Combination of zibotentan and dapagliflozin for use for the treatment of hypertension

Abstract

Methods for treating uncontrolled hypertension, resistant hypertension, systemic hypertension, and pulmonary hypertension in patients by the use of a combination of zibotentan and dapagliflozin are disclosed.

Description

COMBINATION OF ZIBOTENTAN AND DAPAGLIFLOZIN FOR USE FOR THE TREATMENT OF HYPERTENSIONCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 627,893, filed February 1 , 2024, the contents of which are incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] 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 hypertension.INTRODUCTION

[0003] Blood pressure is a measure of the blood pushing against arterial walls in blood vessels. While blood pressure naturally rises and falls throughout the course of a day, prolonged elevated blood pressure, referred to as hypertension, can result in significant health complications. In addition to increasing arterial wall strain, hypertension can also affect the heart. For example, in pulmonary hypertension, the right side of the heart must work harder to adequately supply the lungs with blood, which can weaken the heart muscles and ultimately lead to muscle failure. Hypertension affects approximately 49% of adults in the U.S. and an estimated 1.2 billion individuals worldwide, resulting in more than 17 million deaths globally each year (Chobufo et al., In J Cardiol Hypertens, 2020; NCD Risk Factor Collaboration (NCD-RisC), Lancet, 2021 ; Ojha et al., Am J Cardiovasc Drugs, 2022). Standard of care agents used to treat hypertension include drugs targeting renin-angiotensin-aldosterone system and adrenergic receptors, betablockers, calcium channel blockers, mineralocorticoid receptor antagonists, alpha- adrenergic receptor antagonists, vasodilators, and diuretics (Ojha et al., Am J Cardiovasc Drugs, 2022). However, these standard of care agents are not always effective in treating hypertension. For example, hypertension may be classified as “uncontrolled” or “resistant” when two or more standard of care agents are not effective at reducing a patient’s blood pressure to a target level. Thus, patients having uncontrolled hypertension or resistant hypertension are at an increased risk for adverse outcomes because their blood pressure remains in a hypertensive state despite the use of standard of care agents. Notably, hypertension is associated with a variety of cardiovascular diseases, including stroke, coronary artery disease, heart failure, and atrial fibrillation, as well as chronic kidney disease (Fuchs and Whelton, Hypertension, 2019).

[0004] Endothelin-1 , a peptide secreted by endothelial cells, is a highly potent vasoconstrictor that affects vascular beds, including coronary arterioles (Yanagisawa et al., J Hypertens Suppl, 1998; Davenport et al., J Cardiovasc Pharmacol, 1995; Nohria et al., Hypertension, 2003), and dysregulation of the endothelin system has previously been implicated in the pathogenesis of hypertension (Schiffrin, Vascul Pharmacol., 2005). Hypertension has been shown to be associated with elevated circulating concentrations of endothelin-1 and prolonged exposure to excess endothelin causes inflammation and vascular remodeling (Schiffrin, Vascul Pharmacol., 2005).

[0005] Despite the different treatments currently available, hypertension, including uncontrolled hypertension or resistant hypertension, remains a highly prevalent disease around the world. Thus, there remains a need for improved compounds,compositions, and methods for treating patients with uncontrolled hypertension or resistant hypertension. The present disclosure addresses those unmet needs.BRIEF SUMMARY

[0006] The present disclosure provides, in some embodiments, a method for treating hypertension 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 hypertension. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension.

[0007] The present disclosure additionally provides, in some embodiments, a method of slowing eGFR decline in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to slow the patient’s eGFR decline. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension.

[0008] The present disclosure additionally provides, in some embodiments, a method of reducing UACR in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s UACR. The present disclosure additionally provides, in some embodiments, a method of reducing UACR by about 5% to about 30% in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s UACR by about 5% to about 30%. The present disclosure additionally provides, in some embodiments, a method of reducing UACR to below 300 mg / g in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin inan amount effective to reduce the patient’s UACR to below 300 mg / g. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension.

[0009] The present disclosure additionally provides, in some embodiments, a method of reducing UPCR in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s UPCR. The present disclosure additionally provides, in some embodiments, a method of reducing UPCR by about 5% to about 30% in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s UPCR by about 5% to about 30%. The present disclosure additionally provides, in some embodiments, a method of reducing UPCR to below 1 g / g in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s UPCR to below 1 g / g. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension.

[0010] The present disclosure additionally provides, in some embodiments, a method of improving a hypertension patient’s performance in liver function tests (LFTs), the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to improve the patient’s performance in LFTs. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension.

[0011] The present disclosure additionally provides, in some embodiments, a method of reducing a hypertension patient’s lipid levels, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amounteffective to reduce the patient’s lipid levels. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension.

[0012] The present disclosure additionally provides, in some embodiments, a method of reducing a hypertension patient’s glucose levels, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s glucose levels. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension.

[0013] The present disclosure, additionally provides, in some embodiments, a method of treating pulmonary hypertension in a patient in need thereof, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s pulmonary hypertension. The present disclosure additionally provides, in some embodiments, a method for reducing right ventricular strain in a patient in need thereof, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s right ventricular strain. The present disclosure additionally provides, in some embodiments, a method for slowing and / or delaying a reduction in right ventricular fractional area in a patient in need thereof, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to slow and / or delay a decline in the patient’s right ventricular fractional area.

[0014] In some embodiments, the combination of zibotentan and dapagliflozin is administered to the patient once per day.

[0015] 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 someembodiments, 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.

[0016] 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.

[0017] 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. In some embodiments, for four weeks zibotentan is administered at a dose of 0.75 mg and dapagliflozin is administered at a dose of 10 mg, and then for two weeks zibotentan is administered at a dose of 1.5 mg and dapagliflozin is administered at a dose of 10 mg. In some embodiments, zibotentan and dapagliflozin are administered concurrently or sequentially.

[0018] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean 24-hour ambulatory blood pressure relative to mean 24-hour ambulatory blood pressure prior to the administration. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean 24-hour ambulatory blood pressure relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean 24-hour ambulatory blood pressure relative to administration of one or more standard of care agents.

[0019] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean nighttime blood pressure relative to mean nighttime blood pressure prior to the administration. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean nighttime blood pressure relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean nighttime blood pressure relative to administration of one or more standard of care agents.

[0020] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean daytime blood pressure relative to mean daytime blood pressure prior to the administration. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean daytime blood pressure relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean daytime blood pressure relative to administration of one or more standard of care agents.

[0021] In some embodiments, administration of the combination of zibotentan and dapagliflozin slows the patient’s eGFR decline relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin slows the patient’s eGFR decline relative to administration of one or more standard of care agents.

[0022] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s UACR relative to the patient’s UACR prior to the administration. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s UACR relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s UACR relative to administration of one or more standard of care agents.

[0023] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s UPCR relative to the patient’s UPCR prior to the administration. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s UPCR relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s UPCR relative to administration of one or more standard of care agents.

[0024] In some embodiments, administration of the combination of zibotentan and dapagliflozin improves the patient’s performance in liver function tests (LFTs) relative to performance in LFTs prior to the administration. In some embodiments, administration of the combination of zibotentan and dapagliflozin improves the patient’s performance in LFTs relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin improves the patient’s performance in LFTs relative to administration of one or more standard of care agents.

[0025] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s lipid levels relative to lipid levels prior to the administration. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s lipid levels relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s lipid levels relative to administration of one or more standard of care agents.

[0026] In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s glucose levels relative to glucose levels prior to the administration. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s glucose levels relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s glucose levels relative to administration of one or more standard of care agents.In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s right ventricular strain. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s right ventricular strain relative to placebo. In some embodiments, administration of the combination of zibotentan and dapagliflozin reduces the patient’s right ventricular strain relative to administration of one or more standard of care agents. In some embodiments, administration of the combination of zibotentan and dapagliflozin slows and / or delays a reduction in the patient’s right ventricular fractional area. In some embodiments, administration of the combination of zibotentan and dapagliflozin slows and / or delays a reduction in the patient’s right ventricular fractional area relative to placebo. In some embodiments,administration of the combination of zibotentan and dapagliflozin slows and / or delays a reduction in the patient’s right ventricular fractional area relative to administration of one or more standard of care agents.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG 1 . depicts the crossover study described in Example 1 A.DETAILED DESCRIPTION

[0028] 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.

[0029] 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.

[0030] The effectiveness of the compounds of the present disclosure in treating and / or preventing uncontrolled hypertension, resistant hypertension, 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.

[0031] 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 optimaldose 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.

[0032] 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.

[0033] As used herein, the term “uncontrolled hypertension” refers to hypertension where a patient has (i) an eGFR > 45 mL / min / 1.72 m2, (ii) a target office blood pressure of less than or equal to 140 / 90 mm Hg or a target ambulatory blood pressure of less than or equal to 135 / 85 mm Hg, and (iii) the patient is not at their target blood pressure when taking two or more standard of care agents.

[0034] As used herein, the term “resistant hypertension” refers to hypertension where a patient has (i) an eGFR > 45 mL / min / 1.72 m2, (ii) a target office blood pressureof less than or equal to 140 / 90 mm Hg or a target ambulatory blood pressure of less than or equal to 135 / 85 mm Hg, and (Hi) the patient is not at their target blood pressure when taking three or more standard of care agents.

[0035] As used herein, the term “ambulatory blood pressure” refers to blood pressure measured at regular intervals during normal daily activities. In some embodiments, ambulatory blood pressure is measured over a 24-hour period, and a mean 24-hour ambulatory blood pressure is determined. In some embodiments, blood pressure is measured at least once every hour. In some embodiments, blood pressure is measured more frequently than once an hour, including but not limited to, every half hour, every fifteen minutes, or every ten minutes. In some embodiments, ambulatory blood pressure measured over a 24-hour period is measured once every hour during nighttime hours (10:00PM to 6:00AM) and at least once every hour during daytime hours (6:00AM to 10:00PM).

[0036] As used herein, the term “mean nighttime blood pressure” refers to the mean blood pressure measured at regular intervals over a period of time from 10:00PM to 6:00AM. In some embodiments, nighttime blood pressure is measured once every hour.

[0037] As used herein, the term “mean daytime blood pressure” refers to the mean blood pressure measured at regular intervals over a period of time from 6:00AM to 10:00PM. In some embodiments, daytime blood pressure is measured at least once every hour. In some embodiments, daytime blood pressure is measured more frequently than once an hour, including but not limited to, every half hour, every fifteen minutes, or every ten minutes.

[0038] As used herein, the term “liver function tests” refers to one or more blood tests that provide information as to the overall health of a patient’s liver (e.g., a hepatic panel). Liver function tests (LFTs) can include, but are not limited to, tests for alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyl transferase, serum bilirubin, prothrombin time, the international normalized ratio, and total protein and albumin.

[0039] As used herein, the phrases “slowing eGFR decline” and “slows the patient’s eGFR decline” refer to a statistically and / or clinically significant difference in eGFR slope, or a statistically and / or clinically significant change in eGFR from baseline relative to a comparator therapy. For example, in some embodiments, difference in eGFR slope may be the annualized difference vs comparator of greater than or equal to 0.5 mL / min / year, such as 0.75 mL / min / year or for instance, > 1 mL / min / year.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] A “sterile” formulation is aseptic or essentially free from living microorganisms and their spores.

[0045] 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.

[0046] 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).

[0047] 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.

[0048] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive.

[0049] In an aspect, the disclosure herein provides methods of treating hypertension in a human patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to treat the patient’s hypertension. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0050] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in treating hypertension in a human patient. In someembodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0051] 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 hypertension in a human patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0052] In an aspect, the disclosure herein provides methods of slowing eGFR decline in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to slow eGFR decline. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0053] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in slowing eGFR decline in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0054] In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for slowing eGFR decline in a hypertension patient. In some embodiments, the hypertension is uncontrolledhypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0055] In an aspect, the disclosure herein provides methods of reducing UACR in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to reduce the patient’s UACR. In an aspect, the disclosure herein provides methods of reducing UACR by about 5% to about 30% in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to reduce the patient’s UACR by about 5% to about 30%. In an aspect, the disclosure herein provides methods of reducing UACR to below 300 mg / g in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to reduce the patient’s UACR to below 300 mg / g. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0056] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in reducing UACR in a hypertension patient. In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in reducing UACR by about 5% to about 30% in a hypertension patient. In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in reducing UACR to below 300 mg / g in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In someembodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0057] In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing UACR in a hypertension patient. In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing UACR by about 5% to about 30% in a hypertension patient. In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing UACR to below 300 mg / g in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0058] In an aspect, the disclosure herein provides methods of reducing UPCR in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to reduce the patient’s UPCR. In an aspect, the disclosure herein provides methods of reducing UPCR by about 5% to about 30% in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to reduce the patient’s UPCR by about 5% to about 30%. In an aspect, the disclosure herein provides methods of reducing UPCR to below 1 g / g in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to reduce the patient’s UPCR to below 1 g / g. In some embodiments, the hypertension is uncontrolled hypertension or resistanthypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0059] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in reducing UPCR in a hypertension patient. In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in reducing UPCR by about 5% to about 30% in a hypertension patient. In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in reducing UPCR to below 1 g / g in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0060] In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing UPCR in a hypertension patient. In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing UPCR by about 5% to about 30% in a hypertension patient. In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing UPCR to below 1 g / g in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0061] In an aspect, the disclosure herein provides methods of improving performance in a liver function test (LFT) in a hypertension patient comprisingadministering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to improve the patient’s performance in LFTs. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0062] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in improving performance in a liver function test (LFT) in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0063] In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for improving performance in a liver function test (LFT) in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0064] In an aspect, the disclosure herein provides methods of reducing lipid levels in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to reduce the patient’s lipid levels. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0065] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in reducing lipid levels in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0066] In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing lipid levels in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0067] In an aspect, the disclosure herein provides methods of reducing glucose levels in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to reduce the patient’s glucose levels. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0068] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in reducing glucose levels in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0069] In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing glucose levels in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension. In some embodiments, the hypertension is systemic hypertension.

[0070] In an aspect, the disclosure herein provides methods of reducing right ventricular strain in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in an amount effective to reduce right ventricular strain. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension.

[0071] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in reducing right ventricular strain in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension.

[0072] In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing right ventricular strain in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension.

[0073] In an aspect, the disclosure herein provides methods of slowing and / or delaying a reduction in right ventricular fractional area in a hypertension patient comprising administering zibotentan and dapagliflozin to a patient in need thereof in anamount effective to slowing and / or delaying a reduction in right ventricular fractional area. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension.

[0074] In an aspect, the disclosure herein provides a combination of zibotentan and dapagliflozin for use in slowing and / or delaying a reduction in right ventricular fractional area in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension.

[0075] In an aspect, the disclosure herein provides the use of a combination of zibotentan and dapagliflozin in the manufacture of a medicament for slowing and / or delaying a reduction in right ventricular fractional area in a hypertension patient. In some embodiments, the hypertension is uncontrolled hypertension or resistant hypertension. In some embodiments, the hypertension is pulmonary hypertension.

[0076] In some embodiments, the patient has a UACR > 300 mg / g. In some embodiments, the patient has a UPCR > 1 g / g.

[0077] In some embodiments, the patient has an eGFR > 45 mL / min / 1.72 m2. In some embodiments, the patient has a target office blood pressure of 140 / 90 mm Hg or a target ambulatory blood pressure of 135 / 85 mm Hg. In some embodiments, the patient’s blood pressure is not at the target level when taking two or more standard of care agents for hypertension. In some embodiments, the patient’s blood pressure is not at the target level when taking three or more standard of care agents for hypertension.

[0078] 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.

[0079] 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.

[0080] The selective 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:

[0081] 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.

[0082] 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.

[0083] 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 (i) to improve glycemic control in adults with type 2 diabetes mellitus (as an adjunct to diet and exercise), (ii) to reduce risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure in adults, and (iii) to reduce the risk of kidney function decline, kidney failure, and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression. 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.

[0084] 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:

[0085] 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.

[0086] 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 5.0mg. 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.

[0087] 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.

[0088] 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 ofzibotentan 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.

[0089] 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 10 mg of dapagliflozin or a pharmaceutically acceptable salt thereof, and the dosage is subsequently adjusted to a total daily dose of 1.5 mg of zibotentan or a pharmaceutically acceptable salt thereof and 10 mg of dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the initial dose of 0.75 mg of zibotentan or a pharmaceutically acceptable salt thereof and 10 mg of dapagliflozin or a pharmaceutically acceptable salt thereof is administered for four weeks, and then the adjusted dose of 1 .5 mg of zibotentan or a pharmaceutically acceptable salt thereof and 10 mg of dapagliflozin or a pharmaceutically acceptable salt thereof is administered for two weeks.

[0090] In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceuticallyacceptable salt thereof to a patient in need thereof is in an amount effective to slow a hypertension patient’s eGFR decline.

[0091] 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 is in an amount effective to reduce a hypertension patient’s UACR. 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 is in an amount effective to reduce a hypertension patient’s UACR by about 5% to about 30%. 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 is in an amount effective to reduce a hypertension patient’s UACR to below 300 mg / g.

[0092] 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 is in an amount effective to reduce a hypertension patient’s UPCR. 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 is in an amount effective to reduce a hypertension patient’s UPCR by about 5% to about 30%. In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereofto a patient in need thereof is in an amount effective to reduce a hypertension patient’s UPCR to below 1 g / g.

[0093] 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 hypertension patient in need thereof is in an amount effective to improve the patient’s performance in liver function tests (LFTs).

[0094] 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 hypertension patient in need thereof is in an amount effective to reduce the patient’s lipid levels. In some embodiments, methods for determining the patient’s lipids levels include, but are not limited to, measuring one or more of low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, high- density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol.

[0095] 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 hypertension patient in need thereof is in an amount effective to reduce the patient’s glucose levels. In some embodiments, methods for determining the patient’s glucose levels include, but are not limited to, measuring one or more of fasting plasma glucose levels, glycated albumin levels, fructosamine levels, and glycated hemoglobin (HbA1c) levels.

[0096] 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 mean 24-hourambulatory blood pressure relative to the mean 24-hour ambulatory blood pressure prior to the administration. 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 mean 24-hour ambulatory blood pressure relative to placebo. 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 mean 24-hour ambulatory blood pressure relative to administration of one or more standard of care agents. 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 elevation in the patient’s mean 24-hour ambulatory blood pressure.

[0097] 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 mean nighttime blood pressure relative to the mean nighttime blood pressure prior to the administration. 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 mean nighttime blood pressure relative to placebo. 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 thereofreduces the patient’s mean nighttime blood pressure relative to administration of one or more standard of care agents. 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 elevation in the patient’s mean nighttime blood pressure.

[0098] 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 mean daytime blood pressure relative to the mean daytime blood pressure prior to the administration. 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 mean daytime blood pressure relative to placebo. 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 mean daytime blood pressure relative to administration of one or more standard of care agents. 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 elevation in the patient’s mean daytime blood pressure.

[0099] 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 slows the patient’s eGFR declinerelative to placebo. 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 slows the patient’s eGFR decline relative to administration of one or more standard of care agents. 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 worsening of the patient’s eGFR.

[0100] 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 UACR relative to placebo. 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 UACR relative to administration of one or more standard of care agents. 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 worsening of the patient’s UACR.

[0101] 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 UPCR relative to placebo. 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 UPCR relativeto administration of one or more standard of care agents. 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 worsening of the patient’s UPCR.

[0102] 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 in LFTs relative to the patient’s performance in LFTs prior to the administration. 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 in LFTs relative to placebo. 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 in LFTs relative to administration of one or more standard of care agents. 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 worsening performance in LFTs.

[0103] 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 lipid levels relative to the patient’s lipid levels prior to the administration. In some embodiments, administration of the combination of zibotentan, or a pharmaceutically acceptable saltthereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof to a patient in need thereof reduces the patient’s lipid levels relative to placebo. 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 lipid levels relative to administration of one or more standard of care agents. 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 increased lipid levels.

[0104] 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 glucose levels relative to the patient’s glucose levels prior to the administration. 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 glucose levels relative to placebo. 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 glucose levels relative to administration of one or more standard of care agents. 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 increased glucose levels.

[0105] In some embodiments, the treatment of and / or improvement in disease, 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, and / or improvements relative to treatment with other standard-of-care treatments for hypertension, uncontrolled hypertension, resistant hypertension, pulmonary hypertension, systemic hypertension, and / or diseases, disorders, or conditions associated with hypertension, uncontrolled hypertension, resistant hypertension, pulmonary hypertension, and systemic hypertension.

[0106] 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.

[0107] 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) andtreatment 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).

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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 sodiumcarboxymethyl 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.

[0112] 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.

[0113] 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, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0114] 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.

[0115] 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 5,000 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.

[0116] 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.

[0117] 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-formersor 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] In some embodiments, the pharmaceutical composition may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersingagents. 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.

[0125] 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.

[0126] 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.

[0127] In some embodiments, the pharmaceutical composition is an injectable formulation, wherein the injectable formulation may be sterilized, for example, by filtrationthrough 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.EXAMPLESExample 1

[0134] 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 in patients having uncontrolled hypertension or resistant hypertension. In a six-week study, patients having uncontrolled hypertension or resistant hypertension will be randomized 2:1 into two groups: active (zibotentan and dapagliflozin) or placebo. In an additional 16-week study design, patients having uncontrolled hypertension or resistant hypertension will be randomized 2:1 into two groups in a cross-over study with a four-week washout period: six weeks active (zibotentan and dapagliflozin), four weeks washout, six weeks placebo; or six weeks placebo, four weeks washout, six weeks active (zibotentan and dapagliflozin).

[0135] The study participants will receive the study treatment once daily over the study period. The dosing strategy for administration of the combination of zibotentan and dapagliflozin will be as follows: an initial four-week treatment period where a combination of zibotentan (0.75 mg) and dapagliflozin (10 mg) is administered once daily, followed by a two-week treatment period where a combination of zibotentan (1.5 mg) and dapagliflozin (10 mg) is administered once daily. Ambulatory blood pressure will be measured prior to the administration at the start of the study (baseline), and then again at four weeks and six weeks. Ambulatory blood pressure will be measured at regular intervals over a 24-hour period.

[0136] The primary endpoint of the impact of the combination of zibotentan and dapagliflozin will be the mean 24-hour ambulatory blood pressure level compared tobaseline. The secondary endpoints of the impact of the combination of zibotentan and dapagliflozin on mean nighttime blood pressure compared to baseline, and mean daytime blood pressure compared to baseline. Exploratory endpoints to be measured as well, will include performance LFTs, and changes in eGFR, lipid levels, and glucose levels.EXAMPLE 1A

[0137] The study described in Example 1 was updated with modifications to the dosing protocol and outcomes. The updated study design (FIG. 1) comprises administration of either active dose (zibotentan and dapagliflozin) or placebo for six weeks, followed by a crossover to either placebo or active dose for an additional six weeks. During the active dose period, zibotentan and dapagliflozin are administered at a dose of 0.75 mg and 10 mg, respectively, for four weeks, followed by administration at a dose of 1 .5 mg and 10 mg, respectively for two weeks. A two-week washout period follows the two six-week dosing periods (for a total of 12 weeks), and there is a safety follow up at the end of the two-week washout period.

[0138] The study participants will receive the study treatment once daily over the study period. The dosing strategy for administration of the combination of zibotentan and dapagliflozin will be as follows: an initial four-week treatment period where a combination of zibotentan (0.75 mg) and dapagliflozin (10 mg) is administered once daily, followed by a two-week treatment period where a combination of zibotentan (1.5 mg) and dapagliflozin (10 mg) is administered once daily. Ambulatory blood pressure will be measured prior to the administration at the start of the study (baseline), and then again at four weeks and six weeks. The cross-over period (where either placebo or the active dose (zibotentan and dapagliflozin) follows the same dosing protocol as the initial six-week period, with measurements taken at week 4 and week 6 for this second dosing period. The following measurements are taken at the week 4 assessment: seated blood pressure, bloodwork, automated unattended out-of-office blood pressure, and ambulatory blood pressure. The following measurements are taken at the week 6 assessment (end of treatment period): seated blood pressure, bloodwork (full blood count, urea and electrolytes, liver function tests, international normalized ratio, random blood glucose, and HbA1 C), and automated unattended out-of-office blood pressure.

[0139] The primary endpoint of the impact of the combination of zibotentan and dapagliflozin will be blood pressure, measured by unattended seated automated office systolic blood pressure at the end of each treatment period. Secondary outcome measures include: unattended seated automated office diastolic blood pressure at the end of each treatment period, unattended seated office systolic blood pressure after 4 weeks of each treatment period, unattended seated office diastolic blood pressure after 4 weeks of each treatment period, attended seated office systolic blood pressure at the end of each treatment period, attended seated office diastolic blood pressure at the end of each treatment period, attended seated office systolic blood pressure after 4 weeks of each treatment, attended seated office diastolic blood pressure after 4 weeks of each treatment, 24-hour ambulatory daytime mean systolic blood pressure after 4 weeks of each treatment period, 24-hour ambulatory daytime mean diastolic blood pressure after 4 weeks of each treatment period, 24-hour ambulatory mean systolic blood pressure after 4 weeks of each treatment period, 24-hour ambulatory mean diastolic blood pressure after 4 weeks of each treatment period, and safety as assessed by adverse event and serious adverse event reporting.

[0140] Exploratory endpoints to be measured include serum creatinine and eGFR, HbA1 C, Serum alanine transaminase (ALT), alkaline phosphatase (ALP), gammaglutamyl transferase (GGT), body weight and composition, and plasma aldosterone and renin.

[0141] Inclusion criteria were as follows:• Clinical diagnosis of essential hypertension• Age 18 years or older• Males OR females of non-child bearing potential: o Female participants must be of non-childbearing potential: Female is considered of childbearing potential, i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. o Male participants must be surgically sterile, abstinent or must use in conjunction with their female partner, a highly effective method of contraception from the time they sign the informed consent document and for 3 months after the last dose of study intervention to prevent pregnancy in a partner. In addition, the male participant should use a condom for the duration of the study and for3 months after the last dose of study intervention. Male study participants must not donate or bank sperm during the same period. Highly effective birth-control methods are defined as those that can achieve a failure rate of less than 1 % per year when used consistently and correctly.• Seated attended office BP >140 / and / or >90 mmHg.• Standardised home BP readings or daytime ambulatory BP of >130 and / or >80 mmHg• Currently prescribed and taking at least two antihypertensive drugs at screening• eGFR >45 ml / min / 1 ,73m2at screening• Capable of providing signed informed consent• Willingness to comply with double contraception method (applies to male participants)

[0142] Exclusion criteria were as follows:• Women of childbearing potential or those who are pregnant, breast-feeding, or women with intent of getting pregnant.• Confirmed secondary cause of hypertension (e.g. renal artery stenosis, adrenal adenoma, phaeochromocytoma, etc.)• Seated attended office systolic BP >180 or diastolic of >110 mmHg• Active planning for pregnancy during the trial (applicable to both men and women)• Current or prior medical treatment with an ETA antagonist or SGLT2 inhibitor• Known acute coronary syndrome within 3 months of screening visit• Unstable heart failure requiring hospitalisation within last 6 months at screening visit• Known heart failure with New York Heart Association (NYHA) classification of III or IV• Uncontrolled diabetes (HbA1 C within last 3 months from screening >12%)• Known Type 1 diabetes• Known Type 2 diabetes on insulin• Participants treated with strong CYP3A4 inhibitor• Screening blood pressure indicating hypotension (systolic BP<90 mmHg or diastolic<60 mmHg)• Male in a sexually active relationship with pregnant or breastfeeding partner• History of transplantation (other than corneal)• Severe hepatic impairment at screening (ALT > 3 ULN)• Positive drugs of abuse test at screening• History of alcohol abuse at screening• Known clinical diagnosis of hepatitis or HIVEXAMPLE 2

[0143] The effect of the combination of dapagliflozin and zibotentan on cardiovascular parameters relating to pulmonary hypertension was assessed in a subset of patients that participated in the ZENITH-CKD study. The ZENITH-CKD trial is described in, for example, U.S. Patent Application No. 17 / 371 ,162, filed July 9, 2021 , and issued as U.S. Patent No. 11 ,730,735 on August 22, 2023, the contents of which are incorporated by reference herein in its entirety.

[0144] Briefly, patients were randomized into treatment groups and administered zibotentan and dapagliflozin (0.25 mg / 10 mg or 1.5 mg / 10 mg), or dapagliflozin (10 mg) and placebo, for twelve weeks. Measurements taken at baseline (prior to initiating treatment) were compared to measurements recorded at week 12 of treatment. An analysis of left ventricular ejection fraction was conducted in patients with and without fluid retention (Table 1), which demonstrated that there was no significant change in ejection fraction in patients with fluid retention versus patients without fluid retention. It was noted that the patients involved in this analysis did not have significant left ventricular ejection fraction or right heart strain.Table 1. Left ventricular ejection fraction in patients with fluid retention versus without fluid retention.

[0145] As shown in Table 2, there were no significant changes in left ventricular ejection fraction across the dose range for patients who were administered thecombination of zibotentan and dapagliflozin. In the right ventricle, small improvements were noted in right ventricular global strain for patients receiving the combination of zibotentan and dapagliflozin (Table 3). As shown in Table 4, there were slight increases recorded in the right ventricular fraction area for both doses of the zibotentan / dapagliflozin combination, indicating that there was not a reduction in right ventricular function. It was also noted that there was an improvement in right ventricular longitudinal strain for patients receiving either dose of the combination of zibotentan and dapagliflozin. Thus, the combination of zibotentan and dapagliflozin did not reduce left ventricular function, increased right ventricle fractional area, and improved right ventricle strain relative to treatment with dapagliflozin alone, suggesting that the combination therapy reduces the workload for the right side of the heart. Further, for a given reduction in blood pressure, the combination therapy should result in fewer fluid-related adverse events relative to other endothelin receptor antagonists. While the patients in this study were healthy ( / .e., no pulmonary hypertension), the improvement in measures on the right side of the heart suggest that in pulmonary hypertension patients, where the right side of the heart loses capacity, the combination of zibotentan and dapagliflozin may be effective in treating pulmonary hypertension and delaying right ventricular failure.Table 2. Left ventricular ejection fraction.Table 3. Right ventricular global strain.Table 4. Right ventricular fraction change.Table 5. Right ventricular longitudinal strain.

Claims

CLAIMSWhat is claimed is:

1. A method for treating hypertension 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 hypertension.

2. A method of slowing eGFR decline in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to slow the patient’s eGFR decline.

3. A method of reducing UACR in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s UACR.

4. A method of reducing UACR by about 5% to about 30% in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s UACR by about 5% to about 30%.

5. A method of reducing UACR to below 300 mg / g in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s to below 300 mg / g.

6. A method of reducing UPCR in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s UPCR.

7. A method of reducing UPCR by about 5% to about 30% in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s UPCR by about 5% to about 30%.

8. A method of reducing UPCR to below 1 g / g in a hypertension patient, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s to below 1 g / g.

9. A method of improving a hypertension patient’s performance in liver function tests (LFTs), the method comprising administering to the patient a combination ofzibotentan and dapagliflozin in an amount effective to improve the patient’s performance in LFTs.

10. A method of reducing a hypertension patient’s lipid levels, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s lipid levels.

11. A method of reducing a hypertension patient’s glucose levels, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s glucose levels.

12. A method for treating pulmonary hypertension 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 pulmonary hypertension.

13. A method for reducing right ventricular strain in a patient in need thereof, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’s right ventricular strain.

14. A method for slowing and / or delaying a reduction in right ventricular fractional area in a patient in need thereof, the method comprising administering to the patient a combination of zibotentan and dapagliflozin in an amount effective to slow and / or delay a decline in the patient’s right ventricular fractional area.

15. The method of any one of claims 1-14, wherein the hypertension is uncontrolled hypertension or resistant hypertension.

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

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

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

19. The method of any one of claims 1-17, comprising administering zibotentan at a dose of 0.5 mg.

20. The method of any one of claims 1-17, comprising administering zibotentan at a dose of 0.75 mg.

21. The method of any one of claims 1-17, comprising administering zibotentan at a dose of 1.0 mg.

22. The method of any one of claims 1-17, comprising administering zibotentan at a dose of 1.25 mg.

23. The method of any one of claims 1-17, comprising administering zibotentan at a dose of 1.5 mg.

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

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

26. The method of any one of claims 1-24, comprising administering dapagliflozin at a dose of 5.0 mg.

27. The method of any one of claims 1-24, comprising administering dapagliflozin at a dose of 10.0 mg.

28. The method of any one of claims 1-17, 23, 24, and 27, comprising administering zibotentan at a dose of 1.5 mg and dapagliflozin at a dose of 10 mg.

29. The method of any one of claims 1-17, 22, 24, and 27, comprising administering zibotentan at a dose of 1.25 mg and dapagliflozin at a dose of 10 mg.

30. The method of any one of claims 1-17, 21 , 24, and 27, comprising administering zibotentan at a dose of 1.0 mg and dapagliflozin at a dose of 10 mg.

31. The method of any one of claims 1-17, 20, 24, and 27, comprising administering zibotentan at a dose of 0.75 mg and dapagliflozin at a dose of 10 mg.

32. The method of any one of claims 1-17, 19, 24, and 27, comprising administering zibotentan at a dose of 0.5 mg and dapagliflozin at a dose of 10 mg.

33. The method of any one of claims 1-18, 24, and 27, comprising administering zibotentan at a dose of 0.25 mg and dapagliflozin at a dose of 10 mg.

34. The method according to any one of claims 1-17, 20, 23, 27-28, and 28, wherein for four weeks zibotentan is administered at a dose of 0.75 mg and dapagliflozin is administered at a dose of 10 mg, and then for two weeks zibotentan is administered at a dose of 1.5 mg and dapagliflozin is administered at a dose of 10 mg.

35. The method of any one of the preceding claims, wherein zibotentan and dapagliflozin are administered concurrently or sequentially.

36. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean 24-hour ambulatory blood pressure relative to mean 24-hour ambulatory blood pressure prior to the administration.

37. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean 24-hour ambulatory blood pressure relative to placebo.

38. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean 24-hour ambulatory blood pressure relative to administration of one or more standard of care agents.

39. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean nighttime blood pressure relative to mean nighttime blood pressure prior to the administration.

40. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean nighttime blood pressure relative to placebo.

41. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean nighttime blood pressure relative to administration of one or more standard of care agents.

42. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean daytime blood pressure relative to mean daytime blood pressure prior to the administration.

43. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean daytime blood pressure relative to placebo.

44. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s mean daytime blood pressure relative to administration of one or more standard of care agents.

45. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin slows the patient’s eGFR decline relative to placebo.

46. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin slows the patient’s eGFR decline relative to administration of one or more standard of care agents.

47. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s UACR relative to the patient’s UACR prior to the administration.

48. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s UACR relative to placebo.

49. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s UACR relative to administration of one or more standard of care agents.

50. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s UPCR relative to the patient’s UPCR prior to the administration.

51. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s UPCR relative to placebo.

52. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s UPCR relative to administration of one or more standard of care agents.

53. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin improves the patient’s performance in liver function tests (LFTs) relative to performance in LFTs prior to the administration.

54. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin improves the patient’s performance in LFTs relative to placebo.

55. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin improves the patient’s performance in LFTs relative to administration of one or more standard of care agents.

56. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s lipid levels relative to lipid levels prior to the administration.

57. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s lipid levels relative to placebo.

58. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s lipid levels relative to administration of one or more standard of care agents.

59. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s glucose levels relative to glucose levels prior to the administration.

60. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s glucose levels relative to placebo.

61. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s glucose levels relative to administration of one or more standard of care agents.

62. The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin reduces the patient’s right ventricular strain relative to administration of one or more standard of care agents.The method of any one of the preceding claims, wherein administration of the combination of zibotentan and dapagliflozin slows and / or delays a reduction in the patient’s right ventricular fractional area relative to administration of one or more standard of care agents.

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