WO2023070164A1

WO2023070164A1 - Treatment of heart failure with preserved ejection fraction

Info

Publication number: WO2023070164A1
Application number: PCT/AU2022/051301
Authority: WO
Inventors: Ravi Krishnan; Maria VISTNES; Geir Christensen
Original assignee: Paradigm Biopharmaceuticals Ltd; University Of Oslo; Oslo University Hospital
Priority date: 2021-10-28
Filing date: 2022-10-28
Publication date: 2023-05-04

Abstract

The present invention relates to the use of pentosan polysulfate, including pharmaceutically acceptable salts and compositions thereof, for the treatment of heart failure in a mammal. In particular, the use of pentosan polysulfate, including pharmaceutically acceptable salts and compositions thereof, for the treatment of heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are described.

Description

"Treatment of heart failure with preserved ejection fraction"

Technical Field

[0001] This invention relates to the use of pentosan polysulfate, including pharmaceutically acceptable salts and compositions thereof for the treatment of heart failure in a mammal. In particular, the invention relates to the use of pentosan polysulfate, including pharmaceutically acceptable salts and compositions thereof for the treatment of heart failure with preserved ejection fraction.

[0002] Throughout this disclosure, various publications are referenced. Full citations for these publications, in the order they appear in the application, are presented in a References section immediately before the claims. The disclosures of these referenced publications are incorporated herein in their entirety.

Background

[0003] Pentosan polysulfate (PPS) is a weaker anticoagulant than heparin but has been used post-surgically and prophylactically as a thrombolytic agent. Typically, PPS is used as the sodium salt (NaPPS). When given via the oral and intravesical routes, NaPPS has been used for the treatment of interstitial cystitis. Indeed, NaPPS is the active agent in the drug ELMIRON® which is currently prescribed for interstitial cystitis. The potential use of PPS, and salts thereof, in treatment of inflammatory conditions such as asthma, allergic rhinitis, and/or chronic obstructive pulmonary disease (COPD) has also been described, as has its use in the treatment of osteoporosis and bone marrow edema.

[0004] PPS has been disclosed as effective in the treatment of acute respiratory disease syndrome (ARDS). Particularly, the use of PPS in the treatment of ARDS induced by coronaviruses, such as SARS-CoV-2. [0005] It has also been disclosed that PPS is an effective inhibitor of ADAMTS4 or AD AMTS 5. This property is useful in treating or preventing cardiac remodeling or chronic heart failure in a subject with cardiac remodeling or chronic heart failure or with a condition that may lead to cardiac remodeling or chronic heart failure.

[0006] Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome in which patients have clinical features of heart failure in the presence of normal or near-normal left ventricular ejection fraction, usually defined as ejection fraction at 50% or above. The left ventricle contracts and pumps normally but the muscle may be stiff or thickened. This prevents the ventricle from relaxing properly and filling up with blood all the way. Although the ejection fraction may be normal, the heart has less blood available inside the ventricle to pump out to the rest of the body when the heart contracts.

[0007] Heart failure with reduced ejection (HFrEF) is a clinical syndrome in which patients have clinical features of heart failure in the presence of reduced left ventricular ejection fraction, usually defined as ejection fraction of 40% or less. The left ventricle may be enlarged and cannot contract forcefully enough to pump the right amount of blood to the rest of the body.

[0008] In 2012 in the USA, 5.8 million individuals (2.4% of the population) were diagnosed with heart failure. Approximately 50% of the patients with heart failure had a preserved ejection fraction (HFpEF). A recent study in Olmsted County, Minnesota, USA, found that the overall incidence of heart failure declined by 37.5% over a decade (2000 to 2010). Although the incidence of heart failure declined for both HFpEF and HFrEF, the declines were greater for HFrEF (-45%) than for HFpEF (-28%). However, with the ageing of the world’s population, a higher proportion of individuals are at risk of developing heart failure (such as individuals with obesity, diabetes mellitus and hypertension), and with improved survival from acute myocardial infarctions and valvular heart disease, the prevalence continues to increase regardless of incidence rates. [0009] The risk of HFpEF increases sharply with age. Other common risk factors include obesity, hypertension, smoking, diabetes mellitus, coronary artery disease (CAD), valvular heart disease, and atrial fibrillation.

[0010] Multimorbidity is common in HFpEF with approximately 50% of patients having five or more major comorbidities. Estimates of mortality of patients with HFpEF vary depending on the study design with consistently higher mortality in observational studies than clinical trial populations. At 1 year, mortality in HFpEF ranges from 20% to 29% and, by 5 years, at least half of the patients have died with published mortality estimates ranging from 53% to 74%.

[0011] The prevalence of HFrEF increases with age for both sexes, with men more likely than women to develop HFrEF. Other common risk factors include obesity, hypertension, smoking, diabetes mellitus, left ventricular hypertrophy, and previous myocardial infarction.

[0012] Several comorbidities are commonly observed in patients with HFrEF with approximately 40% of patients having 5 or more comorbidities. A recent clinical trial study in New Zealand and Singapore found that 3-year mortality rates for HFrEF were around 32% while mortality for HFpEF was around 25%.

[0013] Myocardial fibrosis is an important part of cardiac remodeling that leads to heart failure and death. Myocardial fibrosis results from increased myofibroblast activity and excessive extracellular matrix deposition. It is defined by a significant increase in the collagen volume of myocardial tissue. It is a complex process that involves all components of the myocardial tissue and can be triggered by tissue injury from myocardial ischemia (hypoxia), inflammation, and hypertensive overload. Summary

[0014] The present inventors have now found that PPS is effective in the treatment of heart failure with preserved ejection fraction (HFpEF). This is an important finding given the incidence of HFpEF in the community.

[0015] Based on this finding, the present inventors expect that PPS will also be effective in the treatment of heart failure with reduced ejection fraction (HFrEF). This is an important finding given the incidence of HFrEF in the community.

[0016] Accordingly the present disclosure provides a method of treating heart failure with preserved ejection fraction (HFpEF) comprising administering an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0017] The present disclosure further provides a use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of heart failure with preserved ejection fraction (HFpEF).

[0018] The present disclosure still further provides a composition comprising pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the treatment of heart failure with preserved ejection fraction (HFpEF).

[0019] The present disclosure still further provides a method of treating heart failure with reduced ejection fraction (HFrEF) comprising administering an effective amount of pentosan polysulfate, or pharmaceutically acceptable a salt thereof, to a subject in need thereof.

[0020] The present disclosure still further provides a use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of heart failure with reduced ejection fraction (HFrEF). [0021] The present disclosure still further provides a composition comprising pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the treatment of heart failure with reduced ejection fraction (HFrEF).

[0022] The present inventors have also now found that PPS is effective in the treatment of myocardial fibrosis resulting from heart failure with preserved ejection fraction (HFpEF).

[0023] Based on this finding, the present inventors expect that PPS will also be effective in the treatment of myocardial fibrosis resulting from heart failure with reduced ejection fraction (HFrEF).

[0024] The present disclosure also contemplates the prophylactic treatment of an individual diagnosed with a risk of heart failure with preserved ejection fraction (HFpEF).

[0025] Accordingly the present disclosure provides a method of prophylactic ally treating a subject with a risk of heart failure with preserved ejection fraction (HFpEF) comprising administering an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, to the subject.

[0026] The present disclosure further provides a use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prophylactic treatment of a subject at risk of heart failure with preserved ejection fraction (HFpEF).

[0027] The present disclosure still further provides a composition comprising pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the prophylactic treatment of a subject at risk of heart failure with preserved ejection fraction (HFpEF).

[0028] The present disclosure further contemplates the prophylactic treatment of an individual diagnosed with a risk of heart failure with reduced ejection fraction (HFrEF). [0029] Accordingly the present disclosure provides a method of prophylactic ally treating a subject with a risk of heart failure with reduced ejection fraction (HFrEF) comprising administering an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, to the subject.

[0030] The present disclosure further provides a use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prophylactic treatment of a subject at risk of heart failure with reduced ejection fraction (HFrEF).

[0031] The present disclosure still further provides a composition comprising pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the prophylactic treatment of a subject at risk of heart failure with reduced ejection fraction (HFrEF).

Brief Description of Drawings

[0032] Figures 1A and IB demonstrate increased levels of the natriuretic peptides ANP and BNP in ZSF-1 obese rats administered PPS subcutaneously (N=5) compared to vehicle treated animals (N=5) after 15 weeks of treatment.

[0033] Figure 2 shows echocardiographic measurements for diastolic dysfunction and increased filling pressures as a ratio of peak mitral inflow velocity (E) to mitral tissue velocity (e') (E/e').

Description of Embodiments

[0034] Definitions

[0035] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Thus, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly indicates otherwise. For example, reference to “a cell” includes populations of a plurality of cells.

[0036] With regards to the definitions provided herein, unless stated otherwise, or implicit from context, the defined terms and phrases include the provided meanings. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired by a person skilled in the relevant art. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims.

[0037] Throughout the present specification, various aspects and components of the invention can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 2, from 1 to 3, from 1 to 4, from 2 to 3, from 2 to 4, from 2 to 5, from 3 to 4 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, and 5. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification.

[0038] As used herein, the term “about” refers to a range of ± 10% of the specified value or a range associated with the experimental error known to the skilled addressee in measuring the specified value, whichever is the greater.

[0039] The term “acceptable excipient" includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are physiologically compatible and are not deleterious to PPS or a compound as described herein or use thereof. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art. For example as taught in Remington: The Science and Practice of Pharmacy, 21st Edition.

[0040] The term “acceptable salts” include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoro acetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginate, asparaginate, glutamate and the like; metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, discyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.

[0041] Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine. General information on types of acceptable salts and their formation is known to those skilled in the art and is as described in general texts. For example, “Handbook of Pharmaceutical salts” P.H. Stahl, C.G. Wermuth, 1st edition, 2002,

[0042] The terms "administration of" and/or "administering a" compound such as PPS should be understood to mean providing PPS, or a pharmaceutically acceptable salt thereof, to the individual in need of treatment.

[0043] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. [0044] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0045] This disclosure is directed to treatment of human subjects. The treatment of a “human subject” may also be referred to as the treatment of a “patient” or an “individual”. A human subject may be one who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, is treated for a condition, or who has been diagnosed with a condition to be treated or who is suspected of having a condition to be treated.

[0046] As used herein, the terms "treating", "treat" or "treatment" and variations thereof, refer to clinical intervention designed to alter the natural course of the subject during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. A subject is successfully "treated", for example, if one or more of the above treatment outcomes is achieved. As used herein, the terms "treating", "treat" or "treatment" and variations thereof encompass “preventing”, “prevent” or “prevention” which would be understood to refer to clinical intervention designed to avert the development of a course of clinical pathology.

[0047] An "effective amount" encompasses a “therapeutically effective” amount which refers to at least the minimum concentration or amount required to effect a measurable improvement of a particular disease. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the PPS to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the PPS are outweighed by the therapeutically beneficial effects. An "effective amount" also encompasses a "prophylactically effective" amount which refers to the amount of drug or the rate of drug administration needed to produce the desired preventive result. [0048] With respect to any one of the methods, compositions or uses described above, the PPS is selected from the group consisting of: the sodium salt of pentosan polysulfate (NaPPS), the magnesium salt of pentosan polysulfate (MgPPS), the calcium salt of pentosan polysulfate (CaPPS), and the zinc salt of pentosan polysulfate (ZnPPS). In one example, the pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS). In one preferred example, NaPPS is manufactured to the specifications lodged with the US FDA and European Community EMEA by Bene-PharmaChem GmbH & Co KG, Geretsried, Germany.

[0049] It will be recognized by persons skilled in the art, that PPS and PPS compositions suitable for administration by a variety of routes may be formulated by reference to standard textbooks in this field. For example, Remington: The Science and Practice of Pharmacy, 21st Edition.

[0050] These compositions include those formulated for delivery by injection, oral route (including tablets and capsules containing gastro-intestinal drug absorption extenders and enhancers), intravenous, respiratory and the like.

[0051] If a treatment is to be administered orally, it is preferred that PPS is co- administered with a coxib as disclosed in PCT/AU2019/050119, the contents of which are included by way of cross-reference.

[0052] Beneficially, PPS may be co -administered with cardiovascular drugs such as Angiotension Receptor Blockers (ARB); ACEI (angiotensin-converting-enzyme inhibitors) and beta blockers as well as anti-diabetic drugs such as SGLT2 inhibitors.

[0053] The treatment may be by administering through intra-muscular (M) or subcutaneous (SC) routes, intravenously (IV), intra-articularly (IA), peri-articularly, topically, via suppositories or orally. The treatment may also be by administering through a respiratory route. The respiratory route may be an intra-nasal route; an intratracheal or endo-tracheal route. The respiratory route may be a pulmonary route. Administration through the pulmonary route may be achieved using a nebulizer, metered-dose inhaler or dry-power inhaler.

[0054] Thus, the present disclosure contemplates the methods, the compositions or the uses as described above, wherein the treatment is by administering an injection. The injection is, for example, an intra-muscular (IM) injection or subcutaneous (SC) injection. In one example, the treatment is by administering a subcutaneous (SC) injection. In one example, the SC injection is a slow subcutaneous (SC) injection.

[0055] In one example, the treatment is by administering PPS, or the pharmaceutically acceptable salt thereof, to the subject in an effective amount of about 0.1 mg/kg to about 4 mg/kg of the subject per dose. The treatment is, for example, by administering the PPS or the pharmaceutically acceptable salt thereof to the mammal in an effective amount of about 1.5 mg/kg of the subject per dose. In one example, the effective amount is about 0.75 to about 1.5 mg/kg of the subject per dose. In certain examples, the effective amount is about 0.75 to about 1.0 mg/kg of the subject per dose.

[0056] In one example, administration to a human subject is by dosing in a treatment regimen once weekly.

[0057] When administration is by a route that requires supervision, for example injection, this would normally be carried out in a clinical situation by a nurse/doctor.

[0058] It will be understood, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound, such as PPS or a pharmaceutically acceptable salt thereof, employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. Example

[0059] The aim of the study was to investigate the effect of Pentosan Poly sulfate Sodium (PPS) on the development of heart failure, when administered once a week via the subcutaneous route (SC) in ZSF1 obese male rats for 15 consecutive weeks.

[0060] The ZSF1 rat model: So-called 2-hit animal models for HFpEF combines increased afterload by aortic banding or hypertension, with insulin resistance through obesity or diabetes. By crossing the lean female Zucker diabetic fatty (ZDF) rat with the lean male spontaneously hypertensive heart failure (SHHF) rat, both carrying mutations in the leptin receptor, the homozygous offspring develop hypertension, obesity and insulin resistance. These Zucker fatty and spontaneously hypertensive (ZSF1 obese) rats develop HFpEF with diastolic dysfunction by aging (Schauer et al 2020).

[0061] The study involved 2 groups of 6 animals each and was designed as a pilot study with small group sizes and no wild-type control animals.

[0062] Groups were as follows:

• Group 1: Control group dosed with the vehicle (Phosphate Buffered Saline (PBS) only).

• Group 2: Treatment group dosed with PPS at 9.3 mg/kg (Human equivalent dose of 1.5 mg/kg) in PBS

[0063] Treatments were administered by the SC route at a volume of 9.3 mg/kg once a week for 15 consecutive weeks.

[0064] Parameters evaluated in this study included in-life observations and measurements (including morbidity/mortality, body temperature, body weight, food consumption and echocardiographic evaluation at baseline and at week 22, 25 and 29), terminal clinical chemistry, urinalysis, coagulation and hematology, organ weights, necropsy and histopathology. On the day of necropsies, arterial blood pressure and left ventricle performance were assessed using the pres sure- volume (PV) loop procedure in all animals.

[0065] Natriuretic peptides (NPs) are peptide hormones that are synthesized by the heart, brain and other organs. The release of these peptides by the heart is stimulated by atrial and ventricular distension, as well as by neurohumoral stimuli, usually in response to heart failure. The main physiological actions of natriuretic peptides is to reduce arterial pressure by decreasing blood volume and systemic vascular resistance.

[0066] Atrial natriuretic peptide (ANP) is synthesized, stored, and released by atrial myocytes in response to atrial distension, angiotensin II stimulation, endothelin, and sympathetic stimulation (beta-adrenoceptor mediated). Therefore, elevated levels of ANP are found during hypervolemic states (elevated blood volume), such as occurs in heart failure. ANP is first synthesized and stored in cardiac myocytes as prepro-ANP, which is then cleaved to pro-ANP and finally to ANP. ANP is the biologically active peptide.

[0067] Brain (B-type) natriuretic peptide (BNP) is synthesized largely by the ventricles (as well as in the brain where it was first identified). BNP is first synthesized as prepro-BNP, which is then cleaved to pro-BNP and finally to BNP. Like ANP, BNP is released by the same mechanisms that release ANP, and it has similar physiological actions. Proteolysis of pro-BNP results in BNP and the N-terminal piece of pro-BNP (NT-pro-BNP). Both BNP and NT-pro-BNP are sensitive, diagnostic markers for heart failure in patients.

[0068] NPs are involved in the long-term regulation of sodium and water balance, blood volume and arterial pressure. There are two major pathways of natriuretic peptide actions: 1) vasodilator effects, and 2) renal effects that lead to natriuresis and diuresis.

[0069] NPs directly dilate veins (increase venous compliance) and thereby decrease central venous pressure, which reduces cardiac output by decreasing ventricular preload. NPs also dilate arteries, which decreases systemic vascular resistance and systemic arterial pressure. Chronic elevations of NPs appear to decrease arterial blood pressure primarily by decreasing systemic vascular resistance.

[0070] NPs affect the kidneys by increasing glomerular filtration rate (GFR) and filtration fraction, which produces natriuresis (increased sodium excretion) and diuresis (increased fluid excretion). These renal effects of NPs are potassium sparing unlike most diuretic drugs that are used to induce natriuresis and diuresis in patients.

[0071] A second renal action of NPs is that they decrease renin release, thereby decreasing circulating levels of angiotensin II and aldosterone. This leads to further natriuresis and diuresis. Decreased angiotensin II also contributes to systemic vasodilation and decreased systemic vascular resistance.

[0072] Taken together, these actions of NPs decrease blood volume, arterial pressure, central venous pressure, pulmonary capillary wedge pressure, and cardiac output. To summarize, natriuretic peptides serve as a counter-regulatory system for the renin- angiotensin-aldosterone system (RAAS).

[0073] Analysis of the natriuretic peptides, ANP and BNP:

[0074] Deficiency of circulating ANP in HF is associated with several clinical factors, such as age, gender, renal function, obesity, and atrial fibrillation (AF) (Wang et al 2018). Lower serum ANP concentrations in HF may demonstrate an aspect of a deficiency in circulating ANP that contributes to difficulties in treating HF (Triposkiadis et al 2016; Chirinos et al 2018).

[0075] Given that serum ANP and BNP are secreted via the same pathway in response to increased cardiac stress, HFpEF may be associated with relatively low concentrations of ANP as well as BNP. Thus, HFpEF may be a promising factor for predicting the presence of low serum ANP concentrations in patients with increased atrial pressure. Based on its pleiotropic physiological functions, which are typified by natriuretic effects, ANP, as with BNP, represents a rational treatment target in HF.

[0076] PPS treated Animal Nos. 2100310, 2100306 and 2100309 showed an increase of ANP and BNP values. Compared with controls, PPS treatment showed a 4.7- to 10.1-fold increase in ANP and a 3.6-to 5.7-fold increase in BNP. The other 2 animals

(Nos. 2100321 and 2100318) showed ANP and BNP values comparable with controls (Shown below in Table 1).

[0077] Table 1: Analysis of ANP and BNP in the serum of ZSF-1 rats at week 29 following weekly treatments with PPS or vehicle for 15 weeks.

[0078] Figures 1A and IB demonstrate increased levels of the natriuretic peptides

ANP and BNP in ZSF-1 obese rats administered PPS subcutaneously (N=5) compared to vehicle treated animals (N=5) after 15 weeks of treatment.

[0079] Echocardiographic evaluation: [0080] During the study period of 15 weeks, rats developed a progression of diastolic dysfunction and a left atrial dilatation. While the ejection fraction and fractional shortening decreased during the period, which may indicate a potential deterioration of systolic function, or reflect improvement in diastolic function. Aligned with findings from previous studies in this rat model, left ventricular hypertrophy and diastolic dysfunction were already present at week 14, and progressed during the study period.

[0081] In conclusion, a potential signal of PPS could be observed on E' wave, E/E' ratio and E wave deceleration time with a p<0.1 (Figure 2).

[0082] Figure 2 shows echocardiographic measurements for diastolic dysfunction and increased filling pressures. In particular, ratio of peak mitral inflow velocity (E) to mitral tissue velocity (e') (E/e'), is shown in Figure 2. The reduced E/e' ratios in the PPS treatment group compared to the vehicle group are an indication of reduced ‘stiffness’ of the ventricles.

[0083] The effect of PPS treatment on myocardial fibrosis was also investigated.

[0084] Myocardial tissue obtained at necropsy after weekly treatment for 15 weeks were fixed in formalin and embedded in paraffin. Sections were stained in Masson Trichrome stain showing a blue color reaction to collagen. PPS treatment demonstrated a reduction in collagen staining compared to vehicle treated animals.

[0085] This data demonstrates that PPS treatment increased the levels of the cardioprotective natriuretic peptides ANP and BNP and improved diastolic function by reducing the ratio of peak mitral inflow velocity (E) to mitral tissue velocity (e') - E/e' ratio. The cardio-protective effects were further associated with reduced myocardial fibrosis following PPS treatment.

References

[0086] Schauer, A., et al. ZSF1 rat as animal model for HFpEF: Development of reduced diastolic function and skeletal muscle dysfunction. ESC Heart Failure 7, 2123- 2134 (2020). [0087] Wang TJ. Natriuretic peptide deficiency — when there is too little of a good thing. JAMA Cardiol 2018; 3: 7-9.

[0088] Triposkiadis F, Pieske B, Butler J, Parissis J, Giamouzis G, Skoularigis J, Brutsaert D, Boudoulas H. Global left atrial failure in heart failure. Eur J Heart Fail 2016;18: 1307-1320.

[0089] Chirinos JA, Sardana M, Oldland G, Ansari B, Lee J, Hussain A, Mustafa A, Akers SR, Wei W, Lakatta EG, Fedorova OV. Association of arginine vasopressin with low atrial natriuretic peptide levels, left ventricular remodelling, and outcomes in adults with and without heart failure. ESC Heart Fail 2018; 5: 911-919. [0090] Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott

Williams & Wilkins: Philadelphia, PA, 2005.

[0091] “Handbook of Pharmaceutical salts” P .H.Stahl, C.G.Wermuth, 1^st edition, 2002, Wiley- VCH

[0092] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

CLAIMS:

1. A method of treating heart failure with preserved ejection fraction (HFpEF) comprising administering an effective amount of pentosan poly sulfate, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

2. Use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of heart failure with preserved ejection fraction (HFpEF).

3. A composition comprising an effective amount of pentosan polysulfate, or pharmaceutically acceptable a salt thereof, for the treatment of heart failure with preserved ejection fraction (HFpEF).

4. A method of treating heart failure with reduced ejection fraction (HFrEF) comprising administering an effective amount of pentosan poly sulfate, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

5. Use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of heart failure with reduced ejection fraction (HFpEF).

6. A composition comprising pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the treatment of heart failure with reduced ejection fraction (HFpEF).

7. A method of treating myocardial fibrosis resulting from heart failure with reduced ejection fraction (HFrEF) comprising administering to a subject in need thereof an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof.

8. A method of treating myocardial fibrosis resulting from heart failure with preserved ejection fraction (HFpEF) comprising administering to a subject in need

RECTIFIED SHEET (RULE 91) ISA/AU thereof an effective amount of pentosan poly sulfate, or a pharmaceutically acceptable salt thereof.

9. A method of prophy tactically treating a subject with a risk of heart failure with preserved ejection fraction (HFpEF) comprising administering an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, to the subject.

10. A use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prophylactic treatment of a subject at risk of heart failure with preserved ejection fraction (HFpEF).

11. A composition comprising an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the prophylactic treatment of a subject at risk of heart failure with preserved ejection fraction (HFpEF).

12. A method of prophy tactically treating a subject with a risk of heart failure with reduced ejection fraction (HFrEF) comprising administering an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, to the subject.

13. A use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prophylactic treatment of a subject at risk of heart failure with reduced ejection fraction (HFrEF).

14. A composition comprising an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the prophylactic treatment of a subject at risk of heart failure with reduced ejection fraction (HFrEF).

15. The method, composition or use according to any one of claims 1 to 14 comprising pentosan poly sulfate, or a pharmaceutically acceptable salt thereof, in a concentration effective to provide a dose thereof to a subject in an amount of 0.1 to 4.0 mg/kg.

RECTIFIED SHEET (RULE 91) ISA/AU

16. The method, composition or use according to any one of claims 1 to 15 wherein the pentosan poly sulfate, or a pharmaceutically acceptable salt thereof, is administered weekly to the subject.

17. The method, composition or use according to any one of claims 1 to 16 wherein the pentosan poly sulfate is selected from the group consisting of: the sodium salt of pentosan polysulfate (NaPPS), the magnesium salt of pentosan polysulfate (MgPPS), the calcium salt of pentosan poly sulfate (CaPPS), and the zinc salt of pentosan poly sulfate (ZnPPS).

18. The method, composition or use according to claim 17 wherein the pentosan polysulfate is sodium pentosan polysulfate (NaPPS).

RECTIFIED SHEET (RULE 91) ISA/AU