Treatment of heart failure with preserved ejection fraction with guanethidine and guanadrel.

Abstract

The present invention relates to a method of treating patients diagnosed with or suffering from heart failure with preserved ejection fraction (HFpEF) by administering an effective amount of a peripherally acting antihypertensive agent (e.g., guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof) alone or in combination with other agents that reduces excessive venoconstriction.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 376,121, filed September 19, 2022, which is incorporated herein by reference.

[0002] The present invention relates to a method of treating patients diagnosed with or suffering from heart failure with preserved ejection fraction (HFpEF) by administering an effective amount of guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof, alone or in combination with other agents. [Background technology]

[0003] Despite gradual declines in age-adjusted mortality rates from coronary heart disease and hypertensive cardiovascular disease, the incidence and prevalence of heart failure are both rising and are expected to continue to rise well into the 21st century (Tsao et al., Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association, Circulation 145(8):e153-e639, 2022). Heart failure incidence and prevalence are significantly age-dependent, with prevalence rates approaching 10% among adults over 80 years of age in all major demographic subgroups of the U.S. population, and mortality rates increasing exponentially with age. Several factors contribute to the rise in heart failure, with the leading cause being the aging population. The exponential rise in the prevalence of heart failure is thought to be due to the increasing prevalence and cumulative duration of systemic hypertension and coronary artery disease caused by aging and age-related changes in cardiac structure and function, even in the absence of clinically established cardiovascular disease (Lakatta et al., Circulation, 107(1):139-46, 2003; Lakatta et al., Circulation, 107(2):346-54). Consistent with the high morbidity and substantial mortality associated with this disease, heart failure is currently the leading cause of cardiovascular hospitalizations in adults over 65 years of age. It is not only the most common diagnosis in the Medicare population but also one of the most costly, with estimated annual inpatient costs in the United States exceeding $40 billion (Tsao et al. 2022).

[0004] Heart failure currently affects over 7 million Americans, more than half of whom have normal left ventricular systolic function, commonly referred to as HFpEF (e.g., heart failure with preserved ejection fraction). Heart failure annually results in over 280,000 deaths, over 1 million hospitalizations, 1.8 million outpatient visits, and nearly 700,000 emergency room visits in the United States (Benjamin et al., Circulation, 2018, 137:e67-e492). HF hospitalizations account for over 6.5 million hospital days, a significant portion of the billions of dollars spent on HF each year in the United States (Gheorghiade et al., J Am Coll Cardiol, 2013, 61:391-403), which is projected to increase to $53.1 billion by 2030 (Ziaeian et al., Nat Rev Cardiol, 2016, 13:368-78). Worldwide, there are an estimated 30 million individuals with HFpEF.

[0005] Heart failure with preserved ejection fraction, the most common form of heart failure, is a heterogeneous clinical syndrome that has proven difficult to treat. Heart failure is defined by the heart's inability to pump blood to the body at a rate that meets its demands, or to do so only at the expense of high filling pressures. HFpEF is characterized by abnormally elevated left ventricular filling pressures at rest or during exercise in the setting of a preserved ratio of stroke volume to end-diastolic volume (e.g., ejection fraction).

[0006] There continues to be a need for more effective treatments for HFpEF. Summary of the Invention

[0007] The present invention relates to the use of peripherally acting antihypertensive agents that reduce excessive venoconstriction in patients with HFpEF. Such peripherally acting antihypertensive agents include guanethidine, guanadrel, and pharmaceutically acceptable salts thereof. In one embodiment, these peripherally acting antihypertensive agents include those that reduce the release of catecholamines (e.g., norepinephrine), those that deplete peripheral catecholamines, those that reduce peripheral vascular resistance, or any combination of any of the above.

[0008] One embodiment is a method of treating a patient diagnosed with or suffering from HFpEF, comprising administering to the patient an effective amount of guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof.

[0009] Another embodiment is a method for reducing the risk of cardiovascular hospitalization in a patient diagnosed with or suffering from HFpEF, comprising administering to the patient an effective amount of guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof.

[0010] Yet another embodiment is a method for improving exercise capacity or fitness, or both, in a patient with HFpEF, comprising administering to the patient an effective amount of guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof.

[0011] Yet another embodiment is a method of treating a patient diagnosed with or suffering from HFpEF, comprising administering to the patient an effective amount of (a) guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof, and (b) one or more second therapeutic agents selected from a diuretic (e.g., a thiazide diuretic or a loop diuretic), an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor antagonist (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta-blocker, a neprilysin inhibitor, an angiotensin receptor-neprilysin inhibitor, an angiotensin II receptor blocker (ARB), an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the above.

[0012] Yet another embodiment is a method of reducing the risk of cardiovascular hospitalization in a patient diagnosed with or suffering from HFpEF, comprising administering to the patient effective amounts of (a) guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof, and (b) one or more second therapeutic agents selected from a diuretic (e.g., a thiazide diuretic or a loop diuretic), an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor antagonist (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta-blocker, a neprilysin inhibitor, an angiotensin receptor-neprilysin inhibitor, an angiotensin II receptor blocker, an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the above.

[0013] Yet another embodiment is a method of promoting exercise capacity or fitness, or both, in a patient with HFpEF, comprising administering to the patient an effective amount of (a) guanethidine or a pharmaceutically acceptable salt thereof, and (b) one or more second therapeutic agents selected from a diuretic (e.g., a thiazide diuretic or a loop diuretic), an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor antagonist (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta-blocker, a neprilysin inhibitor, an angiotensin receptor-neprilysin inhibitor, an angiotensin II receptor blocker, an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the above.

[0014] A patient's exercise capacity can be assessed by measuring the patient's maximal or submaximal exercise capacity (e.g., a 6-minute walk test (6MWT)). In one embodiment, a patient with HFpEF has less than normal or inadequate maximal exercise capacity. In another embodiment, a patient with HFpEF has less than normal or inadequate submaximal exercise capacity (e.g., as measured by a 6MWT). Normal exercise capacity is that of an average healthy patient of a comparable age. In another embodiment, a patient's exercise capacity is assessed by measuring peak oxygen consumption or duration on a treadmill exercise test.

[0015] In one embodiment, in the methods described herein, the second therapeutic agent is selected from a beta-blocker, an ACE inhibitor, an angiotensin receptor blocker, a diuretic, an aldosterone antagonist, or any combination of any of the above.

[0016] In one embodiment, the patient has been diagnosed with HFpEF prior to administration of guanethidine or a pharmaceutically acceptable salt thereof.

[0017] In another embodiment, the patient has HFpEF and an LVEF greater than 40%, 45%, 50%, or 55%. For example, the patient may have an LVEF greater than 55%. In yet another embodiment, the patient has HFpEF and an LVEF of 40-50% or 40-55%.

[0018] In yet another embodiment, patients with HFpEF present with (i) an LVEF greater than 50% and (ii) evidence of spontaneous (at rest) or induced (e.g., during exercise or fluid challenge) increased left ventricular filling pressures (e.g., elevated natriuretic peptides, noninvasive and / or invasive hemodynamic measures).

[0019] Yet another embodiment is a pharmaceutical composition comprising (a) guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof, and (b) one or more second therapeutic agents selected from a diuretic (e.g., a thiazide diuretic or a loop diuretic), an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta-blocker, a neprilysin inhibitor, an angiotensin receptor-neprilysin inhibitor, an angiotensin II receptor blocker, an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the above. In any of the methods described herein, guanethidine, guanadrel, or a combination thereof, with or without the second therapeutic agent, can be administered in the form of a pharmaceutical composition described herein. The pharmaceutical composition may be in the form of an oral dosage form and may be administered orally. DETAILED DESCRIPTION OF THE INVENTION

[0020] Subjects with HFpEF are characterized by elevated ventricular filling pressure at rest or during exercise to maintain sufficient cardiac output to meet the body's demands.Without being bound by any particular theory, the inventors theorize that the most likely explanation for the high filling pressure is an increase in effective blood volume through structural changes in veins and / or secondary to excessive venous constriction.Excessive venous constriction can be addressed by guanethidine or guanadrel.

[0021] It is clear that gross peripheral vascular abnormalities are an integral part of the hypertension and heart failure syndrome. Zelis et al., Cardiovasc Dis. 1982, 24(6):437-59; Arnold et al., Circulation. 1991, 84(6):2418-25. One reason for the existence of systemic vasoconstriction is activation of the sympathetic nervous system and the renin-angiotensin system. Francis et al., Circulation, 1990, 82(5):1724-9. Vasoconstriction has been demonstrated in both arteries and veins, yet over the past several decades, greater emphasis has been placed on the study of the arterial system.

[0022] Veins serve an important, often overlooked, variable blood storage function. The large volume of these vessels allows this low-pressure reservoir to contain over 70% of the total blood volume, based on data from nonhuman species. Rothe, Physiol Rev. 1983, 63:1281-1342. In normal subjects, more than half of the total blood volume is contained in extrathoracic veins. Extrathoracic venous capacitance is largely under the control of the adrenergic nervous system. Aellig, Br J Clin Pharmacol, 1994, 38(4):289-305. Consequently, reflex changes in venous motor tone provide a rapidly acting mechanism for compensatory redistribution of blood volume. For example, during upright posture, venous constriction acts to partially restore normal cardiac preload. Additionally, Guyton (Banet and Guyton, Am J Physiol, 1971, 220:662-666) demonstrated that intact cardiovascular reflexes, mediated by venous vasoconstriction, prevent blood pooling in the peripheral circulation, which is essential for the development of a full cardiac output response to increased metabolism. Increased central blood volume due to venoconstriction, combined with decreased peripheral venous capacitance, may result in increased preload, providing an explanation for the higher filling pressures characteristic of heart failure in the setting of normal systolic function or heart failure with preserved ejection fraction. Theoretical analysis (Burkhoff et al., Am J Physiol, 1993, 265(5 Pt. 2):H1819-28) suggests that the increase in pulmonary venous pressure that occurs in the setting of acute pulmonary edema is not simply a direct hemodynamic consequence of left ventricular systolic or diastolic dysfunction but is more strongly dictated by sympathetic control of venous volume.

[0023] The majority of patients with heart failure and normal systolic function are elderly. Physiological differences in venous capacitance, venous tone, and possibly venous response to sympathetic stimulation have been described with age, supporting the role of the venous system in the development of HFpEF. Elderly patients exhibit reduced limb venous compliance and capacitance compared with younger subjects. Olsen et al., Am J Physiol. 1998;275(3 Pt 2):H878-H886; Olsen et al., Am J Physiol. 2000;278:H222-H232. Autonomic control of the cardiovascular system, regulated by both α- and β-adrenergic receptors, changes with age. While β-receptor density does not appear to change with age, there is a significant decline in the cardiovascular response to β-adrenergic stimulation with age. Mechanisms include downregulation and decreased agonist binding of β1-receptors, unbinding of β2-receptors, and altered signal transduction. O'Malley et al., J Hypertension, 1988;6(suppl 1):S59-S62. In contrast, α1 receptor-mediated contraction is maintained with age, at least into the seventh decade of life. Klein et al., Clin Pharmacol Ther. 1990;47:535-539. For example, the ability of phenylephrine (an α1 agonist) to increase blood pressure does not change with age in human subjects. Shigemi et al., Am J Physiol. 1994;267:H210-H210. The combination of a decrease in venodilator β2 receptors and preservation of contractile α1 receptors may result in increased resting venous tone. This, combined with a decrease in peripheral venous capacity, would result in an increase in central compartment volume. Increased venous tone in healthy elderly subjects has been suggested in one study. Gascho et al., Am J Cardiol. 1989;63:1267-1270.

[0024] In hypertensive subjects without documented heart failure, effective compliance, a measure of the effect of blood volume on central venous pressure, was lower than in controls (Walsh et al., Cardiovasc Res 1969, 3:338). Because the arterial system does not contribute significantly to effective compliance (Guyton et al., Am J Physiol 1959;5:1008-1014; Echt et al., Circ Res 1974;33:61), compliance of the entire circulation is primarily related to the properties of the venous side of the circulation. Thus, reduced effective compliance in hypertensive patients suggests reduced venous distensibility, possibly as a result of sympathetic stimulation. Indeed, the compensatory increase in preload caused by venous constriction in essential hypertension may explain why these patients have high cardiac output despite very high arteriolar resistance (Liu et al., 1993, Circulation, 88(4 Pt 1):1893-906) and normalized effective arterial elastance as shown in our data (Maurer et al., J Am Coll Cardiol, 2007 Mar, 49(9):972-81).

[0025] In summary, the venous system is not only an understudied and neglected regulator of cardiovascular function, but based on classical physiological principles, it may play an important mechanistic role in the development of the syndrome of heart failure with preserved ejection fraction (HFpEF). Without being bound by any particular theory, we theorize that the decrease in peripheral venous capacitance due to sympathetic stimulation, which leads to an increase in central volume, is one of the major pathophysiological mechanisms underlying the mortality associated with HFpEF.

[0026] Although studies have focused on abnormalities in left or right ventricular structure or function as the principle cause of high filling pressures, classical Guytonian physiology (Guyton et al., Annu Rev Physiol. 1972, 34:13-46; Guyton et al., Clin Anesth. 1964, 3:1-34) states that ventricular filling pressures are determined primarily by changes in loading conditions (preload rather than afterload) and less by chamber properties. In mammals, 70% of blood volume is stored in the venous system (Rothe, Physiol Rev. 1983, 63:1281-1342), and the compliance of the venous system is approximately 30 times greater than that of the arterial system (Gelman, Anesthesiology, 2008, 108(4):735-748). Cardiovascular simulations (Burkhoff et al., Am J Physiology, 1993, 265(5 Pt 2):H1819-28) and physiological experiments (Tyberg, Pflugers Arch. 2002, 445(1):10-7; Tyberg et al., Adv Exp Med Biol. 1993, 346:313-7) have demonstrated that changes in venous capacitance (Fudim et al., J Am Coll Cardiol. 2022, 10;79(18):1858-1869) by modulating the relationship between blood volume gain and blood volume loss are important factors contributing to excessive increases in left ventricular filling pressures during exercise or acute decompensation in patients with HFpEF. Further supporting the role of venous abnormalities in the development of HFpEF, a disorder common in older adults, is the fact that venous properties change significantly with human aging, resulting in a marked decline in venous dilatation capacity, primarily due to changes in beta-receptor density and sensitivity (Pan et al., J Pharmacol Exp Ther. 1986, 239(3):802-7). Thus, changes in venous properties may be an important, previously overlooked, mechanism underlying exercise intolerance and the development of less severe forms of acute decompensated heart failure leading to acute pulmonary edema and hospitalization.Thus, although limitations in exercise and the ability to perform activities of daily living in HFpEF may be due to many mechanisms, there is growing evidence of a profoundly abnormal hemodynamic response to exercise characterized by rapid and significant increases in right and left heart filling pressures that typically return to baseline values ​​during recovery (Bourlaug et al., Circ Heart Fail., 2010, 3(5):588-595). These rapid increases in filling pressures may be mediated primarily by venous constriction shifting blood volume from the splanchnic bed to the central circulation. Although studies using device-based therapies to remove sympathetic control of the venous splanchnic bed (see, e.g., Clinicaltrials.gov identifier: NCT04592445) are being evaluated as therapies for HFpEF, there are currently no approved pharmacological therapies to address these venous abnormalities in HFpEF. Previous studies of nitrates have failed to demonstrate clinical benefit in patients with HFpEF (Redfield et al., N Engl J Med., 2015, 373(24):2314-24). However, nitrates have complex effects on both venous and arterial properties and may result in tachycardial resistance.

[0027] Guanethidine is a peripherally acting antihypertensive agent that reduces the release of catecholamines such as norepinephrine. Guanethidine is transported across sympathetic nerve membranes by the same mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the drug's action. Upon entering the nerve, guanethidine is concentrated in transmitter vesicles, where it replaces norepinephrine. It can also inhibit granule release by reducing norepinephrine. Guanethidine blocks normal sympathetic reflexes, reducing venous return and cardiac output and blunting the responsiveness of resistance and capacitance vessels to sympathetic stimulation, resulting in a fall in blood pressure (Woosley et al., N Eng J Med, 1976, 295:1053-57). Without being bound by any particular theory, the inventors hypothesize that guanethidine may be an effective therapy for patients with HFpEF by blunting the sympathetic stimulation that causes venous constriction and promotes distribution of blood volume to the central circulation.

[0028] Guanethidine is uniquely directed to the peripheral sympathetic nervous system and relaxes the peripheral venous system. Its selective action results from the fact that the drug is a substrate for the pump that transports norepinephrine to nerve terminals. Guanethidine is actively transported into neurons by this "norepinephrine pump," and inhibition of the norepinephrine pump also inhibits guanethidine uptake and action. Upon entering adrenergic neurons, guanethidine binds to norepinephrine storage vesicles, releasing norepinephrine from nerve terminals. In addition to depleting norepinephrine, guanethidine blocks the release of catecholamines normally produced by nerve stimulation.

[0029] Other peripherally acting antihypertensive agents that reduce excessive venoconstriction in patients can be used in place of guanethidine or guanadrel. Such agents include those that reduce the release of catecholamines (e.g., norepinephrine), those that deplete peripheral catecholamines, those that decrease peripheral vascular resistance, or any combination of any of the above.

[0030] As used herein, the term "or" is understood to be inclusive unless otherwise specified or clear from the context.

[0031] As used herein, the terms "a," "an," and "the" are understood to be singular or plural unless otherwise specified or clear from the context.

[0032] Ranges provided herein are understood to be shorthand for all of the values ​​within the range.

[0033] As used herein, the term "about" is understood to mean within the normal tolerance of error in the art, for example, within two standard deviations of the mean, unless otherwise specified or clear from the context. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless otherwise clear from the context, all numerical values ​​provided herein can be modified with the term about.

[0034] In the context of administering therapy to a patient, the terms "treat," "treatment," and "treating" refer to the reduction or inhibition of the progression and / or persistence of a disease or condition, the reduction or amelioration of the severity of a disease or condition, and / or the amelioration of one or more symptoms thereof, resulting from the administration of one or more therapies.

[0035] The term "administering" includes, but is not limited to, oral administration, administration as a suppository, topical contact, intravenous, transdermal, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, rectal, percutaneous, or subcutaneous administration to a subject, or implantation of a sustained-release device, such as a mini-osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) routes. Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. In embodiments, administering does not include administration of any active agent other than the listed active agents. One preferred route of administration is oral.

[0036] The term "combination" refers to a collection of reagents (e.g., active ingredients or drugs) for use in therapy, either by simultaneous delivery, concurrent delivery, or fixed-dose combination delivery. Concurrent delivery refers to the delivery of an admixture of drugs (whether a true mixture, suspension, emulsion, or other physical combination). In this case, the combination can be an admixture of guanethidine (or a pharmaceutically acceptable salt thereof) and a second drug combined immediately prior to delivery, or in separate containers. Concurrent delivery refers to the separate delivery of guanethidine (or a pharmaceutically acceptable salt thereof) and a second drug at the same time or close enough in time to observe additive or, preferably, synergistic activity compared to the activity of either guanethidine (or a pharmaceutically acceptable salt thereof) or the cardiovascular drug alone. Fixed-dose combination delivery refers to the delivery of two or more drugs contained in a single dosage form for oral administration, such as a capsule or tablet.

[0037] An "effective amount" is an amount sufficient for a compound to achieve its stated purpose (e.g., produce the intended effect of its administration, treat a disease, reduce enzyme activity, increase enzyme activity, decrease a signal transduction pathway, or alleviate one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to treat, prevent, delay, suppress, arrest, or alleviate one or more symptoms of a disease or disorder, which is sometimes referred to as a "therapeutically effective amount." "Alleviation" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptom(s), or eliminating the symptom(s). An "effective amount" of a drug may be the amount of drug that, when administered to a subject, will have the intended prophylactic effect, for example, the effect of preventing or delaying the occurrence (or recurrence) of an injury, disease, condition, or pathology, or a symptom thereof, or the effect of reducing the likelihood of the occurrence (or recurrence) of an injury, disease, condition, or pathology, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amount will depend on the purpose of the treatment and can be determined by one of ordinary skill in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). Dosages can vary depending on the requirements of the patient and the compound being used. In the context of the present disclosure, the dosage administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.The size of the dose also will depend on the existence, nature, and extent of any adverse side effects. Determination of the proper dosage for a particular situation is within the skill of the art.

[0038] As used herein, the terms "subject" and "patient" are used interchangeably and refer to a human or mammalian patient unless otherwise specified. Suitable mammals include, but are not limited to, domestic animals (e.g., cats and dogs), horses, sheep, goats, and pigs. In a preferred embodiment, the patient is a human patient. In one embodiment, the patient is at least 40 years old. In another embodiment, the patient is at least 50 years old. In yet another embodiment, the patient is at least 60 or 65 years old.

[0039] "HFpEF" or "heart failure with preserved ejection fraction (also known as diastolic heart failure)" is typically diagnosed by distinguishing between heart failure and preserved ejection fraction. Ejection fraction can be assessed by two-dimensional transthoracic echocardiography (TTE). HFpEF can be diagnosed based on the AHA / ACC / HFSA Guidelines for the Management of Heart Failure, 2022 (Circulation, 2022, 145(18):e895-e1032) (see Sections 2.2 and 2.3), which are incorporated herein by reference in their entirety. HFpEF is Common symptoms include, but are not limited to, fatigue, weakness, dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and edema. HFpEF may be characterized by decreased left ventricular compliance or, as the inventors hypothesize, altered loading conditions that result in elevated pressure in the left ventricle. HFpEF often presents with increased left atrial size as a result of chronically or intermittently elevated left ventricular end-diastolic pressure and, therefore, elevated left atrial pressure. HFpEF corresponds to diagnosis code I50.3 in the 2022 ICD-10-CM (the clinical modification of ICD-10).

[0040] In one embodiment, the patient with HFpEF exhibits an LVEF greater than 40%. In another embodiment, the patient with HFpEF exhibits an LVEF of at least 45% (e.g., the patient exhibits an LVEF of at least 45% within 6 months of initiating treatment with the methods herein). In yet another embodiment, the patient with HFpEF exhibits an LVEF greater than 50%.

[0041] In another embodiment, patients with HFpEF present with (i) an LVEF greater than 50% and (ii) evidence of spontaneous (at rest) or induced (e.g., during exercise or fluid challenge) increased left ventricular filling pressures (e.g., elevated natriuretic peptides, noninvasive and / or invasive hemodynamic measures).

[0042] In yet another embodiment, patients with HFpEF present with (i) an LVEF greater than 50% and (ii) evidence of spontaneous (at rest) or induced (e.g., during exercise or fluid challenge) increased left ventricular filling pressures (e.g., elevated natriuretic peptides, noninvasive and / or invasive hemodynamic measures).

[0043] In one embodiment, the patient has HFpEF and exercise-induced left atrial hypertension (EILAH). In one embodiment, EILAH is defined as a resting pulmonary capillary wedge pressure (PCWP) of 15 mmHg or less, but an exercise-induced PCWP of at least 25 mmHg, measured in the supine position. In another embodiment, the patient has been diagnosed with HFpEF and EILAH.

[0044] In another embodiment, a patient with HFpEF (i) exhibits an LVEF of at least 45% (e.g., an LVEF of at least 45% within 6 months prior to initiation of treatment with the methods described herein), (ii) exhibits chronic heart failure, and (iii) exhibits an exercise-induced PCWP of at least 25 mmHg but a resting PCWP measured in the supine position of 15 mmHg or less. In one embodiment, the patient is over 40 years old. Chronic heart failure may be defined as one or more of the following: (a) symptoms of heart failure requiring treatment (intermittent or continuous) with a diuretic for at least 30 days; (b) New York Heart Association (NYHA) class II plus a history of at least NYHA class II in the previous year, NYHA class III, or ambulatory NYHA class IV symptoms (e.g., paroxysmal nocturnal dyspnea, orthopnea, or dyspnea with mild or moderate exertion) or signs of heart failure (e.g., any rales after coughing or a chest x-ray showing pulmonary congestion); or (c) at least one of the following: (i) at least one HF hospitalization (with heart failure as a primary or secondary diagnosis) within 12 months of treatment initiation, (ii) treatment with intravenous (IV) diuretics or augmented oral diuresis for heart failure within 12 months of treatment initiation, (iii) N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels greater than 150 pg / ml in normal sinus rhythm and / or greater than 450 pg / ml in atrial fibrillation within the past 6 months, or (iv) B-type natriuretic peptide (BNP) levels greater than 50 pg / ml in normal sinus rhythm and / or greater than 150 pg / ml in atrial fibrillation within the past 6 months.

[0045] Patients with HFpEF are at high risk for congestive heart failure, atrial fibrillation, and pulmonary hypertension. Risk factors include hypertension, hyperlipidemia, diabetes, obesity, smoking, and obstructive sleep apnea. In this type of heart failure, the heart muscle contracts adequately, but the ventricles do not fill adequately with blood during diastole.

[0046] Guanethidine Guanethidine has the chemical name guanidine, [2-(hexahydro-1(2H)-azocinyl)ethyl]- and may be in its sulfate form, guanethidine sulfate or guanethidine monosulfate (CAS 645-43-2), which has the chemical name guanidine, [2-(hexahydro-1(2H)-azocinyl)ethyl]-, sulfate (1:1). Guanethidine is commercially available under the trade name Ismelin (U.S. Food and Drug Administration New Drug Application No. 012329). Pharmaceutically acceptable salts of guanethidine include, but are not limited to, guanethidine sulfate.

[0047] Guanethidine or a pharmaceutically acceptable salt thereof can be administered in the form of a dosage form containing one or more pharmaceutically acceptable excipients, for example, an oral dosage form (e.g., tablets, capsules, granules, or oral liquid). Guanethidine or a pharmaceutically acceptable salt thereof can be administered once a day, twice a day, or more frequently. In one preferred embodiment, guanethidine or a pharmaceutically acceptable salt thereof is administered once a day, for example, in an immediate-release or sustained-release oral dosage form. Preferably, guanethidine or a pharmaceutically acceptable salt thereof is administered orally.

[0048] The total daily dosage of guanethidine or a pharmaceutically acceptable salt thereof can range from about 0.5 or 1 mg to about 100 mg (based on guanethidine free base). In one embodiment, the total daily dosage of guanethidine or a pharmaceutically acceptable salt thereof can range from about 25 mg to about 50 mg, or from about 50 mg to about 100 mg. In a preferred embodiment, the total daily dosage of guanethidine or a pharmaceutically acceptable salt thereof ranges from about 0.5, 2, or 5 mg to about 25 mg. In one embodiment, about 1, 2, 3, 4, 5, 7.5, or 10 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) is administered daily. In another embodiment, about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) is administered daily. In yet another embodiment, about 0.5, 1, 2.5, 5, 10, or 25 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) is administered daily. In another embodiment, about 1 to about 3 mg (e.g., 1, 2, or 3 mg) of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) is administered daily. For example, the total daily dosage of guanethidine or a pharmaceutically acceptable salt thereof can be 10 mg (based on guanethidine free base). Additionally, in a preferred embodiment, guanethidine or a pharmaceutically acceptable salt thereof is administered once daily.

[0049] In one embodiment, the patient receives 10 mg of guanethidine orally once daily.

[0050] Treatment with guanethidine may be initiated without a loading dose.

[0051] Guanadrel Guanadrel has the chemical name guanidine, 2-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)guanidine, and may be in its sulfate form, 2-(1,4-dioxaspiro[4.5]decan-3-ylmethyl)guanidine, sulfate, guanadrel. Guanadrel is commercially available under the trade name Hylorel (U.S. Food and Drug Administration New Drug Application No. 018104). Pharmaceutically acceptable salts of guanadrel include, but are not limited to, guanadrel sulfate. Guanadrel and its pharmaceutically acceptable salts can be prepared as described in U.S. Patent No. 3,547,951.

[0052] Guanadrel or its pharmaceutically acceptable salt can be administered in the form of a dosage form containing one or more pharmaceutically acceptable excipients, for example, an oral dosage form (for example, tablets, capsules, granules, or oral liquid).Guanadrel or its pharmaceutically acceptable salt can be administered once a day, twice a day, or more frequently.In a preferred embodiment, guanadrel or its pharmaceutically acceptable salt is administered once a day, for example, in a fast-release dosage form.Preferably, guanadrel or its pharmaceutically acceptable salt is administered orally.

[0053] The total daily dosage of guanadrel or a pharmaceutically acceptable salt thereof can range from about 1 mg to about 100 mg (based on guanadrel free base), preferably from about 10 mg to about 75 mg, or from about 20 mg to about 75 mg. Preferably, guanadrel or a pharmaceutically acceptable salt thereof is administered orally once daily.

[0054] Treatment with guanadrel may be initiated without a loading dose.

[0055] Other drugs The patient may be treated with a combination (eg, a fixed-dose combination) of guanethidine or guanadrel (or a pharmaceutically acceptable salt thereof) with another cardiovascular agent. Suitable cardiovascular agents that may be administered with guanethidine (or a pharmaceutically acceptable salt thereof) include, but are not limited to, diuretics (e.g., thiazide diuretics or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (alone or in combination with a neutral endopeptidase inhibitor), mineralocorticoid antagonists (MRAs), calcium channel blockers, beta-blockers (β-adrenergic receptor blockers), neprilysin inhibitors, angiotensin receptor-neprilysin inhibitors (ARNIs) (e.g., the combination of sacubitril and valsartan, e.g., Entresto®), angiotensin II receptor blockers (ARBs), aldosterone antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and any combination of any of the above. In one preferred embodiment, the cardiovascular agent is selected from beta blockers, ACE inhibitors, ARBs, diuretics, aldosterone antagonists, and any combination of any of the above.

[0056] Thiazide diuretics suitable for use in the methods and compositions described herein include chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, and metolazone.

[0057] Suitable loop diuretics for use in the methods and compositions described herein include furosemide, torsemide, bumetanide, and ethacrynic acid.

[0058] ACE inhibitors suitable for use in the methods and compositions described herein include benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril.

[0059] Suitable MRAs for use in the methods and compositions described herein include spironolactone and eplerenone.

[0060] Calcium channel blockers suitable for use in the methods and compositions described herein include amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine.

[0061] Beta-blockers suitable for use in the methods and compositions described herein include epinephrine, cebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol.

[0062] Neprilysin inhibitors suitable for use in the methods and compositions described herein include thiorphan, candoxatril, and candoxatrilat.

[0063] Suitable ARNIs for use in the methods and compositions described herein include a combination of sacubitril and valsartan, such as Entresto®.

[0064] Angiotensin II receptor blockers (ARBs) suitable for use in the methods and compositions described herein include eprosartan, olmesartan, valsartan, telmisartan, losartan, azilsartan medoxomil, candesartan, and irbesartan.

[0065] Sodium-glucose cotransporter-2 (SGLT-2) inhibitors suitable for use in the methods and compositions described herein include atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin, and tofogliflozin.

[0066] In one embodiment, the patient is treated with a combination (e.g., a fixed-dose combination) of guanethidine or guanadrel (or a pharmaceutically acceptable salt thereof) and one or more of a diuretic, an MRA, an ACE inhibitor, an ARB, an ARNI, and an SGLT-2 inhibitor.

[0067] The recommended starting dose and schedule for Entresto® is 49 / 51 mg (49 mg Sacubitril and 51 mg Valsartan) orally twice daily. After 2-4 weeks, the dose is doubled to a target maintenance dose of 97 / 103 mg twice daily. Sacubitril / valsartan compositions are described in U.S. Patent Nos. 7,468,390, 8,101,659, 8,404,744, 8,796,331, 8,877,938, and 9,388,134, the entire contents of which are incorporated by reference. Preferably, Sacubitril / valsartan is administered in conjunction with an ARB.

[0068] The recommended dosage and schedule for hydralazine is 10 mg orally four times daily for the first two to four days, increasing to 25 mg orally four times daily for the remainder of the first week. For the second and subsequent weeks, this dose is increased to 50 mg orally four times daily. The hydralazine compositions listed herein above are described in U.S. Patent Nos. 6,465,463 and 6,784,177, the entire contents of which are incorporated by reference.

[0069] Each drug may be administered at the doses and in the regimens described above.

[0070] Pharmaceutical Composition Yet another embodiment is a pharmaceutical composition comprising: (a) guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof; and (b) one or more second therapeutic agents selected from a diuretic (e.g., a thiazide diuretic or a loop diuretic), an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor antagonist (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta-blocker, a neprilysin inhibitor, an angiotensin receptor-neprilysin inhibitor, an angiotensin II receptor blocker, an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the above.

[0071] One embodiment is a pharmaceutical composition comprising (a) guanethidine or a pharmaceutically acceptable salt thereof, and (b) one or more second therapeutic agents selected from a diuretic (e.g., a thiazide diuretic or a loop diuretic), an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta-blocker, a neprilysin inhibitor, an angiotensin receptor-neprilysin inhibitor, an angiotensin II receptor blocker, an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the above. For example, the second therapeutic agent can be a diuretic, an MRA, an ACE inhibitor, an ARB, an ARNI, an SGLT-2 inhibitor, or any combination of any of the above.

[0072] The pharmaceutical composition may be in oral dosage form, such as a tablet or liquid. The pharmaceutical composition may be administered according to the methods described herein.

[0073] The following examples are presented to more fully illustrate some embodiments of the invention, but they should in no way be construed as limiting the broad scope of the invention. [Example]

[0074] Hypothetical Example Clinical trials evaluating the safety and efficacy of guanethidine or guanadrel would enroll patients with HFpEF and reduced exercise capacity as evidenced by either treadmill testing, cardiopulmonary exercise testing, or submaximal testing with a 6-minute corridor walk duration, or individuals with reduced health status. More thorough phenotyping of subjects would require exercise hemodynamic testing demonstrating a significant increase in pulmonary capillary wedge pressure during exercise. Such subjects would then be randomly assigned to receive an active agent (e.g., guanethidine (e.g., guanethidine sulfate) or guanadrel (e.g., guanadrel sulfate)) or a matching placebo. Repeat testing after several weeks of treatment could assess the effects of guanethidine or guanadrel on central hemodynamics, maximal or submaximal exercise capacity, or health status.

[0075] All patent and non-patent literature cited herein is incorporated by reference in its entirety.

Claims

1. 1. A method for treating a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), comprising administering to the patient an effective amount of guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof.

2. A method for reducing the risk of cardiovascular hospitalization in a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), comprising administering to the patient an effective amount of guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof.

3. A method for improving exercise capacity, fitness, or both in a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), comprising administering to the patient an effective amount of guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof.

4. 1. A method of treating a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), comprising administering to said patient an effective amount of (a) guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof, and (b) one or more second therapeutic agents selected from diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid antagonists (MRAs), calcium channel blockers, beta-blockers, neprilysin inhibitors, angiotensin receptor-neprilysin inhibitors, angiotensin II receptor blockers, aldosterone antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or any combination of any of the above. The method comprises administering

5. 1. A method for reducing the risk of cardiovascular hospitalization in a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), comprising administering to said patient an effective amount of (a) guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof, and (b) one or more second therapeutic agents selected from diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid antagonists (MRAs), calcium channel blockers, beta-blockers, neprilysin inhibitors, angiotensin receptor-neprilysin inhibitors, angiotensin II receptor blockers, aldosterone antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or any combination of any of the above. The method comprises administering

6. 1. A method for enhancing exercise capacity, fitness, or both in a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), comprising administering to said patient an effective amount of (a) guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof, and (b) one or more second therapeutic agents selected from diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid antagonists (MRAs), calcium channel blockers, beta-blockers, neprilysin inhibitors, angiotensin receptor-neprilysin inhibitors, angiotensin II receptor blockers, aldosterone antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or any combination of any of the above. The method comprises administering

7. 7. The method of any one of claims 4-6, wherein the second therapeutic agent is selected from a beta-blocker, an ACE inhibitor, an angiotensin receptor blocker, a diuretic, an aldosterone antagonist, an SGLT-2 inhibitor, or any combination of any of the above.

8. 10. The method of any one of the preceding claims, wherein the patient has been diagnosed with HFpEF prior to administration of guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof.

9. 10. The method of any one of the preceding claims, wherein the patient has been diagnosed with HFpEF and has a LVEF greater than 45%.

10. 10. The method of any one of the preceding claims, wherein the patient has been diagnosed with HFpEF and has a LVEF greater than 50%.

11. 10. The method of any one of the preceding claims, wherein the patient has been diagnosed with HFpEF and exercise-induced left atrial hypertension.

12. 10. The method of any one of the preceding claims, wherein the method comprises orally administering about 0.5 to about 100 mg of guanethidine (based on guanethidine free base) or a pharmaceutically acceptable salt thereof.

13. 10. The method of any one of the preceding claims, wherein the method comprises daily oral administration of about 0.5 to about 25 mg of guanethidine (based on guanethidine free base) or a pharmaceutically acceptable salt thereof.

14. 10. The method of any one of the preceding claims, wherein the method comprises daily oral administration of about 0.5 to about 10 mg of guanethidine (based on guanethidine free base) or a pharmaceutically acceptable salt thereof.

15. 10. The method of any one of the preceding claims, wherein the method comprises daily oral administration of about 0.5, 1, 2, 3, 4, 5, 7.5 or 10 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base).

16. 10. The method of any one of the preceding claims, wherein the method comprises daily oral administration of about 0.5, 1, 2.5, 5, 10, or 25 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base).

17. 10. The method of any one of the preceding claims, wherein the method comprises orally administering about 10 mg of guanethidine (based on guanethidine free base) or a pharmaceutically acceptable salt thereof.

18. 10. The method of any one of the preceding claims, wherein the method comprises administering guanethidine free base.

19. 19. The method of any one of claims 1-18, wherein the method comprises administering guanethidine sulfate.

20. 12. The method of any one of claims 1-11, wherein the method comprises orally administering guanadrel or a pharmaceutically acceptable salt thereof.

21. 21. The method of any one of claims 1-11 and 20, wherein the method comprises administering guanadrel sulfate.

22. 1. A method of treating a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), comprising administering to the patient an effective amount of a peripherally acting antihypertensive agent that reduces excessive venoconstriction in the patient.

23. 23. The method of claim 22, wherein the peripherally acting antihypertensive agent reduces the release of catecholamines, depletes peripheral catecholamines, decreases vascular resistance, or any combination of any of the above.

24. 1. A pharmaceutical composition comprising: (a) guanethidine, guanadrel, or a pharmaceutically acceptable salt thereof, and (b) one or more second therapeutic agents selected from diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid antagonists (MRAs), calcium channel blockers, beta-blockers, neprilysin inhibitors, angiotensin receptor-neprilysin inhibitors, angiotensin II receptor blockers, aldosterone antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or any combination of any of the above. The pharmaceutical composition comprising:

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