, Pharmazie 51:337-341; Fotherby, 1996, Contraception 54:59-69; lohnson, 1995, J. Pharm. Sci. 84:1144-1146; Rohatagi, 1995, Pharmazie 50:610-613; Brophy, 1983, Eur. J. Clin. Pharmacol. 24:103-108; the latest Remington’s, supra].
  • the active agents bioavailability, metabolism, clearance, and the like
  • compositions used as pharmaceuticals can be used as guidance to determine the dosage regimen, i.e., dose schedule and dosage levels, administered practicing the methods as provided herein are correct and appropriate.
  • formulations can be given depending on the dosage and frequency as required by the AHF symptoms of patient.
  • the formulations should provide a sufficient quantity of active agent to effectively treat or prevent or ameliorate a conditions, diseases or symptoms as described herein.
  • a correct treatment of AHF or related disease by selectively normalizing a depressed biochemical activity underlying the symptoms of subset of patients, may be expected to selectively improve the symptoms and to reduce the incidence of unwanted side effects produced by the available drugs either during hospital staying or after discharge.
  • the term prevention is applicable when the continuous monitoring of the pulmonary pressure is possible with the appropriate chronic implantable devices that provide measurements of heart function parameters.
  • an effective amount of istaroxime or equivalent of a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to an individual with AHF symptoms and who is presenting with acute myocardial ischemia at a dosing schedule, e.g., from about 0.1 pg/kg/min to about 3.0 pg/kg/min, e.g., 0.1 pg/kg/min, 0.15 pg/kg/min, 0.2 pg/kg/min, 0.25 pg/kg/min, 0.3 pg/kg/min, 0.35 pg/kg/min, 0.4 pg/kg/min, 0.45 pg/kg/min, 0.5 pg/kg/min, 0.55 pg/kg/min, 0.6 pg/kg/min, 0.7 pg/kg/min, 0.75 pg/kg/min, 0.8 pg/kg/min, 0.85 pg/kg/min, 0.9 pg/kg/
  • istaroxime is administered by infusion at an effective dose from about 0.1 pg/kg/min to about 2.5 pg/kg/min, about 0.2 pg/kg/min to about 2.0 pg/kg/min, or from about 0.5 pg/kg/min to about 1.5 pg/kg/min, or from about 1.0 pg/kg/min to about
  • the istaroxime is administered by intravenous infusion at an effective dose of about 1.5 pg/kg/min.
  • the effective dose of istaroxime can be initiated at about 1.0 pg/kg/min for about 1 to about 2 hours, which is then increased to 1.5 pg/kg/min for the remaining infusion time unless the individual exhibits nausea or other signs of poor or insufficient drug tolerance.
  • the effective dose of istaroxime can be initiated at about 1.5 pg/kg/min for about 1 to about 2 hours, which is then decreased to 1.0 pg/kg/min for the remaining infusion time.
  • an effective amount of PST 3093 or CVie 216 or equivalent of a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to an individual with AHF symptoms and who is presenting with acute myocardial ischemia at a dosing schedule, e.g., from about 0.1 pg/kg/min to about 3.0 pg/kg/min, e.g., 0.1 pg/kg/min, 0.15 pg/kg/min, 0.2 pg/kg/min, 0.25 pg/kg/min, 0.3 pg/kg/min, 0.35 pg/kg/min, 0.4 pg/kg/min, 0.45 pg/kg/min, 0.5 pg/kg/min, 0.55 pg/kg/min, 0.6 pg/kg/min, 0.7 pg/kg/min, 0.75 pg/kg/min, 0.8 pg/kg/min, 0.85 pg/kg/min,
  • an effective amount a compound of Formula II or Formula IV or equivalent of a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to an individual with AHF symptoms and who is presenting with acute myocardial ischemia at a dosing schedule, e.g., from about 0.1 pg/kg/min to about 3.0 pg/kg/min, e.g., 0.1 pg/kg/min, 0.15 p.g/kg/min, 0.2 pg/kg/min, 0.25 pg/kg/min, 0.3 pg/kg/min, 0.35 pg/kg/min, 0.4 pg/kg/min, 0.45 p.g/kg/min, 0.5 pg/kg/min, 0.55 pg/kg/min, 0.6 p.g/kg/min, 0.7 pg/kg/min, 0.75 pg/kg/min, 0.8 p.g/kg/min, 0.85 p.g/kg/
  • the Formula II or Formula IV compounds is selected from the group consisting of 3-beta-hydroxy-5-beta-10-beta-methyl-13- beta-methyl-14-beta-hydroxy-17-beta-(imidazol-4-yl)androstane; 3-beta-hydroxy-5-beta-10- beta-methyl-13-beta-methyl-14-beta-hydroxy-17-beta-(2-guanidino-thiazol-4-yl)androstane; 3- beta-hydroxy-5-beta- 10-beta-methyl- 13-beta- methyl- 14-beta-hydroxy- 17-beta-(pyrazol-3- yl)androstane; 3-beta-hydroxy-5-beta- 10-beta-methyl- 12-beta-hydroxy- 13-beta- methyl- 14-beta- hydroxy- 17-beta-(imidazol-4-yl)androstane; 3-beta-hydroxy-5-beta-
  • compositions for use as a medicament in the treatment of heart failure as well as methods of treating an individual with heart failure; preferably, the heart failure is acute heart failure.
  • the heart failure is AHF- related pre-cardiogenic shock or cardiogenic shock.
  • the individual presents with acute heart failure and acute myocardial ischemia and/or an acute myocardial infarction. Accordingly, this leads to a loss or significant reduction in blood flow to the heart requiring immediate intervention, e.g., reperfusion of the heart. It is therefore an object of this invention that these individuals be treated with one or more of the pharmaceutical compositions described in detail above prior to or during reperfusion.
  • the pharmaceutical compositions provided herein can be used to treat AHF (and related conditions, such as pre- cardiogenic shock or cardiogenic shock) while reducing the risk of or altogether preventing serious myocardial arrhythmias, such as VT or VF. Even more surprising, these pharmaceutical compositions reduce the risk of myocardial arrhythmias even in the individual presenting with AHF and acute myocardial ischemia, and even during reperfusion, which is a period of blood flow oscillation that is high risk for myocardial arrhythmias.
  • the method of therapy includes providing or presenting the individual having heart failure or acute heart failure.
  • a measuring step is first carried out to determine the baseline heart function of the individual. For instance, an individual with heart failure may exhibit impaired or decreased diastolic relaxation function.
  • the measuring step may include measuring one or more parameters of heart failure, such as, but not limited to, decreased heart rate, decreased heart pressure, decreased systolic blood pressure, diastolic blood pressure, reduced left ventricular end-diastolic/systolic volume and function (LVEF), increased E/Ea ratio, increased E/A ratio, reduced Ea ratio, and/or decreased stroke volume.
  • LVEF left ventricular end-diastolic/systolic volume and function
  • any suitable measuring technique available in the art at the time of the measuring step is suitable for use herein, and it is well within the purview of such skilled artisan to select an appropriate measuring technique corresponding to the parameter of interest.
  • a non-limiting list of suitable measuring equipment/techniques includes ECG, echocardiogram, cardiac catheterization (for assessment of pulmonary artery pressures and filling pressures of the left side of the heart), nuclear’ stress test, CAT scan, radionuclide ventriculography scan, stethoscope, sphygmomanometer, and the like.
  • the individual exhibits AHF with acute myocardial ischemia.
  • This ischemia can be detected and monitored using a variety of art standard techniques, including, but not limited to ECG monitoring, echocardiogram, stress test, coronary angiogram, nuclear perfusion imaging, positron emission tomography, cardiovascular magnetic resonance, a chest X-ray, heart MRI or via laboratory blood tests for proteins and enzymes that appear or increase with the heart muscle is damaged, such as elevated troponin or creatine kinase.
  • ECG readings e.g., ST depression equal to or greater than 1 mm
  • ST depression equal to or greater than 1 mm
  • the individual is diagnosed with AHF and acute myocardial ischemia, the latter being detected at the same time as the initial diagnosis or at later time while the individual’s AHF condition is being monitored.
  • the treatment may therefore include the step of reperfusion to reintroduce the flow of blood or increase the blood flow to the heart.
  • Reperfusion can be performed medically by administering one or more active ingredients, such as, but not limited to recombinant tissue plasminogen activator (rTPA), reteplase, anistreplase, desmoteplase, nattokinase, lumbrokinase, serrapeptase, papain, DNAse, bromelain, honiol, tenecteplase,reteplase, urokinase, streptokinase, anticoagulation with heparin, calcium channel blockers, ranolazine, beta blockers, nitrates, aspirin, or cholesterol-lowering compounds.
  • active ingredients such as, but not limited to recombinant tissue plasminogen activator (rTPA), reteplase, anistreplase, desmoteplase,
  • Reperfusion can be performed mechanically using art standard techniques such as, but not limited to balloon angioplasty, stent placement, coronary artery bypass graft, enhanced external counterpulsation, and the like.
  • the reperfusion is performed within 12 hours of the onset of ischemia symptoms; preferably, within 6 hours of the onset of symptoms; more preferably, within the first 2 hours or even 90 minutes of the onset of ischemia symptoms.
  • the method of treatment may also involve monitoring for incidence and duration of acute myocardial arrhythmias using, for example, a ECG with a Holter monitor.
  • a measuring step is first carried out to determine the baseline heart function of the individual. For instance, an individual with heart failure may present with persistent hypotension, dyspnea, and reduced LVEF.
  • the measuring step may include measuring one or more parameters of heart function or heart function impairment, such as, but not limited to, decreased SBP or SBP AUC, reduced left ventricular end-diastolic/systolic volume and function (LVEF), or increased E/Ea or E/A ratios, reduced Ea ratio decreased stroke volume, elevated heart rate, and others.
  • any suitable measuring technique available in the art at the time of the measuring step is suitable for use herein, and it is well within the purview of such skilled artisan to select an appropriate measuring technique corresponding to the parameter of interest.
  • a non-limiting list of suitable measuring equipment/techniques includes echocardiogram, cardiac catheterization, nuclear stress test, CAT scan, radionuclide ventriculography scan, stethoscope, sphygmomanometer, pulmonary capillary wedge pressure (PCWP), and the like.
  • the SBP can be measured by sphygmomanometer or arterial line attached to a pressure transducer.
  • the measuring step may also include monitoring for myocardial arrhythmias using a ECG with Holder monitor.
  • the measuring step may be repeated or performed for the first time following the initiation of istaroxime infusion (or infusion with a derivative thereof) to measure the change in condition, i.c., the improvement in heart function.
  • the measuring step is done after initiation of infusion with istaroxime, a dual mechanism compound, or a pure SERCA2a activator.
  • the measuring step is done before (baseline) and after initiation of infusion.
  • an additional measuring step is done after diagnosis of acute myocardial ischemia and/or during/after reperfusion.
  • these measuring steps can be performed at any time during the treatment process to monitor the individual and determine whether the treatment is effective.
  • an individual is selected for treatment having one or more inclusion criteria.
  • the inclusion criteria includes one or more of clinical presentation with AHF and evidence of acute myocardial ischemia.
  • the methods disclosed herein also include administering to the individual a therapeutically effective amount of istaroxime or istaroxime derivative.
  • the istaroxime is in a pharmaceutical composition, such as any of the combinations discussed above.
  • the istaroxime is administered in a therapeutically effective dose.
  • the istaroxime can be administered to the individual via intravenous infusion with a dose in the range from about 0.1 pg/kg/min to about 3.0 pg/kg/min, e.g..
  • the dose of istaroxime administered to the individual is in the range from about 0.1 pg/kg/min to about 2.5 pg/kg/min or about 0.5 pg/kg/min to about 3.0 pg/kg/min. In a more preferred embodiment, the dose of istaroxime administered to the individual is in the range from about 1.0 pg/kg/min to about 2.0 pg/kg/min, or about 0.5 pg/kg/min to about 1.5 pg/kg/min, or about 1.0 pg/kg/min. or about 1.5 pg/kg/min. In one particular embodiment, the dose of istaroxime administered to the individual is about 1.0 pg/kg/min.
  • the methods disclosed herein include administering to the individual a therapeutically effective amount of CVie 216.
  • the CVie 216 is in a pharmaceutical composition, such as any of the combinations discussed above.
  • the CVie 216 is administered in a therapeutically effective dose.
  • the CVie 216 can be administered to the individual via intravenous infusion with a dose in the range from about 0.1 pg/kg/min to about 3.0 pg/kg/min, e.g..
  • the dose of CVie 216 administered to the individual is in the range from about 0.1 pg/kg/min to about 2.5 pg/kg/min or about 0.5 pg/kg/min to about 3.0 pg/kg/min. In a more preferred embodiment, the dose of CVie 216 administered to the individual is in the range from about 1.0 pg/kg/min to about 2.0 pg/kg/min, or about 1.0 pg/kg/min to about 1.5 pg/kg/min, or about 0.5 pg/kg/min, or about 1.5 pg/kg/min.
  • the methods disclosed herein include administering to the individual a therapeutically effective amount of a dual mechanism compound having a structure according to (i) Formula II, including, but not limited to 3-beta-hydroxy-5-beta-10-beta-methyl- 13-beta-methyl-14-beta-hydroxy-17-beta-(imidazol-4-yl)androstane; 3-beta-hydroxy-5-beta-10- beta-methyl-13-beta-methyl-14-beta-hydroxy-17-beta-(2-guanidino-thiazol-4-yl)androstane; 3- beta-hydroxy-5-beta- 10-beta-methyl- 13-beta- methyl- 14-beta-hydroxy- 17-beta-(pyrazol-3- yl)androstane; 3-beta-hydroxy-5-beta- 10-beta-methyl- 12-beta-hydroxy- 13-beta- methyl- 14-beta- hydroxy-
  • the dual mechanism compound or pure SERCA2a activator is in a pharmaceutical composition, such as any of the combinations discussed above.
  • the compound is administered in a therapeutically effective dose.
  • the compound can be administered to the individual via intravenous infusion with a dose in the range from about 0.1 pg/kg/min to about 3.0 pg/kg/min, e.g.. 0.1 pg/kg/min, 0.15 pg/kg/min.
  • the compound can be administered to the individual at a dose from about 0.1 pg/kg/min to about 2.5 pg/kg/min or about 0.5 pg/kg/min to about 3.0 pg/kg/min or about 1.0 pg/kg/min to about 2.0 pg/kg/min.
  • the time period for the infusion may be at least about 30 minutes to about 48 hours, or more, e.g., 30 m, 45 m, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, lO h, l l h, 12 h, 13 h, 14 h, 15 h,
  • the infusion is carried out from about 3 hours to about 24 hours, or from about 6 hours to about 24 hours, or from about 12 hours to about 24 hours.
  • the individual is administered istaroxime or CVie 216 by intravenous infusion for about 24 hours.
  • the time period for infusion may be greater than 24 hours, e.g., 25 h, 26 h, 27 h, 28 h, 29 h, 30 h, 31 h, 32 h, 33 h, 34 h, 35 h, 36 h, 37 h, 38 h, 39 h, 40 h, 41 h, 42 h, 43 h, 44 h, 45 h, 46 h, 47 h, 48 h, 54 h, 60 h, 66 h, 72 h, 78 h, 84 h, 90 h, 96 h, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days 12 days, 13 days, 14 days, or longer.
  • istaroxime or CVie 216 infusion administered by a pump can be carried out for much longer duration.
  • the method can include one or more measuring steps carried out periodically during the treatment and/or for a period of time post-treatment.
  • the measuring steps may include measuring one or more parameters of heart function as described above prior to beginning of infusion, at the initiation of infusion administration, and/or at one or more time points during and after infusion, e.g., 15 m, 30 m, 45 m, 1 h, 1.25 h, 1.5 h, 1.75 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, lO h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h, 48 h, 72 h, 96 h, 5 days, 6 days, 7 days, 8
  • one or more parameters of heart function can be measured before, during, and 12 h, 24 h , 48, h, 72 h, 96 h, and 30 days following initiation of infusion.
  • the one or more parameters of heart function indicate the efficacy of istaroxime treatment.
  • Improvements in heart function include, but are not limited to, a decrease in E/e’ ratio of at least -2, e.g., -2, -2.2, -2.4, -2.6, -2.8, -3 over a 6 to 24 our period after administration of 0.5
  • the measurements indicative heart function improvement in the individual following initiation of infusion may depend on the particular diagnosis, e.g., AHF with acute myocardial ischemia versus AHF-related cardiogenic shock.
  • a decrease in the level of NT-proBNP or an increase in the level of eGFR indicates treatment of pre-cardiogenic shock or prevention of cardiogenic shock.
  • the absence of serious myocardial arrythmias or the shortening in the duration of serious myocardial arrythmias indicates a reduction in the risk of or prevention of acute myocardial arrhythmias, including, but not limited to, AF, PSVT, VT, or VF.
  • no acute myocardial arrhythmias are detected in an individual with AHF and acute myocardial ischemia after administration by infusion of istaroxime or any one of Formulas II, (e.g., CVielOl), III (e.g., PST3093) or IV (CVie216) for at least about 3 hours after initiation of infusion; preferably, no acute myocardial arrhythmias are detected for at least about 6 hours following initiation of infusion; more preferably, no acute myocardial arrhythmias are detected for at least about 12 hours or at least about 24 hours following initiation of infusion.
  • Formulas II e.g., CVielOl
  • III e.g., PST3093
  • IV e.g., IV
  • the incidence of myocardial arrhythmias are decreased in an individual with AHF and acute myocardial ischemia who is administered istaroxime or Formulas II, III or IV as compared to an individual or the average from among a cohort of individuals with AHF and acute myocardial ischemia who are not administered istaroxime or Formulas II, III or IV.
  • the incidence of myocardial arrhythmias are decreased among a cohort of individuals with AHF and acute myocardial ischemia who are administered istaroxime or Formulas II, III or IV as compared the average number of myocardial arrhythmias occurring in a cohort of individuals with AHF and acute myocardial ischemia and who are not administered istaroxime or Formulas II, III or IV.
  • the absence of acute myocardial arrhythmias or the reduction of incidence of acute myocardial arrhythmias following initiation of infusion of istaroxime or Formulas II, III or IV to the individual is maintained even after perfusion of the heart.
  • the average duration of the acute myocardial arrhythmias are reduced in a cohort of individuals with AHF and acute myocardial ischemia who are administered istaroxime or Formulas II, III or IV as compared to the average duration of acute myocardial arrhythmias in a cohort of individuals with AHF and acute myocardial ischemia who are not administered istaroxime or Formulas II, III or IV.
  • individuals in evaluating the efficacy of a treatment, a treatment regimen or a particular dosage, or to determine if a treatment versus a maintenance dosage should be given, are subject to regular periodic screening for the presence and extent of organ and tissue involvement or damage, e.g., heart (ventricle dilatation, third heart sound cardiac hypertrophy), fatigue, tiredness, reduced exercise tolerance, increased time to recover after exercise, kidney (renal insufficiency, oliguria), lung (orthopnea, paroxysmal nocturnal dyspnea, tachypnea), ankle swelling, elevated jugular venous pressure.
  • heart ventricle dilatation, third heart sound cardiac hypertrophy
  • fatigue e.g., tiredness, reduced exercise tolerance
  • increased time to recover after exercise e.g., kidney (renal insufficiency, oliguria), lung (orthopnea, paroxysmal nocturnal dyspnea, tachypnea), ankle swelling, elevated ju
  • therapy with istaroxime or Formulas II, III or IV or an equivalent of a pharmaceutically acceptable salt, solvate or hydrate thereof as disclosed herein is instituted as early as possible after developing symptoms of AHF and acute myocardial ischemia to prevent worsening of symptoms the development of acute myocardial arrythmias, and further continued after patient’s discharge for years, preferably during the whole life of the patient or at least a period consistent with the way other drugs are used in heart failure.
  • uses and methods as provided herein can further comprise co-administration with other drugs or pharmaceuticals.
  • the present invention selectively corrects a depressed cardiac biochemical function (namely the SERCA2a activity). This certainly contributes to relieving the existing AHF clinical symptoms, with less unwanted side effects than those of the available therapies (just because the selectivity mentioned above).
  • the present invention is potentially associable to existing and future drug classes and/or specific drugs such as: a) drug classes such as, ACE inhibitors, angiotensin receptor blockers (ARBs), diuretics, Ca channel blockers, beta blockers, digitalis, NO donors, vasodilators, SERCA2a stimulators, neprilysin (NEP) inhibitors, myosin filament activators, recombinant relaxin-2 mediators, recombinant NP protein, activators of the soluble Guanylate Cyclase (sGC), beta-arrestin ligand of Angiotensin II receptor; b) specific drugs: hydrochlorothyzide, furosemide, verapamil, diltiazem, carvedilol, metoprolol, hydralazine, eplerenone, spironolactone, lis
  • Istaroxime or Formulas II, III or IV as disclosed in the present invention, as used a therapeutic agent for treating AHF with acute myocardial ischemia, can be combined or co-administered with other therapeutic agents used in the treatment of the same disease and/or the underlying HF.
  • exemplary other therapeutic agents are diuretics, for example furosemide, bumetanide, and torasemide.
  • Metolazone an aldosterone antagonist, such as spironolactone or eplerenone
  • thiazide diuretics such as hydrochlorothiazide, metolazone, and chlorthalidone.
  • agents are ACE inhibitors, for example lisinopril and Ramipril.
  • ARBs such as valsartan, candesartan and losartan can be taken into consideration.
  • Angiotensin receptor/neprilysin inhibitor (ARNI), sacubitril for example, are comprised.
  • Other agents can be selected from Beta-blockers, such as carvedilol and metoprolol for example, or Vasodilators, for example Hydralazine, optionally combined with isosorbidc dinitrate, Nitrates, as nitroglycerin, amlodipine and felodipine; non-dihydropyridines such as diltiazem or verapamil.
  • Still other examplary other therapeutic agents may include phenylephrine, norepinephrine, epinephrine, dopamine, milrinone, dobutamine, and levosimendan.
  • the compounds of the present invention can also be combined with digoxin, if needed.
  • Other drugs, as Ivabradine and other Anticoagulant may be considered.
  • the compounds of the present invention can be combined with other therapeutic agents, in particular agents useful for treating cardiovascular diseases, more in particular in the combination therapy of AHF with other conditions, such as cardiogenic shock or acute myocardial ischemia.
  • the combined active ingredients can be administered according to different protocols, decided by the medical doctor.
  • combination therapy can be carried out by administering istaroxime both at the same time or at different time of the further therapeutically active ingredient or ingredients.
  • the compound of the present invention and the further active ingredient or ingredients can be each formulated in a respective pharmaceutical composition or in the same unitary dosage form.
  • the present invention provides a kit, in particular for the treatment of AHF, comprising separate pharmaceutical compositions containing the compound of the present invention and the further active ingredient or ingredients, respectively.
  • the present invention provides a pharmaceutical unit dosage form kit, in particular for the treatment of AHF, comprising compound of the present invention and the further active ingredient or ingredients in the same unit dosage form.
  • Combination therapy according to the present invention provides advantageous treatment of AHF due to the inotropic-lusitropic effect of istaroxime herein disclosed in addition to or synergically combined with the well-known therapeutic effect of the additional active agents herein disclosed.
  • nanoparticles, nanolipoparticles, vesicles and liposomal membranes comprising compounds used to practice the uses and methods as provided herein, e.g., to deliver pharmaceutically active compounds and compositions as provided herein: istaroxime or Cvie 216 or an equivalent of a pharmaceutically acceptable salt, solvate or hydrate thereof, optionally combined with a further therapeutically active agent as disclosed above to a subject in need thereof.
  • these compositions are designed to target specific molecules, including biologic molecules, such as polypeptides, including cell surface polypeptides, e.g., for targeting a desired cell type, e.g., a myocyte or heart cell, an endothelial cell, and the like.
  • a slow release of istaroxime or derivative thereof may provide a sufficient compound to selectively increase the plasma levels of the metabolite leaving the plasma levels of Istaroxime within very low ranges.
  • multilayered liposomes comprising compounds used to practice methods as provided herein, e.g., as described in U.S. application No. 20070082042.
  • the multilayered liposomes can be prepared using a mixture of oil-phase components comprising squalane, sterols, ceramides, neutral lipids or oils, fatty acids and lecithins, to about 200 to 5000 nm in particle size, to entrap a composition used to practice uses and methods as provided herein.
  • Liposomes can be made using any method, e.g., as described in U.S. Patent No.4,534,899; or U.S. application No. 20070042031, including method of producing a liposome by encapsulating an active agent according to the present invention (or a combination of active agents), the method comprising providing an aqueous solution in a first reservoir; providing an organic lipid solution in a second reservoir, and then mixing the aqueous solution with the organic lipid solution in a first mixing region to produce a liposome solution, where the organic lipid solution mixes with the aqueous solution to substantially instantaneously produce a liposome encapsulating the active agent; and immediately then mixing the liposome solution with a buffer solution to produce a diluted liposome solution.
  • liposome compositions used to practice uses and methods as provided herein comprise a substituted ammonium and/or polyanions, e.g., for targeting delivery of istaroxime or an equivalent of a pharmaceutically acceptable salt, solvate or hydrate thereof used to practice methods as provided herein to a desired cell type, as described, e.g., in U.S. application No. 20070110798.
  • nanoparticles comprising compounds according to the present invention used to practice uses and methods as provided herein in the form of active agent-containing nanoparticles (e.g., a secondary nanoparticle), as described, e.g., in U.S. application No. 20070077286.
  • active agent-containing nanoparticles e.g., a secondary nanoparticle
  • nanoparticles comprising a fat-soluble active agent used to practice a use and method as provided herein or a fat-solubilized water-soluble active agent to act with a bivalent or trivalent metal salt.
  • solid lipid suspensions can be used to formulate and to deliver compositions used to practice uses and methods as provided herein to mammalian cells in vivo, in vitro or ex vivo, as described, e.g., in U.S. application No. 20050136121.
  • compositions and formulations used to practice the uses and methods as provided herein can be delivered by the use of liposomes or nanoliposomes.
  • liposomes particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the active agent into target cells in vivo [see, e.g., U.S. Patents Nos. 6,063,400; 6,007,839; Al-Muhammed, 1996, Microencapsul. 13:293-306; Chonn, 1995, Curr. Opin. Biotechnol. 6:698-708; Ostro, 1989, Am. J. Hosp. Pharm. 46:1576-1587.] A liposome formulation of istaroxime as disclosed in Eur J Pharm Biopharm. 2011;79(2):285-93 is also provided in the present invention.
  • any delivery vehicle can be used to practice the uses and methods as provided herein, e.g., to deliver the compounds provided herein to a subject in need thereof.
  • delivery vehicles comprising polycations, cationic polymers and/or cationic peptides, such as polyethyleneimine derivatives, can be used e.g. as described, e.g., in U.S. application No. 20060083737.
  • a dried polypeptide- surfactant complex is used to formulate a composition used to practice a use and method as provided herein, e.g., as described in U.S. application No. 20040151766.
  • a composition used to practice uses and methods as provided herein can be applied to cells using vehicles with cell membrane-permeant peptide conjugates, e.g., as described in U.S. Patents No. 7,306,783; 6,589,503.
  • the composition to be delivered is conjugated to a cell membrane-permeant peptide.
  • the composition to be delivered and/or the delivery vehicle are conjugated to a transport-mediating peptide, e.g., as described in U.S. Patent No. 5,846,743, describing transport-mediating peptides that arc highly basic and bind to poly-phosphoinositides.
  • electro-permeabilization is used as a primary or adjunctive means to deliver the composition to a cell, e.g., using any electroporation system as described e.g. in U.S. Patents No. 7,109,034; 6,261,815; 5,874,268.
  • Example 1 Evaluation of the effect of istaroxime and CVie 216 on reperfusion arrhythmias in isolated, Langendorff perfused rat hearts
  • Ventricular arrhythmias are serious complications of heart failure (HF).
  • HF heart failure
  • IR ischemia-reperfusion
  • SERCA2a activators derived from the Ista metabolite PST3093 devoid of Na+/K+ ATPase inhibitory activity.
  • the present study assessed if SERCA2a activation could reduce IR arrhythmias both in vitro and in vivo in normal and diabetic rats.
  • istaroxime or derivatives there of e.g, Formulas II and III
  • the pure SERCA2a activator of Formula IV CVie 216
  • isolated rat hearts from a streptozotocin (STZ) diabetic rat model were ligated to induce ischemia and then reperfused to simulate a myocardial arrhythmia.
  • the Sprague-Dawley diabetic rat model is known in the art to be especially suitable for simulating myocardial arrhythmias and was used in this study [see, for example, Hu et al., 2017, Cardiovasc. Diabetol. 16:57].
  • Blood glucose level were determined using a digital glucometer and test strips (Ascensia ELITE®, Bayer Healthcare AG, Leverkusen, Germany). Rats injected with comparable volumes of citrate- buffcrcd saline served as nondiabctic controls.
  • Rats were then anesthetized by intraperitoneal injection of pentobarbital sodium (60 mg/kg body weight).
  • Hearts were rapidly excised, connected immediately to an aortic cannula, and subjected to retrograde perfusion at a constant pressure (70-80 mmHg) in the Langendorff apparatus with K-H buffer (118.5 mM, NaCl; 4.7 mM, KC1; 2.5 mM, CaCh ⁇ HaO; 1.2 mM, MgSCU; 11 mM, glucose; and 25 mM NaHCOa).
  • K-H buffer 118.5 mM, NaCl; 4.7 mM, KC1; 2.5 mM, CaCh ⁇ HaO; 1.2 mM, MgSCU; 11 mM, glucose; and 25 mM NaHCOa.
  • the buffer solution was saturated with a mixture of 95% 02/5% CO2 at 37 °C.
  • LVP left ventricular pressure
  • Istaroxime or CVie 216 was prepared in Krebs-Henseleit buffer. Then, isolated hearts were administered istaroxime, CVie 216, or saline using a perfusion pump (Model 5003, Precidior Infors, Basel, Switzerland). The infusion rate was set to one-hundredth of coronary flow to achieve concentrations of 10 pM or 50 pM of either istaroxime or CVie 216.
  • a 4/0 braided silk suture was passed around the left main coronary artery of the isolated rat heart, and a snare was formed by passing both ends through a piece of polyethylene tubing.
  • Regional ischemia and reperfusion were produced by tightening and loosening the snare as described previously.
  • Occlusion and reperfusion were confirmed by ECG changes, instantaneous changes in perfusion pressure, and the development and relief of cyanosis of the occluded zone. Coronary flow was reduced during occlusions so as to maintain the perfusion pressure at the preocclusion level, and likewise flow was increased again to upon reperfusion.
  • ECG readings were recorded as baseline, and istaroxime or CVie 216 was administered 5 minutes prior to ischemia.
  • the isolated rat hearts were kept in an ischemic state for 10 minutes, and then reperfused. ECG readings were taken during the 5 minute period following reperfusion to measure heart arrythmias.
  • CVie216 The mode of action of istaroxime and its derivative, CVie216, is shown in Figures 1A and IB.
  • CVie216 behaves as a selective SERCA2a activator showing a longer half-life than istaroxime and enhanced in vitro SERCA2a activity in healthy guinea pig preparations and in diseased (STZ) rat preparations.
  • STZ diseased
  • triggered action potentials In preparations from the control rats treated with vehicle, triggered action potentials seldom occurred, whereas triggered activity was largely increased in the vehicle- treated diabetic preparations.
  • CVie216 and Ista administration in diabetic preparations significantly reduced the incidence of triggered activity at 2 Hz. See Figure 2.
  • the action potential duration (APD) at 30% and 50% of repolarization (APD30, APD50) were prolonged significantly in the DM group (* p ⁇ 0.05 vs Ctr), and this phenomenon was prevented by CVie216 and Ista. # p ⁇ 0.05 vs DM.
  • Triggered activity spontaneous action potentials; red double arrow line
  • results are shown as the percentage of preparations (n) inducible into triggered activity /total of preparations.
  • VPCs ventricular premature contractions
  • NVT non-sustained ventricular tachycardia
  • VT sustained ventricular tachycardia
  • VF ventricular fibrillation
  • VF was scored as a 6; VT was scored as a 5; NSVT was scored as a 4; triplets or couplets were scored as 3; less than 50 VPCs were assigned a 2; 5 to 50 VPCs were assigned a 1; and less than 5 VPCs or no arrhythmias were assigned 0.
  • the arrhythmia scores in the presence of 10 and 50 pM CVie216 were averaged among the isolated rat hearts in each cohort, and the results are shown in Figures 3 and 4.
  • CVie 216 In order to evaluate the ability of CVie 216 to reduce the risk of myocardial arrhythmias in hearts of intact rats, STZ diabetic rats (see Example #1) were placed in an ischemic- reperfusion simulation and administered either saline or CVie 216 at 10
  • Rats were lightly anesthetized with sodium pentobarbital (75 mg/kg, intraperitoneal) prior to surgery. Once the rat was anesthetized, it was intubated and ventilated with room air (60- 80 strokes/min, lOml/kg) using small animal ventilator (model 683; Harvard. USA). The jugular vein and carotid artery were cannulated for drug administration and arterial blood pressure monitoring, respectively. The chest was opened by a left thoracotomy, followed by sectioning the fourth and fifth ribs, about 2 mm to the left of the sternum and the epicardium will be opened.
  • Myocardial ischemia was induced by briefly exteriorizing the heart and placing a 4-0 silk slip knot around the left coronary artery, approximately 2-3 mm from its origin, effectively occluding the vessel. Successful occlusion was confirmed by the appearance of epicardium cyanosis and ST-segment elevation. Ischemia was maintained for 10 min, at which time the slip knot was released, initiating reperfusion. CVie216 (0.03-0.14 mg/kg per min) or the equivalent volume of vehicle solution was initiated by intravenous infusion 10 min before occlusion surgery and continued during the duration of the experiment.
  • rats were anesthetized with additional sodium pentobarbital (35 mg/kg, i.p.), and their hearts were excised and placed in ice-cold 0.9% NaCl for the subsequent experiments.
  • the study design is summarized in FIG. 2.
  • VPCs VPCs, couplets, triplets, NSVT, VT, or VF.
  • VF was scored as a 6; VT was scored as a 5; NSVT was scored as a 4; triplets or couplets were scored as 3; less than 50 VPCs were assigned a 2; 5 to 50 VPCs were assigned a 1; and less than 5 VPCs or no arrhythmias were assigned 0.
  • DM diabetes mellitus rats
  • VF ventricular fibrillation
  • VPC ventricular premature contractions
  • MAP mean arterial pressure
  • * P ⁇ 0.05.
  • VF ventricular fibrillation
  • VT ventricular tachycardia
  • arrhythmia scores were measured during early reperfusion.
  • Cardiogenic shock continues to be one of the most common fatal diseases, leading to about 50% mortality after its diagnosis. Even patients with milder forms of cardiogenic shock at presentation often rapidly deteriorate to more severe forms 3 .
  • SBP systolic blood pressure
  • CO cardiac output
  • PCWP pulmonary capillary wedge pressure
  • pre-CS pre-cardiogenic shock
  • stage B SCAT classification patients with clinical signs of peripheral hypoperfusion, venous lactate >2 mmol/L and/or on mechanical support or treatment with intravenous vasodilators, inotropes or vasopressors were excluded.
  • exclusion criteria were concomitant or planned treatment with oral digoxin (could be randomized if the plasma concentration of digoxin at screening was ⁇ 0.5 ng /ml); acute coronary syndrome or stroke within the past 3 months; coronary artery bypass graft or percutaneous coronary intervention within the past month or planned in the next month; life-threatening ventricular arrhythmia or implantable cardio verier defibrillator shock within the past month; sustained ventricular tachycardia in the last 3 months or uncontrolled arrhythmia; fever >38°C; estimated glomerular filtration rate (eGFR) ⁇ 30 ml/min/m2; serum potassium >5.3 or ⁇ 3.5 mmol/L; stroke or transient ischaemic accident within the past 3 months; and acute respiratory distress syndrome.
  • eGFR estimated glomerular filtration rate
  • the patients can be randomized centrally, using an interactive response technology, to receive CVie216 or placebo at a ratio of 1:1.
  • Study medication can be supplied in uniquely- numbered kits containing identical vials of lyophilized powder (CVie216 plus lactose ), reconstituted by adding 5 ml saline to the vial.
  • CVie216 can be administered as a continuous infusion 1.0 pg/kg/min for 24 h.
  • the infusion rate could be decreased at the discretion of the investigator based on the development of tolerability issues (such as nausea), significant bradycardia, or greater than desired BP elevation.
  • the primary efficacy endpoint reflects the area under the curve representing the change in SBP from baseline, start of study drug infusion, through 6 h (SBP AUC).
  • the secondary endpoints also include SBP AUC through 24 h; changes from baseline in SBP (particularly at 6 and 24 h), diastolic blood pressure (DBP) and mean arterial pressure (MAP); changes from baseline in heart rate (HR); treatment failure score (based on death, circulatory, respiratory, or renal mechanical support or intravenous inotrope or vasopressor treatment, and changes in SBP); treatment failure defined as death or need for circulatory, respiratory, or renal mechanical support or intravenous inotrope or vasopressor treatment; increase from baseline in SBP >5% and or > 10 mmHg; changes in quality of life measured by the EuroQol 5 Dimension 5 Level (EQ-5D-5L); change from baseline to 24 h in echocardiography parameters; changes in troponin and N-temiinal pro-B-type natriuretic peptide (NT-proBNP
  • In-hospital worsening heart failure would be defined as worsening signs and/or symptoms of heart failure since the previous assessment that required an intensification of intra venous therapy for heart failure or mechanical ventilatory, renal, or circulatory' support.
  • the safety endpoints can be assessed throughout the study and included the incidence of adverse events; changes in vital signs and in 12-lead electrocardiogram (ECG) parameters; incidence of clinically or haeniodynamically significant episodes of supraventricular' or ventricular arrhythmias detected by continuous ECG monitoring; standard laboratory parameters; renal function measures; cardiac troponin I or T; and mortality through day 30.
  • ECG electrocardiogram
  • CVie216 should prove efficacious as an effect IV drug that in patients with ADHF-related pre-CS providing simultaneous improvements in BP and CO and a reduction in PCWP while not increasing pulse or leading to excess arrythmias. Accordingly, this drug has the potential of becoming the first-line therapy for patients with ADHF-CS.

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Abstract

Sont divulguées des compositions à des fins de perfusion intraveineuse d'istaroxime ou de dérivés associés chez des patients humains atteints d'AHF avec une ischémie myocardique aiguë et/ou un infarctus aigu du myocarde. Le patient peut éventuellement être en choc cardiogénique ou en choc cardiogénique précoce. De même, sont divulguées des méthodes d'administration d'istaroxime ou de dérivés associés à des individus présentant des symptômes de, ou ayant été diagnostiqués comme atteints d'AHF avec une ischémie myocardique aiguë et/ou un infarctus aigu du myocarde. En particulier, est divulguée dans la description une méthode de réduction du risque ou de prévention d'arythmies myocardiques aiguës chez un individu faisant l'objet d'un traitement pour une AHF avec une ischémie myocardique aiguë et/ou un infarctus du myocarde aigu par administration à l'individu d'un régime posologique d'istaroxime ou de CVie 216 par perfusion intraveineuse.
PCT/US2024/058923 2023-12-11 2024-12-06 Istaroxime et dérivés métabolites associés pour réduire le risque d'arythmie myocardique aiguë Pending WO2025128432A1 (fr)

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WO2022159678A1 (fr) * 2021-01-22 2022-07-28 Windtree Therapeutics, Inc. Istaroxime intraveineuse pour le traitement d'une insuffisance cardiaque aiguë
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WO2023205183A1 (fr) * 2022-04-20 2023-10-26 Windtree Therapeutics, Inc. Formulation intraveineuse contenant de l'istaroxime pour le traitement d'un pré-choc cardiogénique et d'un choc cardiogénique

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US20230009312A1 (en) * 2019-10-09 2023-01-12 Windtree Therapeutics, Inc. Androstane Derivatives with Activity as Pure or Predominantly Pure Stimulators of SERCA2a for the Treatment of Heart Failure.
WO2022159678A1 (fr) * 2021-01-22 2022-07-28 Windtree Therapeutics, Inc. Istaroxime intraveineuse pour le traitement d'une insuffisance cardiaque aiguë
WO2023205183A1 (fr) * 2022-04-20 2023-10-26 Windtree Therapeutics, Inc. Formulation intraveineuse contenant de l'istaroxime pour le traitement d'un pré-choc cardiogénique et d'un choc cardiogénique

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