A combination of zibotentan and dapagliflozin for the treatment of hyperproteinuric chronic kidney disease

Abstract

Methods are disclosed for treating hyperproteinuric chronic kidney disease and / or at least one disease, disorder, or condition related thereto in a patient by use of a fixed-dose combination of zibotentan and dapagliflozin.

Description

[Technical Field]

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

[0002] Introduction Chronic kidney disease (CKD) is an endothelin-related disorder associated with the gradual loss of kidney function. In some cases, CKD may be associated with hypertension or diabetes (diabetic kidney disease, DKD). CKD can be diagnosed by measuring the estimated glomerular filtration rate (eGFR) in the blood and by measuring albumin and / or protein levels in the urine. The severity of CKD ranges from stage 1 (eGFR ≥ 90 mL / min / 1.73 m 2 , normal) to stage 5 (eGFR < 15 mL / min / 1.73 m 2 The stage of CKD is determined by a patient's eGFR level, which corresponds to a given stage of the disease, ranging from normal to severe (renal failure). Albuminuria can also be classified as an indicator of disease progression when diagnosing CKD. A urine albumin to creatine ratio (UACR) of <30 mg / g is classified as normal, a UACR of 30-300 mg / g is classified as moderately elevated, and a UACR of >300 mg / g is classified as severely elevated. There is no cure for CKD or a way to reverse it, and current treatments focus on slowing the progression of kidney damage and controlling symptoms.

[0003] Alport syndrome (ASS) is a genetic kidney disease caused by COL4A3 / 4 / 5 mutations and is the second most common cause of inherited CKD. It manifests in many forms, ranging from hematuria and proteinuria to end-stage renal disease. There is no cure for ASS, and current treatments include the administration of renin-angiotensin-aldosterone system inhibitors (RAASi).

[0004] Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis is an autoimmune disease that causes vasculitis and affects kidney function. ANCA vasculitis affects kidney function through glomerular inflammation (glomerulonephritis), leading to scarring and / or permanent kidney damage that can ultimately result in end-stage renal disease. ANCA vasculitis can be treated by targeting inflammation, but treatment can only control inflammation (induction therapy) and then maintain the disease in remission (maintenance therapy). Current treatment for ANCA vasculitis requires the use of immunosuppressants, which may increase an individual's risk of infection.

[0005] IgA nephropathy (IgAN), also known as Berger's disease, is an autoimmune disease caused by the deposition of IgA antibodies in the kidneys. As IgA antibodies accumulate in the small blood vessels of the kidneys, the glomeruli become inflamed and damaged. The inflammation and damage in the kidneys can reduce kidney function and lead to chronic kidney disease. IgAN can have a slow progression and is more likely to progress in individuals with high blood pressure, large amounts of protein in the urine, and / or increased BUN or creatinine levels. Current treatments for IgAN are aimed at alleviating symptoms and slowing the progression of the disease to chronic renal failure and include ACE inhibitors, corticosteroids, and other immunosuppressants, as well as cholesterol-lowering drugs.

[0006] Endothelin-1 (ET-1) is a highly potent systemic vasoconstrictor that binds to endothelin A and B receptors (ET A and E.T. B ET-1 is a driver of kidney disease progression regulated by CKD. In CKD, ET-1 levels increase with UACR and the severity of renal dysfunction (Grenda et al., Nephrol Dial Transplant. 2007;22(12):3487-3494; Kohan Am J Kidney Dis. 1997;29(1):2-26). The pathological effects of ET-1 accumulation, including proteinuria, vasoconstriction, and inflammation, are associated with ET A It is thought to be primarily driven by receptors (Goddard et al., Circulation. 2004;109(9):1186-1193). A Receptor antagonists have demonstrated renal protective effects but have side effects including edema (swelling). In diabetic kidney disease (DKD), ET A Short-term treatment with receptor antagonists demonstrated a 30% reduction in the urinary albumin-to-creatinine ratio (UACR) (Heerspink et al., Diabetes Obes Metab. 2018;20(8):1829-1835; Heerspink et al., Lancet 2019;393(10184):1937-1947). However, ET A Clinical development of receptor antagonists has been limited due to problems with fluid retention and hospitalization for heart failure (Heerspink et al., Lancet 2019;393(10184):1937-1947).

[0007] Zibotentan is an ET drug developed for the treatment of prostate cancer. AZibotentan is a receptor antagonist, but was discontinued in 2011 due to insufficient efficacy in Phase 3 and a 17% increase in the incidence of peripheral edema compared to placebo. Zibotentan, also known as ZD4054, is described in International Publication No. WO 1996040681, including details regarding its chemical synthesis, the teachings of which are incorporated herein by reference. Specific inhibition of the endothelin A receptor by zibotentan has been reported by Morris et al., British Journal of Cancer (2005), 92, 2148-2152. Zibotentan, N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide, has the chemical structure of Formula I:

[0008] [ka]

[0009] Sodium-dependent glucose transporter 2 (SGLT-2) inhibitors produce osmotic diuresis, block glucose reabsorption in the kidney, increase glucose excretion, and lower blood glucose concentrations. In addition to this well-characterized mode of action, SGLT-2 inhibitors lower blood pressure, reduce vascular stiffness, improve endothelial function, and possess anti-inflammatory and anti-fibrotic properties similar to those of endothelin receptor antagonists (HJ Heerspink et al., Circulation (2016), 134(10):752-772). ET ASimilar to receptor antagonists, SGLT2 inhibitors have demonstrated efficacy in reducing the progression of DKD (Stephens et al., Diabetes Obes Metab. 2020;22 Suppl 1:32-45). A side effect associated with the pharmacological effects of SGLT-2 inhibitors is dehydration / intravascular volume reduction, which can result in dehydration, hypovolemia, orthostatic hypotension, or hypotension. Accordingly, SGLT-2 inhibitors generally induce an increase in hematocrit (Hot), a marker of hemoconcentration, and increased blood viscosity, a presumed cause of vascular damage in the setting of peripheral vascular disease.

[0010] Dapagliflozin is a potent, highly selective, orally active inhibitor of human renal SGLT2 that is approved (as an adjunct to diet and exercise) to improve glycemic control in adults with type 2 diabetes. Dapagliflozin, along with details regarding its chemical synthesis, is disclosed in WO2003099836, the teachings of which are incorporated herein by reference.

[0011] Dapagliflozin, whose IUPAC name is (1S)-1,5-anhydro-1-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol, has the chemical structure of Formula II.

[0012] [ka]

[0013] Although there are approved therapies for patients with CKD, there are no approved therapies for patients with hyperproteinuric CKD, which is characterized by high levels of albuminuria and / or proteinuria. In particular, ET, which is required to treat more severe stages of CKD, is needed. AIncreased doses of receptor antagonists are not well tolerated due to side effects, including the risk of edema and congestive heart failure. SGLT2 inhibitors are effective in treating CKD in many settings, but they pose a residual risk in many patients, as evidenced by persistent proteinuria. For example, a post-hoc analysis of the CREDENCE trial showed that canagliflozin, an SGLT2 inhibitor for the treatment of renal events in patients with type 2 diabetes and CKD, was able to reduce UACR levels in the short term, but failed to reduce UACR levels to below 300 mg / g in a significant number of patients, who developed renal and major adverse cardiovascular events due to residual proteinuria (Oshima et al., J Am Soc Nephrol. (2020); 31(12):2925-2936).

[0014] Thus, there remains a need for improved compounds, compositions, and methods for treating patients with hyperproteinuric CKD, ANCA vasculitis, Alport syndrome, and IgAN. The present disclosure addresses these unmet needs. Summary of the Invention

[0015] The present disclosure provides a fixed-dose combination of zibotentan and dapagliflozin for use in treating CKD in a human patient in need of such treatment, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to treat CKD in the patient. In some embodiments, the human patient is a CKD patient who meets the criteria described herein.

[0016] The present disclosure also provides methods of treating hyperproteinuric CKD in a human patient in need of such treatment, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to treat the patient's CKD. In some embodiments, the human patient is a CKD patient who meets the criteria described herein.

[0017] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for treating hyperproteinuric CKD in a human patient in need thereof, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to treat CKD in the patient. In some embodiments, the human patient is a CKD patient who meets the criteria described herein.

[0018] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in treating hyperproteinuric CKD associated with IgA nephropathy (IgAN) in a human patient in need of such treatment, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to treat IgAN in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0019] The present disclosure also provides methods of treating a human patient with hyperproteinuric CKD associated with IgA nephropathy (IgAN), comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to treat IgAN in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0020] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for treating hyperproteinuric CKD associated with IgA nephropathy (IgAN) in a human patient in need thereof, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to treat IgAN in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0021] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in treating IgA nephropathy (IgAN) in a human patient with biopsy-confirmed IgAN in need of such treatment, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to treat the patient's IgAN. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0022] The present disclosure also provides methods of treating a human patient with biopsy-confirmed IgA nephropathy (IgAN), comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to treat IgAN in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0023] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for the treatment of IgA nephropathy (IgAN) in a human patient with biopsy-confirmed IgAN in need of such treatment, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to treat the patient's IgAN. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0024] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in treating a human patient with biopsy-confirmed IgA nephropathy in need of reduction of proteinuria, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to reduce the patient's proteinuria. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0025] The present disclosure also provides methods for reducing proteinuria in a human patient with biopsy-confirmed IgA nephropathy, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce proteinuria in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0026] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing proteinuria in a human patient with biopsy-confirmed IgA nephropathy in need thereof, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to reduce proteinuria in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0027] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in treating a human patient with biopsy-confirmed IgA nephropathy in need of reducing the rate of renal function decline, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to reduce the rate of renal function decline in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0028] The present disclosure also provides methods for reducing the rate of decline in renal function in a human patient with biopsy-confirmed IgA nephropathy, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the rate of decline in renal function in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0029] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the rate of renal function decline in a human patient with biopsy-confirmed IgA nephropathy in need thereof, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to reduce the rate of renal function decline in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0030] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in treating hyperproteinuric CKD associated with focal segmental glomerulosclerosis (FSGS) in a human patient in need of such treatment, the treatment comprising administering to the human patient zibotentan and dapagliflozin in amounts effective to treat FSGS in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0031] The present disclosure also provides methods of treating a human patient with hyperproteinuric CKD associated with focal segmental glomerulosclerosis (FSGS), comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to treat FSGS in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0032] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for treating hyperproteinuric CKD associated with FSGS in a human patient in need thereof, wherein the treatment comprises administering to the human patient zibotentan and dapagliflozin in amounts effective to treat FSGS in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0033] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in slowing the decline in renal function in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to slow the decline in renal function in the human patient. In some embodiments, the human patient meets the criteria described herein.

[0034] The present disclosure also provides methods of slowing the decline in renal function in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to slow the decline in renal function in the patient. In some embodiments, the human patient meets the criteria described herein.

[0035] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for slowing the decline in renal function in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to slow the decline in renal function in the patient. In some embodiments, the human patient meets the criteria described herein.

[0036] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing proteinuria in a human patient, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce proteinuria in the patient. In some embodiments, the human patient meets the criteria described herein.

[0037] The present disclosure also provides methods of reducing proteinuria in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce proteinuria in the patient. In some embodiments, the human patient meets the criteria described herein.

[0038] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing proteinuria in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce proteinuria in the patient. In some embodiments, the human patient meets the criteria described herein.

[0039] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing albuminuria in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce albuminuria in the patient. In some embodiments, the human patient meets the criteria described herein.

[0040] The present disclosure also provides methods of reducing albuminuria in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce albuminuria in the patient. In some embodiments, the human patient meets the criteria described herein.

[0041] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing albuminuria in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce albuminuria in the patient. In some embodiments, the human patient meets the criteria described herein.

[0042] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the incidence of a composite endpoint of a 30% decline in eGFR, reaching end-stage kidney disease (ESKD), or renal death in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of the composite endpoint of a 30% decline in eGFR, reaching ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

[0043] The present disclosure also provides methods of reducing the incidence of a composite endpoint of a 30% decline in eGFR, reaching end-stage kidney disease (ESKD), or renal death in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the incidence of the composite endpoint of a 30% decline in eGFR, reaching ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

[0044] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the incidence of a composite endpoint of a 30% decline in eGFR, reaching end-stage kidney disease (ESKD), or renal death in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of the composite endpoint of a 30% decline in eGFR, reaching ESKD, or renal death in the human patient. In some embodiments, the human patient meets the criteria described herein.

[0045] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the incidence of a composite endpoint of a 40% decline in eGFR, reaching end-stage kidney disease (ESKD), or renal death in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of the composite endpoint of a 40% decline in eGFR, reaching ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

[0046] The present disclosure also provides a method of reducing the incidence of a composite endpoint of a 40% decline in eGFR, reaching end-stage kidney disease (ESKD), or renal death in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the incidence of the composite endpoint of a 40% decline in eGFR, reaching ESKD, or renal death in the patient. In some embodiments, the human patient is a CKD patient who meets the criteria described herein.

[0047] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the incidence of a composite endpoint of a 40% decline in eGFR, reaching end-stage kidney disease (ESKD), or renal death in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of the composite endpoint of a 40% decline in eGFR, reaching ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

[0048] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the incidence of a composite endpoint of a 57% decline in eGFR, reaching end-stage kidney disease (ESKD), or renal death in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of the composite endpoint of a 57% decline in eGFR, reaching ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

[0049] The present disclosure also provides methods of reducing the incidence of a composite endpoint of a 57% decline in eGFR, reaching end-stage kidney disease (ESKD), or renal death in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the incidence of the composite endpoint of a 57% decline in eGFR, reaching ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

[0050] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the incidence of a composite endpoint of a 57% decline in eGFR, reaching end-stage kidney disease (ESKD), or renal death in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of the composite endpoint of a 57% decline in eGFR, reaching ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

[0051] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in preventing hospitalization for heart failure (hHF) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent hHF. In some embodiments, the human patient meets the criteria described herein.

[0052] The present disclosure also provides methods of preventing hospitalization for heart failure (hHF) in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to prevent hHF. In some embodiments, the human patient meets the criteria described herein.

[0053] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for preventing hospitalization for heart failure (hHF) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent hHF. In some embodiments, the human patient meets the criteria described herein.

[0054] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the risk of hospitalization for heart failure (hHF) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the patient's risk of hHF. In some embodiments, the human patient meets the criteria described herein.

[0055] The present disclosure also provides methods of reducing the risk of hospitalization for heart failure (hHF) in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the patient's risk of hHF. In some embodiments, the human patient meets the criteria described herein.

[0056] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the risk of hospitalization for heart failure (hHF) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the patient's risk of hHF. In some embodiments, the human patient meets the criteria described herein.

[0057] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the risk of increased fluid retention in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the patient's risk of increased fluid retention. In some embodiments, the human patient meets the criteria described herein.

[0058] The present disclosure also provides methods of reducing the risk of increased fluid retention in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the patient's risk of increased fluid retention. In some embodiments, the human patient meets the criteria described herein.

[0059] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in reducing the risk of increased fluid retention in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the patient's risk of increased fluid retention. In some embodiments, the human patient meets the criteria described herein.

[0060] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in preventing increased fluid retention in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent increased fluid retention in the patient. In some embodiments, the human patient meets the criteria described herein.

[0061] The present disclosure also provides methods of preventing increased fluid retention in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to prevent increased fluid retention in the patient. In some embodiments, the human patient meets the criteria described herein.

[0062] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for preventing increased fluid retention in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent increased fluid retention in the patient. In some embodiments, the human patient meets the criteria described herein.

[0063] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the risk of elevated brain natriuretic peptide (BNP) levels in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the patient's risk of elevated BNP levels. In some embodiments, the human patient meets the criteria described herein.

[0064] The present disclosure also provides methods of reducing the risk of elevated brain natriuretic peptide (BNP) levels in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the patient's risk of elevated BNP levels. In some embodiments, the human patient meets the criteria described herein.

[0065] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the risk of elevated brain natriuretic peptide (BNP) levels in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of elevated BNP levels in the patient. In some embodiments, the human patient meets the criteria described herein.

[0066] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in preventing an increase in the level of brain natriuretic peptide (BNP) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent an increase in the level of BNP in the patient. In some embodiments, the human patient meets the criteria described herein.

[0067] The present disclosure also provides methods of preventing an increase in the level of brain natriuretic peptide (BNP) in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to prevent an increase in the level of BNP in the patient. In some embodiments, the human patient meets the criteria described herein.

[0068] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for preventing increased levels of brain natriuretic peptide (BNP) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent increased levels of BNP in the patient. In some embodiments, the human patient meets the criteria described herein.

[0069] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the risk of gained weight in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of gained weight in the patient. In some embodiments, the human patient meets the criteria described herein.

[0070] The present disclosure also provides methods of reducing the risk of gained weight in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the patient's risk of gained weight. In some embodiments, the human patient meets the criteria described herein.

[0071] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the risk of gained weight in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of gained weight in the patient. In some embodiments, the human patient meets the criteria described herein.

[0072] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in preventing weight gain in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent weight gain in the patient. In some embodiments, the human patient meets the criteria described herein.

[0073] The present disclosure also provides methods of preventing weight gain in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to prevent weight gain in the patient. In some embodiments, the human patient meets the criteria described herein.

[0074] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for preventing weight gain in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent weight gain in the patient. In some embodiments, the human patient meets the criteria described herein.

[0075] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the risk of increased total body water content in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of increased total body water content in the patient. In some embodiments, the human patient meets the criteria described herein.

[0076] The present disclosure also provides methods of reducing the risk of increased total body water content in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the risk of increased total body water content in the patient. In some embodiments, the human patient meets the criteria described herein.

[0077] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the risk of increased total body water content in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of increased total body water content in the patient. In some embodiments, the human patient meets the criteria described herein.

[0078] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in preventing an increase in total body water in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent an increase in total body water in the patient. In some embodiments, the human patient meets the criteria described herein.

[0079] The present disclosure also provides methods of preventing an increase in total body water in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to prevent an increase in total body water in the patient. In some embodiments, the human patient meets the criteria described herein.

[0080] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for preventing total body water gain in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to prevent total body water gain in the patient. In some embodiments, the human patient meets the criteria described herein.

[0081] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing cholesterol in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce cholesterol in the patient. In some embodiments, the human patient meets the criteria described herein.

[0082] The present disclosure also provides methods of reducing cholesterol in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce cholesterol in the patient. In some embodiments, the human patient meets the criteria described herein.

[0083] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing cholesterol in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce cholesterol in the patient. In some embodiments, the human patient meets the criteria described herein.

[0084] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing hemoglobin A1c (HbA1c) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the patient's HbA1c. In some embodiments, the human patient meets the criteria described herein.

[0085] The present disclosure also provides methods of reducing hemoglobin AIc (HbAIc) in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the patient's HbAIc. In some embodiments, the human patient meets the criteria described herein.

[0086] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing hemoglobin AIc (HbAIc) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the patient's HbAIc. In some embodiments, the human patient meets the criteria described herein.

[0087] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the risk of elevated cholesterol in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of elevated cholesterol. In some embodiments, the human patient meets the criteria described herein.

[0088] The present disclosure also provides methods of reducing the risk of elevated cholesterol in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the risk of elevated cholesterol. In some embodiments, the human patient meets the criteria described herein.

[0089] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the risk of elevated cholesterol in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of elevated cholesterol. In some embodiments, the human patient meets the criteria described herein.

[0090] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the risk of elevated hemoglobin A1c (HbA1c) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of elevated HbA1c. In some embodiments, the human patient meets the criteria described herein.

[0091] The present disclosure also provides methods of reducing the risk of elevated hemoglobin A1c (HbA1c) in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the risk of elevated HbA1c. In some embodiments, the human patient meets the criteria described herein.

[0092] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the risk of elevated hemoglobin A1c (HbA1c) in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of elevated HbA1c. In some embodiments, the human patient meets the criteria described herein.

[0093] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing blood pressure in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the patient's blood pressure. In some embodiments, the human patient meets the criteria described herein.

[0094] The present disclosure also provides methods of reducing blood pressure in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the patient's blood pressure. In some embodiments, the human patient meets the criteria described herein.

[0095] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing blood pressure in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the patient's blood pressure. In some embodiments, the human patient meets the criteria described herein.

[0096] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the risk of elevated blood pressure in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of elevated blood pressure. In some embodiments, the human patient meets the criteria described herein.

[0097] The present disclosure also provides methods of reducing the risk of elevated blood pressure in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the risk of elevated blood pressure. In some embodiments, the human patient meets the criteria described herein.

[0098] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the risk of elevated blood pressure in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of elevated blood pressure. In some embodiments, the human patient meets the criteria described herein.

[0099] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the incidence of antineutrophilic cytoplasmic autoantibody (ANCA) vasculitis in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of ANCA vasculitis. In some embodiments, the human patient meets the criteria described herein.

[0100] The present disclosure also provides methods of reducing the incidence of antineutrophil cytoplasmic antibody (ANCA) vasculitis in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the incidence of ANCA vasculitis. In some embodiments, the human patient meets the criteria described herein.

[0101] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the incidence of antineutrophil cytoplasmic antibody (ANCA) vasculitis in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of ANCA vasculitis. In some embodiments, the human patient meets the criteria described herein.

[0102] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the recurrence of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the recurrence of ANCA vasculitis. In some embodiments, the human patient meets the criteria described herein.

[0103] The present disclosure also provides methods of reducing recurrence of antineutrophil cytoplasmic antibody (ANCA) vasculitis in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce recurrence of ANCA vasculitis. In some embodiments, the human patient meets the criteria described herein.

[0104] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing recurrence of antineutrophil cytoplasmic antibody (ANCA) vasculitis in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce recurrence of ANCA vasculitis. In some embodiments, the human patient meets the criteria described herein.

[0105] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the progression of Alport syndrome in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the progression of Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0106] The present disclosure also provides methods of reducing the progression of Alport syndrome in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the progression of Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0107] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the progression of Alport syndrome in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the progression of Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0108] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in treating Alport syndrome in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to treat Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0109] The present disclosure also provides methods of treating Alport syndrome in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to treat Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0110] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for treating Alport syndrome in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to treat Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0111] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing levels of markers of kidney inflammation (nephritis) associated with Alport syndrome in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce levels of markers of kidney inflammation (nephritis) associated with Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0112] The present disclosure also provides methods for reducing levels of markers of kidney inflammation (nephritis) associated with Alport syndrome in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce levels of markers of kidney inflammation (nephritis) associated with Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0113] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing levels of markers of kidney inflammation (nephritis) associated with Alport syndrome in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce levels of markers of kidney inflammation (nephritis) associated with Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0114] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the incidence of stroke in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of stroke. In some embodiments, the human patient meets the criteria described herein.

[0115] The present disclosure also provides a method of reducing the incidence of stroke in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the incidence of stroke. In some embodiments, the human patient meets the criteria described herein.

[0116] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the incidence of stroke in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the incidence of stroke. In some embodiments, the human patient meets the criteria described herein.

[0117] The present disclosure also provides a fixed-dose combination of zibotentan and dapagliflozin for use in reducing the risk of stroke in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of stroke. In some embodiments, the human patient meets the criteria described herein.

[0118] The present disclosure also provides methods of reducing the risk of stroke in a human patient in need thereof, comprising administering to the human patient separately, sequentially, or simultaneously zibotentan and dapagliflozin in amounts effective to reduce the risk of stroke. In some embodiments, the human patient meets the criteria described herein.

[0119] The present disclosure also provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for reducing the risk of stroke in a human patient in need thereof, wherein the zibotentan and dapagliflozin are administered to the human patient in amounts effective to reduce the risk of stroke. In some embodiments, the human patient meets the criteria described herein.

[0120] In an embodiment, the patient is naive to a sodium-glucose cotransporter-2 (SGLT2) inhibitor.

[0121] In an embodiment, the patient receives a blood flow of 20 to 90 mL / min / 1.73 m 2 have an estimated glomerular filtration rate (eGFR) of

[0122] In an embodiment, the patient has a UPCR of 1 to 1.3 g / g. In an embodiment, the patient has a UACR of 700 to 900 mg / g.

[0123] In an embodiment, the patient has a UPCR of 1 to 1.3 g / g and a UACR of 700 to 900 mg / g.

[0124] In some embodiments, the patient has biopsy-confirmed IgA nephropathy.

[0125] In an embodiment, the fixed dose combination of zibotentan and dapagliflozin is administered to a patient once daily.

[0126] In an embodiment, zibotentan is administered at a dose of 0.25 mg to 1.5 mg. In an embodiment, zibotentan is administered at a dose of 0.25 mg. In an embodiment, zibotentan is administered at a dose of 0.5 mg. In an embodiment, zibotentan is administered at a dose of 0.75 mg. In an embodiment, zibotentan is administered at a dose of 1.0 mg. In an embodiment, zibotentan is administered at a dose of 1.25 mg. In an embodiment, zibotentan is administered at a dose of 1.5 mg.

[0127] In an embodiment, dapagliflozin is administered at a dose of 2.5 mg to 10 mg. In an embodiment, dapagliflozin is administered at a dose of 2.5 mg. In an embodiment, dapagliflozin is administered at a dose of 5.0 mg. In an embodiment, dapagliflozin is administered at a dose of 10.0 mg.

[0128] In an embodiment, zibotentan is administered at a dose of 0.75 mg and dapagliflozin is administered at a dose of 10 mg. In an embodiment, zibotentan is administered at a dose of 0.5 mg and dapagliflozin is administered at a dose of 10 mg. In an embodiment, zibotentan is administered at a dose of 0.25 mg and dapagliflozin is administered at a dose of 10 mg.

[0129] In some embodiments, the patient has an eGFR > 45 mL / min / 1.73 m 2 In some embodiments, the patient has an eGFR<45 mL / min / 1.73 m 2 wherein zibotentan is administered at a dose of 0.25 mg and dapagliflozin is administered at a dose of 10 mg. In some embodiments, the patient has an eGFR of <45 mL / min / 1.73 m 2 and the fixed dose combination of zibotentan and dapagliflozin is adjusted so that zibotentan is administered at a dose of 0.25 mg and dapagliflozin is administered at a dose of 10 mg. In some embodiments, if the patient's eGFR is ≥ 45 mL / min / 1.73 m 2 and the fixed-dose combination of zibotentan and dapagliflozin is adjusted so that zibotentan is administered at a dose of 0.75 mg and dapagliflozin is administered at a dose of 10 mg.

[0130] In one embodiment, the method or use of any of the embodiments disclosed herein reduces the patient's UACR to less than 300 mg / g. In one embodiment, the method or use of any of the embodiments disclosed herein reduces the patient's UPCR to less than 1 g / g. In one embodiment, the method or use of any of the embodiments disclosed herein reduces the patient's UACR to less than 300 mg / g and the patient's UPCR to less than 1 g / g.

[0131] In one embodiment, the method or use of any of the embodiments disclosed herein results in the patient achieving partial remission or remission.

[0132] In one embodiment, the method or use of any of the embodiments disclosed herein reduces the incidence of stroke and / or acute coronary syndrome in a patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

[0133] In any of the above embodiments, the results obtained by the provided methods and uses may be compared to human patients receiving at least one SGLT2 inhibitor (e.g., dapagliflozin, empagliflozin, canagliflozin, etc.) alone or in combination with at least one standard of care CKD medication. In such aspects, the standard of care CKD medication may be an ACE inhibitor (e.g., captopril, enalapril, and lisinopril) and / or an angiotensin II receptor blocker (ARB) (valsartan, losartan, and irbesartan). In some embodiments, the results are compared to dapagliflozin alone. In some embodiments, the results are compared to dapagliflozin in combination with at least one standard of care CKD medication.

[0134] In any of the above embodiments, the results obtained by the provided methods and uses may be compared to patients from baseline, hi some embodiments, the methods and uses are compared to patients from baseline compared to patients receiving dapagliflozin alone or in combination with at least one standard of care treatment for CKD. [Brief explanation of the drawings]

[0135] [Figure 1] Illustrates the study timeline and study groups described in Example 1. [Figure 2] Illustrates the study timeline and study groups described in Example 2. [Figure 3] Illustrates the dose titration groupings described in Example 2. [Figure 4] 1 shows Kaplan-Meier curves illustrating the effect of two different doses of zibotentan and dapagliflozin combination and dapagliflozin monotherapy on fluid events over 12 weeks. [Figure 5] Illustrates the effect of two different doses of zibotentan and dapagliflozin combination and dapagliflozin monotherapy on the change in UACR from baseline levels over 12 weeks. [Figure 6] Illustrates the effect of two different doses of zibotentan and dapagliflozin combination and dapagliflozin monotherapy on the change in systolic blood pressure from baseline levels over 12 weeks. [Figure 7A] Figure 1 shows the effect of two different doses of zibotentan and dapagliflozin combination and dapagliflozin monotherapy on change from baseline in systolic and diastolic blood pressure over 12 weeks in patients with a UACR > 700 mg / g. [Figure 7B] Figure 1 shows the effect of two different doses of zibotentan and dapagliflozin combination and dapagliflozin monotherapy on change from baseline in systolic and diastolic blood pressure over 12 weeks in patients with a UACR > 700 mg / g. [Figure 8] 1 shows the study timeline and study groups described in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0136] As used herein, the terms "about" and "approximately," when used to modify a numerical value or numerical range, indicate that a deviation of up to 10% above and below that value or range remains 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%. Whenever an aspect is described herein using a numerical value or range with the word "about" or "approximately," it is understood that other similar aspects that refer to the specified numerical value or range (excluding "about") are also provided. Also, whenever an embodiment is described herein that refers to a numerical value or range without the use of the words "about" or "approximately," it is understood that other similar embodiments that refer to "about" or "approximately" also provide the particular numerical value or range.

[0137] The terms "treating" or "treatment" or "treat" refer to a therapeutic measure that cures, slows, alleviates, and / or halts the progression of a diagnosed pathological 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 the term.

[0138] The effectiveness of the compounds of the present disclosure in treating and / or preventing chronic kidney disease (CKD) and / or related diseases, disorders, and / or conditions can be easily determined by those skilled in the art. Determining and adjusting the appropriate dosing regimen (e.g., adjusting the amount of compound per dose and / or the number of doses and frequency of administration) can also be easily performed by those skilled in the art. One or any combination of diagnostic methods, including physical examination, evaluation and monitoring of clinical symptoms, and performing analytical tests and methods described herein, can be used to monitor the health status of a patient.

[0139] An effective amount or a 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 in a single dose or as part of a series, is effective to produce at least one therapeutic effect. Optimal doses may generally be determined using experimental models and / or clinical trials. The design and execution of preclinical and clinical trials for each of the therapeutic agents described herein (including when administered for prophylactic benefit) is well within the skill of those of ordinary skill in the relevant art. Optimal doses of therapeutic agents may depend on the patient's body mass, weight, and / or blood volume. 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 of ordinary skill in the art and are described herein. The level of a compound administered to a patient may be monitored by determining the level of the compound (or a metabolite of the compound) in a biological fluid, e.g., blood, a blood fraction (e.g., serum), and / or urine, and / or another biological sample from the patient. Any method practiced in the art for detecting a compound or its metabolites can be used to measure the levels of the compound during the course of a treatment regimen.

[0140] The dosage of the compounds described herein may depend on the patient's condition, i.e., the stage of the disease, the severity of the symptoms caused by the disease, general health, as well as age, sex, and weight, and other factors apparent to those skilled in the medical field. Similarly, the dosage of a therapeutic agent for treating a disease, disorder, and / or condition may be determined according to parameters understood by those skilled in the medical field.

[0141] As used herein, the terms "subject" and "patient" are used interchangeably and refer to a party undergoing medical treatment. In some embodiments, the subject is a human.

[0142] As used herein, the term "albuminuria" refers to the presence of albumin in the urine, which is a marker of chronic kidney disease. Albuminuria is present when the urinary albumin-to-creatine ratio (UACR) is greater than 30 mg / g.

[0143] As used herein, the term "proteinuria" refers to the presence of protein in urine, which is a marker of chronic kidney disease. Proteinuria is present when the urinary protein-to-creatine ratio (UPCR) is greater than 150 mg / g. In some embodiments, proteinuria is present when the UPCR is greater than 200 mg / g.

[0144] As used herein, "severity" of chronic kidney disease (CKD) refers to the stage or grade of CKD as defined by the Kidney Disease Improving Global Outcomes (KIDGO) guidelines. Stage 1 is normal or high eGFR (eGFR > 90 mL / min / 1.73 m 2 Stage 2 is mild CKD (eGFR = 60-89 mL / min / 1.73 m 2 Stage 3A is moderate CKD (eGFR = 45-59 mL / min / 1.73 m 2 Stage 3B is moderate CKD (eGFR = 30-44 mL / min / 1.73 m2 Stage 4 is severe CKD (eGFR = 15-29 mL / min / 1.73 m 2 Stage 5 is end-stage CKD (eGFR < 15 mL / min / 1.73 m 2 ).

[0145] As used herein, the term "end-stage kidney disease (ESKD)" refers to (i) a sustained eGFR < 15 mL / min / 1.73 m 2 (ii) undergoing chronic dialysis treatment, or (iii) undergoing a kidney transplant. In some embodiments, "sustained" refers to confirmation of a similar eGFR measurement with a second eGFR test at three-month intervals.

[0146] As used herein, the term "cholesterol" refers to (i) low-density lipoprotein (LDL) cholesterol, (ii) high-density lipoprotein (HDL) cholesterol, or both.

[0147] As used herein, the phrase "not naive to an SGLT2 inhibitor" refers to patients who (i) have previously received SGLT2 inhibitor therapy and / or (ii) are currently receiving SGLT2 inhibitor therapy.

[0148] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of drugs, such as 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 used with the agents and methods described herein can be found, for example, in 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 embodiments, zibotentan and dapagliflozin are administered orally.

[0149] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and that does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered. Such formulations may be sterile.

[0150] A "pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with therapeutic agents, which together comprise a "pharmaceutical composition" for administration to a subject. Pharmaceutically acceptable carriers are non-toxic to recipients at the dosages and concentrations employed, are suitable for the formulation being used, and are compatible with other ingredients of the formulation.

[0151] A "sterile" preparation is aseptic or essentially free of living microorganisms and their spores.

[0152] The term "prodrug" as used herein refers to, for example, esters and carbonates, which can be converted to zibotentan or dapagliflozin, for example, under physiological conditions or by solvolysis. Thus, the term prodrug includes pharmaceutically acceptable metabolic precursors of zibotentan or dapagliflozin. 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.

[0153] Various forms of prodrugs are known in the art. For example, examples of such prodrug derivatives can be found in: (1) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); 2) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard, pp. 113-191 (1991); (3) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); (4) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and (5) N. Kakeya, et al., Chem Pharm See Bull, 32, 692 (1984).

[0154] Whenever an embodiment is described herein with the word "comprising," it is understood that other similar embodiments described in terms of "consisting of" and / or "consisting essentially of" are also provided. In this disclosure, "comprises," "comprising," "containing," and "having," etc., may mean "includes," "including," etc. "Consisting essentially of" or "consists essentially of" is open-ended, allowing for the presence of more than those recited, but excluding prior art embodiments, so long as the presence of more than those recited does not change the basic or novel characteristics described herein of the recited items.

[0155] Unless specifically stated otherwise or clear from the context, the term "or" as used herein is understood to be inclusive.

[0156] In one aspect, the disclosure herein provides a method of treating proteinuric chronic kidney disease (CKD) in a human patient, comprising administering zibotentan and dapagliflozin to a human patient in need thereof.

[0157] In one aspect, the disclosure herein provides a fixed-dose combination of zibotentan and dapagliflozin for use in the treatment of proteinuric chronic kidney disease (CKD) in a human patient.

[0158] In one aspect, the disclosure herein provides use of a fixed-dose combination of zibotentan and dapagliflozin in the manufacture of a medicament for the treatment of proteinuric chronic kidney disease (CKD) in a human patient, wherein the fixed-dose combination of zibotentan and dapagliflozin is administered.

[0159] In embodiments, the chronic kidney disease (CKD) is stage 1-4 CKD as defined by the Kidney Disease Improving Global Outcomes (KIDGO) guidelines. In embodiments, the CKD is stage 2-3 CKD. In embodiments, the CKD is stage 3-4 CKD. In embodiments, the CKD is stage 2-4 CKD. In embodiments, the CKD is stage 4 CKD. In embodiments, the CKD is stage 3 CKD. In embodiments, the CKD is stage 3A or 3B CKD. In embodiments, the CKD is stage 2 CKD.

[0160] In an embodiment, the patient is a CKD human patient with type 2 diabetes. In an embodiment, the patient is a CKD human patient without type 2 diabetes.

[0161] In an embodiment, the patient receives a blood flow of 20 to 90 mL / min / 1.73 m 2 In some embodiments, patients have an estimated glomerular filtration rate (eGFR) of 20-29 mL / min / 1.73 m 2 In some embodiments, the patient has an eGFR of 30-44 mL / min / 1.73 m 2 In some embodiments, the patient has an eGFR of 45 to 59 mL / min / 1.73 m 2 In some embodiments, the patient has an eGFR of 60 to 89 mL / min / 1.73 m 2 have an eGFR of

[0162] In embodiments, the patient has a urinary protein-to-creatine ratio (UPCR) greater than 2.0 g / g. In embodiments, the patient has a UPCR greater than 1.0 g / g. In embodiments, the patient has a UPCR between 1.0 and 2.0 g / g. In embodiments, the patient has a UPCR between 1.0 and 1.5 g / g. In embodiments, the patient has a UPCR between 1.0 and 1.3 g / g.

[0163] In embodiments, the patient has a urinary albumin-to-creatine ratio (UACR) greater than 1.5 g / g. In embodiments, the patient has a UACR greater than 700 mg / g. In embodiments, the patient has a UACR between 700 mg / g and 1.5 g / g. In embodiments, the patient has a UACR between 700 mg / g and 1.0 g / g. In embodiments, the patient has a UACR between 700 and 900 mg / g.

[0164] In an embodiment, the patient receives a blood flow of 20 to 90 mL / min / 1.73 m 2 and a UACR of greater than 700 mg / g. In embodiments, the patient has an eGFR of 20-90 mL / min / 1.73 m 2 In embodiments, the patient has an eGFR of greater than 700 mg / g and a UPCR of greater than 1.0 g / g. In embodiments, the patient has a UACR of greater than 700 mg / g and a UPCR of greater than 1.0 g / g. In embodiments, the patient has an eGFR of 20-90 mL / min / 1.73 m 2 have an eGFR of >700 mg / g, a UACR of >1.0 mg / g, and a UPCR of >1.0 mg / g.

[0165] In an embodiment, the patient receives a blood flow of 20 to 90 mL / min / 1.73 m 2 and a UACR of greater than 700-900 mg / g. In embodiments, the patient has an eGFR of 20-90 mL / min / 1.73 m 2 and a UPCR of greater than 1.0-1.3 g / g. In embodiments, the patient has a UACR of 700-900 mg / g and a UPCR of 1.0-1.3 g / g. In embodiments, the patient has a UACR of 20-90 mL / min / 1.73 m 2 eGFR of 700-900 mg / g, UACR of 700-900 mg / g, and UPCR of 1.0-1.3 g / g.

[0166] In embodiments, the patient has Alport syndrome. In embodiments, the patient has high proteinuria (UACR>700 mg / g) and Alport syndrome. In embodiments, the patient has antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. In embodiments, the patient has high proteinuria (UACR>700 mg / g) and ANCA vasculitis.

[0167] In some embodiments, the patient has IgA nephropathy (IgAN). In some embodiments, the patient has hyperproteinuria (UACR>700 mg / g and / or UPCR>1.0 g / g) and IgAN. In some embodiments, the patient has eGFR>30 mL / min / 1.73 m2, hyperproteinuria (UACR>700 mg / g and / or UPCR>1.0 g / g), and IgAN. In some embodiments, the patient's diagnosis of IgAN is confirmed by biopsy. In some embodiments, patients with IgAN are at risk for rapid disease progression.

[0168] In embodiments, the patient is naive to a sodium-glucose cotransporter 2 (SGLT2) inhibitor. In some embodiments where the patient is naive to an SGLT2 inhibitor, the patient receives dapagliflozin (induction) before receiving the fixed-dose combination of zibotentan and dapagliflozin. In some embodiments where the patient is naive to an SGLT2 inhibitor, the patient receives a 4-week induction of dapagliflozin before receiving the fixed-dose combination of zibotentan and dapagliflozin. In embodiments, the patient is not naive to an SGLT2 inhibitor.

[0169] In embodiments, the patient is naïve to an SGLT2 inhibitor and receives a blood glucose level of 20 to 90 mL / min / 1.73 m 2 In embodiments, the patient is naive to an SGLT2 inhibitor and has an eGFR of 20-90 mL / min / 1.73 m 2 In embodiments, the patient is naive to an SGLT2 inhibitor and has an eGFR of greater than 700 mg / g and a UPCR of greater than 1.0 g / g. In embodiments, the patient is naive to an SGLT2 inhibitor and has an UACR of greater than 700 mg / g and a UPCR of greater than 1.0 g / g. In embodiments, the patient is naive to an SGLT2 inhibitor and has an IV blood glucose level of 20-90 mL / min / 1.73 m 2 have an eGFR of >700 mg / g, a UACR of >1.0 mg / g, and a UPCR of >1.0 mg / g.

[0170] In embodiments, the patient is naïve to an SGLT2 inhibitor and receives a blood glucose level of 20 to 90 mL / min / 1.73 m2 In an embodiment, the patient is naive to an SGLT2 inhibitor and has an eGFR of 20-90 mL / min / 1.73 m and a UACR of 700-900 mg / g. 2 and a UPCR of 1.0-1.3 g / g. In embodiments, the patient is naive to an SGLT2 inhibitor and has a UACR of 700-900 mg / g and a UPCR of 1.0-1.3 g / g. In embodiments, the patient is naive to an SGLT2 inhibitor and has an eGFR of 20-90 mL / min / 1.73 m 2 eGFR of 700-900 mg / g, UACR of 700-900 mg / g, and UPCR of 1.0-1.3 g / g.

[0171] In embodiments, the patient is not naive to an SGLT2 inhibitor and receives a blood glucose level between 20 and 90 mL / min / 1.73 m 2 In embodiments, the patient is not naive to an SGLT2 inhibitor and has an eGFR of 20-90 mL / min / 1.73 m 2 In embodiments, the patient is not naive to an SGLT2 inhibitor and has an eGFR of greater than 700 mg / g and a UPCR of greater than 1.0 g / g. In embodiments, the patient is not naive to an SGLT2 inhibitor and has an UACR of 20-90 mL / min / 1.73 m 2 have an eGFR of >700 mg / g, a UACR of >700 mg / g, and a UPCR of >1.0 mg / g.

[0172] In embodiments, the patient is not naive to an SGLT2 inhibitor and receives a blood glucose level between 20 and 90 mL / min / 1.73 m 2 and a UACR of 700-900 mg / g. In embodiments, the patient is not naive to an SGLT2 inhibitor and has an eGFR of 20-90 mL / min / 1.73 m 2 In embodiments, the patient is not naive to an SGLT2 inhibitor and has an eGFR of 700-900 mg / g and a UPCR of 1.0-1.3 g / g. In embodiments, the patient is not naive to an SGLT2 inhibitor and has a UACR of 20-90 mL / min / 1.73 m2 eGFR of 700-900 mg / g, UACR of 700-900 mg / g, and UPCR of 1.0-1.3 g / g.

[0173] In embodiments, the patients described herein are administered a fixed-dose combination of zibotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof.

[0174] In embodiments, zibotentan or a pharmaceutically acceptable salt thereof is administered once daily.

[0175] In an embodiment, the total daily dose of zibotentan or a pharmaceutically acceptable salt thereof administered is 0.25 to 1.5 mg. In an embodiment, the total daily dose of zibotentan is 0.25 mg. In an embodiment, the total daily dose of zibotentan is 0.5 mg. In an embodiment, the total daily dose of zibotentan is 0.75 mg. In an embodiment, the total daily dose of zibotentan is 1.0 mg. In an embodiment, the total daily dose of zibotentan is 1.25 mg. In an embodiment, the total daily dose of zibotentan is 1.5 mg.

[0176] 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 containing one or more pharmaceutically acceptable excipients. In some embodiments, the composition contains one or more pharmaceutical diluents, one or more pharmaceutical disintegrants, or one or more pharmaceutical lubricants.

[0177] In embodiments, dapagliflozin or a pharmaceutically acceptable salt thereof is administered once daily.

[0178] In one embodiment, 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 an amorphous 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 an (S)-propylene glycol ((S)-PG) solvate having the following structure:

[0179] [ka]

[0180] In embodiments provided herein, dapagliflozin is administered orally to a patient. In embodiments provided herein, dapagliflozin is administered to a patient in tablet form.

[0181] In an embodiment, the total daily dose of dapagliflozin or a pharmaceutically acceptable salt thereof administered is 2.5 to 10 mg. In an embodiment, the total daily dose of dapagliflozin is 2.5 mg. In an embodiment, the total daily dose of dapagliflozin is 3.0 mg. In an embodiment, the total daily dose of dapagliflozin is 4.0 mg. In an embodiment, the total daily dose of dapagliflozin is 5.0 mg. In an embodiment, the total daily dose of dapagliflozin is 6.0 mg. In an embodiment, the total daily dose of dapagliflozin is 7.0 mg. In an embodiment, the total daily dose of dapagliflozin is 7.5 mg. In an embodiment, the total daily dose of dapagliflozin is 8.0 mg. In an embodiment, the total daily dose of dapagliflozin is 9.0 mg. In an embodiment, the total daily dose of dapagliflozin is 10.0 mg.

[0182] In an embodiment, zibotentan or a pharmaceutically acceptable salt thereof is administered once daily in a fixed dose combination with dapagliflozin or a pharmaceutically acceptable salt thereof.

[0183] In one embodiment, the fixed-dose combination of zibotentan and dapagliflozin is administered containing a total daily dose of 0.25 to 1.5 mg of zibotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 2.5 to 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof. In another embodiment, the fixed-dose combination of zibotentan and dapagliflozin is administered containing 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 another embodiment, the fixed-dose combination of zibotentan and dapagliflozin is administered containing 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 an embodiment, the fixed dose combination of zibotentan and dapagliflozin is administered to comprise a total daily dose of 0.75 mg zibotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 10.0 mg dapagliflozin or a pharmaceutically acceptable salt thereof.

[0184] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof results in partial remission or remission of CKD. In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof results in partial remission or remission of proteinuria. In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof results in partial remission or remission of albuminuria. In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof results in partial remission or remission of eGFR decline.

[0185] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof does not result in hospitalization for heart failure (hHF) for the patient. In embodiments, administering a fixed dose 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 risk of hHF for the patient.

[0186] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof does not result in increased fluid retention in the patient. In embodiments, administering a fixed dose 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 risk of increased fluid retention for the patient.

[0187] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof does not result in an increase in brain natriuretic peptide (BNP) levels in the patient. In embodiments, administering a fixed dose 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 risk of increased BNP levels in the patient.

[0188] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof does not result in an increase in total body water in the patient. In embodiments, administering a fixed dose 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 risk of increased total body water in the patient.

[0189] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof does not result in weight gain in the patient. In embodiments, administering a fixed dose 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 risk of gained weight for the patient.

[0190] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof results in a reduction in the patient's blood pressure. In embodiments, administering a fixed dose 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 risk of elevated blood pressure in the patient.

[0191] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof results in reduced cholesterol in the patient. In embodiments, administering a fixed dose 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 risk of elevated cholesterol in the patient.

[0192] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof results in a reduction in hemoglobin AIc (HbAIc) in the patient. In embodiments, administering a fixed dose 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 risk of elevated HbAIc in the patient.

[0193] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient with ANCA vasculitis in need thereof results in a reduced incidence of ANCA vasculitis in the patient. In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient with ANCA vasculitis in need thereof results in a reduced recurrence of ANCA vasculitis in the patient.

[0194] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient with Alport syndrome in need thereof results in a reduction in the progression of Alport syndrome in the patient. In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient with Alport syndrome in need thereof results in a reduction in markers of kidney inflammation (nephritis) associated with Alport syndrome in the patient. In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient with Alport syndrome in need thereof treats Alport syndrome in the patient.

[0195] In embodiments, administering a fixed-dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient with biopsy-confirmed IgAN in need thereof results in a reduction in proteinuria in the patient. In embodiments, administering a fixed-dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient with biopsy-confirmed IgAN at risk of rapid disease progression in need thereof results in a reduction in the progression of IgAN-associated renal function decline in the patient. In embodiments, administering a fixed-dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient with biopsy-confirmed IgAN in need thereof treats IgAN in the patient.

[0196] In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof results in a reduced incidence of stroke in the patient. In embodiments, administering a fixed dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof to a patient in need thereof results in a reduced risk of stroke in the patient.

[0197] In some embodiments, disease improvement, reduced incidence, reduced risk, and other beneficial effects provided through administration of the fixed-dose combination of zibotentan and dapagliflozin described herein and described in the preceding embodiments may represent an improvement compared to no therapy, an improvement compared to placebo treatment, an improvement compared to treatment with dapagliflozin alone, and / or an improvement compared to treatment with other standard therapies for a disease, disorder, or condition associated with hyperproteinuric chronic kidney disease.

[0198] In embodiments, the fixed-dose combination of zibotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof is administered simultaneously. In embodiments, zibotentan or a pharmaceutically acceptable salt thereof is administered before administration of dapagliflozin or a pharmaceutically acceptable salt thereof. In embodiments, zibotentan or a pharmaceutically acceptable salt thereof is administered after administration of dapagliflozin or a pharmaceutically acceptable salt thereof.

[0199] Pharmaceutical compositions can be administered in any manner appropriate to the disease, disorder, and / or condition being treated, as determined by one skilled in the medical arts. The appropriate dose and suitable duration and frequency of administration can be determined by factors such as those discussed herein, including the patient's condition, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose (or effective dose) and treatment regimen will provide the compositions described herein in an amount sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms, or other benefits described in detail above).

[0200] The pharmaceutical compositions can be formulated using conventional solid or liquid vehicles, diluents, and pharmaceutical additives appropriate for the desired mode of administration. The pharmaceutical compositions can be administered by various routes, including orally in the form of, for example, tablets, capsules, granules, powders, etc., parenterally in the form of injectable preparations, intranasally, rectally, and transdermally in the form of patches, for example.

[0201] The above dosage forms may also include pharmaceutically acceptable carriers (i.e., non-toxic inert solid, semi-solid, or liquid fillers, diluents, encapsulating materials, or formulation auxiliary agents of any type), excipients, lubricants, buffers, antibacterial agents, bulking agents (such as mannitol), adjuvants, and the like.

[0202] Some examples of materials that can function as pharmaceutically acceptable carriers are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffers, as well as other non-toxic compatible lubricants, for example, sodium lauryl sulfate and magnesium stearate; colorants; release agents; coating agents; sweetening agents; flavorings and fragrances; preservatives; and antioxidants.

[0203] Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (olive oil, etc.), 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.

[0204] Examples of adjuvants include preservatives, wetting agents, emulsifying agents, dispersing agents, suspending agents, sweeteners, flavoring agents, and aromatic agents. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars and sodium chloride. Prolonged absorption of injectable pharmaceutical forms can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin. Suspending agents include, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0205] Various pharmaceutical compositions used in the methods of the present disclosure can optionally include one or more fillers or excipients in amounts ranging from about 0% to about 90% by weight, and in some embodiments from about 1% to about 80% by weight. Examples of suitable fillers or excipients include, but are not limited to, lactose, sugars, cornstarch, modified cornstarch, mannitol, sorbitol, inorganic salts (e.g., calcium carbonate), and cellulose derivatives (e.g., wood cellulose and microcrystalline cellulose).

[0206] One or more binders may be present in addition to or in place of the filler in an amount ranging from about 0% to about 35%. In some embodiments, the binder is present in an amount ranging from about 0.5% to about 30% by weight of the composition. Examples of suitable binders include polyvinylpyrrolidone (molecular weight ranging from about 5000 to about 80,000, in some embodiments about 40,000), lactose, starches (e.g., cornstarch, modified cornstarch), sugar, acacia gum, and the like, as well as finely powdered (less than 500 microns) wax binders (e.g., carnauba wax, paraffin, spermaceti, polyethylene, and microcrystalline wax).

[0207] In some embodiments, the pharmaceutical composition is in the form of a tablet, and the tablet comprises one or more tableting lubricants in an amount ranging from about 0.2% to about 8% by weight of the composition. In some embodiments, the tableting lubricant is in an amount ranging from about 0.5% to about 2% by weight of the composition. 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 may optionally be present, including, for example, preservatives, stabilizers, colorants, anti-adherents, and silica flow conditioners or lubricants, such as Syloid brand silicon dioxide.

[0208] In some embodiments, the pharmaceutical composition is in the form of a tablet, and the tablet includes a coating layer, which may comprise about 0% to about 15% by weight of the tablet composition. The coating layer may include any conventional coating formulation, which may include, for example, one or more film-forming agents or binders and / or one or more plasticizers. Examples of suitable film-forming agents or binders include, but are not limited to, hydrophilic polymers (e.g., hydroxypropylmethylcellulose), hydrophobic polymers (e.g., methacrylic acid esters), neutral polymers, ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, β-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 the core tablet and the coating formulation may contain aluminum lake to provide color.

[0209] In some embodiments, the pharmaceutical composition is in the form of a tablet and the film-forming agent is 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 ethyl methyl ketone, chlorinated hydrocarbons such as methylene chloride, dichloroethane, and 1,1,1-trichloroethane.

[0210] In some embodiments, the pharmaceutical composition is in the form of a tablet and the color is applied along with a film-forming agent, a plasticizer, and a solvent composition.

[0211] In some embodiments, the pharmaceutical composition for use in the methods of the present disclosure in the form of a tablet comprises: a) mixing inactive ingredients with at least one compound of formula (I); b) formulating the granules; c) drying and / or sieving the granules; d) blending the granules, and e) compressing the blend obtained in (d) into tablets.

[0212] In some embodiments, step a) of the process uses 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 lubricant and a filler.

[0213] In some embodiments, the pharmaceutical composition in the form of a capsule comprises: a) mixing inert ingredients with at least one compound of formula (I) using a combination of blending and grinding processes; b) formulating the granules; c) drying and / or sieving the granules, and d) filling the granules into capsules.

[0214] In some embodiments, step a) of the process uses 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.

[0215] In some embodiments, pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0216] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injection. In some embodiments, this can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. In some embodiments, delayed absorption is achieved by dissolving or suspending the drug in an oil vehicle.

[0217] In some embodiments, the pharmaceutical composition is in an injectable depot form. In some embodiments, the injectable depot form comprises a microencapsulated matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the nature of the particular polymer employed. Examples of other suitable biodegradable polymers for use herein include poly(orthoesters) and poly(anhydrides). In some embodiments, the depot injectable formulations are prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0218] In some embodiments, the pharmaceutical compositions are injectable formulations, which can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0219] In some embodiments, the pharmaceutical composition is in a solid dosage form suitable for oral administration.Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.In some embodiments, at least one compound selected from the compounds of formula (I) and its prodrugs is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) a filler or extender such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) a binder such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) a humectant such as glycerol, d) agar. - mixed with disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders 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 glycol, sodium lauryl sulfate, and mixtures thereof. In some embodiments, the dosage form may also contain buffering agents.

[0220] 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.

[0221] 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 formulation art. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0222] In some embodiments, at least one compound selected from the compounds of formula (I) and / or the compounds of formula (II) and / or their prodrugs may be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0223] In some embodiments, the pharmaceutical composition may be in a 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 water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0224] The following examples provide illustrative embodiments of the present disclosure. Those skilled in the art will recognize numerous modifications and variations that may be made without altering the spirit or scope of the present disclosure. Such modifications and variations are encompassed within the scope of the present disclosure. The provided examples are not intended to limit the present disclosure in any way. [Example]

[0225] Example 1 Clinical trials of the fixed-dose combination of dapagliflozin and zibotentan are ongoing, including a randomized, double-blind, parallel-group, controlled trial to evaluate the efficacy of the fixed-dose combination of dapagliflozin and zibotentan compared with dapagliflozin monotherapy in patients with CKD and hyperproteinuria.

[0226] Study design Figure 1 illustrates the study timeline. Patients with documented CKD (eGFR ≥ 20 to < 90 mL / min / 1.73 m) who met the eligibility criteria listed in Table 1 (inclusion criteria) and Table 2 (exclusion criteria) were enrolled. 2 Approximately 1,500 patients aged ≥18 years with a UACR of ≥700 to <900 mg / g or UPCR of ≥1.0 to <1.3 g / g, and naive to SGLT2 inhibitors, will be randomized in a 1:1 ratio to receive a fixed-dose combination of zibotentan and dapagliflozin or dapagliflozin monotherapy, as shown in Table 3. Patients will be recruited over an approximately 18-month period, followed by a 24-month treatment period and a 1-month safety follow-up for a total study duration of approximately 43 months, with a mean follow-up of approximately 33 months. All variables will be collected to verify the inclusion criteria and additional demographics, such as race / ethnicity, serum creatinine, and height. A minimum of 30% of patients will have type 2 diabetes, and 30% of patients without type 2 diabetes will be randomized between study arms.

[0227] [Table 1]

[0228] [Table 2-1]

[0229] [Table 2-2]

[0230] [Table 3]

[0231] Patients will receive either dapagliflozin (10 mg) monotherapy once daily or a fixed-dose combination of zibotentan (0.75 mg) and dapagliflozin (10 mg) once daily. Patients not already receiving a stable dose of an SGLT2 inhibitor will undergo a 4-week run-in period during which they will receive 10 mg of an SGLT2 inhibitor once daily before the start of the treatment period. Endpoints and objectives will be assessed in participants at pre-randomization screening, at the site visit corresponding to randomization, and at study days 14 (±3), 90 (±10), 180 (±10), 270 (±10), 360 (±10), 480 (±10), 600 (±10), and 720 (±7).

[0232] Objectives and Endpoints The primary endpoint measures the effect of the fixed-dose combination of zibotentan and dapagliflozin versus dapagliflozin monotherapy on eGFR, UPCR, and UACR. Endpoints and objectives, including secondary endpoints and objectives, are summarized in Table 4.

[0233] [Table 4] Appendix A (EQ-5D-5L Questionnaire) Health status questionnaire Under each heading, check one box that best describes your health today. mobility No problems with walking □ I have slight problems walking. Moderate walking problems Severe walking problems Unable to walk □ self management No problems washing or dressing yourself Have slight problems washing or dressing themselves Have moderate problems washing or dressing themselves Have severe problems washing or dressing themselves Unable to wash or dress yourself Daily activities (e.g. work, study, household chores, family or leisure activities) No problems performing daily activities I have slight problems performing daily activities. Have moderate problems performing daily activities I have severe problems carrying out daily activities. Unable to carry out daily activities pain / discomfort No pain or discomfort I have slight pain or discomfort. Moderate pain or discomfort Severe pain or discomfort Extreme pain or discomfort Anxiety / depression Not anxious or depressed Slightly anxious or depressed Moderately anxious or depressed Severely anxious or depressed Extremely anxious or depressed It tells you how good or bad your health is today. · This scale is numbered from 0 to 100. 100 you can imagine The best It means health status. 0, you can imagine The worst It means health status. Mark an X on the scale to indicate how healthy you are today. ·Write the numbers you marked on the scale in the boxes below.

[0234]

number

[0235] Example 2 Clinical trials of the fixed-dose combination (FDC) of zibotentan and dapagliflozin are ongoing, including a randomized, double-blind, parallel-group, controlled study to evaluate the efficacy of the FDC of zibotentan and dapagliflozin compared with dapagliflozin monotherapy in patients with CKD and hyperproteinuria (see Example 1). Example 2 provides a modified protocol including dose titration for zibotentan in the fixed-dose combination.

[0236] Study design Figure 2 illustrates the study timeline. Approximately 1500 patients who meet the eligibility criteria (see inclusion and exclusion criteria in Tables 5A and 5B, respectively) will be randomized in a 1:1 ratio to one of two treatment groups. Zibotentan / dapagliflozin was administered orally once daily at FDC. Dapagliflozin 10 mg was administered orally once daily (active control).

[0237] [Table 5] 1 Highly effective birth control methods include: Complete abstinence (defined as abstinence from heterosexual intercourse for the entire period of risk associated with the study treatment) if consistent with the participant's usual lifestyle. Note that cyclical abstinence (e.g., calendar, ovulation, symptom-temperature, post-ovulation methods), declared abstinence for the duration of exposure to the study intervention, and pull-out are not acceptable methods of contraception. Vasectomized partner, Implanon®, bilateral tubal occlusion, intrauterine device / levonorgestrel intrauterine system, Depo-Provera™ injection, oral contraceptives containing ethinyl estradiol and levonorgestrel, Evra Patch™, Xulane™, or NuvaRing®.

[0238] [Table 6]

[0239] Throughout the study, until at least one month after the last dose of study intervention, women of childbearing potential (WOCBP) will use adequate contraception with at least two methods of birth control. The two methods of birth control will be (1) a highly effective method of birth control (see Inclusion Criteria 4 for a definition and list of highly effective methods of contraception), plus (2) condom use by the male partner for sexual intercourse. Pregnancy testing and contraceptive adherence checks will be conducted.

[0240] A screening failure occurs when a participant consents to participate in a clinical trial but is not subsequently randomized. A minimum set of screening failure information is required to meet the Consolidated Standards of Reporting Trials (CONSORT) disclosure requirements and to ensure transparent reporting of screening failure participants in response to inquiries from regulatory authorities. The minimum information includes demographics, details of the screening failure, eligibility criteria, and any serious adverse events (SAEs).

[0241] Individuals who do not meet the criteria for inclusion in this study (screening failures) may be re-screened once in their entirety. Re-screened participants will re-sign the informed consent and will be assigned the same participant number as in the initial screening.

[0242] If the following investigational values: blood pressure, eGFR, ACR, ALT, spot urine for AST, and bilirubin are outside the normal range for the participant during screening based on medical history, they may be retested twice without the need for rescreening.

[0243] Study participants not already receiving an SGLT2i at the first screening visit (Visit 1) will receive a 28-day run-in intervention with a once-daily SGLT2i. All participants, including those already receiving a stable dose of an SGLT2i at the first screening visit (Visit 1), will take their last prescribed dose of SGLT2i one day before randomization (Day -1) and switch to the study intervention according to their randomized treatment group assignment at Visit 2 (Day 1). Dosage of the zibotentan / dapagliflozin fixed-dose combination or dapagliflozin monotherapy will be determined according to eGFR status at the first screening visit (Visit 1), as specified below and in Figure 3. ·eGFR<45mL / min / 1.73m 2 Randomized 1:1 to zibotentan / dapagliflozin 0.25mg / 10mg FDC QD, dapagliflozin 10mg QD, or dapagliflozin 10mg QD (active control) ·eGFR≧45mL / min / 1.73m 2 Randomized 1:1 to zibotentan / dapagliflozin 0.75mg / 10mg FDC QD or dapagliflozin 10mg QD (active control)

[0244] Capping was assessed for participants with or without type 2 diabetes (T2D) and by eGFR status at screening (eGFR < or ≥ 45 mL / min / 1.73 m 2 ) to ensure proper presentation.

[0245] To ensure blinding to treatment, the zibotentan / dapagliflozin 0.25 mg / 10 mg FDC, zibotentan / dapagliflozin 0.75 mg / 10 mg FDC, and dapagliflozin 10 mg tablets are identical in appearance (matching and indistinguishable from the zibotentan / dapagliflozin FDC). Participants, site personnel, and sponsors will all be blinded to the study intervention. Information about the study intervention is provided in Table 6 below.

[0246] [Table 7] a Zibotentan / dapagliflozin dose was based on eGFR status at screening (Visit 1): eGFR < 45 mL / min / 1.73 m 2 , 0.25 mg / 10 mg FDC, eGFR ≥ 45 mL / min / 1.73 m 2 For , 0.75mg / 10mg FDC. b Dose adjustments are made as described herein. FDC = fixed dose combination, IMP = investigational drug, NIMP = non-investigational drug, QD = once daily.

[0247] Participants will receive the blinded study intervention from Day 1 until the end-of-treatment (EoT) visit. The common treatment end date (CTED), defined as 2 years after the randomization date of the last participant in the study, will be used to determine when the EoT visit should occur. The EoT visit will preferably occur within 14 days and no later than 28 days after CTED for all participants. At the EoT visit, participants will stop the blinded study intervention and begin open-label dapagliflozin 10 mg monotherapy until the safety follow-up visit (last study visit).

[0248] In the event of early discontinuation of the blinded study intervention, participants will continue in the study and receive open-label dapagliflozin 10 mg monotherapy unless, in the investigator's opinion, the participant cannot tolerate dapagliflozin. The EoT visit is the last study visit for these participants.

[0249] All participants will be followed in the study for up to 24 months after the last participant is randomized. The recruitment period is 18 months, therefore the study duration is approximately 43 months, with a mean follow-up period of approximately 33 months.

[0250] Participants will have four visits during the first three months of treatment (Days 1, 14, 30, and 90), after which visits will occur every three months for the first year (until Day 360) and every four months thereafter. One additional visit will be required one week after Visit 11 (Day 720). Once CTED is determined, an EoT visit may be scheduled to occur within 28 days after CTED. A safety follow-up visit will occur one month after the EoT visit.

[0251] The timeline of study activities is outlined in Tables 7A, 7B, and 7C: screening and randomization of SGLT2i-naive participants (Table 7A), screening and randomization of SGLT2i-treated participants (Table 7B), and on-treatment, intervention discontinuation, and safety follow-up (Table 7C).

[0252] [Table 8] NOTE: The PRO questionnaire should be completed before any other study procedures or discussions (after informed consent), including medication, to avoid biasing participants' responses to the questions. aIndividuals who do not meet the criteria for inclusion in this study (screening failures) may be fully re-screened once. Re-screened participants will be required to re-sign the informed consent and will be assigned the same participant number as at the initial screening. If the following investigational values: blood pressure, spot urine for eGFR, UACR, and UPCR, ALT, AST, and bilirubin are outside the participant's normal range during screening based on medical history, they may be re-tested up to two times without the need for re-screening. b The 10-day window at Visit 1 (days -34 [± 5]) is to allow for turnaround time for central laboratory results before the 28-day run-in. Participants not already on a stable dose of SGLT2i will enter a 28-day run-in with SGLT2i from day -28 to day -1. During the run-in period, SGLT2i may be provided as an adjunct. c A negative pregnancy test (serum) is required for all women at enrollment / prior to the first dose of study intervention. d Monthly pregnancy tests (urine) and contraceptive adherence checks are required for all WOCBPs from randomization until one month after the last dose. If positive, treatment should be discontinued and procedures should be followed if contraceptive failure or pregnancy is suspected. Companies may consider the option of home pregnancy testing by a healthcare professional for months when no visits are scheduled. e Women of non-childbearing potential are identified at screening by meeting one of the following criteria: a) postmenopause, defined as amenorrhea for at least 12 months after cessation of all exogenous hormone therapy, and FSH levels in the postmenopausal range. A single FSH measurement is insufficient to define postmenopausal criteria in the absence of 12 months of amenorrhea. Women should be considered of childbearing potential during perimenopause or periods of infrequent fluctuations in FSH levels, or (b) documentation of irreversible sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. f Includes signs of fluid retention. g Tests included: B-hemoglobin, B-white blood cell differential (absolute count), B-platelet count, B-HbA1c, B-hematocrit, B-white blood cell count, B-BNP, B-red blood cell count, S-bicarbonate, S-chloride, S-GGT, S-glucose, S-albumin, S-ALP, S-ALT, S-AST, total S-bilirubin, S-BUN, total S-calcium, S-creatine kinase, S-creatinine (including eGFR assessment), S-magnesium, S-phosphorus, S-potassium, and S-sodium. h Plasma, serum, and urine samples for potential future biomarker studies are optional. i Participation in Genomics Initiative studies is optional and subject to separate consent by the participant. AE = adverse event, AESI = adverse event of special interest, ALP = alkaline phosphatase, ALT = alanine transaminase AST = aspartate aminotransferase, B = blood, BNP = B-type natriuretic peptide, BP = blood pressure, CV = cardiovascular, DAE = adverse event leading to discontinuation of study drug, eGFR = estimated glomerular filtration rate, ECG = electrocardiogram, EQ-5D-5L = European Quality of Life Five Dimension Five Level questionnaire, EQ-VAS = Visual Analogue Scale (VAS) = European Quality of Life Life Visual Analog Scale, FSH = follicle-stimulating hormone, GGT = gamma-glutamyltransferase, HbA1c = glycosylated hemoglobin, HIV = human immunodeficiency virus, IRT = interactive response technique, NYHA = New York Heart Association, PRO = patient-reported outcome, PTDV = early treatment discontinuation visit, Q4M = every 4 months, RTSM = randomization and trial supply management, S = serum, SAE = serious adverse event, S-BUN = S-blood urea nitrogen, SGLT2i = sodium-glucose cotransporter 2 inhibitor, SPFQ = trial participant feedback questionnaire, UACR = urine albumin-to-creatinine ratio, UPCR = urine protein-to-creatinine ratio, WOCBP = women of childbearing potential.

[0253] [Table 9] NOTE: The PRO questionnaire should be completed before any other study procedures or discussions (after informed consent), including medication, to avoid biasing participants' responses to the questions. a Individuals who do not meet the criteria for inclusion in this study (screening failures) may be fully re-screened once. Re-screened participants will be required to re-sign the informed consent and will be assigned the same participant number as at the initial screening. If the following investigational values: blood pressure, spot urine for eGFR, UACR, and UPCR, ALT, AST, and bilirubin are outside the participant's normal range during screening based on medical history, they may be re-tested up to two times without the need for re-screening. b Participants were already receiving a stable dose of SGLT2i. c A negative pregnancy test (serum) is required for all women at enrollment / prior to the first dose of study intervention. d Monthly pregnancy tests (urine) and contraceptive adherence checks are required for all WOCBPs from randomization until one month after the last dose. If positive, treatment should be discontinued and procedures should be followed if contraceptive failure or pregnancy is suspected. Companies may consider the option of home pregnancy testing by a healthcare professional for months when no visits are scheduled. e Women of non-childbearing potential are identified at screening by meeting one of the following criteria: a) postmenopause, defined as amenorrhea for at least 12 months after cessation of all exogenous hormone therapy, and FSH levels in the postmenopausal range. A single FSH measurement is insufficient to define postmenopausal criteria in the absence of 12 months of amenorrhea. Women should be considered of childbearing potential during perimenopause or periods of infrequent fluctuations in FSH levels, or (b) documentation of irreversible sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. f Includes signs of fluid retention. g Tests included: B-hemoglobin, B-white blood cell differential (absolute count), B-platelet count, B-HbA1c, B-hematocrit, B-white blood cell count, B-BNP, B-red blood cell count, S-bicarbonate, S-chloride, S-GGT, S-glucose, S-albumin, S-ALP, S-ALT, S-AST, total S-bilirubin, S-BUN, total S-calcium, S-creatine kinase, S-creatinine (including eGFR assessment), S-magnesium, S-phosphorus, S-potassium, and S-sodium. h Plasma, serum, and urine samples for potential future biomarker studies are optional. i Participation in Genomics Initiative studies is optional and subject to separate consent by the participant. AE = adverse event, AESI = adverse event of special interest, ALP = alkaline phosphatase, ALT = alanine transaminase AST = aspartate aminotransferase, B = blood, BNP = B-type natriuretic peptide, BP = blood pressure, CV = cardiovascular, DAE = adverse event leading to discontinuation of study drug, eGFR = estimated glomerular filtration rate, ECG = electrocardiogram, EQ-5D-5L = European Quality of Life Five Dimension Five Level questionnaire, EQ-VAS = Visual Analogue Scale (VAS) = European Quality of Life Life Visual Analog Scale, FSH = follicle-stimulating hormone, GGT = gamma-glutamyltransferase, HbA1c = glycosylated hemoglobin, HIV = human immunodeficiency virus, IRT = interactive response technique, NYHA = New York Heart Association, PRO = patient-reported outcome, PTDV = early treatment discontinuation visit, Q4M = every 4 months, RTSM = randomization and trial supply management, S = serum, SAE = serious adverse event, S-BUN = S-blood urea nitrogen, SGLT2i = sodium-glucose cotransporter 2 inhibitor, SPFQ = trial participant feedback questionnaire, UACR = urine albumin-to-creatinine ratio, UPCR = urine protein-to-creatinine ratio, WOCBP = women of childbearing potential.

[0254] [Table 10] NOTE: The PRO questionnaire should be completed before any other study procedures or discussions (after informed consent), including medication, to avoid biasing participants' responses to the questions. a CTED is defined as 2 years after the date of randomization of the last participant in the study and is used to determine when the EoT visit should be scheduled. The EoT visit should occur preferably within 14 days and no later than 28 days after CTED for all participants, including those who discontinue the blinded study intervention early. At the EoT visit, participants still receiving blinded treatment will discontinue the blinded study intervention and begin open-label monotherapy with dapagliflozin 10 mg QD until the safety follow-up visit. For participants who discontinue the study intervention early but remain in the study due to the SoA, the EoT visit will be the final study visit. b Visit 4: Phone call to assess fluid retention and related conditions. c Monthly pregnancy tests (urine) and contraceptive adherence checks are required for all WOCBPs from randomization until one month after the last dose. If positive, treatment should be discontinued and procedures should be followed if contraceptive failure or pregnancy is suspected. Companies may consider the option of home pregnancy testing by a healthcare professional for months when no visits are scheduled. d Women of non-childbearing potential are identified at screening by meeting one of the following criteria: a) postmenopausal, defined as at least 12 months of amenorrhea after cessation of all exogenous hormone therapy and FSH levels in the postmenopausal range (a single FSH measurement is insufficient to define postmenopausal criteria in the absence of 12 months of amenorrhea after menopause). Women should be considered of childbearing potential if they are in perimenopause or a period of infrequent fluctuations in FSH levels, or (b) documentation of irreversible sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. eIncludes signs of fluid retention and heart failure. f Tests included: B-hemoglobin, B-white blood cell differential (absolute count), B-platelet count, B-HbA1c, B-hematocrit, B-white blood cell count, B-BNP, B-red blood cell count, S-bicarbonate, S-chloride, S-GGT, S-glucose, S-albumin, S-ALP, S-ALT, S-AST, total S-bilirubin, S-BUN, total S-calcium, S-creatine kinase, S-creatinine (including eGFR assessment), S-magnesium, S-phosphorus, S-potassium, and S-sodium. g The mean eGFR value for Visit 11 is calculated from the eGFR values ​​for Visit 11 and Visit 11.1. h PK samples will be collected pre-dose at Visits 3, 6, and 9. i Except for Visits 3, 6, and 9, the study intervention will be administered at home. j Plasma, serum, and urine samples for potential future biomarker studies are optional. AE = adverse event, AESI = adverse event of special interest, ALP = alkaline phosphatase, ALT = alanine transaminase AST = aspartate aminotransferase, B = blood, BNP = B-type natriuretic peptide, BP = blood pressure, CV = cardiovascular, DAE = adverse event leading to discontinuation of study drug, eGFR = estimated glomerular filtration rate, EoT = end of treatment, ECG = electrocardiogram, EQ-5D-5L = European Quality of Life Five Dimension Five Level questionnaire, EQ-VAS = European Quality of Life Visual Analog Scale, FSH = follicle-stimulating hormone, GGT = gamma-glutamyltransferase, HbA1c = glycosylated hemoglobin, HIV = human immunodeficiency virus, NYHA = New York Heart Association, PK = pharmacokinetics, PRO = patient-reported outcome, PTDV = early treatment discontinuation visit, Q4M = every 4 months, QD = once daily, S = serum, SAE = serious adverse event, S-BUN = S-blood urea nitrogen, SGLT2i = sodium-glucose cotransporter 2 inhibitor, SPFQ = Study Participant Feedback Questionnaire, UACR = urine albumin-to-creatinine ratio, UPCR = urine protein-to-creatinine ratio, WOCBP = women of childbearing potential.

[0255] Testing Compliance Participants will receive treatment in the clinic on the indicated visit dates and at home in all other cases. If participants are dosed at the site, they will receive the study intervention directly from the investigator or designee under medical supervision. The date, and if applicable, time, of doses administered at the clinic will be recorded on the source document and in the electronic case reporting form (eCRF). The dose of study intervention and the identity of the study participant will be verified at the time of dosing by a member of study site staff other than the person administering the study intervention. If participants self-administer the study intervention at home, compliance with the study intervention will be assessed at each visit.

[0256] Compliance is assessed by direct questioning and by counting returned tablets during site visits and recording them on source documentation and the eCRF. Deviations from the prescribed medication regimen are recorded on the eCRF.

[0257] Records of the amounts of zibotentan / dapagliflozin 0.25mg / 10mg and zibotentan / dapagliflozin 0.75mg / 10mg FDC and dapagliflozin 10mg tablets dispensed and administered to each participant will be maintained and reconciled with study intervention and compliance records. Intervention start and end dates, including dates of intervention delays and / or dose reductions, will also be recorded on the eCRF.

[0258] Dose modification Participants randomized to either the high-dose FDC (zibotentan / dapagliflozin 0.75 mg / 10 mg) or the corresponding dapagliflozin monotherapy may be down-titrated to the low-dose FDC (zibotentan / dapagliflozin 0.25 mg / 10 mg) or may have a sham down-titration if receiving dapagliflozin monotherapy (double-blindness maintained) after consultation with the medical monitor, including for the following reasons: Signs and / or symptoms of fluid retention are assessed as related to the investigational medicinal product (IMP) that do not resolve with intervention. Symptomatic hypotension did not resolve with adjustment of concomitant antihypertensive medications.

[0259] Additionally, patients randomized to either high-dose FDC (zibotentan / dapagliflozin 0.75 mg / 10 mg) or corresponding pagliflozin monotherapy had a blood glucose level of <30 mL / min / 1.73 m as confirmed by a central laboratory at either a scheduled or unscheduled study visit. 2 Participants with eGFR decline to 0.25 mg / 10 mg, regardless of symptoms, will be down-titrated to a low-dose FDC (zibotentan / dapagliflozin 0.25 mg / 10 mg) or, in the case of dapagliflozin monotherapy, will undergo sham down-titration (double-blindness will be maintained).

[0260] Because these conditions are known to occur in patients with CKD and hyperproteinuria, clinical judgment should be used to determine whether they are related to medical history or an adverse event (AE).

[0261] There will be no dose modifications for participants on low-dose FDC (zibotentan / dapagliflozin 0.25 mg / 10 mg) or corresponding dapagliflozin monotherapy. However, the IMP dose may be retained if clinically indicated (applicable to both high and low dose levels). In the event of a missed or delayed dose for any reason, subsequent doses should be administered according to the original schedule (i.e., at the time planned for the first dose of IMP).

[0262] Overdose Dapagliflozin was well tolerated in single-dose studies in healthy volunteers at doses up to 500 mg / day and in 14-day multiple-dose studies in healthy volunteers and patients with type 2 diabetes at doses up to 100 mg / day. If overdose is suspected, vital signs and treatment should be monitored appropriately.

[0263] Currently, there is no information regarding zibotentan overdose in humans. For the purposes of this study, overdose is defined as the use of the study intervention at a dose greater than that specified in the protocol.

[0264] In the event of an overdose, the investigator / treating physician will: Evaluate participants and, if possible, in consultation with the study clinical lead, determine whether the study intervention should be discontinued or the dose reduced. Participants will be closely monitored for any AEs / SAEs and laboratory abnormalities.

[0265] Concomitant medications Any medications or vaccines (including over-the-counter or prescription drugs, recreational drugs, vitamins, and / or herbal supplements) that participants are taking at the time of enrollment or will receive during the study (excluding screen failures) will be recorded along with the following: ·Reason for use. Dates of administration, including start and end dates. · Medication information, including dose, frequency, and route.

[0266] Because ET-1 has a potential role in maintaining blood pressure, hypotension may be encountered after ET blockade. Although only a slight reduction in blood pressure was observed in patients, more significant changes may occur in hypertensive patients, especially those taking antihypertensive therapy such as ACE inhibitors, calcium antagonists, or alpha blockers. If symptomatic hypotension occurs, subjects remain supine until symptoms resolve. If persistent hypotension is observed, adjustment of concomitant medications for blood pressure control will be considered. Intravenous fluid support will be considered for cases deemed severe by the investigator.

[0267] Participants using medications that can cause hypoglycemia in T2DM patients, including insulin or sulfonylurea (SU), may require a 10%-20% (total daily dose) reduction in insulin and a 25%-50% reduction in SU. In addition, more frequent blood glucose monitoring will be considered in participants receiving insulin and / or SU and with a baseline HbA1c of ≤7% at randomization.

[0268] The medications and supplements listed below are prohibited from the time of consent and for the duration of the study. Participants taking any of these medications at the time of randomization will not be included in the study. Strong or moderate CYP3A4 inducers Cyclosporine or tacrolimus. Receiving cytotoxic, immunosuppressive, or other immunotherapy for primary or subsequent renal disease within 6 months prior to screening other than stable maintenance treatment (see Exclusion Criteria). Tolvaptan, any other ERA, or budesonide (when used to treat IBD or IgAN).

[0269] Additionally, because all participants will receive the SGLT2i dapagliflozin as part of the IMP from randomization, the last dosing date of any SGLT2i will be the day before the randomization visit.

[0270] If a participant's medical condition requires rescue therapy, the participant will be treated and withdrawn from study intervention administration at the investigator's discretion. Rescue therapy will be recorded on the eCRF.

[0271] Diabetic participants may require adjustment of other glucose-lowering treatments at the start of the blinded study intervention to avoid hypoglycemia (due to the potential for dapagliflozin treatment).

[0272] Initiation and / or titration of diuretic therapy will be used for participants assessed as having new or worsening signs / symptoms of fluid overload.

[0273] Exam Cancellation It may be necessary for a participant to permanently discontinue the study intervention (definitive discontinuation). An individual participant may discontinue the study intervention in the following circumstances: Participant's decision. Participants are free to discontinue treatment at any time without prejudice to further treatment. An AE that, in the opinion of the investigator or sponsor, justifies discontinuation of further dosing. Severe non-compliance with clinical study protocols (CSPs). ·Continued treatment may expose the participant to undue risk, as determined by the investigator and / or sponsor.

[0274] Individual participants will discontinue the study intervention in the following circumstances: If a participant becomes pregnant during the course of the study, the study intervention should be discontinued immediately and sponsor personnel notified. Diabetic ketoacidosis (DKA): DKA, including euglycemic DKA, has been reported with the use of dapagliflozin. If DKA is suspected, temporary interruption of study treatment will be considered. Participants will be promptly evaluated. If DKA is confirmed, study intervention will be permanently discontinued. If DKA is not confirmed, resumption of study intervention will be considered. Symptomatic hypotension (defined as systolic blood pressure <90mmHg or diastolic blood pressure <60mmHg) without an identified reversible cause and not resolved by adjustment of concomitant medications. Hospitalization for HF. End-stage renal disease. · Increase in systemic immunosuppressive dose beyond that tolerated at the time of enrollment.

[0275] Please note that discontinuation from the study intervention is not the same as withdrawal from the study. If the study intervention is permanently discontinued, participants will complete an Early Treatment Discontinuation Visit, continue with study visits, and complete further assessments according to the schedule of activities.

[0276] Predisposing factors for ketoacidosis include pancreatic disorders (e.g., type 1 diabetes, pancreatitis, or history of pancreatic surgery), reduced insulin dose, reduced caloric intake or increased insulin requirements due to infection, illness, or surgery, and low beta-cell functional reserve due to alcohol abuse. Dapagliflozin should be used with caution in these participants.

[0277] Participants treated with dapagliflozin who exhibit signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, fatigue, and shortness of breath, will be evaluated for ketoacidosis, even if their blood glucose level is less than 14 mmol / L (250 mg / dL). If ketoacidosis is suspected, discontinuation or temporary interruption of study treatment will be considered, and the participant should be promptly evaluated.

[0278] Exposure to ERAs, including zibotentan, during gestation is associated with major embryo-fetal harm. Endothelin receptor antagonists have been demonstrated to induce teratogenic effects in animals when administered during organogenesis in early pregnancy. When administered to pregnant rabbits during the period of major embryonic organogenesis, zibotentan caused teratogenic effects at dose levels of 1 mg / kg / day and above, consistent with an ERA. Due to established teratogenic effects, pregnant women or WOCBPs not practicing reliable methods of contraception should not receive zibotentan.

[0279] Dapagliflozin is not used during the second and third trimesters of pregnancy due to the increased incidence and / or severity of renal pelvic and tubular dilatation in offspring. If pregnancy is detected, dapagliflozin is discontinued. However, because zibotentan is teratogenic in early pregnancy, the more restrictive guidance for zibotentan continues for the combination drug.

[0280] If pregnancy occurs while a WOCBP is taking zibotentan at any dose, even for a short period of time, there is a very high risk of embryo-fetal harm, potentially affecting the fetus exposed during pregnancy.

[0281] Pregnancy testing is required monthly during treatment and one month after discontinuation of treatment with the study intervention. All WOCBP participants are required to use adequate contraception (see inclusion criteria) before initiating treatment, during treatment, and for one month after discontinuation of treatment with the study intervention.

[0282] The investigator will educate and counsel the WOCBP participants about the risks of embryo-fetal toxicity and unintended pregnancy. The investigator will assess the WOCBP participants' adherence to required contraceptive methods during the study monthly and according to the activity schedule.

[0283] In the event of sexual intercourse without the correct use of adequate contraception, the investigator must be notified immediately and the study intervention will be interrupted. Participants will be informed of the availability of emergency contraception (pill or intrauterine device) if the suspected failure occurs within the last 5 days. Emergency methods of contraception will be approved by the relevant authorities in the participant's region. Study treatment will be resumed at least 4 weeks after the suspected contraceptive failure, provided a negative reliable serum pregnancy test (S-hCG) is obtained, adequate pregnancy prevention is correctly used by the participant, and its resumption is deemed appropriate by the investigator.

[0284] If pregnancy is suspected based on signs or symptoms of early pregnancy, such as cessation of menstruation, nausea, fatigue, feeling unwell, or breast tenderness, participants will notify the investigator and an unscheduled pregnancy test will be performed. Participants will be promptly evaluated, a negative test will be confirmed with a reliable serum test (S-hCG), and study intervention will be suspended until pregnancy can be reliably excluded.

[0285] If the urine test is positive, discontinue the study intervention and immediately confirm pregnancy using a reliable serum test (S-hCG).

[0286] If pregnancy is confirmed, the study intervention will be discontinued and the investigator will immediately notify sponsor personnel following emergency unblinding procedures. Access to diagnostic testing will be provided to determine gestational age and reveal any detectable fetal malformations. Participants will be provided with counseling that takes into account the risks associated with the participant's underlying condition, the teratogenicity of the treatment received, the potential period of inadvertent embryo-fetal exposure, and the risk of complications. Participants will be assured of medical follow-up. Participants will be offered the option to terminate their participation or remain in the study for safety monitoring. Pregnancies will be tracked and reported.

[0287] Investigator-initiated withdrawal of a participant from the study may occur as described below. Participants may discontinue the study at any time at the investigator's discretion for safety, behavioral, compliance, or administrative reasons. · If the participant has not discontinued the study intervention when the study is stopped.

[0288] Voluntary withdrawal from the study by a participant may occur as described below: Participants may withdraw from the study at any time, for any reason (or without providing any reason), at their own request. Participants who wish to withdraw from the study will be informed by the investigator of modified follow-up options (e.g., telephone contact, contact with relatives or treating physician, or information from medical records). If a participant withdraws consent for future disclosure of information, the sponsor may continue to retain and use any data collected prior to such withdrawal of consent. If a participant withdraws from the study, he / she will be asked whether he / she still consents to their existing samples being used in accordance with their original consent. If he / she requests to withdraw consent for the use of samples, the destruction of any samples collected but not tested will be carried out in accordance with the informed consent and local regulations. The investigator will document the decision regarding the use of existing samples in the site study record and notify the respective site monitor, who will then inform the global study team.

[0289] Participants are considered lost to follow-up if they do not return for repeated scheduled visits and cannot be contacted by the study site.

[0290] If a participant does not return to the study site for a required study visit, the following actions will be taken: The site will contact the participant and attempt to reschedule any missed visits as soon as possible. Participants will be counseled on the importance of maintaining their assigned visit schedule. At this point, the participant will be asked if they wish to continue in the study or if they intend to continue in the study. Before a participant is considered lost to follow-up, the investigator or designee will make every effort to re-establish contact with the participant (at least three phone calls, texts, emails, and, if necessary, a certificate to the participant's last known mailing address or local equivalent, if possible). These contact attempts will be documented in the participant's medical record. Site personnel, or an independent third party, will attempt to collect participant vital status within legal and ethical boundaries for all randomized participants, including those who did not receive the study intervention. Public sources will be searched for vital status information. If the vital status is determined to be deceased, this will be documented and the participant will not be considered lost to follow-up. Sponsor personnel will not be involved in any attempts to collect vital status information.

[0291] Objectives and Endpoints The study objectives and endpoints are outlined in Table 8.

[0292] [Table 11] AE = adverse event, AESI = adverse event of special interest, CV = cardiovascular, DAE = AE leading to discontinuation of IMP, ECG = electrocardiogram, eGFR = estimated glomerular filtration rate, ECG = electrocardiogram, EQ-5D-5L = European Quality of Life Five Dimension Five Level Questionnaire, EQ-VAS = European Quality of Life Visual Analogue Scale, ESKD = ​​end-stage renal disease, IMP = investigational drug, MI = myocardial infarction, SAE = serious adverse event, UACR = urine albumin-to-creatinine ratio, UPCR = urine protein-to-creatinine ratio.

[0293] Potential endpoint events will be identified when questioning participants about their overall health, through laboratory data (see Schedule of Activities (Tables 7A-7C) for laboratory assessments and timing), or through information received through standard medical practice. Investigators are encouraged to have a low threshold for reporting any potential / possible events that could represent an endpoint.

[0294] The following potential endpoint events will be recorded on the eCRF and submitted for central review: ·death Heart failure (adverse event of special interest (AESI))

[0295] For each potential endpoint event, the investigator or representative records endpoint-specific information in the eCRF. If the event is subject to adjudication, associated source documentation is collected. The source documentation and associated eCRF data are submitted for central adjudication.

[0296] Detailed instructions regarding endpoint reporting will be provided to the study site. The clinical event adjudication (CEA) committee will have no administrative authority and will be blinded to the randomization group. Further details regarding the evaluation of potential endpoint events will be described in the CEA charter. Potential endpoint events will also be reported as AEs / SAEs.

[0297] Primary variable: eGFR

[0298] Race will be excluded from the calculation of eGFR, in accordance with current recommendations (Delgado et al., 2022, Inker et al., 2021). In this study, the lower limit of eGFR (eGFR ≥ 20 ml / min) will be set as the limit at which participants can progress but still have time for their eGFR to decline before an ESKD event occurs. The upper limit of CKD (eGFR < 90 ml / min) will be set in terms of benefit / risk. Participants' eGFR will be calculated according to the 2021 CKD-EPI equation: Calculated based on sCr concentration alone (Inker et al. 2021): eGFR1 = 142 × min(S cr / κ,1) -0.241(女性の場合) / -0.302(男性の場合) ×max(S cr / κ,1) -1.200 ×0.994 年齢 ×1.012 [for women] During the ceremony, SCr = serum creatinine (mg / dL) κ = 0.7 (female) and 0.9 (male). Min = minimum value of Scr / κ or 1 Max = maximum value of Scr / κ or 1

[0299] Blood samples for determination of serum creatinine and calculation of estimated eGFR will be collected at the time points described in the schedule of activities (Tables 7A-7C) and analyzed centrally.

[0300] Subvariable: UACR

[0301] UACR is an important marker for assessing renal function. UACR is the ratio between two measured substances (urinary albumin and creatinine), which estimates 24-hour urinary albumin excretion. UACR is calculated as follows: UACR (mg / g) = urinary albumin (mg / dL) / urinary creatinine (g / dL)

[0302] Urine samples for determination of albumin and creatinine levels and calculation of UACR will be collected and analyzed centrally at the times described in the Activity Schedule (Tables 7A-7C). Samples will also be used for determination of exploratory urinary parameters.

[0303] Secondary variable: UPCR

[0304] UPCR is an important marker for assessing renal function. It is the ratio between two measured substances (urinary protein and creatinine) and estimates 24-hour urinary protein excretion. UPCR is calculated as follows: UPCR (mg / g) = urinary protein measured by the assay (mg / dL) / urinary creatinine (g / dL)

[0305] Urine samples for determination of protein and creatinine levels and calculation of UPCR will be collected at the times described in the activity schedule (Tables 7A-7C) and analyzed centrally.

[0306] Secondary variables: renal composite endpoint

[0307] The secondary objective of this study is to determine whether zibotentan and dapagliflozin are superior to dapagliflozin alone in reducing the time to a 40% sustained reduction in FDC or the first occurrence of any of the components of the renal composite endpoint of ESKD or renal death.

[0308] Endpoints associated with eGFR decline.

[0309] Laboratory values ​​associated with declining eGFR will trigger action by the facility in the following circumstances: Local laboratory values ​​obtained outside of the study procedure resulted in a decrease in eGFR of ≥ 40% compared to baseline or ≥ 10 mL / min / 1.73 m 2 To indicate that it is less than. As soon as possible, participants will come to the testing facility to have local laboratory values ​​confirmed by central laboratory testing. or A decrease in eGFR of ≥ 40% compared to baseline or ≥ 10 mL / min / 1.73 m 2 Median laboratory values ​​collected during the study visit showing that the mean age was less than 18 years.

[0310] The central laboratory determined that eGFR was <10 mL / min / 1.73 m 2 Notify the facility if there is a ≥ 40% decline in eGFR compared to baseline. Re-sampling will occur at an unscheduled visit at least 4 weeks after the initial sampling, preferably no later than 6 weeks. Central laboratory values ​​< 10 mL / min / 1.73 m 2 If there is a > 40% decrease in eGFR compared to baseline, it will be recorded as a potential endpoint in the eCRF.

[0311] The central laboratory will calculate eGFR using the CKD-EPI formula, which is based solely on sCr concentrations (Inker et al., 2021).

[0312] Dialysis and kidney transplants

[0313] If a participant starts dialysis and / or undergoes a kidney transplant, this will be recorded on the eCRF. ESKD is defined as: Sustained eGFR <10 mL / min / 1.73 m 2 , or Chronic dialysis treatment (dialysis ongoing for more than 28 days), or · Undergoing a kidney transplant

[0314] renal death

[0315] CEA committee members will adjudicate and classify all deaths based on the definitions outlined in the CEA charter. Renal death is defined as death due to ESKD in the absence of dialysis. The investigator will record the classification of renal death on the eCRF.

[0316] Exploratory variables: patient-reported outcomes (EuroQol five-dimensional five-level questionnaire)

[0317] Patient-reported outcomes (PROs) are an umbrella term that refers to all outcomes and symptoms directly reported by participants. PROs have become important endpoints for regulatory and reimbursement authorities when evaluating the effectiveness of treatments in clinical trials. The following PROs will be administered in the study: EQ-5D-5L (see Appendix A in Example 1). Participants will be asked to complete the EQ-5D-5L at clinic visits as specified in the Schedule of Activities (Tables 7A-7C).

[0318] The EQ-5D-5L is a self-report questionnaire used to derive standardized measures of health status, also referred to as utility scores. EQ-5D-5L utility scores are widely accepted by reimbursement authorities and are used to support health economic evaluations.

[0319] PROs may be administered electronically. Randomized participants complete PRO assessments at their site using a handheld electronic device (ePRO). Each site assigns responsibility for administering ePRO to a specific individual and, if possible, assigns backup personnel in the individual's absence. All assessments are completed as follows: Participants will not receive help from relatives, friends, or facility staff to answer or clarify the PRO questionnaire to avoid bias. If a participant uses visual aids (e.g., glasses or contact lenses) to read and does not have them on hand, the participant will be excused from completing the PRO questionnaire at that visit. · Before any other testing procedures are performed at a given visit. Before seeing the investigator. · PRO questionnaires will be completed privately by participants. Designated site personnel explain the value and relevance of the ePRO assessment to the participant and inform them that these questions are being asked directly from the participant to find out how they feel. Designated site personnel also emphasize that the information is confidential. Designated site personnel will demonstrate to participants how to use the ePRO device according to the instructions provided. Designated site staff will remind participants that there are no right or wrong answers, and participants will be given sufficient time to complete the PRO questionnaire. If a participant is unable to read the questionnaire (e.g., blind or illiterate), the participant may be exempt from completing the PRO questionnaire and still participate in the study.

[0320] safety Safety and tolerability will be assessed in terms of AEs, SAEs, DAEs, SAEs with fatal outcomes, AESIs (HF, fluid retention, and hepatotoxicity), clinical laboratories, vital signs, and ECGs.

[0321] Planned time points for all safety evaluations are provided in the Schedule of Activities (Tables 7A-7C).

[0322] Physical examination

[0323] A complete physical examination will include evaluation of the following: general appearance, respiratory, cardiovascular, abdominal, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities), nervous system, and volume status. A targeted physical examination will focus on volume status, including signs and symptoms of fluid retention and heart failure. Physical examinations and height assessments will be performed at the time points specified in the Schedule of Activities (Tables 7A-7C).

[0324] Vital signs

[0325] Vital signs will be taken at the times specified in the Schedule of Activities (Tables 7A-7C).

[0326] Pulse and blood pressure (BP)

[0327] Pulse and BP are measured three times per time point, and all measurements are recorded on the eCRF. Measurements are taken after participants have sat and rested for at least 5 minutes in a quiet setting free from distractions (e.g., television, cell phones), and before any blood sampling using a standardized calibration cuff adapted to the participant's arm size. Preferably, the same group is used at all visits.

[0328] body weight

[0329] Participants will be weighed wearing light clothing and no shoes. If the participant has a prosthesis, this will be worn consistently or not during all weigh-ins.

[0330] electro-cardiogram

[0331] Record a 12-lead ECG (standard ECG with a recording paper speed of 25-50 mm / s covering at least six consecutive beats) at the clinic visits outlined in the Schedule of Activities (Table 7A-Table 7C) after the participant has rested in a supine position for at least 5 minutes.

[0332] Clinical Safety Laboratory Testing

[0333] Blood and urine specimens for clinical chemistry, hematology, and urinalysis determinations will be collected at the visits indicated in the Schedule of Activities (Tables 7A-7C).

[0334] Additional safety samples will be collected at the investigator's discretion if clinically indicated. The date, time of collection, and results (values, units, and reference ranges) will be recorded on the appropriate eCRF.

[0335] Clinical chemistry, hematology, and urine chemistry will be performed in a central laboratory. The date of central laboratory sample collection will be recorded on the eCRF.

[0336] Other safety laboratory tests include assessment for pregnancy (serum at screening or serum or urine at other time points), serology for hepatitis B and C, and HIV antibody testing. At Visit 2 (randomization), prior to the first intake of study intervention, the urine pregnancy test is negative.

[0337] All samples will be collected by appropriately trained facility personnel and handled as directed. Updated reference ranges will be provided during testing, and laboratory results will be compared to laboratory standard normal ranges and reported back to the facility.

[0338] Samples sent to the central laboratory are collected, labeled, stored, and shipped as directed.

[0339] The investigator will evaluate the laboratory results for clinically relevant abnormalities. Test results will be signed, dated, and retained at the study site as the source data for the laboratory variables. Laboratory safety variables are outlined in Table 8.

[0340] [Table 12] Special Note: If a participant exhibits an AST or ALT ≥ 3 × ULN along with a TBL ≥ 2 × ULN, please see Appendix E for further instructions.

[0341] Adverse events (AEs)

[0342] The participant (or, where appropriate, their caregiver, representative, or legally authorized representative) will notify the investigator or designee of symptoms related to AEs and SAEs, which will then be evaluated by the investigator and, if deemed an AE or SAE, will be reported by the investigator.

[0343] The investigator and any designee are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE (see Table 9)

[0344] [Table 13]

[0345] Adverse Events of Special Interest (AESI)

[0346] Based on potential risks (HF and fluid retention) identified for zibotentan in previous oncology clinical trials, additional monitoring and data collection will be conducted during the study for the following safety events classified as AESIs: Hepatotoxicity, which has been highlighted as a risk associated with several other ERAs, has not been observed with zibotentan to date. New diagnosis of HF or worsening of a pre-existing HF condition: Any treatment-emergent symptoms suggestive of HF should be appropriately evaluated by the investigator to ensure timely and appropriate management of the participant's condition. Other signs of fluid retention or worsening of fluid retention (e.g., fluid retention, fluid overload, hypervolemia, any edema, ascites, exudate, etc.). Hepatotoxicity, including possible drug-related liver injury (e.g., liver failure, non-infectious hepatitis, DILI, other liver-related signs and symptoms, etc.).

[0347] Adverse events will be collected from randomization throughout the treatment period, including safety follow-up. Serious AEs will be recorded from the time of signing the informed consent form (ICF).

[0348] If the investigator becomes aware of an SAE with a suspected causal relationship to the investigational drug that occurs in a treated participant after the end of the clinical trial, the investigator will report the SAE to the sponsor without undue delay.

[0349] Any AE that is unresolved at the participant's last AE assessment in the study will be tracked by the investigator without further recording on the eCRF, as long as medically indicated. The sponsor reserves the right to request additional information about any participant with an ongoing AE / SAE at the end of the study, if deemed necessary.

[0350] The investigator will assess the causal relationship between the IMP and each AE, answering "yes" or "no" to the question, "Do you think there is a reasonable possibility that the event could have been caused by the IMP?"

[0351] For SAEs, causality will also be assessed for other medications and study procedures. Note that for SAEs that can be associated with any study procedure, causality will be implied as "yes."

[0352] Deterioration compared to baseline in protocol-specified laboratory values, vital signs, and ECG parameters will be reported as AEs only if they meet any of the following: Meet one of the SAE standards. · It is the reason for the cancellation of IMP. May include, but is not limited to, consideration of whether clinically relevant interventions or unscheduled visits were required as determined by the investigator, or whether other actions, such as dose adjustments or drug interruptions, were taken in conjunction with the IMP.

[0353] If a deterioration in laboratory values / vital signs is associated with clinical signs and symptoms, the sign or symptom will be reported as an AE and the associated laboratory results / vital signs will be considered additional information. Whenever possible, reporting investigators will use clinical rather than laboratory terms (e.g., anemia vs. low hemoglobin levels). In the absence of clinical signs or symptoms, clinically relevant deterioration in non-essential parameters will be reported as an AE.

[0354] Any new or worsening clinically relevant abnormal medical finding on physical examination compared to the baseline assessment will be reported as an AE.

[0355] All signs or symptoms spontaneously reported by participants, reported in response to the open question from study site staff: "Have you had any health problems since your last visit / last time you were asked?", or revealed by observation will be collected and recorded on the eCRF.

[0356] When collecting AEs, recording a diagnosis is preferred (if possible) over recording a list of signs and symptoms. However, if the diagnosis is known and there are other signs or symptoms that are not typically part of the diagnosis, the diagnosis and each sign or symptom are recorded separately.

[0357] Further evaluation may be required if participants exhibit elevated liver biochemistries, and the occurrence of alanine transaminase (ALT) ≥ 3 × upper limit of normal (ULN) along with aspartate aminotransferase / transaminase (AST) or total bilirubin (TBL) ≥ 2 × ULN may need to be reported as an SAE. All SAEs will be reported regardless of whether they are considered causally related to the IMP. All SAEs will be recorded on the eCRF. If any SAE occurs during the study, the investigator or other site personnel will notify the appropriate sponsor personnel immediately within 1 day, i.e., when he or she becomes aware of it, but no later than 24 hours.

[0358] Designated sponsor personnel, in collaboration with the investigator, will ensure that all required information is provided to the Sponsor Patient Safety Data Entry Site within one calendar day of initial receipt for fatal and life-threatening events and within five calendar days of initial receipt for all other SAEs.

[0359] Active follow-up will occur immediately for fatal or life-threatening AEs for which important or relevant information is missing. The investigator or other site personnel will notify sponsor personnel of any follow-up information regarding a previously reported SAE within one calendar day, i.e., immediately upon his or her becoming aware of it but no later than 24 hours.

[0360] When the investigator or other site personnel indicate an AE as serious in the Electronic Data Capture (EDC) system, an automated email alert will be sent to designated sponsor personnel.

[0361] If an EDC system is not available, the investigator or other study site staff will report the SAE to the appropriate sponsor representative via a secure method.

[0362] If the EDC is temporarily inaccessible, sponsor study personnel should ensure that investigators / site staff enter the SAE into the sponsor EDC when access resumes.

[0363] Sample collection Blood samples will be collected pre-dose for measurement of zibotentan and dapagliflozin plasma concentrations as specified in the schedule of activities (Tables 7A-7C).

[0364] Samples may be collected at additional time points during the study if needed and agreed upon between the investigator and sponsor, e.g., for emergency safety reasons, and these samples may not be part of the pharmacokinetic (PK) analysis set and reporting. Sampling timing may be modified during the study based on newly available data (e.g., to obtain data closer to the peak or to obtain trough matrix concentrations) to ensure appropriate monitoring.

[0365] Plasma samples will be used to analyze the PK of zibotentan and dapagliflozin. Samples collected for analysis of zibotentan and dapagliflozin plasma concentrations may also be used to evaluate aspects of safety or efficacy relevant to concerns that arise during or after the study.

[0366] PK samples will be destroyed upon completion of the Bioanalytical Report or six months after issuance of the Draft Bioanalytical Report (whichever occurs first), unless consent is given to future analysis.

[0367] Additional analyses can be performed on de-identified, pooled, or individual PK samples to further evaluate and validate the analytical method. Any results from such analyses can be reported separately from the clinical study report (CSR).

[0368] Samples for determination of zibotentan and dapagliflozin concentrations in plasma will be assayed by the sponsor or by a bioanalytical testing laboratory operated on behalf of the sponsor using appropriately validated bioanalytical methods. Zibotentan and dapagliflozin plasma concentrations will be measured separately.

[0369] Drug concentration information that could unblind the study will not be reported to the investigational site or blinded personnel until the study is unblinded. A contaminating sample reproducibility analysis, if any, will be performed in parallel with the bioanalysis of the study samples. Results from the evaluation, if performed, will be reported in a separate bioanalytical report.

[0370] Test Procedure Visit 1 (screening, all participants) and Visit 1.1 (SGLT2i-naive induction participants only)

[0371] At enrollment, following the provision of signed informed consent, screening assessments and procedures will be performed as described in the schedule of activities for SGLT2i-naive participants (Table 7A) and for SGLT2i-treated participants (Table 7B). Further procedures will follow after review of the inclusion and exclusion criteria by the investigator, including laboratory evaluation and confirmation of a negative serum pregnancy test.

[0372] SGLT2i-naive participants who meet all inclusion / exclusion criteria, including a negative serum pregnancy test, will enter a 28-day run-in period of SGLT2i therapy. The specific SGLT2i during run-in will be selected by the investigator and provided as an adjunct, either prescribed by the investigator or locally sourced, at the dose indicated for CKD. The 28-day run-in period will begin so that the last dose of SGLT2i is administered the day before Visit 2 (i.e., Day -1). During the run-in period, participants will return to the clinic for Visit 1.1, 3 days prior to Visit 2, for laboratory assessments. These laboratory assessments are for baseline measurements and do not require further inclusion or exclusion from the study.

[0373] Participants who are SGLT2i-treated and meet all inclusion and exclusion criteria, including a negative serum pregnancy test, will proceed to Visit 2 without requiring an induction or Visit 1.1 assessment. The last dose of SGLT2i will be administered the day before Visit 2 (i.e., Day -1).

[0374] Visit 2 (randomization)

[0375] Participants will discontinue prior SGLT2i therapy the day before Visit 2 (i.e., Day -1). All assessments and procedures will be conducted according to the schedule of activities (Table 7A for SGLT2i-naive participants and Table 7B for SGLT2i-treated participants). The investigator will review the eGFR values ​​obtained at Visit 1 to determine medication assignment. The study intervention will be distributed to participants via interactive responsive technology (IRT) / randomization and trial supply management (RTSM). Participants will be instructed to receive the study intervention according to the protocol without interruption, with the first dose taken at the clinic after completion of the assessments and procedures at Visit 2.

[0376] Monthly urine pregnancy test and contraceptive adherence check (WOCBP only)

[0377] Female participants of childbearing potential will have monthly urine pregnancy tests and contraceptive adherence checks as described in the activity schedule from randomization until one month after the last dose. The results of the urine pregnancy test will be reviewed with the participant, along with a thorough review of adherence to contraceptive requirements. If contraceptive failure is suspected or pregnancy is suspected or confirmed, the procedure described herein will determine whether the participant will continue or withdraw from the study.

[0378] Early treatment discontinuation visit

[0379] If the study intervention is permanently discontinued, participants will complete a premature treatment discontinuation visit (PTDV) and continue study visits and assessments according to the schedule of activities (Table 7C). The PTDV visit will occur within 28 days after the last dose, after which subsequent visits will follow the schedule of activities based on the last visit before discontinuation of the study intervention. Participants will continue in the study and receive open-label dapagliflozin 10 mg monotherapy until the EoT visit unless, in the investigator's opinion, the participant is intolerant to dapagliflozin. Dapagliflozin 10 mg monotherapy will be adjunctively prescribed by the investigator or supplied locally.

[0380] End of treatment visit

[0381] The EoT visit will occur after CTED is reached. CTED is defined as 2 years from the date of randomization of the last participant in the study and will be used to determine when the EoT visit should be scheduled. For all participants, the EoT visit will preferably occur within 14 days and no later than 28 days after CTED is declared. At the EoT visit, all assessments and procedures will be performed as described in the activity schedule (Table 7C). Participants will discontinue the blinded study intervention until the safety follow-up visit (last study visit) and begin open-label dapagliflozin 10 mg monotherapy. Open-label dapagliflozin 10 mg monotherapy will be an adjunct medication prescribed by the investigator or supplied locally.

[0382] For participants who discontinue the study intervention early but remain in the study due to an activity schedule, the EoT visit will be the final study visit. After the final study visit, participants will return to usual treatment with standard of care at the investigator's discretion. This may include treatment with an SGLT2i (including dapagliflozin) if deemed clinically indicated by the investigator or the participant's treating physician.

[0383] Safety Follow-Up Visit

[0384] The safety follow-up visit will occur 30 days after the EoT visit. At the safety follow-up visit, all assessments and procedures will be performed as described in the activity schedule (Table 7C). This is the final study visit for the participant in the study (barring early discontinuation as described above). After the final study visit, participants will return to their usual treatment at the investigator's discretion. This may include treatment with an SGLT2i (including dapagliflozin) if deemed clinically indicated by the investigator or the participant's treating physician.

[0385] Statistical considerations All personnel involved in the analysis of the study will remain blinded until database lock and protocol violations are identified and documented. An independent Data Monitoring Committee (DMC) will monitor the data (unblinded) regularly throughout the conduct of the study. The DMC's mandate is detailed in the DMC charter.

[0386] The true difference in change from baseline eGFR between treatment groups was 2.0 mL / min / 1.73 m 2 , and assuming a standard deviation of 15.5 using a two-sided alpha level of 5%, 1500 participants would provide a statistical power of 90%.

[0387] Main analysis: The primary efficacy variable of change from baseline in eGFR at 24 months will be assessed through an estimand defined by the following attributes:

[0388] Population: Patients with CKD and hyperproteinuria, with or without T2DM, and who meet the eligibility criteria defined by the inclusion and exclusion criteria.

[0389] Treatment: zibotentan / dapagliflozin FDC QD or dapagliflozin (active comparator) QD.

[0390] Intercurrent events: Early study treatment discontinuation, IMP dose modification, and concomitant medication modification: all treatment strategy implemented by including available data. · RRT or renal death: A combined strategy implemented by defining eGFR=0 for the 24-month visit whenever RRT or renal death occurred earlier. · Non-renal death: implemented by a hypothesis strategy, handling framework for missing data.

[0391] Population-level summary: Differences between treatment groups in mean change from baseline to 24 months post-treatment.

[0392] The main estimator of the primary endpoint was obtained by mixed models for repeated measures (MMRM). The change in eGFR from baseline to the 24-month visit was the dependent variable, and all interim visits were included in the MMRM analysis. Baseline was defined as the mean of two eGFR measurements at or before randomization. The model included baseline eGFR as a continuous variable and stratification factors, treatment group, visit, and treatment-by-visit interaction as fixed-effect factors.

[0393] Measurements after the initiation of dialysis are not included in the analysis. Missing post-baseline eGFR estimates are implicitly handled in likelihood-based parameter estimation, assuming that values ​​in subjects with missing data are similar to values ​​in subjects with observed data with the same treatment assignment and covariate values ​​(i.e., missing at random).

[0394] The analysis focuses on the effect of treatment on irreversible disease progression. For this purpose, estimates of the change from baseline (the mean of the last two values ​​obtained before randomization) to the mean of the two values ​​obtained at 24 months and subsequent visits are utilized. Least-squares mean estimates are presented for each treatment group with 95% confidence intervals, for differences between treatment groups with 95% confidence intervals, as well as p-values.

[0395] Secondary analyses The secondary endpoints of change from baseline in UACR, UPCR, and systolic blood pressure will be analyzed using methodology similar to that described for the primary endpoint.

[0396] Secondary endpoints assessing the renal composite endpoint of 40% sustained decline or ESKD or renal death will be analyzed by time to event using a Cox proportional hazards model with a factor for treatment, stratified by randomization factors and adjusted for eGFR at baseline as a continuous variable.

[0397] Safety analysis Safety and tolerability will be assessed with respect to AEs, vital signs, clinical laboratory variables, and ECG. In addition, the following AESIs will be additionally assessed: fluid retention, hepatotoxicity.

[0398] The purpose of the analysis of safety data is to evaluate general safety objectives that would be assessed in a scenario where study treatment is not discontinued prematurely. Two analytical approaches are considered complementary to evaluate this hypothetical scenario for all safety endpoints: Unbiased under the assumption that on-treatment and censoring following early treatment discontinuation are uninformative. On-study, unbiased under the assumption that the risk of the event is independent of continued treatment. Note that this approach can also be described as handling early treatment discontinuation with a treatment policy approach.

[0399] Thus, the general safety goal is assessed through an estimand defined by the following attributes:

[0400] Population: Patients with CKD and hyperproteinuria, with or without T2DM, and who meet the eligibility criteria defined by the inclusion and exclusion criteria.

[0401] Treatment: zibotentan / dapagliflozin FDC QD or dapagliflozin (active comparator) QD.

[0402] Current Event (ICE): Premature study treatment discontinuation: All analyses are presented using two complementary approaches unless otherwise stated: The hypothesis that this ICE would not occur was implemented using the on-treatment analysis period and by excluding / censoring early study treatment discontinuation and day 28 data. ○ Treatment strategy by ignoring this ICE, implemented by including all available data using the on-study analysis period. Initiation or change of concomitant medications, including rescue medications: These ICEs are ignored, i.e., handled using a treatment policy approach. Death: This ICE is hypothetically treated as if it could never happen, and is implemented by censoring time to event data at the time of death and not entering data after death.

[0403] Population-level summaries and estimators for each analysis:

[0404] Probability of an event (e.g., AE, laboratory abnormality) occurring before a given time point. The difference between these between treatment groups, as well as the HR (over the entire time period of interest). For repeated measures (e.g., laboratory assessments performed at several time points), the distribution of measurements at each time point.

[0405] This estimate requires that, whenever possible, randomized participants included in the analysis set used for safety will be followed (for the planned treatment period and safety follow-up) regardless of study intervention compliance and adherence to the study protocol.

[0406] Analysis: Hazard ratios comparing treatment groups are estimated based on a Cox proportional hazards regression model with a factor for treatment group, using a fully defined analysis period (on-study and on-treatment, respectively). The cumulative distribution function (CDF) of the time to the event of interest in each treatment group is estimated using the Kaplan-Meier estimator. The probability of the event of interest occurring before a given time point is estimated using the Kaplan-Meier estimator at one or more time points determined based on the extent of participant follow-up (updated in the statistical analysis plan before clinical data lock (CDL) by treatment group for the defined analysis period (on-study and on-treatment, respectively)), and treatment group differences are estimated at one of the selected time points (the selected previous CDL).

[0407] Comparisons between treatment groups are presented with their associated 95% confidence intervals. Because all safety analyses are descriptive, p-values ​​are not presented; confidence intervals are provided as an illustration of the precision of the estimates.

[0408] The on-study analysis period begins on the date of randomization visit and ends on the date of the last clinical event assessment, unless the participant dies during follow-up, at which point the period ends. If the participant withdraws consent to continue in the study, the on-study analysis period ends on this date at the latest.

[0409] The on-treatment analysis period begins on the day of the randomization visit and ends on the date of the last dose of IMP or 28 days after the end of the on-study analysis period, whichever occurs first.

[0410] Example 3 The safety and efficacy of the combination of zibotentan and dapagliflozin was evaluated in patients with an eGFR of ≥ 20 mL / min / 1.73 m 2 The study was conducted in patients with chronic kidney disease and a UACR of ≥ 150 mg / g and ≤ 5000 mg / g. Two fixed-dose combinations of zibotentan and dapagliflozin were evaluated, with zibotentan administered at doses of 0.25 mg or 1.5 mg and dapagliflozin administered at a dose of 10 mg. The fixed-dose combination of zibotentan and dapagliflozin was administered once daily for 12 weeks.

[0411] Figure 4 shows the change in fluid-related events compared to baseline for study participants receiving dapagliflozin (10 mg, short-dashed line), a low-dose combination of zibotentan and dapagliflozin (0.25 mg / 10 mg, respectively, solid line), and a high-dose combination of zibotentan and dapagliflozin (1.5 mg / 10 mg, respectively, long-dashed line) in participants with a baseline UACR >700 mg / g. Only 4 of a total of 39 subjects receiving the low-dose combination of zibotentan and dapagliflozin (0.25 mg / 10 mg) experienced fluid-related events, amounting to a relative event rate of 15.9%. The number and event rate of fluid-related events were comparable to and not significantly different from those of participants receiving dapagliflozin alone (8 / 80 events and a relative event rate of 17.0%). Study participants receiving high doses of zibotentan and dapagliflozin (1.5 mg / 10 mg) showed an increased relative event rate (47.0%) for fluid-related events, with 18 / 75 participants experiencing an event, which was significantly increased relative to participants receiving dapagliflozin (10 mg) alone. These results indicate that the combination of zibotentan and dapagliflozin is safe up to at least the 1.5 mg / 10 mg (zibotentan / dapagliflozin) dose.

[0412] Figure 5 shows the change in UACR over 12 weeks compared to baseline levels for study participants with a UACR > 700 mg / g receiving dapagliflozin (10 mg, green line with circle symbols), a low-dose combination of zibotentan and dapagliflozin (0.25 mg / 10 mg, respectively, blue line with triangle symbols), and a high-dose combination of zibotentan and dapagliflozin (1.5 mg / 10 mg, respectively, red line with square symbols). Over 12 weeks, participants receiving dapagliflozin alone showed a slight decrease in the mean percent change in UACR compared to baseline, with the percent change plateauing at approximately a 20% decrease from baseline. Participants receiving both the low-dose (0.25 mg zibotentan and 10 mg dapagliflozin) and high-dose (1.5 mg zibotentan and 10 mg dapagliflozin) combination showed a significant decrease in UACR levels compared to baseline, with both the low-dose and high-dose treatment groups showing a change in UACR levels of approximately 45% at the end of the 12-week period compared to baseline levels. These results indicate that both tested doses of the zibotentan and dapagliflozin combination are effective in reducing UACR in individuals with high proteinuria (UACR > 700 mg / g).

[0413] Figure 6 shows the change in systolic blood pressure over the 12-week treatment period and 2-week post-treatment follow-up compared to baseline levels for study participants with a UACR < 700 mg / g and study participants with a UACR > 700 mg / g. Over 12 weeks, participants receiving dapagliflozin plus placebo (short-dashed line, dapagliflozin 10 mg plus placebo (PBO)) showed a modest decrease in systolic blood pressure of 3.4% (90% CI: -5.8, -1.0), which was consistent over the course of the study. After administration of the final planned dose, systolic blood pressure for participants receiving dapagliflozin plus placebo returned to baseline levels measured at week 14. Participants receiving either the dapagliflozin and zibotentan combination showed a more significant reduction in blood pressure compared to baseline. Participants receiving the lower dose of zibotentan and dapagliflozin (long-dashed line, 0.25 mg zibotentan and 10 mg dapagliflozin) demonstrated a mean reduction in systolic blood pressure from baseline of 7.1% (90% CI: -10, -4.1), while participants receiving the higher dose of zibotentan and dapagliflozin (solid line, 1.5 mg zibotentan and 10 mg dapagliflozin) demonstrated a mean reduction in systolic blood pressure from baseline of 11.0% (90% CI: -13.5, -8.4). Mean systolic blood pressure levels for participants receiving the zibotentan and dapagliflozin combination remained below baseline levels two weeks after administration of the final planned dose. Results from this study regarding systolic blood pressure measurements are further detailed in Tables 10A and 10B.

[0414] [Table 14]

[0415] [Table 15]

[0416] 7A and 7B show the change in systolic and diastolic blood pressure, respectively, over the 12-week treatment period for study participants with a UACR >700 mg / g compared to baseline levels. Over 12 weeks, study participants receiving dapagliflozin plus placebo (short-dashed line, dapagliflozin 10 mg and placebo) show a modest decrease in systolic and diastolic blood pressure, with a mean reduction in systolic blood pressure from baseline of slightly more than 4% and a mean reduction in diastolic blood pressure of approximately 2% at the end of the 12-week period compared to baseline. Patients receiving a lower dose of the combination of zibotentan and dapagliflozin (long-dashed line, zibotentan 0.25 mg and dapagliflozin 10 mg) showed a more significant decrease in systolic and diastolic blood pressure from baseline compared to patients receiving dapagliflozin plus placebo. In the group receiving the low-dose combination of zibotentan and dapagliflozin, a mean reduction of approximately 8% from baseline systolic blood pressure and a mean reduction of approximately 6% from baseline diastolic blood pressure were recorded at the end of the 12-week study. For the higher dose of the combination of zibotentan and dapagliflozin (solid line, 1.25 mg zibotentan and 10 mg dapagliflozin), a mean reduction of more than 12% from baseline was recorded in systolic blood pressure and a mean reduction of approximately 6% was recorded in diastolic blood pressure. The mean reduction in diastolic blood pressure was statistically significant at both the low and high doses of the combination of zibotentan and dapagliflozin compared to the dapagliflozin + placebo group (p=0.052 and p=0.024, respectively). The mean reduction in systolic blood pressure for the higher dose of zibotentan and dapagliflozin combination was also statistically significant (p<0.001) compared to the group receiving dapagliflozin plus placebo. Results from this study for systolic and diastolic blood pressure in patients with a UACR>700 mg / g are further detailed in Table 11A and Table 11B, respectively.

[0417] [Table 16] * p=0.192, ** p<0.001

[0418] [Table 17] * p=0.052, ** p=0.024

[0419] Example 4 Clinical trials of the fixed-dose combination of zibotentan and dapagliflozin are ongoing, including an international, multicenter, randomized, double-blind, active-controlled, parallel-group study, to evaluate the efficacy of the FDC of zibotentan and dapagliflozin compared with dapagliflozin alone (i.e., dapagliflozin monotherapy) in study participants with IgAN.

[0420] Study design Figure 8 provides an overview of the study. Approximately 500 participants will be randomized in a 1:1 ratio to one of two treatment groups: zibotentan (doses described below) and dapagliflozin (10 mg) once daily; or dapagliflozin (10 mg) once daily. For participants receiving the FDC of zibotentan and dapagliflozin, the dose of zibotentan will be determined by their eGFR status at the first screening visit, with eGFR < 45 mL / min / 1.72 m 2 Participants with zibotentan at a dosage of 0.25 mg and an eGFR ≥ 45 mL / min / 1.72 m 2 Participants with eGFR<45 mL / min / 1.72 m will receive zibotentan at a dosage of 0.75 mg. 2 and ≥ 45 mL / min / 1.72 m 2 Study participants with ≥ 1 year of age will be stratified 1:1 between the FDC (zibotentan and dapagliflozin) and dapagliflozin monotherapy treatment groups. Study participants will receive blinded study intervention from Day 1 through Month 36. At the 36-month visit, participants will begin open-label dapagliflozin therapy (10 mg). Participants not already receiving an SGLT2i at the first screening visit will receive a 28-day induction intervention with an SGLT2i once daily before starting the study.

[0421] The objectives of the study were divided into two stages: Stage 1 (9 months) and Stage 2 (36 months) and are detailed in Table 12.

[0422] [Table 18]

[0423] The main inclusion and exclusion criteria of the study are listed in Table 13 below.

[0424] [Table 19]

[0425] Screening of study participants and randomization into the study will occur according to the activity schedules set forth in Tables 14A and 14B. Assessments during the study will occur according to the activity schedule set forth in Table 15.

[0426] [Table 20] a Individuals who do not meet the criteria for inclusion in this study (screening failures) may be fully re-screened once. Re-screened participants will be required to re-sign the informed consent and will be assigned the same participant number as in the initial screening. If the following investigational values: spot urine for BP, eGFR, UACR, and UPCR, ALT, AST, and bilirubin are outside the participant's normal range during screening based on medical history, they may be re-tested up to two times without the need for re-screening. b The 10-day window at Visit 1 (days -34 [± 5]) is to allow for turnaround time for central laboratory results before the 28-day run-in. Participants not already on a stable dose of SGLT2i will enter a 28-day run-in with SGLT2i from day -28 to day -1. During the run-in period, SGLT2i may be provided as an adjunct. c A negative pregnancy test (serum) is required for all women at enrollment / prior to the first dose of study intervention. d At Visit 2, a negative urine pregnancy test result must be obtained before participants can be randomized. Monthly urine pregnancy tests and contraceptive adherence checks are required for all WOCBPs from randomization until one month after the last dose. If positive, treatment should be discontinued and procedures should be followed if contraceptive failure or pregnancy is suspected. For months when no visits are scheduled, the option of a home pregnancy test by a medical professional may be considered. e Women of non-childbearing potential are identified at screening by meeting one of the following criteria: a) postmenopausal status, defined as amenorrhea for at least 12 months after cessation of all exogenous hormone therapy, and FSH levels in the postmenopausal range (the postmenopausal range must be checked for the specific FSH assay used). A single FSH measurement is insufficient to define postmenopausal status in the absence of 12 months of amenorrhea. Women should be considered of childbearing potential in the event of perimenopause or a period of infrequent fluctuations in FSH levels, or (b) documentation of irreversible sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. f Includes signs of fluid retention and heart failure. g Tests included: B-red blood cell count, B-hematocrit, B-hemoglobin, B-white blood cell differential (absolute count), B-white blood cell count, B-platelet count, B-BNP, B-HbA1c, S-albumin, S-ALT, S-ALP, S-AST, S-bicarbonate, total S-bilirubin, S-BUN, total S-calcium, S-chloride, S-GGT, S-glucose, S-creatinine (including eGFR assessment), S-cystatin C, S-creatine kinase, S-magnesium, S-phosphorus, S-potassium, and S-sodium. hPRO questionnaires should be completed before any other study procedures or discussions (after informed consent), including medication, to avoid biasing participants' responses to the questions. i Participation in Genomics Initiative studies is optional and subject to separate consent by the participant. j At baseline, two samples will be collected for UPCR and UACR: one at home and one at the facility.

[0427] [Table 21] a Individuals who do not meet the criteria for inclusion in this study (screening failures) may be fully re-screened once. Re-screened participants will be required to re-sign the informed consent and will be assigned the same participant number as in the initial screening. If the following investigational values: spot urine for BP, eGFR, UACR, and UPCR, ALT, AST, and bilirubin are outside the participant's normal range during screening based on medical history, they may be re-tested up to two times without the need for re-screening. b Participants were already receiving a stable dose of SGLT2i. c Participants will be identified as of childbearing potential once at the most recent sign-up before randomization. d A negative pregnancy test (serum) is required for all women at enrollment / prior to the first dose of study intervention. e At Visit 2, a urine pregnancy test result must be negative before participants can be randomized. Monthly pregnancy tests (urine) and contraceptive adherence checks are required for all WOCBP from randomization until one month after the last dose. If positive, treatment should be discontinued and procedures should be followed if contraceptive failure or pregnancy is suspected. For months when no visits are scheduled, the option of a home pregnancy test by a medical professional may be considered. f Women of non-childbearing potential are identified at screening by meeting one of the following criteria: a) postmenopausal status, defined as amenorrhea for at least 12 months after cessation of all exogenous hormone therapy, and FSH levels in the postmenopausal range (the postmenopausal range must be checked for the specific FSH assay used). A single FSH measurement is insufficient to define postmenopausal status in the absence of 12 months of amenorrhea. Women should be considered of childbearing potential in the event of perimenopause or a period of infrequent fluctuations in FSH levels, or (b) documentation of irreversible sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. g Includes signs of fluid retention and heart failure. h Tests included: B-red blood cell count, B-hematocrit, B-hemoglobin, B-white blood cell differential (absolute count), B-white blood cell count, B-platelet count, B-BNP, B-HbA1c, S-albumin, S-ALT, S-ALP, S-AST, S-bicarbonate, total S-bilirubin, S-BUN, total S-calcium, S-chloride, S-GGT, S-glucose, S-creatinine (including eGFR assessment), S-cystatin C, S-creatine kinase, S-magnesium, S-phosphorus, S-potassium, and S-sodium. i PRO questionnaires should be completed before any other study procedures or discussions (after informed consent), including medication, to avoid biasing participants' responses to the questions. j Participation in Genomics Initiative studies is optional and subject to separate consent by the participant. k At baseline, two samples will be collected for UACR and UACR: one at home and one at the facility.

[0428] [Table 22] aAt Visit 14.1, participants still receiving blinded treatment will discontinue the blinded study intervention and begin open-label monotherapy with dapagliflozin 10 mg QD, provided as adjunctive medication until the safety follow-up visit. For participants who discontinue the study intervention early but remain in the study due to an SoA, Visit 14.1 will be the final study visit. b Visit 4: Phone call to assess fluid retention and related conditions. c Monthly pregnancy tests (urine) and contraceptive adherence checks are required for all WOCBPs from randomization until one month after the last dose. If positive, treatment should be discontinued and procedures should be followed if contraceptive failure or pregnancy is suspected. Companies may consider the option of home pregnancy testing by a healthcare professional for months when no visits are scheduled. d Women of non-childbearing potential are identified at screening by meeting one of the following criteria: a) postmenopause, defined as amenorrhea for at least 12 months after cessation of all exogenous hormone therapy, and FSH levels in the postmenopausal range (a single FSH measurement is insufficient to define postmenopausal criteria in the absence of 12 months of amenorrhea; women should be considered of childbearing potential during perimenopause or periods of infrequent fluctuations in FSH levels), or (b) documentation of irreversible sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. e Includes signs of fluid retention and heart failure. f Tests included the following: B-red blood cell count, B-hematocrit, B-hemoglobin, B-differential white blood cell count (absolute count), B-white blood cell count, B-platelet count, B-BNP, B-HbA1c, S-albumin, S-ALT, S-ALP, S-AST, S-bicarbonate, total S-bilirubin, S-BUN, total S-calcium, S-chloride, S-GGT, S-glucose, S-creatinine (including eGFR assessment), S-cystatin C, S-creatine kinase, S-magnesium, S-phosphorus, S-potassium, and S-sodium. gThe mean eGFR value at Visit 14 is calculated from the eGFR values ​​at Visit 14 and Visit 14.1. h PK samples will be collected pre-dose at Visits 3, 5, 6, and 12. For participants who permanently discontinue study intervention, PK samples should not be collected if more than 7 days have passed since the last dose. i PRO questionnaires should be completed before any other study procedures or discussions (after informed consent), including medication, to avoid biasing participants' responses to the questions. j If possible, the remaining (previously incomplete) sections of the SPFQ should be completed in the PTDV only if the participant withdraws early from the study. k Except for Visits 3, 5, 6, and 12, the study intervention will be administered at home. l At Visit 6 (6 months), tubes for collecting urine will be distributed so that at Visit 7 (9 months), there will be two samples for UACR and UACR: one collected at home and one collected at the facility. At visits other than screening, randomization, and 9 months, only one urine sample will be collected at the facility. m Excluding visit 14

Claims

1. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) a method of treating chronic kidney disease in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to treat the patient's chronic kidney disease.

2. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of slowing the decline in renal function in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to slow the decline in renal function in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

3. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of reducing proteinuria in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce proteinuria in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

4. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing albuminuria in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce albuminuria in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

5. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the incidence of a composite endpoint of a 30% sustained decline in eGFR or ESKD or renal death in human patients with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the incidence of the composite endpoint in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

6. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the incidence of a composite endpoint of a 40% sustained decline in eGFR or ESKD or renal death in human patients with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce said incidence of said composite endpoint in said patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

7. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the incidence of a composite endpoint of a 57% sustained decline in eGFR or ESKD or renal death in human patients with a urinary albumin-to-creatine ratio (UACR) greater than 700 g / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce said incidence of said composite endpoint in said patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

8. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the incidence of antineutrophil cytoplasmic antibody (ANCA) vasculitis in human patients with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the incidence of ANCA vasculitis in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

9. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of reducing recurrence of antineutrophil cytoplasmic antibody (ANCA) vasculitis in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce recurrence of the ANCA vasculitis in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

10. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of treating Alport syndrome in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to treat Alport syndrome in the patient.

11. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of reducing the progression of Alport syndrome in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the progression of Alport syndrome in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

12. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of reducing the level of kidney inflammation (nephritis) associated with Alport syndrome in human patients with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the level of kidney inflammation (nephritis) associated with Alport syndrome in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

13. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the incidence of hospitalization for heart failure in human patients with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the incidence of hospitalization for heart failure in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

14. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of reducing the risk of hospitalization for heart failure in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the risk of hospitalization for heart failure in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

15. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of reducing blood pressure in a human patient having a urinary albumin to creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed dose combination of zibotentan and dapagliflozin in amounts effective to reduce the blood pressure in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

16. 1. A method of reducing blood pressure in a human patient having a urinary albumin-to-creatine ratio (UACR) of less than 700 mg / g, comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the blood pressure in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

17. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the risk of elevated blood pressure in a human patient having a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the risk of elevated blood pressure in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

18. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) a method for preventing increased fluid retention in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to prevent increased fluid retention in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

19. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the risk of increased fluid retention in a human patient having a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the risk of increased fluid retention in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

20. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for preventing an increase in the level of brain natriuretic peptide (BNP) in a human patient having a urinary albumin-to-creatine ratio (UACR) of greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to prevent increased BNP levels in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

21. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the risk of elevated brain natriuretic peptide (BNP) levels in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the risk of said increased BNP levels in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

22. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for preventing an increase in total body water in a human patient having a urinary albumin-to-creatine ratio (UACR) of greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to prevent increased total body water in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

23. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the risk of increased total body water in a human patient with a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to prevent increased total body water in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

24. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for preventing weight gain in a human patient with a urinary albumin to creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed dose combination of zibotentan and dapagliflozin in amounts effective to prevent gained weight in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

25. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the risk of gained weight in a human patient with a urinary albumin to creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed dose combination of zibotentan and dapagliflozin in amounts effective to prevent gained weight in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

26. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) a method of treating IgA nephropathy (IgAN) in a human patient with biopsy-confirmed IgAN having a urinary albumin-to-creatine ratio (UACR) of greater than 700 mg / g, comprising: administering to the patient a fixed dose combination of zibotentan and dapagliflozin in amounts effective to treat IgAN in the patient.

27. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of reducing proteinuria in a human patient with biopsy-confirmed IgA nephropathy having a urinary albumin-to-creatine ratio (UACR) of greater than 700 mg / g, comprising: administering to the patient a fixed dose combination of zibotentan and dapagliflozin in amounts effective to reduce proteinuria in the patient.

28. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method of reducing the rate of renal function decline in human patients with biopsy-confirmed IgA nephropathy who have a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the rate of renal function decline in the patient.

29. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing cholesterol in a human patient having a urinary albumin to creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce cholesterol in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

30. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the risk of elevated cholesterol in a human patient having a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the risk of elevated cholesterol in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

31. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing hemoglobin A1c (HbA1c) in a human patient having a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce HbA1c in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

32. a) a urinary protein-to-creatine ratio (UPCR) of greater than 1 g / g, or b) A method for reducing the risk of elevated hemoglobin A1c (HbA1c) in a human patient having a urinary albumin-to-creatine ratio (UACR) greater than 700 mg / g, comprising: administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in amounts effective to reduce the risk of elevated HbA1c in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

33. The method of any one of claims 1 to 32, wherein the patient is naive to a sodium-glucose cotransporter-2 (SGLT2) inhibitor.

34. The patient has a blood pressure of 20-90 mL / min / 1.73 m ２ 34. The method of any one of claims 1 to 33, wherein the patient has an estimated glomerular filtration rate (eGFR) of

35. 35. The method of any one of claims 1 to 34, wherein the patient has a UPCR of 1 to 1.3 g / g.

36. 36. The method of any one of claims 1 to 35, wherein the patient has a UACR of 700 to 900 mg / g.

37. 37. The method of any one of claims 1 to 36, wherein the patient has a UPCR of 1 to 1.3 g / g and a UACR of 700 to 900 mg / g.

38. 38. The method of any one of claims 1 to 37, comprising administering to the patient the fixed-dose combination of zibotentan and dapagliflozin once daily.

39. 39. The method of any one of claims 1 to 38, comprising administering zibotentan at a dose of 0.25 mg to 1.5 mg.

40. 40. The method of any one of claims 1 to 39, comprising administering zibotentan at a dose of 0.25 mg.

41. 40. The method of any one of claims 1 to 39, comprising administering zibotentan at a dose of 0.5 mg.

42. 40. The method of any one of claims 1 to 39, comprising administering zibotentan at a dose of 0.75 mg.

43. 40. The method of any one of claims 1 to 39, comprising administering zibotentan at a dose of 1.0 mg.

44. 40. The method of any one of claims 1 to 39, comprising administering zibotentan at a dose of 1.25 mg.

45. 40. The method of any one of claims 1 to 39, comprising administering zibotentan at a dose of 1.5 mg.

46. 46. ​​The method of any one of claims 1 to 45, comprising administering dapagliflozin at a dose of 2.5 mg to 10 mg.

47. 47. The method of any one of claims 1 to 46, comprising administering dapagliflozin at a dose of 2.5 mg.

48. 47. The method of any one of claims 1 to 46, comprising administering dapagliflozin at a dose of 5.0 mg.

49. 47. The method of any one of claims 1 to 46, comprising administering dapagliflozin at a dose of 10.0 mg.

50. 39. The method of any one of claims 1 to 38, comprising administering zibotentan at a dose of 0.75 mg and dapagliflozin at a dose of 10 mg.

51. 39. The method of any one of claims 1 to 38, comprising administering zibotentan at a dose of 0.5 mg and dapagliflozin at a dose of 10 mg.

52. 39. The method of any one of claims 1 to 38, comprising administering zibotentan at a dose of 0.25 mg and dapagliflozin at a dose of 10 mg.

53. The patient has a blood glucose level of <45 mL / min / 1.73 m ２ and administering zibotentan at a dose of 0.25 mg and dapagliflozin at a dose of 10 mg when the patient has an eGFR of ≥ 45 mL / min / 1.73 m ２ and administering zibotentan at a dose of 0.75 mg and dapagliflozin at a dose of 10 mg when the patient has an eGFR of

54. The fixed-dose combination of zibotentan and dapagliflozin is administered to patients with an eGFR of <45 mL / min / 1.73 m ２ 54. The method of claim 53, wherein the dose is adjusted from 0.75 mg zibotentan and 10 mg dapagliflozin to 0.25 mg zibotentan and 10 mg dapagliflozin when the dose is changed from 0.75 mg zibotentan and 10 mg dapagliflozin to 0.25 mg zibotentan and 10 mg dapagliflozin.

55. The fixed-dose combination of zibotentan and dapagliflozin is administered to a patient whose eGFR is ≥ 45 mL / min / 1.73 m ２ 54. The method of claim 53, wherein the dose is adjusted from 0.25 mg zibotentan and 10 mg dapagliflozin to 0.75 mg zibotentan and 10 mg dapagliflozin when the dose is changed from 0.25 mg zibotentan and 10 mg dapagliflozin to 0.75 mg zibotentan and 10 mg dapagliflozin.

56. 56. The method of any one of claims 1-55, wherein administration of the fixed dose combination of zibotentan and dapagliflozin reduces the patient's UACR to less than 300 mg / g.

57. 57. The method of any one of claims 1-56, wherein administration of the fixed dose combination of zibotentan and dapagliflozin reduces the patient's UPCR to less than 1 g / g.

58. 58. The method of any one of claims 1-57, wherein administration of the fixed dose combination of zibotentan and dapagliflozin reduces the patient's UACR to less than 300 mg / g and the patient's UPCR to less than 1 g / g.

59. 59. The method of any one of claims 1 to 58, wherein the patient achieves partial remission or complete remission.

60. 60. The method of any one of claims 1 to 59, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the incidence of stroke and / or acute coronary syndrome in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

61. 61. The method of any one of claims 1-7 and 9-60, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the incidence of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

62. 62. The method of any one of claims 1-8 and 9-61, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces recurrence of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

63. 63. The method of any one of claims 1-9 and 11-62, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin treats Alport syndrome in the patient.

64. 64. The method of any one of claims 1-10 and 12-63, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the progression of Alport syndrome in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

65. 65. The method of any one of claims 1-11 and 13-64, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the level of kidney inflammation (nephritis) associated with Alport syndrome in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

66. 66. The method of any one of claims 1-12 and 14-65, wherein administration of the fixed dose combination of zibotentan and dapagliflozin does not lead to hospitalization for heart failure for the patient.

67. 67. The method of any one of claims 1-13 and 15-66, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of heart failure hospitalization in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

68. 68. The method of any one of claims 1-14 and 17-67, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces blood pressure in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

69. 69. The method of any one of claims 1-14 and 17-68, wherein administration of the fixed dose combination of zibotentan and dapagliflozin reduces the patient's blood pressure compared to a dosing regimen in which the patient receives dapagliflozin alone, and the patient's blood pressure remains reduced compared to a dosing regimen in which the patient receives dapagliflozin alone, for at least two weeks after administration of the fixed dose combination of zibotentan and dapagliflozin is stopped.

70. 70. The method of any one of claims 1-16 and 18-69, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of elevated blood pressure in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

71. 71. The method of any one of claims 1-17 and 19-70, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin does not increase fluid retention in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

72. 72. The method of any one of claims 1-18 and 20-71, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of increased fluid retention in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

73. 73. The method of any one of claims 1-19 and 21-72, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin does not increase the level of brain natriuretic peptide (BNP) in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

74. 74. The method of any one of claims 1-20 and 22-73, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of elevated brain natriuretic peptide (BNP) levels in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

75. 75. The method of any one of claims 1-21 and 23-74, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin does not increase total body water in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

76. 76. The method of any one of claims 1-22 and 24-75, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of increased total body water in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

77. 77. The method of any one of claims 1-23 and 25-76, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin does not cause the patient to gain weight compared to a dosing regimen in which the patient receives dapagliflozin alone.

78. 78. The method of any one of claims 1-24 and 26-77, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of said gained weight in said patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

79. 79. The method of any one of claims 1-26 and 28-78, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces proteinuria in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

80. 80. The method of any one of claims 1-27 and 29-79, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the rate of renal function decline in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

81. 81. The method of any one of claims 1-28 and 30-80, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces cholesterol in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

82. 82. The method of any one of claims 1-29 and 31-81, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of elevated cholesterol in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

83. 83. The method of any one of claims 1-30 and 32-82, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces HbA1c in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

84. 84. The method of any one of claims 1-31 and 33-83, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of elevated HbA1c in the patient compared to a dosing regimen in which the patient receives dapagliflozin alone.

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