WO2025133907A1 - Combination of zibotentan and dapagliflozin for the treatment of microvascular angina - Google Patents

Abstract

Methods for treating microvascular angina in patients by the use of a combination of zibotentan and dapagliflozin are disclosed.

Description

COMBINATION OF ZIBOTENTAN AND DAPAGLIFLOZIN FOR THE TREATMENT OF MICROVASCULAR ANGINA

TECHNICAL FIELD

[0001 ] The present disclosure relates to a combination of the endothelin receptor antagonist (ERA) zibotentan and the sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for use in treatment of microvascular angina.

INTRODUCTION

[0002] Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Microvascular angina is a common presentation of CVD often described as chest discomfort/pain. Microvascular angina is a chronic condition characterized by abnormal myocardial blood flow leading to ischemic symptoms, and impairments in exercise capacity and health-related quality of life (Panting et al., N Engl J Med, 2002; Ford et al., Heart, 2018). Importantly, microvascular angina is not synonymous with obstructive coronary artery disease (CAD).

[0003] Endothelin-1 , a peptide secreted by endothelial cells, is a highly potent constrictor of the human coronary arterioles (Yanagisawa et al., J Hypertens Suppl, 1998; Davenport et al., J Cardiovasc Pharmacol, 1995), and dysregulation of the endothelin system has previously been implicated in the pathogenesis of microvascular angina (Kaski et al., Br Heart, 1995; Ford et al., Eur Heart J, 2020). Microvascular angina has been shown to be associated with elevated circulating concentrations of endothelin-1 and prolonged exposure to excess endothelin causes vasoconstriction and vascular remodeling (Kaski et al., Br Heart, 1995; Cox et al., J Am Coll Cardiol, 1999). Notably, endothelin-1 has been shown to mediate enhanced vasoconstriction in the peripheral arterioles of participants with microvascular angina compared to control subjects (Ford et al., Eur Heart J, 2018).

[0004] Currently, there are no evidence-based, disease-modifying therapies available for treating microvascular angina. Thus, there remains a need for improved compounds, compositions, and methods for treating patients with microvascular angina. The present disclosure addresses those unmet needs.

BRIEF SUMMARY

[0005] The present disclosure provides a method for treating microvascular angina in a patient in need thereof, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to treat the patient’s microvascular angina. In some embodiments, the patient has microvascular angina as defined by Coronary Vasomotor Disorders International Study Group (COVADIS) criteria.

[0006] In some embodiments, the combination of zibotentan and dapagliflozin is administered to the patient once per day.

[0007] In some embodiments, zibotentan is administered at a dose of 0.25 mg to 1.5 mg. In some embodiments, zibotentan is administered at a dose of 0.25 mg. In some embodiments, zibotentan is administered at a dose of 0.5 mg. In some embodiments, zibotentan is administered at a dose of 0.75 mg. In some embodiments, zibotentan is administered at a dose of 1.0 mg. In some embodiments, zibotentan is administered at a dose of 1.25 mg. In some embodiments, zibotentan is administered at a dose of 1.5 mg.

[0008] In some embodiments, dapagliflozin is administered at a dose of 2.5 mg to 10 mg. In some embodiments, dapagliflozin is administered at a dose of 2.5 mg. In some embodiments, dapagliflozin is administered at a dose of 5.0 mg. In some embodiments, dapagliflozin is administered at a dose of 10.0 mg.

[0009] In some embodiments, zibotentan is administered at a dose of 1 .5 mg and dapagliflozin is administered at a dose of 10 mg. In some embodiments, zibotentan is administered at a dose of 1.25 mg and dapagliflozin is administered at a dose of 10 mg. In some embodiments, zibotentan is administered at a dose of 1 .0 mg and dapagliflozin is administered at a dose of 10 mg. In some embodiments, zibotentan is administered at a dose of 0.75 mg and dapagliflozin is administered at a dose of 10 mg. In some embodiments, zibotentan is administered at a dose of 0.5 mg and dapagliflozin is administered at a dose of 10 mg. In some embodiments, zibotentan is administered at a dose of 0.25 mg and dapagliflozin is administered at a dose of 10 mg.

[0010] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the incidence of one or more major adverse cardiovascular event in the patent relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for one or more major adverse cardiovascular event relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments the one or more major adverse cardiovascular event is selected from: myocardial infarction, stroke, cardiovascular death, and cardiovascular hospitalization.

[0011] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the incidence of cardiovascular death in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for cardiovascular death relative to a dosing regimen in which the patient receives dapagliflozin alone.

[0012] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the incidence of hospitalization for angina relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for hospitalization for angina relative to a dosing regimen in which the patient receives dapagliflozin alone.

[0013] In some embodiments, administration of the combination of zibotentan and dapagliflozin improves coronary flow reserve in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for diminished coronary flow reserve relative to a dosing regimen in which the patient receives dapagliflozin alone.

[0014] In some embodiments, administration of the combination of zibotentan and dapagliflozin improves the patient’s Seattle angina questionnaire score relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the risk of a worsening in the patient’s Seattle angina questionnaire score relative to a dosing regimen in which the patient receives dapagliflozin alone.

[0015] In some embodiments, administration of the combination of zibotentan and dapagliflozin improves the patient’s performance on a treadmill exercise test relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the risk of a worsening in the patient’s performance on a treadmill exercise test relative to a dosing regimen in which the patient receives dapagliflozin alone.

[0016] In some embodiments, administration of the combination of zibotentan and dapagliflozin improves microvascular function in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for reduced microvascular function relative to a dosing regimen in which the patient receives dapagliflozin alone.

[0017] In some embodiments, administration of the combination of zibotentan and dapagliflozin improves renal blood flow in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for decreased renal blood flow relative to a dosing regimen in which the patient receives dapagliflozin alone.

[0018] In some embodiments, administration of the combination of zibotentan and dapagliflozin improves myocardial blood flow in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for decreased myocardial blood flow relative to a dosing regimen in which the patient receives dapagliflozin alone.

[0019] In some embodiments, the coronary flow reserve, microvascular function, renal blood flow, or myocardial blood flow is measured by one or more of: magnetic resonance imaging (MRI), myocardial perfusion imaging (MPI), and/or single-photon emission computed tomography (SPECT).

[0020] In some embodiments, the patient has a minor G allele of the non-coding single nucleotide polymorphism rs9349379. In some embodiments, the patient does not have a minor G allele of the non-coding single nucleotide polymorphism rs9349379.

DETAILED DESCRIPTION

[0021] As used herein, the terms “about” and “approximately,” when used to modify a numeric value or numeric range, indicate that deviations of up to 10% above and down to 10% below the value or range remain within the intended meaning of the recited value or range. In some embodiments, “about” refers to ± 10%. In some embodiments, “about” refers to ± 9%. In some embodiments, “about” refers to ± 8%. In some embodiments, “about” refers to ± 7%. In some embodiments, “about” refers to ± 6%. In some embodiments, “about” refers to ± 5%. In some embodiments, “about” refers to ± 4%. In some embodiments, “about” refers to ± 3%. In some embodiments, “about” refers to ± 2%. In some embodiments, “about” refers to ± 1 %. It is understood that wherever aspects are described herein with the language “about” or “approximately” a numeric value or range, otherwise analogous aspects referring to the specific numeric value or range (without “about”) are also provided. It is also understood that wherever aspects are described herein referring to a numeric value or range without the language “about” or “approximately,” otherwise analogous aspects referring to “about” or “approximately” the specific numeric value or range are also provided.

[0022] The terms “treating” or “treatment” or “to treat” refer to therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic disease, disorder, or condition. Treatment need not result in a complete cure of the condition; partial inhibition or reduction of the condition being treated is encompassed by this term.

[0023] The effectiveness of the compounds of the present disclosure in treating and/or preventing microvascular angina and/or diseases, disorders, and/or conditions associated therewith can readily be determined by a person of ordinary skill in the relevant art. Determining and adjusting an appropriate dosing regimen (e.g., adjusting the amount of compound per dose and/or number of doses and frequency of dosing) within the scope of the disclosed methods can also readily be performed by a person of ordinary skill in the relevant art. One or any combination of diagnostic methods, including physical examination, assessment and monitoring of clinical symptoms, and performance of analytical tests and methods described herein, may be used for monitoring the health status of the patient.

[0024] An “effective amount” or “therapeutically effective amount” refers to an amount of at least one compound of the present disclosure or a pharmaceutical composition comprising at least one such compound that, when administered to a patient, either as a single dose or as part of a series of doses, is effective to produce at least one therapeutic effect. Optimal doses may generally be determined using experimental models and/or clinical trials. Design and execution of pre-cl inical and clinical studies for each of the therapeutics (including when administered for prophylactic benefit) described herein are well within the skill of a person of ordinary skill in the relevant art. The optimal dose of a therapeutic may depend upon the body mass, weight, and/or blood volume of the patient. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the disease, disorder, and/or condition being treated or prevented, which assays will be familiar to those having ordinary skill in the art and are described herein. The level of a compound that is administered to a patient may be monitored by determining the level of the compound (or a metabolite of the compound) in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or another biological sample from the patient. Any method practiced in the art to detect the compound, or metabolite thereof, may be used to measure the level of the compound during the course of a therapeutic regimen.

[0025] The dose of a compound described herein may depend upon the patient’s condition, that is, stage of the disease, seventy of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person of ordinary skill in the medical art. Similarly, the dose of the therapeutic for treating a disease, disorder, and/or condition may be determined according to parameters understood by a person of ordinary skill in the medical art.

[0026] As used herein, the terms “subject” and “patient” are used interchangeably to refer to a party receiving a medical treatment. In some aspects, the subject is a human.

[0027] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to methods that may be used to enable delivery of a drug, e.g., zibotentan or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof and dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof, as described herein. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition, Pergamon; and Remington's, Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, Pa. In some aspects, zibotentan and dapagliflozin are administered orally.

[0028] The terms “pharmaceutical formulation” and “pharmaceutical composition” refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations may be sterile.

[0029] A “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a “pharmaceutical composition” for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed, is appropriate for the formulation employed, and is compatible with other ingredients of the formulation.

[0030] A “sterile” formulation is aseptic or essentially free from living microorganisms and their spores.

[0031] As used herein, the term “prodrug” refers to, for example, esters and carbonates that may be converted, for example, under physiological conditions or by solvolysis, to zibotentan or dapagliflozin. Thus, the term prodrug includes metabolic precursors of zibotentan or dapagliflozin that are pharmaceutically acceptable. The term prodrug also includes covalently bonded carriers that release zibotentan or dapagliflozin in vivo when such prodrug is administered to a patient. Non-limiting examples of prodrugs include esters and carbonates. [0032] Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: (1) Design of Prodrugs, edited by Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by Widder, et al. (Academic Press, 1985); (2) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and Bundgaard, Chapter 5 “Design and Application of Prodrugs.” by Bundgaard p. 113-191 (1991); (3) Bundgaard, Adv. Drug Deliv. Rev., 1992; (4) Bundgaard, et al., J. Pharm. Sci., 77, 285 (1988); and (5) Kakeya, et al., Chem. Pharm. Bull., 1984).

[0033] It is understood that for wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of” and/or “consisting essentially of” are also provided. In this disclosure, “comprises,” “comprising,” “containing,” and “having” and the like can mean “includes,” “including,” and the like; “consisting essentially of’ or “consists essentially” are open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics as described herein of that which is recited are not changed by the presence of more than that which is recited, but excludes prior art aspects.

[0034] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive.

[0035] In an aspect, the disclosure herein provides methods of treating microvascular angina in a human patient comprising administering effective amounts of zibotentan and dapagliflozin to a patient in need thereof.

[0036] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in treating microvascular angina in a human patient. [0037] In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for the treatment of microvascular angina in a human patient.

[0038] In some embodiments, microvascular angina has been diagnosed in the human patient based on the Coronary Vasomotor Disorders International Study Group (COVADIS) criteria. The COVADIS was established to produce an international standardization of diagnostic criteria for certain diseases, including microvascular angina. There are four clinical criteria set forth by COVADIS that are used to establish a diagnosis of microvascular angina:

1. Symptoms of myocardial ischemia, shown by: a. effort and/or rest angina. b. angina equivalents (i.e. , shortness of breath).

2. Absence of obstructive CAD (<50% diameter reduction and/or fractional flow reserve of >0.80), shown by: a. coronary computed tomography angiography. b. invasive coronary angiography.

3. Objective evidence of myocardial ischemia, shown by: a. ischemic electrocardiogram (ECG) changes during an episode of chest pain. b. stress-induced chest pain and/or ischemic ECG changes in the presence or absence of transient/reversible abnormal myocardial perfusion and/or wall motion abnormality.

4. Evidence of impaired coronary microvascular function, shown by: a. Impaired coronary flow reserve (cut-off values between <2.0 and <2.5, depending on methodology used. b. Abnormal coronary microvascular resistance indices (e.g., index of microcirculatory resistance (iMR) of > 25). c. Coronary microvascular spasm, defined as reproduction of symptoms and ischemic ECG shifts, but no epicardial spasm during acetylcholine testing. d. Coronary slow flow phenomenon, defined as a thrombolysis in myocardial infarction (TIMI) frame count > 25.

[0039] In some embodiments, the human patient has a minor G allele of the noncoding single nucleotide polymorphism (SNP) rs9349379. In some embodiments, the human patient does not have a minor G allele of the non-coding SNP rs9349379. The minor G allele of the non-coding SNP rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, and increases the circulating concentrations of ET-1. Notably, the prevalence of the minor G allele is higher in patients with ischemic heart disease (Morrow et al., Am Heart J., 2020).

[0040] In some embodiments, the patients described herein are administered effective amounts of a combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, zibotentan, or a pharmaceutically acceptable salt thereof, is administered once daily. Zibotentan, also referred to as ZD4054, along with details on its chemical synthesis, is described in WO1996040681 , the contents of which are incorporated by reference herein in its entirety. Zibotentan is a highly selective ERA antagonist developed for treatment of prostate cancer but was abandoned in 2011 due to insufficient efficacy in Phase 3 and a 17% increase in incidence of peripheral oedema compared to placebo. Additionally, ETA receptor antagonists have previously been linked to issues of fluid retention and hospitalization for heart failure.

[0042] The specific inhibition of the endothelin A receptor with zibotentan has been reported by Morris et al., Br J Cancer, 2005. Zibotentan, N-(3-methoxy-5- methylpyrazin-2-yl)-2-[4-(1 ,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide, has the following chemical structure:

[0043] In some embodiments, the total administered daily dose of zibotentan, or the pharmaceutically acceptable salt thereof, is 0.25 mg to 1 .5 mg. In some embodiments, the total daily dose of zibotentan is 0.25 mg. In some embodiments, the total daily dose of zibotentan is 0.5 mg. In some embodiments, the total daily dose of zibotentan is 0.75 mg. In some embodiments, the total daily dose of zibotentan is 1.0 mg. In some embodiments, the total daily dose of zibotentan is 1.25 mg. In some embodiments, the total daily dose of zibotentan is 1.5 mg.

[0044] In some embodiments, zibotentan, or a pharmaceutically acceptable salt thereof, is in tablet form. In some embodiments, zibotentan, or a pharmaceutically acceptable salt thereof, is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises one or more pharmaceutical diluents, one or more pharmaceutical disintegrants, or one or more pharmaceutical lubricants.

[0045] In some embodiments, dapagliflozin, or a pharmaceutically acceptable salt thereof, is administered once daily. Dapagliflozin, along with details on its chemical synthesis, has been disclosed in W02003099836, the contents of which are incorporated by reference herein in its entirety. Dapagliflozin is a potent, highly selective, and orally active inhibitor of human renal sodium-dependent glucose transporter 2 (SGLT-2) that has been approved to improve glycemic control in adults with type 2 diabetes mellitus (as an adjunct to diet and exercise). SGLT-2 inhibitors block glucose reabsorption in the kidney, increase glucose excretion, and lower blood glucose concentration. A side effect associated with the pharmacological effects of SGLT-2 inhibitors is volume depletion/intravascular volume contraction, potentially leading to dehydration, hypovolemia, orthostatic hypotension, or hypotension. Thus, SGLT-2 inhibitors generally induce an increase in hematocrit (Hot) a marker of hemoconcentration and increased blood viscosity, a putative cause of vascular injury in a context of peripheral vascular disease.

[0046] In some embodiments, dapagliflozin is in the form of a pharmaceutically acceptable solvate, mixed solvate, or complex. In some aspects provided herein, dapagliflozin is in the form of a non-crystalline solid. In some aspects provided herein, dapagliflozin is in the form of a crystalline solid. In some aspects provided herein, dapagliflozin is in the form of a (S)-propylene glycol ((S)-PG) solvate which has the structure:

[0047] In aspects provided herein, dapagliflozin is administered to the patient orally. In aspects provided herein, dapagliflozin is administered to the patient in a tablet form.

[0048] In some embodiments, the total administered daily dose of dapagliflozin, or the pharmaceutically acceptable salt thereof, is 2.5 mg to 10 mg. In some embodiments, the total daily dose of dapagliflozin is 2.5 mg. In some embodiments, the total daily dose of dapagliflozin is 3.0 mg. In some embodiments, the total daily dose of dapagliflozin is 4.0 mg. In some embodiments, the total daily dose of dapagliflozin is 5.0 mg. In some embodiments, the total daily dose of dapagliflozin is 6.0 mg. In some embodiments, the total daily dose of dapagliflozin is 7.0 mg. In some embodiments, the total daily dose of dapagliflozin is 7.5 mg. In some embodiments, the total daily dose of dapagliflozin is 8.0 mg. In some embodiments, the total daily dose of dapagliflozin is 9.0 mg. In some embodiments, the total daily dose of dapagliflozin is 10.0 mg. [0049] In some embodiments, zibotentan, or a pharmaceutically acceptable salt thereof, is administered once daily in a combination with dapagliflozin, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, a combination of zibotentan and dapagliflozin is administered comprising a total daily dose of 0.25 mg to 1.5 mg of zibotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 2.5 mg to 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, a combination of zibotentan and dapagliflozin is administered comprising a total daily dose of 0.25 mg of zibotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, a combination of zibotentan and dapagliflozin is administered comprising a total daily dose of 0.5 mg of zibotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, a combination of zibotentan and dapagliflozin is administered comprising a total daily dose of 0.75 mg of zibotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, a combination of zibotentan and dapagliflozin is administered comprising a total daily dose of 1.0 mg of zibotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, a combination of zibotentan and dapagliflozin is administered comprising a total daily dose of 1.25 mg of zibotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, a combination of zibotentan and dapagliflozin is administered comprising a total daily dose of 1.5 mg of zibotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the incidence of one or more major adverse cardiovascular event in the patient. In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the patient’s risk for one or more major adverse cardiovascular event.

[0052] In some embodiments, the major adverse cardiovascular event is chosen from myocardial infarction, stroke, cardiovascular death, and cardiovascular hospitalization. In some embodiments, the cardiovascular hospitalization is related to unstable or stable angina pectoris, heart failure, and/or coronary revascularization.

[0053] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the incidence of cardiovascular death in the patient. In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the patient’s risk for cardiovascular death. [0054] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the incidence of hospitalization for angina. In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the patient’s risk for hospitalization for angina.

[0055] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof improves coronary flow reserve in the patient. In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the patient’s risk for diminished coronary flow reserve. In some embodiments, coronary flow reserve is assessed by one or more of: magnetic resonance imaging (MRI), myocardial perfusion imaging (MPI), and/or single-photon emission computed tomography (SPECT).

[0056] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof improves the patient’s Seattle angina questionnaire score. The Seattle angina questionnaire is a 19-item self-administered questionnaire that measures five dimensions of CAD: physical limitation, anginal stability, anginal frequency, treatment satisfaction, and disease perception. The Seattle angina questionnaire is described, for example, in Spertus et al., J Am Coll Cardiol., 1995. [0057] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof improves the patient’s performance on a treadmill exercise test. Exercise testing on treadmills is used in the diagnosis and evaluation of cardiovascular diseases, including microvascular angina (see, e.g., Bruce et al., Am Heart J, 1973; Epstein et al., Circulation, 1991 ; Lanza et al., Circ J., 2018; Lopez et al., J Am Coll Cardiol Img., 2022).

[0058] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof improves microvascular function in the patient. In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the patient’s risk for microvascular dysfunction. In some embodiments, microvascular function and/or dysfunction are assessed by one or more of: magnetic resonance imaging (MRI), myocardial perfusion imaging (MPI), and/or single-photon emission computed tomography (SPECT).

[0059] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof improves renal blood flow in the patient. In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the patient’s risk for reduced renal blood flow. In some embodiments, renal blood flow is assessed by one or more of: magnetic resonance imaging (MRI), myocardial perfusion imaging (MPI), and/or singlephoton emission computed tomography (SPECT).

[0060] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof improves myocardial blood flow in the patient. In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the patient’s risk for reduced myocardial blood flow. In some embodiments, myocardial blood flow is assessed by one or more of: magnetic resonance imaging (MRI), myocardial perfusion imaging (MPI), and/or single-photon emission computed tomography (SPECT).

[0061] In some embodiments, the improvement in disease, reduction of incidence, reduction of risk, and other beneficial effects described herein and provided for through administration the combination of zibotentan and dapagliflozin as described in the preceding embodiments can represent improvements relative to the absence of therapy, improvements relative to placebo treatment, improvements relative to treatment with dapagliflozin alone, and/or improvements relative to treatment with other standard- of-care treatments for microvascular angina and/or diseases, disorders, or conditions associated with microvascular angina.

[0062] In some embodiments, the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, are administered concurrently. In some embodiments, zibotentan, or a pharmaceutically acceptable salt thereof, is administered prior to administration of dapagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, zibotentan, or a pharmaceutically acceptable salt thereof, is administered after administration of dapagliflozin, or a pharmaceutically acceptable salt thereof.

[0063] Pharmaceutical compositions may be administered in any manner appropriate to the disease, disorder, and/or condition to be treated as determined by persons of ordinary skill in the medical arts. An appropriate dose and a suitable duration and frequency of administration falling within the scope of the disclosed methods will be determined by such factors as discussed herein, including the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose (or effective dose) and treatment regimen provides the composition(s) as described herein in an amount sufficient to provide therapeutic and/or prophylactic benefit (for example, an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease- free and/or overall survival, or a lessening of symptom severity or other benefit as described in detail above).

[0064] In some embodiments, zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, ora pharmaceutically acceptable salt thereof are co-formulated as a single pharmaceutical composition. In some embodiments, zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof are formulated as separate pharmaceutical compositions.

[0065] The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles, diluents, and pharmaceutical additives as appropriate for the mode of desired administration. The pharmaceutical compositions can be administered by a variety of routes including, for example, orally, in the form of tablets, capsules, granules, powders, and the like, parenterally, in the form of injectable preparations, intranasally, rectally, and transdermally, in the form of patches, for example.

[0066] The above dosage forms can also include a pharmaceutically acceptable carrier (i.e., a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type), excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), adjuvant, and the like.

[0067] Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such a propylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate; coloring agents; releasing agents; coating agents; sweetening; flavoring; and perfuming agents; preservatives; and antioxidants.

[0068] Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0069] Examples of adjuvants include preservative agents, wetting agents, emulsifying agents, dispersing agents, suspending agents, sweetening, flavoring, and perfuming agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Suspending agents include, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0070] The various pharmaceutical compositions employed in the methods of the disclosure can optionally include one or more fillers or excipients. Examples of suitable fillers or excipients include, but are not limited to, lactose, sugar, com starch, modified com starch, mannitol, sorbitol, inorganic salts, such as calcium carbonate, and cellulose derivatives, such as wood cellulose and microcrystalline cellulose.

[0071] One or more binders can be present in addition to or in lieu of the fillers. Examples of suitable binders include polyvinylpyrrolidone (molecular weight ranging from about 5000 to about 80,000 and in some embodiments about 40,000), lactose, starches, such as com starch, modified com starch, sugars, gum acacia and the like, as well as a wax binder in finely powdered form (less than 500 microns), such as carnauba wax, paraffin, spermaceti, polyethylenes and microcrystalline wax.

[0072] In some embodiments, the pharmaceutical composition is in the form of a tablet, wherein the tablet includes one or more tableting lubricants. Examples of suitable tableting lubricants include, but are not limited to, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, and the like. Other ingredients can optionally be present, including, for example, preservatives, stabilizers, colorants, antiadherents and silica flow conditioners or glidants, such as Syloid brand silicon dioxide.

[0073] In some embodiments, the pharmaceutical composition is in the form of a tablet, wherein the tablet includes a coating layer. The coating layer can comprise any conventional coating formulations that can include, for example, one or more film-formers or binders and/or one or more plasticizers. Examples of suitable film-formers or binders include, but are not limited to, hydrophilic polymers, such as hydroxypropylmethylcellulose, hydrophobic polymers, such as methacrylic acid esters, neutral polymers, ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, p-pinene polymers, glyceryl esters of wood resins and the like. Examples of suitable plasticizers include, but are not limited to, triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate, castor oil and the like. Both core tablets as well as coating formulations can contain aluminum lakes to provide color.

[0074] In some embodiments, the pharmaceutical composition is in the form of a tablet, wherein film-formers are applied to the tablet from a solvent system containing one or more solvents including water, alcohols such as methyl alcohol, ethyl alcohol and isopropyl alcohol, ketones such as acetone and ethylmethyl ketone, chlorinated hydrocarbons such as methylene chloride, dichloroethane, and 1 ,1 ,1 -trichloroethane.

[0075] In some embodiments, the pharmaceutical composition is in the form of a tablet, wherein color is applied together with the film former, plasticizer, and solvent compositions.

[0076] In some embodiments, the pharmaceutical composition for use in the methods of the disclosure in the form of a tablet can be obtained by a process comprising the steps of: a) mixing the inactive ingredients with the at least one of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof; b) formulating granules; c) drying and/or screening the granules; d) blending the granules; and e) tableting the blend obtained in (d) into tablets.

[0077] In some embodiments, step a) of the process employs impact blending or milling and/or sizing equipment. In some embodiments, the granules in step b) of the process are formulated by dry granulation, wet granulation, or direct compression. In some embodiments, the granules are formulated by dry granulation. In some embodiments, the granules in step d) of the process are blended with a tableting aid or a lubricant and filler.

[0078] In some embodiments, the pharmaceutical composition in the form of a capsule can be obtained by a process comprising the steps of: a) mixing the inactive ingredients with the at least one of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof using a combination of blending and milling processes; b) formulating granules; c) drying and/or screening the granules; and d) loading the granules into capsules.

[0079] In some embodiments, step a) of the process employs impact milling or blending and/or sizing equipment. In some embodiments, the granules in step b) of the process are formulated by dry granulation, wet granulation, or direct compression. In some embodiments, the granules are formulated by dry granulation.

[0080] In some embodiments, the pharmaceutical composition may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0081] In some embodiments, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. In some embodiments, this is accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. In some embodiments, delayed absorption is accomplished by dissolving or suspending the drug in an oil vehicle.

[0082] In some embodiments, the pharmaceutical composition is in an injectable depot form. In some embodiments, the injectable depot form comprises microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers suitable for use herein include poly(orthoesters) and poly(anhydrides). In some embodiments, depot injectable formulations are prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0083] In some embodiments, the pharmaceutical composition is an injectable formulation, wherein the injectable formulation may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0084] In some embodiments, the pharmaceutical composition is a solid dosage form suitable for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the combination of zibotentan and dapagliflozin is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay, and/or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In some embodiments, the dosage form may also comprise buffering agents.

[0085] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0086] In some embodiments, tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well- known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

[0087] In some embodiments the combination of zibotentan and dapagliflozin may be in micro-encapsulated form, if appropriate, with one or more of the above- mentioned excipients.

[0088] In some embodiments the pharmaceutical composition may be in liquid dosage form suitable for oral administration including pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In some embodiments, the liquid dosage form may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

[0089] The following examples provide illustrative embodiments of the disclosure. One of ordinary skill in the art will recognize the numerous modifications and variations that may be performed without altering the spirit or scope of the disclosure. Such modifications and variations are encompassed within the scope of the disclosure. The examples provided do not in any way limit the disclosure.

EXAMPLES

Example 1

[0090] Clinical trials of the combination of zibotentan and dapagliflozin are ongoing and being planned, including a study to assess the safety and efficacy of the combination of zibotentan and dapagliflozin compared to dapagliflozin alone, in patients having microvascular angina. In a 12-week study, patients having microvascular angina diagnosed by the COVAD IS criteria will be stratified into two groups: a group receiving the combination of zibotentan and dapagliflozin (0.75 mg and 10 mg, respectively; n=20), and a group receiving dapagliflozin along (10 mg; n=10). The study participants will receive the study treatment once daily over the 12-week period. The primary endpoint of the impact of the combination of zibotentan and dapagliflozin compared to dapagliflozin alone on microvascular function will be measured by one or more of: MRI, MPI, and/or SPECT. The secondary endpoints of the impact of the combination of zibotentan and dapagliflozin compared to dapagliflozin alone on CFR will be assessed by SPECT, and MRI will also be used to assess renal blood flow. Exploratory endpoints to be measured as well, will include performance on the treadmill exercise test, the Seattle angina questionnaire, and the participant’s G allele status, and the impact of G allele status on the various study outcomes.

[0091] The 12-week study may also comprise three groups receiving the combination of zibotentan and dapagliflozin: a low-dose group (low-dose zibotentan, 10 mg dose dapagliflozin; n=35), a mid-dose group (mid-dose zibotentan, 10 mg dose dapagliflozin; n=35), and a high-dose group (high-dose zibotentan, 10 mg dose dapagliflozin; n=35), as well as an expanded group receiving dapagliflozin alone (10 mg; n =35).

Example 2

[0092] In a future Phase 3 trial, study participants will receive a combination of zibotentan and dapagliflozin (zibotentan dose determined based on the results of earlier studies, 10 mg dose dapagliflozin; n=750) or dapagliflozin alone (10 mg; n=750). Primary endpoints in this study will include the incidence of death/cardiovascular death, major adverse cardiovascular events, and hospitalization for angina.

Claims

CLAIMS What is claimed is:

1 . A method for treating microvascular angina in a patient in need thereof, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to treat the patient’s microvascular angina.

2. The method of claim 1 , wherein the patient has microvascular angina as defined by Coronary Vasomotor Disorders International Study Group (COVADIS) criteria.

3. The method of any one of the preceding claims, comprising administering the combination of zibotentan and dapagliflozin to the patient once per day.

4. The method of any one of the preceding claims, comprising administering zibotentan at a dose of 0.25 mg to 1 .5 mg.

5. The method of any one of the preceding claims, comprising administering zibotentan at a dose of 0.25 mg.

6. The method of any one of claims 1-4, comprising administering zibotentan at a dose of 0.5 mg.

7. The method of any one of claims 1-4, comprising administering zibotentan at a dose of 0.75 mg.

8. The method of any one of claims 1-4, comprising administering zibotentan at a dose of 1.0 mg.

9. The method of any one of claims 1-4, comprising administering zibotentan at a dose of 1.25 mg.

10. The method of any one of claims 1-4, comprising administering zibotentan at a dose of 1.5 mg.

11. The method of any one of the preceding claims, comprising administering dapagliflozin at a dose of 2.5 mg to 10 mg.

12. The method of any one of the preceding claims, comprising administering dapagliflozin at a dose of 2.5 mg.

13. The method of any one of claims 1-11 , comprising administering dapagliflozin at a dose of 5.0 mg.

14. The method of any one of claims 1-11 , comprising administering dapagliflozin at a dose of 10.0 mg.

15. The method of any one of claims 1-4, 10, 11 , and 14, comprising administering zibotentan at a dose of 1.5 mg and dapagliflozin at a dose of 10 mg.

16. The method of any one of claims 1-4, 9, 11 , and 14, comprising administering zibotentan at a dose of 1.25 mg and dapagliflozin at a dose of 10 mg.

17. The method of any one of claims 1-4, 8, 11 , and 14, comprising administering zibotentan at a dose of 1.0 mg and dapagliflozin at a dose of 10 mg.

18. The method of any one of claims 1-4, 7, 11 , and 14, comprising administering zibotentan at a dose of 0.75 mg and dapagliflozin at a dose of 10 mg.

19. The method of any one of claims 1-4, 6, 11 , and 14, comprising administering zibotentan at a dose of 0.5 mg and dapagliflozin at a dose of 10 mg.

20. The method of any one of claims 1-5, 11 , and 14, comprising administering zibotentan at a dose of 0.25 mg and dapagliflozin at a dose of 10 mg.

21. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the incidence of one or more major adverse cardiovascular event in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

22. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for one or more major adverse cardiovascular event relative to a dosing regimen in which the patient receives dapagliflozin alone.

23. The method of claim 21 or 22, wherein the one or more major adverse cardiovascular event is selected from: myocardial infarction, stroke, cardiovascular death, and cardiovascular hospitalization.

24. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the incidence of cardiovascular death in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

25. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for cardiovascular death relative to a dosing regimen in which the patient receives dapagliflozin alone.

26. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the incidence of hospitalization for angina relative to a dosing regimen in which the patient receives dapagliflozin alone.

27. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for hospitalization for angina relative to a dosing regimen in which the patient receives dapagliflozin alone.

28. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin improves coronary flow reserve in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

29. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for diminished coronary flow reserve relative to a dosing regimen in which the patient receives dapagliflozin alone.

30. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin improves the patient’s Seattle angina questionnaire score relative to a dosing regimen in which the patient receives dapagliflozin alone.

31. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the risk of a worsening in the patient’s Seattle angina questionnaire score relative to a dosing regimen in which the patient receives dapagliflozin alone.

32. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin improves the patient’s performance on a treadmill exercise test relative to a dosing regimen in which the patient receives dapagliflozin alone.

33. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the risk of a worsening in the patient’s performance on a treadmill exercise test relative to a dosing regimen in which the patient receives dapagliflozin alone.

34. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin improves microvascular function in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

35. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for reduced microvascular function relative to a dosing regimen in which the patient receives dapagliflozin alone.

36. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin improves renal blood flow in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

37. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for decreased renal blood flow relative to a dosing regimen in which the patient receives dapagliflozin alone.

38. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin improves myocardial blood flow in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

39. The method of any of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s risk for decreased myocardial blood flow relative to a dosing regimen in which the patient receives dapagliflozin alone.

40. The method of any one of claims 28-29 or 34-39, wherein the coronary flow reserve, microvascular function, renal blood flow, or myocardial blood flow is measured by one or more of: magnetic resonance imaging (MRI), myocardial perfusion imaging (MPI), and/or single-photon emission computed tomography (SPECT).

41. The method of any of the preceding claims, in which the patient has a minor G allele of the non-coding single nucleotide polymorphism rs9349379.

42. The method of any of claims 1-30, in which the patient does not have a minor G allele of the non-coding single nucleotide polymorphism rs9349379.