Combination of zipotentan and dapagliflozin for treatment of high proteinuria chronic kidney disease

Abstract

Disclosed are methods for treating high proteinuria chronic kidney disease and / or at least one disease, disorder or condition associated therewith in a patient by using a fixed dose combination of zipotentan and dapagliflozin.

Description

Technical Field

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

[0002] Chronic kidney disease (CKD) is an endothelin-related disease associated with a gradual loss of kidney function. In some cases, CKD may be associated with high blood pressure or diabetes (diabetic nephropathy, 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 is determined by the patient's eGFR levels, which are correlated with a given stage of the disease, ranging from stage 1 (eGFR ≥ 90 mL / min / 1.73 m 2 ; normal) to stage 5 (eGFR <15mL / min / 1.73m 2 When CKD is diagnosed, albuminuria can also be classified as an indicator of disease progression. A urine albumin-to-creatine ratio (UACR) of less than 30 mg / g is classified as normal, a UACR between 30 mg / g and 300 mg / g is classified as moderately increased, and a UACR >300 mg / g is classified as severely increased. CKD is incurable and irreversible, and current treatment focuses on slowing the progression of kidney damage and controlling symptoms.

[0003] Alport syndrome is an inherited kidney disease caused by mutations in COL4A3 / 4 / 5 and is the second most common cause of inherited CKD. Alport syndrome has a variety of manifestations, ranging from hematuria and proteinuria to end-stage renal disease. There is no cure for Alport syndrome, and current treatment includes 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 inflammation of the glomeruli (glomerulonephritis), leading to scarring and / or permanent kidney damage, which may ultimately lead to end-stage renal disease. While ANCA vasculitis can be treated by targeting inflammation, treatment can only control inflammation (induction therapy) and then maintain remission (maintenance therapy). Current treatments for ANCA vasculitis require the use of immunosuppressants, which increase an individual's risk of infection.

[0005] IgA nephropathy (IgAN), also known as Buerger'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. Inflammation and damage in the kidneys can reduce renal function and lead to chronic kidney disease. IgAN may progress slowly, and progression is more likely to occur in individuals with high blood pressure, high levels of protein in the urine, and / or elevated levels of BUN or creatinine. Current treatments for IgAN are aimed at relieving symptoms and delaying the progression of the disease to chronic renal failure, and include ACE inhibitors, corticosteroids and other immunosuppressants, and cholesterol-lowering drugs.

[0006] Endothelin-1 (ET-1) is a potent systemic vasoconstrictor and a driver of renal disease progression, regulated by endothelin A and B receptors (ET A and ET B ) regulation. In CKD, ET-1 levels increase with UACR and the severity of renal impairment (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 believed to be mainly caused by ET A Receptor driven (Goddard et al., Circulation. 2004; 109(9): 1186-1193). A Receptor antagonists have been shown to have renoprotective effects but have side effects including edema (swelling). In diabetic nephropathy (DKD), ET A Short-term treatment with ET receptor antagonists has been shown to reduce the urine albumin to creatinine ratio (UACR) by 30% (Heerspink et al., Diabetes Obes Metab. 2018; 20(8):1829-1835; Heerspink et al., Lancet 2019; 393(10184):1937-1947). However, due to problems with fluid retention and hospitalization for heart failure, ET is still a treatment option. A Clinical development of receptor antagonists is limited (Heerspink et al., Lancet 2019;393(10184):1937-1947).

[0007] Zibotentan is an ET AA receptor antagonist that was developed for the treatment of prostate cancer but was abandoned in 2011 due to insufficient efficacy in Phase 3 and a 17% increase in the incidence of peripheral edema compared to placebo. Zipotentan, also known as ZD4054, is described in WO1996040681, which details its chemical synthesis, and these teachings are incorporated herein by reference. Morris et al., British Journal of Cancer (2005), 92, 2148-2152 reported specific inhibition of endothelin A receptors with zilpotentan. Zilpotentan, 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]

[0009] Sodium-dependent glucose transporter 2 (SGLT-2) inhibitors cause osmotic diuresis and block renal glucose reabsorption, increasing glucose excretion and lowering blood glucose concentrations. In addition to this well-characterized mode of action, SGLT-2 inhibitors can also lower blood pressure, reduce vascular stiffness, improve endothelial function, and have anti-inflammatory and anti-fibrotic properties similar to endothelin receptor antagonists (HJ Heerspink et al., Circulation (2016), 134(10):752-772). A Like SGLT2 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). Side effects associated with the pharmacological effects of SGLT-2 inhibitors are volume loss / intravascular volume contraction, which may lead to dehydration, hypovolemia, orthostatic hypotension, or hypotension. Therefore, SGLT-2 inhibitors typically induce an increase in hematocrit (Hot) (a sign of hemoconcentration) and increased blood viscosity (a putative cause of vascular damage in the context of peripheral vascular disease).

[0010] Dapagliflozin is an effective, highly selective, orally effective human kidney SGLT2 inhibitor that has been approved for improving glycemic control (as an adjunct to diet and exercise) in adults with type 2 diabetes. Dapagliflozin has been disclosed in WO2003099836, and its chemical synthesis is described in detail, and these teachings 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]

[0013] While there are approved therapies for patients with CKD, there are no approved therapies for patients with hyperalbuminuric CKD characterized by high levels of albuminuria and / or proteinuria. Notably, ET is required to treat more advanced stages of CKD. A The dose increase of receptor antagonists is not well tolerated due to the side effects including edema and congestive heart failure risk. Although SGLT2 inhibitors are effective in treating CKD in many cases, many patients still have residual risks, as demonstrated by persistent proteinuria. For example, a post-hoc analysis of the CREDENCE trial showed that although canagliflozin (an SGLT2 inhibitor for treating renal events in patients with type 2 diabetes and CKD) can reduce UACR levels in the short term, it failed to reduce the UACR levels of a large number of patients to less than 300 mg / g, and these patients developed renal events and major adverse cardiovascular events due to residual proteinuria (Oshima et al., J Am Soc Nephrol. (2020); 31 (12): 2925-2936).

[0014] Therefore, 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 zilpotentan and dapagliflozin for use in treating CKD in a human patient in need of such treatment, wherein the treatment comprises administering zilpotentan and dapagliflozin to the human patient in an amount effective to treat the patient's CKD. In some embodiments, the human patient is a CKD patient who meets the criteria described herein.

[0016] The present disclosure also provides a method of treating hyperproteinuric CKD in a human patient in need of such treatment, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for treating hyperproteinuric CKD in a human patient in need thereof, wherein the treatment comprises administering zilpotentan and dapagliflozin to the human patient in an amount effective to treat the patient's CKD. 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 zilpotentan 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 zilpotentan and dapagliflozin to the human patient in an amount effective to treat the patient's IgAN. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0019] The present disclosure also provides a method for treating a human patient with hyperproteinuric CKD associated with IgA nephropathy (IgAN), the method comprising administering to the human patient, alone, sequentially, or simultaneously, zilpotentan and dapagliflozin in an amount effective to treat the patient's IgAN. In some embodiments, the human patient is a hyperproteinuric CKD patient who meets the criteria described herein.

[0020] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin for the preparation of a medicament for treating hyperproteinuric CKD associated with IgA nephropathy (IgAN) in a human patient in need thereof, wherein the treatment comprises administering zilpotentan and dapagliflozin to the human patient in an amount effective to treat the patient's IgAN. 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 zilpotentan and dapagliflozin for use in treating biopsy-confirmed IgA nephropathy (IgAN) in a human patient in need of such treatment, wherein the treatment comprises administering zilpotentan and dapagliflozin to the human patient in an amount effective to treat the patient's IgAN. In some embodiments, the human patient is a hyperproteinuric CKD patient meeting the criteria described herein.

[0022] The present disclosure also provides a method of treating a human patient with biopsy-confirmed IgA nephropathy (IgAN), the method comprising administering to the human patient, alone, sequentially, or simultaneously, zilpotentan and dapagliflozin in an amount effective to treat the patient's IgAN. In some embodiments, the human patient is a hyperproteinuric CKD patient meeting the criteria described herein.

[0023] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin for the preparation of a medicament for treating biopsy-confirmed IgA nephropathy (IgAN) in a human patient in need thereof, wherein the treatment comprises administering zilpotentan and dapagliflozin to the human patient in an amount effective to treat the patient's IgAN. In some embodiments, the human patient is a hyperproteinuric CKD patient meeting the criteria described herein.

[0024] The present disclosure also provides a fixed-dose combination of zilpotentan and dapagliflozin for use in reducing proteinuria in a human patient with biopsy-confirmed IgA nephropathy in need of such treatment, wherein the treatment comprises administering zilpotentan and dapagliflozin to the human patient in an amount effective to reduce proteinuria in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient meeting the criteria described herein.

[0025] The present disclosure also provides a method of reducing proteinuria in a human patient with biopsy-confirmed IgA nephropathy, the method comprising administering to the human patient, alone, sequentially, or simultaneously, zilpotentan and dapagliflozin in an amount effective to reduce proteinuria in the patient. In some embodiments, the human patient is a hyperproteinuric CKD patient meeting the criteria described herein.

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

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

[0028] The present disclosure also provides a method of reducing the rate of decline in renal function in a human patient with biopsy-confirmed IgA nephropathy, the method comprising administering to the human patient, alone, sequentially, or simultaneously, zilpotentan and dapagliflozin in an amount effective to reduce the rate of decline in the patient's renal function. In some embodiments, the human patient is a hyperproteinuric CKD patient meeting the criteria described herein.

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

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

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

[0032] The present disclosure also provides for the use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for treating hyperproteinuric CKD associated with FSGS in a human patient in need thereof, wherein the treatment comprises administering zilpotentan and dapagliflozin to the human patient in an amount effective to treat the patient's FSGS. 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 zilpotentan and dapagliflozin for use in slowing the decline of renal function in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to slow the decline of renal function in the human patient. In some embodiments, the human patient meets the criteria described herein.

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

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

[0037] The present disclosure also provides a method of reducing proteinuria in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for reducing proteinuria in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in reducing albuminuria in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the patient's albuminuria. In some embodiments, the human patient meets the criteria described herein.

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

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

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

[0043] The present disclosure also provides a method for reducing the incidence of a composite endpoint of a 30% decrease in eGFR, end-stage renal disease (ESKD), or renal death in a human patient in need thereof, the method comprising administering zilpotentan and dapagliflozin to the human patient, alone, sequentially, or simultaneously, in an amount effective to reduce the incidence of a composite endpoint of a 30% decrease in eGFR, ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

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

[0045] The present disclosure also provides a fixed-dose combination of zilpotentan and dapagliflozin for use in reducing the incidence of a composite endpoint of a 40% decrease in eGFR, end-stage renal disease (ESKD), or renal death in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the incidence of a composite endpoint of a 40% decrease in eGFR, 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 for reducing the incidence of a composite endpoint of a 40% decrease in eGFR, end-stage renal disease (ESKD), or renal death in a human patient in need thereof, the method comprising administering zilpotentan and dapagliflozin to the human patient, alone, sequentially, or simultaneously, in an amount effective to reduce the incidence of a composite endpoint of a 40% decrease in eGFR, ESKD, or renal death in the patient. In some embodiments, the human patient is a CKD patient meeting the criteria described herein.

[0047] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin for the preparation of a medicament for reducing the incidence of a composite endpoint of a 40% decrease in eGFR, end-stage renal disease (ESKD), or renal death in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the incidence of a composite endpoint of a 40% decrease in eGFR, 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 zilpotentan and dapagliflozin for use in reducing the incidence of a composite endpoint of a 57% decrease in eGFR, end-stage renal disease (ESKD), or renal death in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the incidence of a composite endpoint of a 57% decrease in eGFR, ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

[0049] The present disclosure also provides a method for reducing the incidence of a composite endpoint of a 57% decrease in eGFR, end-stage renal disease (ESKD), or renal death in a human patient in need thereof, the method comprising administering zilpotentan and dapagliflozin to the human patient, alone, sequentially, or simultaneously, in an amount effective to reduce the incidence of a composite endpoint of a 57% decrease in eGFR, ESKD, or renal death in the patient. In some embodiments, the human patient meets the criteria described herein.

[0050] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin for the preparation of a medicament for reducing the incidence of a composite endpoint of a 57% decrease in eGFR, end-stage renal disease (ESKD), or renal death in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the incidence of a composite endpoint of a 57% decrease in eGFR, 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 zilpotentan and dapagliflozin for use in preventing hospitalization for heart failure (hHF) in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to prevent hHF. In some embodiments, the human patient meets the criteria described herein.

[0052] The present disclosure also provides a method of preventing hospitalization for heart failure (hHF) in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for preventing hospitalization for heart failure (hHF) in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in reducing the risk of hospitalization for heart failure (hHF) in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of reducing the risk of hospitalization for heart failure (hHF) in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan and dapagliflozin in an amount 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for reducing the risk of hospitalization for heart failure (hHF) in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in reducing the risk of increased fluid retention in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of reducing the risk of increased fluid retention in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan and dapagliflozin in amounts effective to reduce the risk of increased fluid retention in the patient. In some embodiments, the human patient meets the criteria described herein.

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

[0060] The present disclosure also provides a fixed-dose combination of zilpotentan and dapagliflozin for use in preventing increased fluid retention in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of preventing increased fluid retention in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for preventing increased fluid retention in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in reducing the risk of elevated brain natriuretic peptide (BNP) levels in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the risk of elevated BNP levels in the patient. In some embodiments, the human patient meets the criteria described herein.

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

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

[0067] The present disclosure also provides a method for preventing elevated brain natriuretic peptide (BNP) levels in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan and dapagliflozin in an amount effective to prevent elevated BNP levels in the patient. In some embodiments, the human patient meets the criteria described herein.

[0068] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin for the preparation of a medicament for preventing elevated levels of brain natriuretic peptide (BNP) in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to prevent elevated 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 zilpotentan and dapagliflozin for use in reducing the risk of weight gain in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the patient's risk of weight gain. In some embodiments, the human patient meets the criteria described herein.

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

[0071] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for reducing the risk of weight gain in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the patient's risk of weight gain. In some embodiments, the human patient meets the criteria described herein.

[0072] The present disclosure also provides a fixed-dose combination of zilpotentan and dapagliflozin for use in preventing weight gain in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of preventing weight gain in a human patient in need thereof, comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for preventing weight gain in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in reducing the risk of total body water gain in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the risk of total body water gain in the patient. In some embodiments, the human patient meets the criteria described herein.

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

[0077] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for reducing the risk of total body water gain in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the risk of total body water gain 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 zilpotentan and dapagliflozin for use in preventing total body water gain in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to prevent total body water gain in the patient. In some embodiments, the human patient meets the criteria described herein.

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

[0080] The present disclosure also provides for the use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for preventing total body water gain in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in lowering cholesterol in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to lower the patient's cholesterol. In some embodiments, the human patient meets the criteria described herein.

[0082] The present disclosure also provides a method of lowering cholesterol in a human patient in need thereof, comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan and dapagliflozin in amounts effective to lower the patient's cholesterol. In some embodiments, the human patient meets the criteria described herein.

[0083] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for lowering cholesterol in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to lower the patient's cholesterol. In some embodiments, the human patient meets the criteria described herein.

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

[0085] The present disclosure also provides a method of lowering hemoglobin A1c (HbA1c) in a human patient in need thereof, the method comprising administering to the human patient separately, sequentially, or simultaneously zilpotentan and dapagliflozin in amounts effective to lower the patient's HbA1c. In some embodiments, the human patient meets the criteria described herein.

[0086] The present disclosure also provides for use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for lowering hemoglobin A1c (HbA1c) in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to lower the patient's HbA1c. In some embodiments, the human patient meets the criteria described herein.

[0087] The present disclosure also provides a fixed-dose combination of zilpotentan and dapagliflozin for use in reducing the risk of elevated cholesterol in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of reducing the risk of elevated cholesterol in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for reducing the risk of elevated cholesterol in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in reducing the risk of elevated hemoglobin A1c (HbA1c) in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of reducing the risk of elevated hemoglobin A1c (HbA1c) in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 for use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for reducing the risk of elevated hemoglobin A1c (HbA1c) in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in lowering blood pressure in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to lower the patient's blood pressure. In some embodiments, the human patient meets the criteria described herein.

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

[0095] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for lowering blood pressure in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to lower 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 zilpotentan and dapagliflozin for use in reducing the risk of elevated blood pressure in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of reducing the risk of elevated blood pressure in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for reducing the risk of elevated blood pressure in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in reducing the incidence of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of reducing the incidence of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis in a human patient in need thereof, the method comprising administering to the human patient, alone, sequentially, or simultaneously, zilpotentan and dapagliflozin in an amount 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin for the preparation of a medicament for reducing the incidence of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in reducing the recurrence of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of reducing the recurrence of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis in a human patient in need thereof, the method comprising administering to the human patient, alone, sequentially, or simultaneously, zilpotentan and dapagliflozin in an amount effective to reduce the recurrence of ANCA vasculitis. In some embodiments, the human patient meets the criteria described herein.

[0104] The present disclosure also provides a use of a fixed-dose combination of zilpotentan and dapagliflozin for the preparation of a medicament for reducing the recurrence of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the 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 zilpotentan and dapagliflozin for use in reducing the progression of Alport syndrome in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 a method of reducing the progression of Alport syndrome in a human patient in need thereof, the method comprising administering to the human patient, alone, sequentially, or simultaneously, zilpotentan and dapagliflozin in an amount 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin for the preparation of a medicament for reducing the progression of Alport syndrome in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for treating Alport syndrome in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to treat Alport syndrome. In some embodiments, the human patient meets the criteria described herein.

[0109] The present disclosure also provides a method of treating Alport syndrome in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for treating Alport syndrome in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 zilpotentan and dapagliflozin for use in reducing the levels of markers of kidney inflammation (nephritis) associated with Alport syndrome in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the 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 a method for reducing the level of a marker of kidney inflammation (nephritis) associated with Alport syndrome in a human patient in need thereof, the method comprising administering zilpotentan and dapagliflozin, alone, sequentially, or simultaneously, to the human patient in an amount effective to reduce the level of a marker 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 a fixed-dose combination of zilpotentan and dapagliflozin for use in the preparation of a medicament for reducing the levels of markers of kidney inflammation (nephritis) associated with Alport syndrome in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount effective to reduce the 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 zilpotentan and dapagliflozin for use in reducing the incidence of stroke in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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, the method comprising administering to the human patient zilpotentan and dapagliflozin, either separately, sequentially, or simultaneously, in an amount effective to reduce the incidence of stroke. In some embodiments, the human patient meets the criteria described herein.

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

[0118] The present disclosure also provides a method of reducing the risk of stroke in a human patient in need thereof, the method comprising administering to the human patient, separately, sequentially, or simultaneously, zilpotentan 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 a use of a fixed-dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for reducing the risk of stroke in a human patient in need thereof, wherein zilpotentan and dapagliflozin are administered to the human patient in an amount 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 sodium-glucose cotransporter-2 (SGLT2) inhibitor naive.

[0121] In the embodiment, the patient has a 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 The estimated glomerular filtration rate (eGFR).

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

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

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

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

[0126] In embodiments, zilpotentan is administered at a dose of 0.25 mg to 1.5 mg. In embodiments, zilpotentan is administered at a dose of 0.25 mg. In embodiments, zilpotentan is administered at a dose of 0.5 mg. In embodiments, zilpotentan is administered at a dose of 0.75 mg. In embodiments, zilpotentan is administered at a dose of 1.0 mg. In embodiments, zilpotentan is administered at a dose of 1.25 mg. In embodiments, zilpotentan 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, zilpotentan is administered at a dose of 0.75 mg and dapagliflozin is administered at a dose of 10 mg. In an embodiment, zilpotentan is administered at a dose of 0.5 mg and dapagliflozin is administered at a dose of 10 mg. In an embodiment, zilpotentan is administered at a dose of 0.25 mg and dapagliflozin is administered at a dose of 10 mg.

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

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

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

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

[0133] In any of the above embodiments, the results produced by the provided methods and uses can be relative to a human patient receiving at least one SGLT2 inhibitor (e.g., dapagliflozin, empagliflozin, canagliflozin, etc.) alone or in combination with at least one standard of care CKD agent. In these aspects, the standard of care CKD agent can be an ACE inhibitor (e.g., captopril, enalapril, and lisinopril) and / or angiotensin II receptor blocker (ARB) (valsartan, losartan, and irbesartan). In some embodiments, the results are relative to a single dapagliflozin. In some embodiments, the results are relative to a dapagliflozin combined with at least one standard of care CKD agent.

[0134] In any of the above embodiments, the results produced by the provided methods and uses can be relative to the patient's baseline. In some embodiments, the methods and uses thereof can be relative to the patient's baseline compared to patients receiving dapagliflozin alone or in combination with at least one CKD standard of care. BRIEF DESCRIPTION OF THE DRAWINGS

[0135] Figure 1 The study timeline and study groups shown in Example 1 are illustrated.

[0136] Figure 2 The study timeline and study groups shown in Example 2 are illustrated.

[0137] Figure 3 The dose-titration groupings shown in Example 2 are exemplified.

[0138] Figure 4 Shown are Kaplan-Meier curves illustrating the effect of the combination of two different doses of zilpotentan and dapagliflozin and dapagliflozin monotherapy on fluid events over a 12-week period.

[0139] Figure 5 The effects of two different doses of the combination of zilpotentan and dapagliflozin, as well as dapagliflozin monotherapy, on the change from baseline in UACR over a 12-week period are illustrated.

[0140] Figure 6 The effects of two different doses of the combination of zilpotentan and dapagliflozin, as well as dapagliflozin monotherapy, on the change from baseline in systolic blood pressure over a 12-week period are illustrated.

[0141] Figure 7A and Figure 7B The effects of two different doses of the combination of zilpotentan and dapagliflozin and dapagliflozin monotherapy on the change from baseline in systolic and diastolic blood pressure over 12 weeks in patients with UACR >700 mg / g are described.

[0142] Figure 8 The study timeline and study groups shown in Example 4 are depicted. DETAILED DESCRIPTION

[0143] As used herein, when used to modify a numerical value or numerical range, the terms "about" and "approximately" mean that the deviation of up to 10% above the numerical value or range and up to 10% below the numerical value or range is still within the intended meaning of the enumerated numerical value or range. In some embodiments, "about" refers to ±10%. In some embodiments, "about" refers to ±9%. In some embodiments, "about" refers to ±8%. In some embodiments, "about" refers to ±7%. In some embodiments, "about" refers to ±6%. In some embodiments, "about" refers to ±5%. In some embodiments, "about" refers to ±4%. In some embodiments, "about" refers to ±3%. In some embodiments, "about" refers to ±2%. In some embodiments, "about" refers to ±1%. It should be understood that no matter where in this article, the language "about" or "approximately" numerical value or range is used to describe aspects, other similar aspects related to specific numerical values ​​or ranges (without "about") are also provided. It should also be understood that no matter where in this article, the aspects described relate to numerical values ​​or ranges without the language "about" or "approximately", other similar aspects related to "about" or "approximately" specific numerical values ​​or ranges are also provided.

[0144] The terms "treating" or "treatment" or "to treat" refer to therapeutic measures that cure, slow down, alleviate the symptoms of, and / or halt the progression of a diagnosed pathological disease, disorder, or condition. Treatment need not result in a complete cure of the condition; the term encompasses partial inhibition or alleviation of the condition being treated.

[0145] Those skilled in the art can easily determine the effectiveness of the compounds of the present invention in treating and / or preventing chronic kidney disease (CKD) and / or diseases, disorders and / or conditions associated therewith. Those skilled in the art can also easily determine and adjust appropriate dosing regimens (e.g., adjusting the amount and / or dosage number and frequency of administration of each dose of compound). The health status of the patient can be monitored using one or any combination of diagnostic methods (including physical examination, assessment and monitoring of clinical symptoms and the execution of analytical tests and methods described herein).

[0146] An effective amount or therapeutically effective amount refers to the amount of at least one compound of the present invention or a pharmaceutical composition comprising at least one such compound, which, when administered to a patient in a single dose or as part of a series of doses, effectively produces at least one therapeutic effect. The optimal dose can generally be determined using experimental models and / or clinical trials. The design and execution of preclinical and clinical studies of each therapeutic agent described herein (including when administered for preventive benefit) are entirely within the skill of those of ordinary skill in the relevant art. The optimal dose of the therapeutic agent may depend on the patient's body mass, weight, and / or blood volume. The therapeutic effect of the patient can generally be monitored using assays suitable for the disease, disorder, and / or condition being treated or prevented, which are familiar to those of ordinary skill in the art and are described herein. The level of the compound administered to the patient can be monitored by measuring the level of the compound (or 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. The level of the compound can be measured over the course of the treatment regimen using any method of detecting a compound or its metabolite practiced in the art.

[0147] 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, the overall state of health, and age, sex, and weight, as well as other factors apparent to those of ordinary skill in the medical arts. Similarly, the dosage of therapeutic agents used to treat diseases, disorders, and / or conditions can be determined according to parameters understood by those of ordinary skill in the medical arts.

[0148] As used herein, the terms "subject" and "patient" are used interchangeably to refer to a person receiving medical treatment. In some aspects, the subject is a human.

[0149] As used herein, the term "albuminuria" refers to the presence of albumin in the urine, a marker of chronic kidney disease. Albuminuria occurs when the urine albumin to creatine ratio (UACR) is above 30 mg / g.

[0150] As used herein, the term "proteinuria" refers to the presence of protein in the urine, a marker of chronic kidney disease. Proteinuria occurs when the urine protein to creatine ratio (UPCR) is greater than 150 mg / g. In some embodiments, proteinuria occurs when the UPCR is greater than 200 mg / g.

[0151] As used herein, the "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 2Stage 2 is mild CKD (eGFR = 60 mL / min / 1.73 m 2 -89mL / min / 1.73m 2 Stage 3A is moderate CKD (eGFR = 45 mL / min / 1.73 m 2 -59mL / min / 1.73m 2 Stage 3B is moderate CKD (eGFR = 30 mL / min / 1.73 m 2 -44mL / min / 1.73m 2 Stage 4 is severe CKD (eGFR = 15 mL / min / 1.73 m 2 -29mL / min / 1.73m 2 Stage 5 is end-stage CKD (eGFR < 15 mL / min / 1.73 m 2 ).

[0152] As used herein, the term "end-stage renal disease (ESKD)" refers to (i) a patient with a blood pressure <15 mL / min / 1.73 m 2 In some embodiments, "sustained" refers to a second eGFR test performed 3 months apart to confirm a similar eGFR measurement.

[0153] As used herein, the term "cholesterol" refers to (i) low-density lipoprotein (LDL) cholesterol, (ii) high-density lipoprotein (HDL) cholesterol, or both.

[0154] As used herein, the phrase "not SGLT2 inhibitor naive" means that the patient (i) has previously received SGLT2 inhibitor therapy; and / or (ii) is currently receiving SGLT2 inhibitor therapy.

[0155] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to achieve delivery of a drug, such as zilpotentan 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 aspects, zilpotentan and dapagliflozin are administered orally.

[0156] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to preparations that are in such form that the biological activity of the active ingredient is effective and that contain no additional components that are unacceptably toxic to a subject to which the formulation would be administered. Such preparations can be sterile.

[0157] "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, formulation adjuvant or vehicle conventional in the art used with a therapeutic agent to form a "pharmaceutical composition" for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration employed, is suitable for the formulation employed, and is compatible with the other ingredients of the formulation.

[0158] A "sterile" preparation is sterile or substantially free of viable microorganisms and their spores.

[0159] As used herein, the term "prodrug" refers to, for example, esters and carbonates that can be converted to zilpotentan or dapagliflozin under physiological conditions or by solvolysis. Thus, the term prodrug includes pharmaceutically acceptable metabolic precursors of zilpotentan or dapagliflozin. The term prodrug also includes covalently bonded carriers that release zilpotentan or dapagliflozin in vivo when such prodrug is administered to a patient. Non-limiting examples of prodrugs include esters and carbonates.

[0160] Various forms of prodrugs are known in the art. Examples of such prodrug derivatives are shown 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", edited 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 Bull, 32, 692 (1984).

[0161] It should be understood that wherever aspects are described herein with the language "comprising," other similar aspects described with the terms "consisting of" and / or "consisting essentially of" are also provided. In this disclosure, "comprises," "comprising," "containing," and "having" and the like may mean "includes," "including," and the like; "consisting essentially of" or "consists essentially of" are open-ended, allowing for the presence of more than those listed, as long as the basic or novel characteristics of the listed ones, as described herein, are not altered by the presence of the more than those listed, but excluding prior art aspects.

[0162] Unless otherwise specified or obvious from the context, as used herein, the term "or" should be understood to be inclusive.

[0163] In one aspect, the disclosure herein provides a method of treating hyperproteinuric chronic kidney disease (CKD) in a human patient comprising administering zilpotentan and dapagliflozin to a patient in need thereof.

[0164] In one aspect, the disclosure herein provides a fixed-dose combination of zilpotentan and dapagliflozin for use in treating hyperalbuminuric chronic kidney disease (CKD) in human patients.

[0165] In one aspect, the disclosure herein provides use of a fixed dose combination of zilpotentan and dapagliflozin in the preparation of a medicament for treating hyperproteinuric chronic kidney disease (CKD) in a human patient, wherein the fixed dose combination of zilpotentan and dapagliflozin is administered.

[0166] In embodiments, chronic kidney disease (CKD) is stage 1 to 4 CKD as defined by the Kidney Disease Improving Global Outcomes (KIDGO) guidelines. In embodiments, CKD is stage 2-3 CKD. In embodiments, CKD is stage 3-4 CKD. In embodiments, CKD is stage 2-4 CKD. In embodiments, CKD is stage 4 CKD. In embodiments, CKD is stage 3 CKD. In embodiments, CKD is stage 3A or stage 3B CKD. In embodiments, CKD is stage 2 CKD.

[0167] In embodiments, the patient is a CKD human patient with type 2 diabetes. In embodiments, the patient is a CKD human patient without type 2 diabetes.

[0168] In the embodiment, the patient has a 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In some embodiments, the patient has an estimated glomerular filtration rate (eGFR) of 20 mL / min / 1.73 m 2 -29mL / min / 1.73m 2 In some embodiments, the patient has an eGFR of 30 mL / min / 1.73 m 2 -44mL / min / 1.73m 2 In some embodiments, the patient has an eGFR of 45 mL / min / 1.73 m 2 -59mL / min / 1.73m 2 In some embodiments, the patient has an eGFR of 60 mL / min / 1.73 m 2 -89mL / min / 1.73m 2 eGFR.

[0169] In embodiments, the patient has a urine 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 of 1.0 g / g-2.0 g / g. In embodiments, the patient has a UPCR of 1.0 g / g-1.5 g / g. In embodiments, the patient has a UPCR of 1.0 g / g-1.3 g / g.

[0170] In embodiments, the patient has a urine 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 mg / g and 900 mg / g.

[0171] In the embodiment, the patient has a 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In one embodiment, the patient has an eGFR of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In one embodiment, the patient has an eGFR greater than 700 mg / g and a UPCR greater than 1.0 g / g. In one embodiment, the patient has an eGFR greater than 700 mg / g and a UPCR greater than 1.0 g / g. In one embodiment, the patient has an eGFR greater than 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 eGFR, UACR greater than 700 mg / g and UPCR greater than 1.0 g / g.

[0172] In the embodiment, the patient has a 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In the embodiment, the patient has an eGFR of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In one embodiment, the patient has an eGFR of 700 mg / g to 900 mg / g and a UPCR of 1.0 g / g to 1.3 g / g. In one embodiment, the patient has an eGFR of 700 mg / g to 900 mg / g and a UPCR of 1.0 g / g to 1.3 g / g. In one embodiment, the patient has an eGFR of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2eGFR, UACR of 700mg / g-900mg / g and UPCR of 1.0g / g-1.3g / g.

[0173] In embodiments, the patient has Alport syndrome. In embodiments, the patient has hyperproteinuria (UACR>700 mg / g) and Alport syndrome. In embodiments, the patient has anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. In embodiments, the patient has hyperproteinuria (UACR>700 mg / g) and ANCA vasculitis.

[0174] In some embodiments, the patient suffers from IgA nephropathy (IgAN). In some embodiments, the patient suffers from hyperproteinuria (UACR>700mg / g and / or UPCR>1.0g / g) and IgAN. In some embodiments, the patient has an eGFR>30mL / min / 1.73m2, hyperproteinuria (UACR>700mg / g and / or UPCR>1.0g / g) and IgAN. In some embodiments, the patient's IgAN diagnosis is biopsy-confirmed. In some embodiments, the patient with IgAN is at risk of rapid disease progression.

[0175] In the embodiments, the patient is new to sodium-glucose cotransporter 2 (SGLT2) inhibitors. In some embodiments where the patient is new to SGLT2 inhibitors, the patient receives dapagliflozin (introduction) prior to receiving the fixed-dose combination of zilpotentan and dapagliflozin. In some embodiments where the patient is new to SGLT2 inhibitors, the patient receives 4 weeks of dapagliflozin introduction prior to receiving the fixed-dose combination of zilpotentan and dapagliflozin. In the embodiments, the patient is not new to SGLT2 inhibitors.

[0176] In the embodiment, the patient is SGLT2 inhibitor naive and has a blood pressure of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In the embodiment, the patient is SGLT2 inhibitor-naive and has an eGFR of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In one embodiment, the patient is a SGLT2 inhibitor first-time user and has an eGFR greater than 700 mg / g and a UPCR greater than 1.0 g / g. In one embodiment, the patient is a SGLT2 inhibitor first-time user and has an eGFR greater than 700 mg / g and a UPCR greater than 1.0 g / g. In one embodiment, the patient is a SGLT2 inhibitor first-time user and has an eGFR greater than 20 mL / min / 1.73 m 2 -90mL / min / 1.73m2 eGFR, UACR greater than 700 mg / g and UPCR greater than 1.0 g / g.

[0177] In the embodiment, the patient is SGLT2 inhibitor naive and has a blood pressure of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In the embodiment, the patient is SGLT2 inhibitor-naive and has an eGFR of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In one embodiment, the patient is SGLT2 inhibitor-naive and has an eGFR of 700 mg / g-900 mg / g and a UPCR of 1.0 g / g-1.3 g / g. In one embodiment, the patient is SGLT2 inhibitor-naive and has an eGFR of 700 mg / g-900 mg / g and a UPCR of 1.0 g / g-1.3 g / g. In one embodiment, the patient is SGLT2 inhibitor-naive and has an eGFR of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 eGFR, UACR of 700mg / g-900mg / g and UPCR of 1.0g / g-1.3g / g.

[0178] In the embodiment, the patient is not SGLT2 inhibitor naive and has a blood pressure of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In the embodiment, the patient is not SGLT2 inhibitor naive and has an eGFR of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In one embodiment, the patient is not a SGLT2 inhibitor naive user and has a UACR greater than 700 mg / g and a UPCR greater than 1.0 g / g. In one embodiment, the patient is not a SGLT2 inhibitor naive user and has a UACR greater than 700 mg / g and a UPCR greater than 1.0 g / g. 2 -90mL / min / 1.73m 2 eGFR, UACR greater than 700 mg / g and UPCR greater than 1.0 g / g.

[0179] In the embodiment, the patient is not SGLT2 inhibitor naive and has a blood pressure of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2In the embodiment, the patient is not SGLT2 inhibitor naive and has an eGFR of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 In one embodiment, the patient is not SGLT2 inhibitor naive and has a UACR of 700 mg / g-900 mg / g and a UPCR of 1.0 g / g-1.3 g / g. In one embodiment, the patient is not SGLT2 inhibitor naive and has a UACR of 20 mL / min / 1.73 m 2 -90mL / min / 1.73m 2 eGFR, UACR of 700mg / g-900mg / g and UPCR of 1.0g / g-1.3g / g.

[0180] In an embodiment, a fixed dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, is administered to a patient described herein.

[0181] In an embodiment, zilpotentan or a pharmaceutically acceptable salt thereof is administered once daily.

[0182] In embodiments, the total daily dose of zilpotentan or a pharmaceutically acceptable salt thereof administered is 0.25 mg to 1.5 mg. In embodiments, the total daily dose of zilpotentan is 0.25 mg. In embodiments, the total daily dose of zilpotentan is 0.5 mg. In embodiments, the total daily dose of zilpotentan is 0.75 mg. In embodiments, the total daily dose of zilpotentan is 1.0 mg. In embodiments, the total daily dose of zilpotentan is 1.25 mg. In embodiments, the total daily dose of zilpotentan is 1.5 mg.

[0183] In an embodiment, zilpotentan or a pharmaceutically acceptable salt thereof is in tablet form. In an embodiment, zilpotentan or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises one or more pharmaceutical diluents, one or more pharmaceutical disintegrants, or one or more pharmaceutical lubricants.

[0184] In an embodiment, dapagliflozin or a pharmaceutically acceptable salt thereof is administered once daily.

[0185] 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 a non-crystalline solid. In some aspects provided herein, dapagliflozin is in the form of a crystalline solid. In some aspects provided herein, dapagliflozin is in the form of a (S)-propylene glycol ((S)-PG) solvate having the following structure:

[0186]

[0187] In aspects provided herein, dapagliflozin is administered to a patient orally. In aspects provided herein, dapagliflozin is administered to a patient in tablet form.

[0188] In an embodiment, the total daily dose of dapagliflozin or a pharmaceutically acceptable salt thereof administered is 2.5 mg 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.

[0189] In an embodiment, zilpotentan, or a pharmaceutically acceptable salt thereof, is administered once daily in a fixed-dose combination with dapagliflozin, or a pharmaceutically acceptable salt thereof.

[0190] In an embodiment, a fixed-dose combination of zilpotentan and dapagliflozin is administered, comprising a total daily dose of 0.25 mg to 1.5 mg of zilpotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 2.5 mg to 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof. In an embodiment, a fixed-dose combination of zilpotentan and dapagliflozin is administered, comprising a total daily dose of 0.25 mg of zilpotentan 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, a fixed-dose combination of zilpotentan and dapagliflozin is administered, comprising a total daily dose of 0.5 mg of zilpotentan 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, a fixed-dose combination of zilpotentan and dapagliflozin is administered, comprising a total daily dose of 0.75 mg of zilpotentan or a pharmaceutically acceptable salt thereof and a total daily dose of 10.0 mg of dapagliflozin or a pharmaceutically acceptable salt thereof.

[0191] In embodiments, administration of a fixed-dose combination of zilpotentan, 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, administration of a fixed-dose combination of zilpotentan, 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, administration of a fixed-dose combination of zilpotentan, 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, administration of a fixed-dose combination of zilpotentan, 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 decreased eGFR.

[0192] In embodiments, administration of a fixed-dose combination of zilpotentan, 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 of the patient for heart failure (hHF). In embodiments, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof reduces the patient's risk of hHF.

[0193] In embodiments, administration of the fixed-dose combination of zilpotentan, 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, administration of the fixed-dose combination of zilpotentan, 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 in the patient.

[0194] In embodiments, administration of a fixed-dose combination of zilpotentan, 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 the patient's brain natriuretic peptide (BNP) level. In embodiments, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof reduces the risk of an increase in the patient's BNP level.

[0195] In embodiments, administration of the fixed-dose combination of zilpotentan, 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 the patient's total body water. In embodiments, administration of the fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof reduces the risk of an increase in the patient's total body water.

[0196] In an embodiment, administration of a fixed-dose combination of zilpotentan, 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 an embodiment, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof reduces the risk of weight gain in the patient.

[0197] In embodiments, administration of a fixed-dose combination of zilpotentan, 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, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof reduces the risk of an increase in the patient's blood pressure.

[0198] In embodiments, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof results in a lowering of cholesterol in the patient. In embodiments, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof reduces the patient's risk of elevated cholesterol.

[0199] In embodiments, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof results in a decrease in hemoglobin A1c (HbA1c) in the patient. In embodiments, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof reduces the risk of an elevated HbA1c in the patient.

[0200] In embodiments, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof having ANCA vasculitis results in a reduced incidence of ANCA vasculitis in the patient. In embodiments, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof having ANCA vasculitis results in a reduced recurrence of ANCA vasculitis in the patient.

[0201] In embodiments, administration of a fixed-dose combination of zilpotentan, 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 the patient's Alport syndrome. In embodiments, administration of a fixed-dose combination of zilpotentan, 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, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient with Alport syndrome in need thereof treats the patient's Alport syndrome.

[0202] In embodiments, administration of a fixed-dose combination of zilpotentan, 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, administration of a fixed-dose combination of zilpotentan, or a pharmaceutically acceptable salt thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, to a patient with biopsy-confirmed IgAN at risk for rapid disease progression in need thereof results in a reduction in the progression of renal function decline associated with IgAN in the patient. In embodiments, administration of a fixed-dose combination of zilpotentan, 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 the patient's IgAN.

[0203] In embodiments, administration of a fixed-dose combination of zilpotentan, 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, administration of a fixed-dose combination of zilpotentan, 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.

[0204] In some embodiments, the disease modification, morbidity reduction, risk reduction, and other beneficial effects described herein and provided by administration of the fixed-dose combination of zilpotentan and dapagliflozin as described in the preceding embodiments may represent an improvement over no therapy, an improvement over placebo treatment, an improvement over treatment with dapagliflozin alone, and / or an improvement over treatment with other standard therapies for CKD and / or a disease, disorder, or condition associated with hyperalbuminuric chronic kidney disease.

[0205] In an embodiment, the fixed dose combination of zilpotentan or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof is administered simultaneously. In an embodiment, zilpotentan or a pharmaceutically acceptable salt thereof is administered before the administration of dapagliflozin or a pharmaceutically acceptable salt thereof. In an embodiment, zilpotentan or a pharmaceutically acceptable salt thereof is administered after the administration of dapagliflozin or a pharmaceutically acceptable salt thereof.

[0206] Pharmaceutical composition can be used in any manner suitable for the disease to be treated, illness and / or the patient's condition, as determined by those of ordinary skill in the medical field. Appropriate dosage and suitable duration of application and frequency will be determined by factors discussed herein, including the patient's condition, the type and severity of the patient's disease, the specific form of active ingredient and the method of administration. In general, appropriate dosage (or effective dose) and treatment regimen provide compositions as described herein in an amount sufficient to provide treatment and / or prevention benefit (e.g., improved clinical outcome, such as more frequent complete or partial remission, or longer disease-free and / or overall survival, or the alleviation of symptom severity or other benefits as described in detail above).

[0207] The pharmaceutical composition can be formulated using conventional solid or liquid vehicles, diluents, and pharmaceutical additives suitable for the desired mode of administration. The pharmaceutical composition can be administered by a variety of routes, including, for example, oral administration in the form of tablets, capsules, granules, powders, parenteral administration in the form of injectable preparations, intranasal administration, rectal administration, and transdermal administration (e.g., in the form of patches).

[0208] 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 any type of formulation auxiliary), excipients, lubricants, buffers, antibacterial agents, fillers (such as mannitol), adjuvants, etc.

[0209] Some examples of materials that can be used 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, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, 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; ethanol; and phosphate buffered solutions, and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coating agents; sweeteners; flavoring agents; and fragrances; preservatives; and antioxidants.

[0210] 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 (such as olive oil) and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating (such as lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0211] The example of adjuvant comprises preservative, wetting agent, emulsifier, dispersant, suspending agent, sweetener, flavoring agent and aromatic.Can ensure the effect of preventing microorganism by various antibacterial and antifungal (for example, paraben, chlorobutanol, phenol sorbic acid etc.).Also may wish to comprise isotonic agent, for example sugar, sodium chloride etc..Can prolong the absorption of injectable drug form by using the medicament (such as aluminum monostearate and gelatin) of delayed absorption.Suspending agent comprises for example ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth gum and their mixture.

[0212] The various pharmaceutical compositions employed in the methods of the present disclosure may optionally include one or more fillers or excipients in an amount 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, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts (such as calcium carbonate), and cellulose derivatives (such as wood cellulose and microcrystalline cellulose).

[0213] In addition to filler or instead of filler, one or more adhesives can also be present, and its amount is in the scope of about 0% to about 35%.In some embodiments, adhesive exists with the amount of about 0.5 % by weight to about 30 % by weight of composition.The example of suitable adhesive comprises polyvinylpyrrolidone (molecular weight range is about 5000 to about 80,000, and is about 40,000 in some embodiments), lactose, starch (such as corn starch, modified corn starch), sugar, gum arabic etc., and the wax adhesive of fine powder (less than 500 microns), such as carnauba wax, paraffin wax, spermaceti, polyethylene and microcrystalline wax.

[0214] In some embodiments, the pharmaceutical composition is in the form of a tablet, wherein the tablet includes one or more tableting lubricants in an amount of about 0.2% to about 8% by weight of the composition. In some embodiments, the amount of tableting lubricant is in the range of 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 silicon dioxide flow regulators or glidants, such as Syloid brand silicon dioxide.

[0215] In some embodiments, the pharmaceutical composition is in the form of a tablet, wherein the tablet includes a coating layer, which may account for about 0% to about 15% of the tablet composition weight. The coating layer may include any conventional coating formulation, which may include, for example, one or more film formers or binding agents and / or one or more plasticizers. Examples of suitable film formers or binding agents include, but are not limited to, hydrophilic polymers (such as hydroxypropyl methylcellulose), hydrophobic polymers (such as methacrylate), neutral polymers, ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, β-pinene polymers, glycerides of wood resins, etc. Examples of suitable plasticizers include, but are not limited to, triethyl citrate, diethyl phthalate, propylene glycol, glycerol, butyl phthalate, castor oil, etc. Tablet core and coating formulations may contain aluminum lakes to provide color.

[0216] In some embodiments, the pharmaceutical composition is in the form of a tablet, wherein the film-forming agent is applied to the tablet from a solvent system containing one or more solvents including water, alcohols (such as methanol, ethanol, and isopropanol), ketones (such as acetone and ethyl methyl ketone), chlorinated hydrocarbons (such as dichloromethane, dichloroethane, and 1,1,1-trichloroethane).

[0217] In some embodiments, the pharmaceutical composition is in tablet form, wherein the color is applied along with the film former, plasticizer, and solvent composition.

[0218] In some embodiments, the pharmaceutical composition in tablet form used in the methods of the present disclosure can be obtained by a method comprising the following steps:

[0219] a) mixing inactive ingredients with at least one compound of formula (I);

[0220] b) preparing granules;

[0221] c) drying and / or sieving the granules;

[0222] d) mixing particles; and

[0223] e) The blend obtained in (d) is compressed into tablets.

[0224] In some embodiments, step a) of the method employs impact blending or grinding and / or screening equipment. In some embodiments, the granules in step b) of the method are prepared by dry granulation, wet granulation, or direct compression. In some embodiments, the granules are prepared by dry granulation. In some embodiments, the granules in step d) of the method are blended with a tableting aid or lubricant and a filler.

[0225] In some embodiments, the pharmaceutical composition in capsule form can be obtained by a method comprising the steps of:

[0226] a) mixing inactive ingredients with at least one compound of formula (I) using a combination of blending and milling methods;

[0227] b) preparing granules;

[0228] c) drying and / or sieving the granules; and

[0229] d) Filling the granules into capsules.

[0230] In some embodiments, step a) of the method employs impact milling or blending and / or screening equipment. In some embodiments, the granules in step b) of the method are prepared by dry granulation, wet granulation, or direct compression. In some embodiments, the granules are prepared by dry granulation.

[0231] In some embodiments, the pharmaceutical composition may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. The effects of microorganisms can be prevented by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol sorbic acid, etc.). It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. The absorption of injectable drug forms can be prolonged by including agents that delay absorption (such as aluminum monostearate and gelatin).

[0232] In some embodiments, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection. In some embodiments, this is achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. In some embodiments, delayed absorption is achieved by dissolving or suspending the drug in an oily vehicle.

[0233] In some embodiments, the pharmaceutical composition is an injectable depot form. In some embodiments, the injectable depot form comprises a microcapsule matrix of the drug in a biodegradable polymer (such as polylactide-polyglycolide). According to the ratio of the drug to the polymer and the properties of the specific polymer adopted, the drug release rate can be controlled. Examples of other biodegradable polymers suitable for use herein include poly(orthoesters) and poly(anhydrides). In some embodiments, a depot-type injectable formulation is prepared by embedding the drug in a liposome or microemulsion compatible with body tissues.

[0234] In some embodiments, the pharmaceutical compositions are injectable preparations, which can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0235] In some embodiments, the pharmaceutical composition is a solid dosage form suitable for oral administration.Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In some embodiments, at least one compound selected from the group consisting of compounds of formula (I) and prodrugs thereof is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In some embodiments, the dosage form may also contain a buffer.

[0236] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (milk sugar) as well as high molecular weight polyethylene glycols and the like.

[0237] In some embodiments, tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0238] In some embodiments, at least one compound selected from the compounds of formula (I) and / or compounds of formula (II) and / or prodrugs thereof can be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0239] In some embodiments, the pharmaceutical composition can be 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 also contain inert diluents (e.g., water or other solvents), solubilizers and emulsifiers commonly used in the art, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0240] The following examples provide illustrative embodiments of the present disclosure. Those skilled in the art will recognize that various modifications and variations may be made without altering the spirit or scope of the present disclosure. Such modifications and variations are within the scope of the present disclosure. The examples provided are not intended to limit the present disclosure in any way.

[0241] Example

[0242] Example 1

[0243] Clinical trials of the fixed-dose combination of dapagliflozin and zilpotentan are ongoing, including randomized, double-blind, parallel-group, active-controlled studies, to evaluate the efficacy of the fixed-dose combination of dapagliflozin and zilpotentan compared with dapagliflozin monotherapy in patients with CKD and hyperalbuminuria.

[0244] Study Design

[0245] Figure 1 The study timeline is illustrated. Approximately 1500 patients aged ≥18 years with documented CKD (eGFR ≥20 mL / min / 1.73 m 2 -<90mL / min / 1.73m 2, UACR ≥ 700 mg / g-< 900 mg / g or UPCR ≥ 1.0 g / g-< 1.3 g / g, and first-time SGLT2 inhibitor users) will be randomly assigned to a fixed-dose combination of zilpotentan and dapagliflozin or dapagliflozin monotherapy in a 1:1 ratio, as shown in Table 3. Patients will be recruited for approximately 18 months, followed by a 24-month treatment period and a 1-month safety follow-up, with a total study length of approximately 43 months and an average follow-up period of approximately 33 months. All variables will be collected to verify inclusion criteria and other demographic data, such as race / ethnicity, serum creatine, and height. A minimum of 30% of patients will have type 2 diabetes, and 30% of patients without type 2 diabetes will be randomly assigned between study groups.

[0246] Table 1. Inclusion criteria

[0247]

[0248] Table 2. Exclusion criteria

[0249]

[0250]

[0251]

[0252] Table 3. Study groups of Example 1

[0253]

[0254] Patients will receive either dapagliflozin (10 mg) monotherapy once daily or a fixed-dose combination of zilpotentan (0.75 mg) and dapagliflozin (10 mg) once daily. Patients who are not already receiving a stable dose of an SGLT2 inhibitor will undergo a 4-week lead-in, during which they will receive 10 mg of an SGLT2 inhibitor once daily prior to the start of the treatment period. Participants will be assessed for endpoints and objectives at study center visits corresponding to pre-randomization screening, randomization, and on study days 14 (±3), 90 (±10), 180 (±10), 270 (±10), 360 (±10), 480 (±10), 600 (±10), and 720 (±7).

[0255] Goals and End Points

[0256] The primary endpoint will measure the effect of the fixed-dose combination of zilpotentan and dapagliflozin relative to dapagliflozin monotherapy on eGFR, UPCR, and UACR. Table 4 summarizes the endpoints and objectives (including secondary endpoints and objectives).

[0257] Table 4. Primary, Secondary, Exploratory, and Safety End Points and Objectives

[0258]

[0259]

[0260] Appendix A (EQ-5D-5L Questionnaire)

[0261] Health Questionnaire

[0262] Under each heading, please check the box that best describes your health status today.

[0263] Activity

[0264]

[0265] Self-care

[0266]

[0267] Daily activities (such as work, school, housework, family, or leisure activities)

[0268]

[0269] pain / discomfort

[0270]

[0271]

[0272] We would like to know whether your health status is good or bad today.

[0273] The scale is numbered from 0 to 100.

[0274] 100 means what you can imagine optimal Health status.

[0275] 0 means you can imagine Worst Health status.

[0276] Mark an X on the scale to indicate your health status today.

[0277] Now, write the number you marked on the scale in the box below.

[0278]

[0279] United States (English) 2009 EuroQol Group. EQ-5D TMis a trademark of EuroQol Group Example 2

[0280] A clinical trial of a fixed-dose combination of dapagliflozin and zilpotentan is underway, including a randomized, double-blind, parallel-group, active-controlled study to evaluate the efficacy of a fixed-dose combination (FDC) of dapagliflozin and zilpotentan compared to dapagliflozin monotherapy in patients with CKD and hyperproteinuria (see Example 1). Example 2 provides an improved regimen involving dose titration of zilpotentan in the fixed-dose combination.

[0281] Study Design

[0282] Figure 2 The study timeline is illustrated. Approximately 1500 patients who met the eligibility criteria (see inclusion and exclusion criteria in Tables 5A and 5B, respectively) were randomly assigned in a 1:1 ratio to one of two treatment groups:

[0283] Zipotentan / dapagliflozin is administered orally once daily as a FDC.

[0284] Dapagliflozin 10 mg, administered orally once daily (active comparator).

[0285] Table 5A. Study inclusion criteria.

[0286]

[0287]

[0288] 1 Highly effective contraceptive methods include:

[0289] Complete abstinence, as long as this is the participant's usual lifestyle (defined as avoiding heterosexual intercourse throughout the risk period associated with the study treatment). Note that periodic abstinence (e.g., calendar method, ovulation method, temperature method, post-ovulation method), declared abstinence during the study intervention, and discontinuation of medication are not acceptable contraceptive methods.

[0290] ·Partners who have had a vasectomy, Bilateral fallopian tube obstruction, intrauterine device / levonorgestrel intrauterine system, Depo-Provera TM injection, oral contraceptive containing ethinyl estradiol and levonorgestrel, Evra Patch TM Xulane TM or

[0291] Table 5B. Study exclusion criteria.

[0292]

[0293]

[0294] Throughout the study and until at least 1 month after the last dose of the study intervention, women of childbearing potential (WOCBP) will use adequate contraception with at least 2 methods of contraception; the 2 methods will include (1) a highly effective method of contraception (see Inclusion Criteria 4 for the 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 will be performed.

[0295] Screen failure occurs when a participant agrees to participate in a clinical study but is subsequently not randomized. A minimum set of screen failure information is required to ensure transparent reporting of participants with screen failures to meet Consolidated Standards of Reporting Trials (CONSORT) publication requirements and respond to inquiries from regulatory agencies. This minimum information includes demographics, screen failure details, eligibility criteria, and any serious adverse events (SAEs).

[0296] Individuals who do not meet the criteria for participation in this study (screening failure) may need to undergo a full re-screening. Re-screened participants will re-sign the informed consent form and be assigned the same participant number as the initial screening.

[0297] If during the screening period, the values ​​for the following studies are outside the participant's normal range based on the participant's medical history, 2 retests will be performed without rescreening: blood pressure, eGFR, ACR, ALT, AST, and spot urine for bilirubin.

[0298] Study participants who have not yet received an SGLT2i at the initial screening visit (Visit 1) will receive a 28-day run-in intervention with a once-daily SGLT2i. All participants, including those who were already receiving a stable dose of an SGLT2i at the initial screening visit (Visit 1), will take their last dose of a prescribed SGLT2i on the day before randomization (Day -1) and will switch to the study intervention at Visit 2 (Day 1) based on their randomized treatment group assignment. The dose of the fixed-dose combination of zilpotentan / dapagliflozin or dapagliflozin monotherapy will be determined based on eGFR status at the initial screening visit (Visit 1) as described below and Figure 3 As stipulated in:

[0299] eGFR <45 mL / min / 1.73 m 2 : Randomized 1:1 to zilpotentan / dapagliflozin 0.25mg / 10mg FDC QD or dapagliflozin 10mg QD (active comparator)

[0300] eGFR ≥ 45 mL / min / 1.73 m 2: Randomized 1:1 to zilpotentan / dapagliflozin 0.75mg / 10mg FDC QD or dapagliflozin 10mg QD (active comparator)

[0301] Ceiling measures will be used to ensure that participants with or without type 2 diabetes (T2D) and eGFR status at screening (eGFR < or ≥ 45 mL / min / 1.73 m 2 ) are sufficiently representative.

[0302] To ensure blinding of treatment, the zilpotentan / dapagliflozin 0.25 mg / 10 mg FDC, zilpotentan / dapagliflozin 0.75 mg / 10 mg FDC, and dapagliflozin 10 mg tablets will be identical in appearance (matched and indistinguishable from the zilpotentan / dapagliflozin FDC). Participants, study center personnel, and the sponsor will be blinded to the study interventions. Table 6 below provides information about the study interventions.

[0303] Table 6. Study interventions.

[0304]

[0305] aZilpotentan / dapagliflozin dose will be based on eGFR status at screening (Visit 1): If eGFR < 45 mL / min / 1.73 m 2 , then 0.25mg / 10mg FDC, if eGFR ≥ 45mL / min / 1.73m 2 , then it is 0.75mg / 10mg FDC.

[0306] bDose modifications were performed as described herein.

[0307] FDC = fixed-dose combination; IMP = investigational medicinal product; NIMP = non-investigational medicinal product; QD = once daily.

[0308] Participants will receive blinded study interventions from Day 1 until the end-of-treatment (EoT) visit. The common end-of-treatment date (CTED) (defined as 2 years after the last participant's randomization date in the study) will be used to determine when the EoT visit should occur. For all participants, the EoT visit will preferably occur within 14 days and no more than 28 days after the CTED. At the EoT visit, participants will stop blinded study interventions and will start open-label dapagliflozin 10 mg monotherapy until the safety follow-up visit (last study visit).

[0309] In the event of premature discontinuation of the blinded study intervention, participants will continue on study and receive open-label dapagliflozin 10 mg monotherapy unless the investigator determines that the participant cannot tolerate dapagliflozin. The EoT visit will be the last study visit for these participants.

[0310] All participants will be followed in the study until 24 months after the last participant is randomized. The participant recruitment period is 18 months, so the study length will be approximately 43 months, with an average follow-up period of approximately 33 months.

[0311] Participants will have four visits during the first three months of treatment (Days 1, 14, 30, and 90), followed by visits every three months during the first year (until Day 360) and every four months thereafter. An additional visit will be required one week after Visit 11 (Day 720). When a CTED is determined, the End of Time (EoT) visit will be scheduled within 28 days of the CTED. A safety follow-up visit will be conducted one month after the EoT visit.

[0312] Tables 7A, 7B, and 7C summarize the schedule of study activities, including screening and randomization of SGLT2i-naive participants (Table 7A), screening and randomization of SGLT2i-treated participants (Table 7B), receipt of treatment, discontinuation of study intervention, and safety follow-up (Table 7C).

[0313] Table 7A. Schedule of Activities: Screening and Randomization of Participants Naive to SGLT2 Inhibitors.

[0314]

[0315]

[0316] NOTE: PRO questionnaires should be completed prior to any other study procedures or discussions (after informed consent), including medications,

[0317] This is to avoid biasing participants' responses to questions.

[0318] a Individuals who do not meet the criteria for participation in this study (screening failure) may need to be re-screened. Re-screened participants should re-sign the informed consent form and be assigned the same participant number as the initial screening. If, during the screening period, the values ​​of the following studies are outside the participant's normal range based on the participant's medical history, up to two retests may be performed without re-screening: blood pressure, eGFR, UACR and UPCR, ALT, AST, and random urine for bilirubin.

[0319] bThe 10-day window (-34 [±5] days) for Visit 1 is to allow for turnaround time for central laboratory results before the 28-day run-in. Participants not already receiving a stable dose of an SGLT2i will enter a 28-day SGLT2i run-in from Day -28 to Day -1. During the run-in period, the SGLT2i will be provided as an adjunctive medication.

[0320] c Negative pregnancy test required for all women at enrollment / before the first dose of study intervention.

[0321] d All WOCBP patients will require monthly pregnancy testing (urine) and contraceptive adherence monitoring from randomization until 1 month after the last dose. If the result is positive, treatment should be discontinued and the procedures for suspected contraceptive failure or suspected pregnancy should be followed. The company may consider the option of having a healthcare professional perform a home pregnancy test in months when no visit is scheduled.

[0322] e Women who meet one of the following criteria at screening are considered infertile: (a) postmenopausal, defined as amenorrhea for at least 12 months or longer after cessation of all exogenous hormone therapy, and with an FSH level within the postmenopausal range. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to define postmenopausal status. In the rare case of perimenopausal women or those with variable FSH levels, they should be considered fertile; or (b) documented irreversible surgical sterilization, including hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, excluding tubal ligation.

[0323] f Include signs of fluid retention.

[0324] g Tests include: B-hemoglobin, B-white blood cell differential count (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, S-sodium.

[0325] h Plasma, serum, and urine samples for potential future biomarker studies are optional.

[0326] i Participation in the Genome Initiative research is optional and requires separate consent from the participant.

[0327] AE = adverse event; AESI = adverse event of special interest; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 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 Questionnaire (5 dimensions, 5 levels); EQ-VAS = European Quality of Life Visual Analogue Scale; FSH = follicle-stimulating hormone; GGT = gamma-glutamyltransferase; HbA1c = glycated hemoglobin protein; HIV = human immunodeficiency virus; IRT = interactive response technology; NYHA = New York Heart Association; PRO = patient-reported outcome; PTDV = premature discontinuation of treatment 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 = study participant feedback questionnaire; UACR = urine albumin-to-creatinine ratio; UPCR = urine protein-to-creatinine ratio; WOCBP = women of childbearing potential.

[0328] Table 7B. Activity Schedule: Screening and Randomization of Participants for SGLT2 Inhibitor Therapy.

[0329]

[0330]

[0331] NOTE: The PRO questionnaire should be completed before any other study procedures or discussions (after informed consent), including medication, to avoid biasing participant responses to the questions.

[0332] a Individuals who do not meet the criteria for participation in this study (screening failure) may need to be re-screened. Re-screened participants should re-sign the informed consent form and be assigned the same participant number as the initial screening. If, during the screening period, the values ​​of the following studies are outside the participant's normal range based on the participant's medical history, up to two retests may be performed without re-screening: blood pressure, eGFR, UACR and UPCR, ALT, AST, and random urine for bilirubin.

[0333] b Participants were already receiving a stable dose of an SGLT2i.

[0334] c Negative pregnancy test required for all women at enrollment / before the first dose of study intervention.

[0335] dAll WOCBP patients will require monthly pregnancy testing (urine) and contraceptive adherence monitoring from randomization until 1 month after the last dose. If the result is positive, treatment should be discontinued and the procedures for suspected contraceptive failure or suspected pregnancy should be followed. The company may consider the option of having a healthcare professional perform a home pregnancy test in months when no visit is scheduled.

[0336] e Women who meet one of the following criteria at screening are considered infertile: (a) postmenopausal, defined as amenorrhea for at least 12 months or longer after cessation of all exogenous hormone therapy, and with an FSH level within the postmenopausal range. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to define postmenopausal status. In the rare case of perimenopausal women or those with variable FSH levels, they should be considered fertile; or (b) documented irreversible surgical sterilization, including hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, excluding tubal ligation.

[0337] f Include signs of fluid retention.

[0338] g Tests include: B-hemoglobin, B-white blood cell differential count (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, S-sodium.

[0339] h Plasma, serum, and urine samples for potential future biomarker studies are optional.

[0340] i Participation in the Genome Initiative research is optional and requires separate consent from the participant.

[0341] AE = adverse event; AESI = adverse event of special interest; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 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 Questionnaire (5 dimensions, 5 levels); EQ-VAS = European Quality of Life Visual Analogue Scale; FSH = follicle-stimulating hormone; GGT = gamma-glutamyltransferase; HbA1c = glycated hemoglobin protein; HIV = human immunodeficiency virus; IRT = interactive response technology; NYHA = New York Heart Association; PRO = patient-reported outcome; PTDV = premature discontinuation of treatment 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 = study participant feedback questionnaire; UACR = urine albumin-to-creatinine ratio; UPCR = urine protein-to-creatinine ratio; WOCBP = women of childbearing potential.

[0342] Table 7C. Schedule of Activities: Treatment Receipt, Study Intervention Discontinuation, and Safety Follow-up.

[0343]

[0344]

[0345]

[0346] NOTE: The PRO questionnaire should be completed before any other study procedures or discussions (after informed consent), including medication, to avoid biasing participant responses to the questions.

[0347] a The CTED is defined as 2 years after the randomization date of the last participant in the study and will be used to determine when the EoT visit will be scheduled. For all participants (including those who discontinue the blinded study intervention early), the EoT visit should preferably occur within 14 days and no more than 28 days after the CTED. At the EoT visit, participants who are still receiving blinded treatment will discontinue the blinded study intervention and start 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 according to the SoA, the EoT visit will be the final study visit.

[0348] b Visit 4: Phone call to assess fluid retention and related conditions.

[0349] cAll WOCBP patients will require monthly pregnancy testing (urine) and contraceptive adherence monitoring from randomization until 1 month after the last dose. If the result is positive, treatment should be discontinued and the procedures for suspected contraceptive failure or suspected pregnancy should be followed. The company may consider the option of having a healthcare professional perform a home pregnancy test in months when no visit is scheduled.

[0350] d Women who meet one of the following criteria at screening are considered infertile: (a) postmenopausal, defined as amenorrhea for at least 12 months or longer after cessation of all exogenous hormone therapy, and with an FSH level within the postmenopausal range. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to define postmenopausal criteria. In the rare case of perimenopausal women or those with variable FSH levels, they should be considered fertile; or (b) documented irreversible surgical sterilization, including hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, excluding tubal ligation.

[0351] e These include fluid retention and signs of heart failure.

[0352] f Tests include: B-hemoglobin, B-white blood cell differential count (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, S-sodium.

[0353] g The mean eGFR value at Visit 11 will be calculated based on the eGFR values ​​at Visit 11 and Visit 11.1.

[0354] h PK samples will be collected pre-dose at Visits 3, 6, and 9.

[0355] i Except for Visits 3, 6, and 9, study interventions will be delivered at home.

[0356] j Plasma, serum, and urine samples for potential future biomarker studies are optional.

[0357] AE = adverse event; AESI = adverse event of special interest; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 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 Questionnaire (5 dimensions, 5 levels); EQ-VAS = European Quality of Life Visual Analogue Scale; FSH = follicle-stimulating hormone; GGT = gamma-glutamyltransferase; Hb A1c = glycated hemoglobin; HIV = human immunodeficiency virus; NYHA = New York Heart Association; PK = pharmacokinetics; PRO = patient-reported outcome; PTDV = premature discontinuation of treatment 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.

[0358] Study compliance

[0359] Participants will be treated in the clinic on designated visit days and at home in all other cases. When participants are dosed at the study center, they will receive the study intervention directly from the investigator or designated personnel under medical supervision. The date and time of the dose administered in the clinic (if applicable) will be recorded in the source document and recorded in the electronic case report form (eCRF). The dose of the study intervention and the identity of the study participant will be confirmed at the time of administration by a member of the study center staff, not the person administering the study intervention. When participants self-administer the study intervention at home, their compliance with the study intervention will be assessed at each visit.

[0360] Adherence will be assessed by direct questioning, counting returned tablets during site visits, and documented in source documents and the eCRF. Deviations from the prescribed dosing regimen will be documented in the eCRF.

[0361] Records of the number of zilpotentan / dapagliflozin 0.25 mg / 10 mg and zilpotentan / dapagliflozin 0.75 mg / 10 mg FDCs and dapagliflozin 10 mg tablets allocated to and administered to each participant will be maintained and reconciled with study intervention and adherence records. Intervention start and stop dates (including dates of intervention delays and / or dose reductions) will also be recorded in the eCRF.

[0362] Dose modifications

[0363] Participants randomized to the high-dose FDC (zipotentan / dapagliflozin 0.75 mg / 10 mg) or matching dapagliflozin monotherapy may be down-titrated to the low-dose FDC (zipotentan / dapagliflozin 0.25 mg / 10 mg) or pseudo-down-titrated if on dapagliflozin monotherapy, in consultation with the medical monitor, for the following reasons (to maintain double-blind):

[0364] Signs and / or symptoms of fluid retention assessed as related to the investigational medicinal product (IMP) that are not resolved with intervention.

[0365] Symptomatic hypotension that is not resolved by adjustment of concomitant antihypertensive medications.

[0366] In addition, any participant randomized to high-dose FDC (zipotentan / dapagliflozin 0.75 mg / 10 mg) or matching dapagliflozin monotherapy who had a centrally confirmed decline in eGFR to <30 mL / min / 1.73 m2 at a scheduled or unscheduled study visit was eligible for admission. 2 If the patient's symptoms persisted, they would be stepped down to a low-dose FDC (zipotentan / dapagliflozin 0.25 mg / 10 mg), or if using dapagliflozin monotherapy, a sham step-down would be performed, regardless of symptoms (maintaining double-blind).

[0367] 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 adverse events (AEs).

[0368] No dose adjustment will be made for participants receiving low-dose FDC (zipotentan / dapagliflozin 0.25 mg / 10 mg) or matched dapagliflozin monotherapy. However, the IMP dose (applicable to both the high and low dose levels) may be maintained as clinically indicated. 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 scheduled time relative to the first dose of IMP).

[0369] excess

[0370] In single-dose studies in healthy volunteers, dapagliflozin was well tolerated at doses up to 500 mg / day, and in 14-day repeated-dose studies in healthy volunteers and patients with type 2 diabetes, dapagliflozin was well tolerated at doses up to 100 mg / day. If overdose is suspected, vital function monitoring will be performed and appropriate treatment will be implemented.

[0371] There is currently no information on human overdose with zilpotentan. For the purposes of this study, overdose was defined as the use of the study intervention at a dose exceeding that specified in the protocol.

[0372] In the event of an overdose, the investigator / treating physician will:

[0373] Assess the participant and, if possible, consult with the study clinical lead to determine whether the study intervention should be interrupted or the dose should be reduced.

[0374] Closely monitor participants for any AEs / SAEs and laboratory abnormalities.

[0375] Concomitant medication

[0376] Any medications or vaccines (including over-the-counter or prescription medications, recreational drugs, vitamins, and / or herbal supplements) that the participant received at enrollment or during the study (except for screening failures)

[0377] Will be recorded along with the following information:

[0378] Reason for use.

[0379] Dates of application, including start and end dates.

[0380] Dosage information, including dose, frequency, and route.

[0381] Because ET-1 has a potential role in maintaining blood pressure, hypotension may occur after ET blockade. Although only a slight decrease in blood pressure was observed in patients, more significant changes may occur in hypertensive patients, especially those taking hypotensive therapies (such as ACE inhibitors, calcium antagonists, or alpha blockers). If symptomatic hypotension occurs, the subject will remain supine until the symptoms disappear. If persistent hypotension is observed, consideration will be given to adjusting concomitant medications for blood pressure control. Intravenous fluid support will be considered for cases deemed severe by the investigator.

[0382] Participants using medications that may cause hypoglycemia in patients with T2DM, including insulin or sulfonylureas (SUs), may need to reduce insulin by 10% to 20% (total daily dose) and SUs by 25% to 50%. In addition, more frequent blood glucose monitoring will be considered for participants receiving insulin and / or SUs and with a baseline HbA1c ≤7% at randomization.

[0383] The following medications and supplements are prohibited from use from the date 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:

[0384] Strong or moderate CYP3A4 inducers

[0385] Cyclosporine or tacrolimus.

[0386] Receipt of cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary renal disease within 6 months prior to screening, except for stable maintenance therapy (see Exclusion Criteria).

[0387] Tolvaptan, any other ERA, or budesonide (used to treat IBD or IgAN).

[0388] Additionally, the last dosing day of any SGLT2i will be the day before the randomization visit, as all participants will receive the SGLT2i dapagliflozin as part of the IMP from randomization.

[0389] If a participant's medical condition requires rescue therapy, the participant will be treated and withdrawn from the study intervention at the investigator's discretion. Rescue therapy will be recorded in the eCRF.

[0390] Participants with diabetes may need to adjust other glucose-lowering therapies at the time of initiation of the blinded study intervention (due to the potential for dapagliflozin treatment) to avoid hypoglycemia.

[0391] Initiation and / or titration of diuretic therapy will be used for participants assessed as experiencing new or worsening signs / symptoms of fluid overload.

[0392] Study discontinuation

[0393] Participants may need to permanently discontinue (definitely discontinue) the study intervention. The study intervention may be discontinued for an individual participant in the following circumstances:

[0394] Participant decision. Participants are free to discontinue treatment at any time without affecting further treatment.

[0395] AEs (in the opinion of the investigator or sponsor) necessitating discontinuation of further dosing.

[0396] Serious non-compliance with the clinical study protocol (CSP).

[0397] The investigator and / or sponsor judges that continuing treatment may place the participant at excessive risk for safety reasons.

[0398] The study intervention will be discontinued for an individual participant if:

[0399] If a participant becomes pregnant during the study, the study intervention should be discontinued immediately and the sponsor's representative should be notified.

[0400] Diabetic ketoacidosis (DKA): DKA, including DKA in the presence of normoglycemia, has been reported with 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, reinitiation of study intervention will be considered.

[0401] Symptomatic hypotension (defined as systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg and associated symptoms) with no identifiable reversible cause and in which adjustments in concomitant medications do not resolve symptoms.

[0402] Hospitalization for HF.

[0403] End-stage renal disease.

[0404] An increase in the dose of systemic immunosuppression above that permitted at the time of enrollment.

[0405] It is important to note that discontinuing a study intervention is not the same as withdrawing from the study. If the study intervention is permanently discontinued, the participant will complete an early treatment discontinuation visit, continue with the study visit, and complete further assessments according to the activity schedule.

[0406] Predisposing factors for ketoacidosis include low beta-cell functional reserve due to pancreatic disorders (e.g., type 1 diabetes, pancreatitis, or a history of pancreatic surgery), decreased insulin doses, decreased caloric intake or increased insulin requirements due to infection, illness, or surgery, and alcohol abuse. Dapagliflozin should be used with caution in these participants.

[0407] Participants treated with dapagliflozin who develop signs and symptoms consistent with ketoacidosis (including nausea, vomiting, abdominal pain, malaise, 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 evaluated promptly.

[0408] Exposure to ERAs, including zilpotentan, during pregnancy has been associated with major embryo-fetal harm. Endothelin receptor antagonists have been shown to induce teratogenic effects in animals during early gestational organogenesis. When administered to pregnant rabbits during the period of major embryonic organogenesis, zilpotentan caused teratogenic effects at doses of 1 mg / kg / day and above, consistent with the ERAs. Because of the established teratogenic effects, pregnant women or women with cervical cancer who are not using reliable contraceptive methods should not receive zilpotentan.

[0409] Due to the increased incidence and / or severity of dilated renal pelvis and tubules in offspring, dapagliflozin will not be used in the third trimester of pregnancy. Dapagliflozin will be discontinued when pregnancy is detected. However, due to the teratogenicity of zilpotentan in the first trimester, the stricter guidance for zilpotentan will be followed for this combination.

[0410] If pregnancy occurs while a WOCBP is taking any amount of zilpotentan (even for a short period of time), there is a very high risk of embryo-fetal harm. Potentially, any fetus exposed during pregnancy could be affected.

[0411] Pregnancy testing will be required monthly during treatment and one month after discontinuation of the study intervention. All WOCBP participants must use adequate contraception before the start of treatment, during treatment, and one month after discontinuation of the study intervention (see Inclusion Criteria).

[0412] The researchers will provide WOCBP participants with education and guidance on the risks of embryo-fetal toxicity and unintended pregnancy. The researchers will assess WOCBP participants' adherence to the required contraceptive methods monthly during the study and according to the activity schedule.

[0413] If sexual intercourse occurs without the proper use of adequate contraception, the investigator must be notified immediately and the study intervention will be discontinued. If contraceptive failure is suspected within the past 5 days, the participant will be informed that emergency contraception (pill or intrauterine device) is available. Emergency contraception methods will be approved by the relevant authorities in the participant's area. If a highly reliable serum pregnancy test (S-hCG) is negative, the participant is properly using adequate pregnancy prevention measures, and the investigator deems resumption of treatment appropriate, study treatment will be resumed at least 4 weeks after suspected contraceptive failure.

[0414] If pregnancy is suspected based on signs or symptoms of early pregnancy (such as missed periods, nausea, tiredness, mood swings, or breast pain), the participant will notify the investigator and undergo an unplanned pregnancy test. The participant will be promptly evaluated, a negative test confirmed by a highly reliable serum test (S-hCG), and the study intervention will be discontinued until pregnancy can be reliably ruled out.

[0415] In the event of a positive urine test, study intervention will be discontinued and pregnancy will be promptly confirmed using a highly reliable serum test (S-hCG).

[0416] If pregnancy is confirmed, study intervention will be discontinued, and the investigator will follow emergency unblinding procedures and immediately notify the sponsor's representative. Diagnostic testing will be available to determine the duration of pregnancy and reveal any detectable fetal abnormalities. Participants will be counseled regarding the risks associated with their underlying medical conditions, the teratogenicity of the treatment being administered, the potential duration of unintended embryo-fetal exposure, and the risk of complications. Medical follow-up will be ensured. Participants will have the option of discontinuing participation or remaining in the study for safety monitoring. Pregnancy will be tracked and reported.

[0417] Discontinuation of a participant from the study by the Investigator may occur as follows:

[0418] Participants may be discontinued from the study at any time at the discretion of the investigator for safety, behavioral, compliance, or administrative reasons.

[0419] At the time of study discontinuation, if the participant has not discontinued the study intervention.

[0420] Voluntary withdrawal of a participant from a study may occur as follows:

[0421] • Participants may withdraw from the study at any time for any reason (or no reason) at the participant's own request.

[0422] For participants who wish to withdraw from the study, the investigator will inform them of the revised follow-up options

[0423] (e.g., telephone contact, contact with relatives or treating physicians, or information from medical records).

[0424] If a participant withdraws consent for future disclosure of information, the sponsor will retain and continue to use any data collected before the withdrawal of consent.

[0425] If a participant withdraws from the study, it will be confirmed whether they still consent to the use of existing samples as per the original consent form. If they request to withdraw consent for sample use, any collected but untested samples will be destroyed as described in the informed consent form and local regulations. The investigator will document the decision to use existing samples in the site study records and notify the appropriate site monitor, who will then notify the global study team.

[0426] If a participant failed to return for a scheduled visit multiple times and the study center was unable to contact the participant, the participant was considered lost to follow-up.

[0427] If a participant fails to return to the study center for a required study visit, the following actions will be taken:

[0428] The study center will attempt to contact the participant and reschedule the missed visit as soon as possible. We will counsel the participant on the importance of maintaining the assigned visit schedule. At this time, we will determine whether the participant is willing or wishes to continue in the study.

[0429] Before a participant is considered lost to follow-up, the investigator or designee will make every effort to re-establish contact with the participant (where possible, at least three phone calls, text messages, emails, and, if necessary, a certified letter or local equivalent sent to the participant's last known mailing address). These attempts to contact will be documented in the participant's medical record.

[0430] Study center personnel or an independent third party will attempt to collect vital status information for all randomized participants (including those who do not receive the study intervention), within legal and ethical boundaries. Public sources will be searched for vital status information. If vital status is determined to be deceased, this will be recorded 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.

[0431] Goals and End Points

[0432] The study objectives and endpoints are summarized in Table 8.

[0433] Table 8. Objectives and endpoints.

[0434]

[0435]

[0436]

[0437] AE = adverse event; AESI = adverse event of special interest; CV = cardiovascular; DAE = AE leading to IMP discontinuation; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ECG = electrocardiogram; EQ-5D-5L = European Quality of Life 5-dimension 5-level questionnaire; EQ-VAS = VAS = European Quality of Life Visual Analogue Scale; ESKD = ​​end-stage renal disease; IMP = investigational medicinal product; MI = myocardial infarction; SAE = serious adverse event; UACR = urine albumin-to-creatinine ratio; UPCR = urine protein-to-creatinine ratio.

[0438] Potential endpoint events will be identified by laboratory data when the participant is questioned about his / her general health (see Activity Plan (Tables 7A to 7C) for laboratory assessments and timing) or by information obtained through standard medical practice. Investigators will be encouraged to submit any potential / possible events that may represent endpoints at a lower threshold.

[0439] The following potential endpoints will be documented in the eCRF and submitted for central adjudication:

[0440] ·die

[0441] Heart failure (Adverse Event of Specific Interest (AESI))

[0442] For each potential endpoint event, the investigator or delegate will record endpoint details in the eCRF. If the event is subject to adjudication, relevant source documents will be collected. The source documents and relevant eCRF data will be sent for central adjudication.

[0443] Detailed instructions for endpoint reporting will be provided to the study centers. The Clinical Event Adjudication (CEA) Committee will not have any governance authority and will be blinded to the randomized groups. Further details regarding the assessment of potential endpoint events will be described in the CEA charter. Potential endpoint events will also be reported as AEs / SAEs.

[0444] Primary variable: eGFR

[0445] According to current recommendations, race will be ignored in the calculation of eGFR. (Delgado et al., 2022; Inker et al., 2021). In this study, the lower limit of eGFR (eGFR ≥ 20 ml / min) was set as the limit at which participants' disease progression could occur but there would still be time for eGFR to decline before an ESKD event occurred. The upper limit of CKD (eGFR < 90 ml / min) was set based on the benefit / risk setting. Participants' eGFR will be calculated according to the 2021 CKD-EPI formula, based on

[0446] Individual sCr concentrations (Inker et al. 2021):

[0447] eGFR1=142×min(S cr / κ、1) -0.241(如果是女性) / -0.302(如果是男性) ×max(S cr / κ、1) -1.200 ×0.994 年龄 ×1.012 [if female]

[0448] in:

[0449] SCr = serum creatinine (mg / dL)

[0450] For women, κ = 0.7; for men, κ = 0.9

[0451] min = the minimum of Scr / κ or 1

[0452] max = the maximum of Scr / κ or 1

[0453] Blood samples for determination of serum creatinine and calculation of estimated eGFR will be collected at the time points described in the activity schedule ( Table 7A to FIG. 7C ) and analyzed centrally.

[0454] Secondary variable: UACR

[0455] UACR is a key 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:

[0456] UACR (mg / g) = urine albumin (mg / dL) / urine creatinine (g / dL)

[0457] Urine samples for determination of albumin and creatinine levels and calculation of UACR will be collected and analyzed centrally at the time points described in the activity plan (Tables 7A to 7C). Samples will also be used to measure exploratory urine parameters.

[0458] Secondary variables: UPCR

[0459] UPCR is a key marker for assessing kidney function. UPCR is the ratio between two measured substances (urine protein and creatinine), which estimates 24-hour urine protein excretion. UPCR is calculated as follows:

[0460] UPCR (mg / g) = urine protein measured by the assay (mg / dL) / urine creatinine (g / dL)

[0461] Urine samples for determination of protein and creatinine levels and calculation of UPCR will be collected and analyzed centrally at the time points described in the activity plan (Tables 7A to 7C).

[0462] Secondary variables: renal composite endpoint

[0463] The secondary objective of the study was to determine whether zilpotentan and dapagliflozin in FDC were superior to dapagliflozin alone in shortening the time to first occurrence of a 40% sustained decline or any component of the renal composite endpoint of ESKD or renal death.

[0464] Endpoints associated with decline in eGFR.

[0465] Laboratory values ​​associated with a decline in eGFR will trigger site action if:

[0466] If local laboratory values ​​are obtained outside of study procedures and indicate a decrease in eGFR of ≥40% or less than 10 mL / min / 1.73 m2 compared to baseline 2 .

[0467] ○ Participants will arrive at the study center as soon as possible to have local laboratory values ​​confirmed by central laboratory testing.

[0468] or

[0469] Central laboratory values ​​collected during a study visit that demonstrate a ≥40% decrease in eGFR from baseline or less than 10 mL / min / 1.73 m 2 .

[0470] If eGFR is < 10 mL / min / 1.73 m 2 If the central laboratory value is <10 mL / min / 1.73 m 2 When the eGFR decreased by ≥40% compared with baseline, it was recorded as a potential endpoint in the eCRF.

[0471] The central laboratory will calculate eGFR based solely on sCr concentration using the CKD-EPI formula (Inker et al. 2021).

[0472] Dialysis and kidney transplantation

[0473] If a participant initiates dialysis and / or undergoes a kidney transplant, this will be recorded on the eCRF. ESKD is defined as:

[0474] Sustained eGFR <10 mL / min / 1.73 m 2 or,

[0475] Chronic dialysis treatment (dialysis lasting more than 28 days) or,

[0476] Receiving a kidney transplant

[0477] Kidney death

[0478] All deaths will be adjudicated and classified by CEA committee members based on the definitions described in the CEA Charter. Renal death will be defined as death due to ESKD when dialysis is not ongoing. Investigators will record the classification of renal death in the eCRF.

[0479] Exploratory variables: Patient-reported outcomes (EuroQol five-dimensional five-level questionnaire)

[0480] Patient-reported outcomes (PROs) are an umbrella term for all outcomes and symptoms directly reported by participants. PROs have become important endpoints for regulatory and reimbursement agencies 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 the visits specified in the activity plan (Tables 7A to 7C).

[0481] The EQ-5D-5L is a self-report questionnaire used to derive a standardized measure of health status, also known as a utility score. The EQ-5D-5L utility score is widely accepted by reimbursement agencies and will be used to support health economic evaluations.

[0482] PROs will be administered electronically. Randomized participants will complete PRO assessments at the study center using a handheld electronic device (ePRO). Each study center will assign responsibility for administering the ePRO to a specific individual and, if possible, assign a backup individual to replace that individual if they are unavailable. All assessments will be completed as follows:

[0483] To avoid bias, participants will not receive help from relatives, friends, or study center personnel to answer or clarify the PRO questionnaire. If a participant uses a visual aid (e.g., glasses or contact lenses) for reading and does not have a visual aid at hand, the participant will be excused from completing the PRO questionnaire for that visit.

[0484] Before any other study procedures at a given visit.

[0485] Before being seen by researchers.

[0486] The PRO questionnaire will be completed privately by participants.

[0487] Designated study center personnel will explain the value and relevance of the ePRO assessment to participants,

[0488] The participants were informed that these questions were asked to learn directly from them how they felt.

[0489] Designated study center personnel will also emphasize that the information is confidential.

[0490] Designated study center personnel will demonstrate to participants how to use the ePRO device according to the instructions provided.

[0491] Designated study center personnel will remind participants that there are no right or wrong answers and will allow participants ample time to complete the PRO questionnaire.

[0492] If a participant is unable to read the questionnaire (e.g., blind or illiterate), the participant will be exempted from completing the PRO questionnaire and may still participate in the study.

[0493] Security

[0494] Safety and tolerability will be assessed based on AEs, SAEs, DAEs, SAEs leading to death, AESIs (HF, fluid retention, and hepatotoxicity), clinical laboratories, vital signs, and ECG.

[0495] The planned timings for all safety assessments are provided in the activity plan (Tables 7A to 7C).

[0496] Physical examination

[0497] A comprehensive physical examination will include an assessment 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), neurologic, and volume status. A targeted physical examination will focus on volume status, including signs and symptoms of fluid retention and heart failure. Physical examinations, as well as height assessments, will be performed at the time points specified in the activity plan (Tables 7A through 7C).

[0498] Vital signs

[0499] Vital signs will be taken at the time points specified in the activity plan (Tables 7A to 7C).

[0500] Pulse and blood pressure (BP)

[0501] Pulse and BP will be measured 3 times at each time point, and all measurements will be recorded in the eCRF. Measurements will be taken after the participant has been seated and rested in a quiet environment for at least 5 minutes without distractions (e.g., television, mobile phone), using a standardized calibrated cuff appropriate for the participant's arm size, before any blood sampling. Preferably, the same arm will be used in all visits.

[0502] weight

[0503] Participants' weight will be measured while wearing light clothing and without shoes. If participants have a prosthesis, they will be weighed with or without it at all times.

[0504] electrocardiogram

[0505] After the participant rested in the supine position for at least 5 minutes, a 12-lead ECG (standard ECG with a paper speed of 25 mm / s to 50 mm / s, covering at least 6 consecutive heartbeats) was recorded at the visits listed in the activity plan (Tables 7A to 7C).

[0506] Clinical safety laboratory testing

[0507] Blood and urine samples for clinical chemistry, hematology, and urinalysis were collected at the visits indicated in the activity schedule (Tables 7A to 7C).

[0508] If clinically indicated, additional safety samples will be collected at the investigator's discretion. The date, time of collection, and results (value, units, and reference range) will be recorded on the appropriate eCRF.

[0509] Clinical chemistry, hematology, and urine chemistry will be performed in a central laboratory. The date of central laboratory sample collection will be recorded in the eCRF.

[0510] Other safety laboratory tests include pregnancy assessment (serum at screening or serum or urine at other time points), hepatitis B, hepatitis C serology, and HIV antibody testing. At Visit 2 (randomization), before the first dose of the study intervention, a urine pregnancy test will be negative.

[0511] All specimens will be collected by fully trained study center personnel and processed as directed. Up-to-date reference ranges will be provided during the study, and laboratory results will be compared to laboratory standard normal ranges and reported back to the site.

[0512] Samples sent to the central laboratory will be collected, labeled, stored, and shipped according to instructions.

[0513] The investigator will assess laboratory results for clinically relevant abnormalities. Laboratory results will be signed and dated and retained at the study center as source data for laboratory variables. Laboratory safety variables are summarized in Table 8.

[0514] Table 8. Laboratory safety variables.

[0515] Hematology / Hemostasis (whole blood) Clinical chemistry (serum or plasma) B-Red blood cell (RBC) count S-albumin B-hematocrit S-alanine aminotransferase (ALT) B-hemoglobin (Hb) S-alkaline phosphatase (ALP) B-white blood cell differential count (absolute count) S-aspartate aminotransferase (AST) B-white blood cell count S-bicarbonate B-platelet count S-Bilirubin, total S-blood urea nitrogen (BUN) Urine chemistry S-Calcium, total U-protein (including UPCR) S-chloride U-albumin (including UACR) S-γ-glutamyltransferase (GGT) U-creatinine S-glucose S-creatine (including eGFR assessment) S-creatine kinase S-Magnesium S-phosphorus S-potassium S-sodium B-type natriuretic peptide (BNP) B-Hemoglobin A1c (HbA1c)

[0516] NOTE: In the event that participants present with AST or ALT ≥ 3 × ULN and TBL ≥ 2 × ULN, see Appendix E.

[0517] for further instructions.

[0518] Adverse events (AEs)

[0519] The participant (or, where appropriate, the caregiver, surrogate, or legally authorized representative of the participant) will notify the investigator or designee of symptoms associated with AEs and SAEs. These will then be assessed by the investigator and, if considered to be AEs or SAEs, will be reported by the investigator.

[0520] The investigator and any designated personnel are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE (see Table 9).

[0521] Table 9. AE and SAE variables collected and reported.

[0522] Adverse event variables collected Significant adverse event variables collected AE (verbatim) Date the AE meets SAE standards Dates when AE started and stopped Date the investigator became aware of the SAE Maximum intensity AE Description Is the AE serious? AEs are serious due to Investigator's causality rating for the IMP (yes or no) Date of hospitalization Measures taken against IMP Discharge date AE leading to participant withdrawal from the study (yes or no) Probable cause of death result Date of death Perform an autopsy Causality assessment related to study procedures Causality assessment for other drugs

[0523] Adverse Events of Specific Interest (AESI)

[0524] Based on the potential risks of zilpotentan (HF and fluid retention) identified in previous oncology clinical studies, additional monitoring and data collection will be conducted during the study for the following safety events classified as AESIs. Although hepatotoxicity has been highlighted as a risk associated with some other ERAs, it has not been observed with zilpotentan to date:

[0525] Newly diagnosed HF or worsening of existing HF: Any treatment-emergent symptoms suggestive of HF should be appropriately assessed by the investigator to ensure timely and appropriate management of the participant's condition.

[0526] Fluid retention or other signs of worsening fluid retention (e.g., fluid retention, fluid overload, hyperemia, edema of any location, ascites, effusions, etc.).

[0527] Hepatotoxicity, which includes possible drug-related liver disorders (e.g., liver failure, non-infectious hepatitis, DILI, other liver-related signs and symptoms, etc.).

[0528] Adverse events will be collected from randomization throughout the treatment period (including the safety follow-up period). Serious AEs will be recorded starting from the time of signing the informed consent form (ICF).

[0529] If the investigator becomes aware of a SAE with a suspected causal relationship to the investigational drug that has occurred after the completion of the clinical study in a treated participant, the investigator will report the SAE to the sponsor without undue delay.

[0530] The Investigator will follow up on any AEs that are not resolved at the last AE assessment for a participant in the study for as long as medically indicated but will not further document them in the eCRF. The Sponsor reserves the right to request additional information from any participant with an ongoing AE / SAE at the end of the study if deemed necessary.

[0531] The investigator will assess the causal relationship between the IMP and each AE and answer “yes” or “no” to the question “Do you think it is possible that the event was caused by the IMP?”

[0532] For SAEs, causality will also be assessed for other drugs and study procedures. Note that for SAEs that could be associated with any study procedure, causality is implied as "yes."

[0533] Worsening of protocol-specified laboratory values, vital signs, and ECG parameters compared to baseline will be reported as AEs only if they meet any of the following criteria:

[0534] Meet any SAE standard.

[0535] Is the reason for IMP abort.

[0536] Is clinically relevant, as judged by the Investigator (which may include, but is not limited to, consideration of whether an intervention or unplanned visit or other action on the IMP is needed, e.g., dose adjustment or drug interruption).

[0537] If a worsening of a laboratory value / vital sign is associated with clinical signs and symptoms, the sign or symptom will be reported as an AE, and the associated laboratory result / vital sign will be considered as additional information. Whenever possible, the reporting investigator will use clinical terms rather than laboratory terms (e.g., anemia versus low hemoglobin value). In the absence of clinical signs or symptoms, a clinically relevant worsening of a non-mandatory parameter will be reported as an AE.

[0538] Any new or worsening clinically relevant abnormal medical finding on physical examination compared with the baseline assessment will be reported as an AE.

[0539] All signs or symptoms reported spontaneously by participants or in response to an open-ended question from study center staff: "Have you had any health problems since your last visit / last question?" or revealed by observation will be collected and recorded in the eCRF.

[0540] When collecting AEs, recording of the diagnosis (when possible) is preferred over recording a list of signs and symptoms. However, if the diagnosis is known and there are other signs or symptoms that are not normally part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.

[0541] Participants demonstrating elevated liver biochemistries may require further evaluation, and the occurrence of aspartate aminotransferase / transaminase (AST) or alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN) and total bilirubin (TBL) ≥2×ULN may need to be reported as a SAE.

[0542] All SAEs will be reported, regardless of whether they are considered causally related to the IMP. All SAEs will be recorded in the eCRF. If any SAE occurs during the study, the investigator or other site personnel will notify the appropriate Sponsor representative within one day (i.e., immediately upon becoming aware of the event but no later than 24 hours).

[0543] The designated Sponsor representative will work with the Investigator to ensure that all necessary information is provided to the Sponsor's Patient Safety Data Entry Site within one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days of initial receipt for all other SAEs.

[0544] Prompt active follow-up will be performed for fatal or life-threatening AEs for which important or relevant information is missing. The investigator or other site personnel will notify the sponsor representative of any subsequent information regarding a previously reported SAE within one calendar day (i.e., immediately but no later than 24 hours after he or she becomes aware of the SAE).

[0545] Once the investigator or other site personnel indicates in the electronic data capture (EDC) system that an AE is serious, an automated email alert is sent to the designated sponsor representative.

[0546] If the EDC system is not available, the investigator or other site staff will report the SAE to the appropriate sponsor representative via secure means.

[0547] When the EDC is temporarily inaccessible, the sponsor study representative should confirm that the investigator / site staff enters the SAE into the sponsor's EDC when access is restored.

[0548] Sample collection

[0549] Blood samples will be collected pre-dose as specified in the activity schedule (Tables 7A to 7C) for measurement of plasma concentrations of zilpotentan and dapagliflozin.

[0550] If necessary and agreed upon between the investigator and the sponsor, for example, for urgent safety reasons, samples may be collected at additional time points during the study; these samples may not be part of the pharmacokinetic (PK) analysis set and report. The timing of sampling may be changed during the study based on newly available data (for example, to obtain data closer to the time of peak or trough matrix concentrations) to ensure appropriate monitoring.

[0551] Plasma samples will be used to analyze the PK of zilpotentan and dapagliflozin. Samples collected for analysis of zilpotentan and dapagliflozin plasma concentrations may also be used to assess safety or efficacy aspects related to concerns that arise during or after the study.

[0552] Unless agreed for future analysis, PK samples will be processed upon completion of the bioanalytical report or 6 months after issuance of the draft bioanalytical report, whichever is earlier.

[0553] Additional analyses may be performed on anonymized, pooled, or individual PK samples to further evaluate and validate the analytical method. Any results from such analyses may be reported separately from the Clinical Study Report (CSR).

[0554] Samples for determination of zilpotentan and dapagliflozin concentrations in plasma will be assayed by a bioanalytical testing facility operated by or on behalf of the sponsor using appropriately validated bioanalytical methods. Plasma concentrations of zilpotentan and dapagliflozin will be measured separately.

[0555] Drug concentration information for potential unblinding studies will not be reported to the site or blinding personnel until the study has been unblinded. Any sample reproducibility analysis that occurs, if any, will be performed in conjunction with the bioanalysis of the test samples. If an assessment is performed, the results of the assessment will be reported in a separate bioanalytical report.

[0556] Study Procedure

[0557] Visit 1 (Screening; all participants) and Visit 1.1 (SGLT2i-naive import participants only)

[0558] At enrollment, after providing signed informed consent, screening assessments and procedures will be performed as described in the activity schedule for SGLT2i-naive participants (Table 7A) and SGLT2i-treated participants (Table 7B). Further procedures will proceed after the investigator reviews the inclusion and exclusion criteria (including laboratory assessments and confirmation of a negative serum pregnancy test).

[0559] The SGLT2i that meets all inclusion / exclusion criteria (including serum pregnancy test negative) is used for the first time by the participant to enter the 28 day lead-in phase of SGLT2i therapy.Specific SGLT2i during the lead-in phase will be selected by the researcher and will be provided as adjuvant medicine, and it is prescribed by the researcher or purchased locally and will be the dosage specified for CKD.The 28 day lead-in phase will start so that the last time taking SGLT2i occurs in the day before visit 2 (that is, the-1 day).During the lead-in phase, the participant will return to the clinic 3 days before visit 2 and make a visit 1.1, to carry out laboratory assessment.These laboratory assessments will be used for baseline measurement, and do not need to further determine inclusion or exclusion of research.

[0560] Participants who are SGLT2i-treated patients and meet all inclusion and exclusion criteria (including a negative serum pregnancy test) will proceed to Visit 2 without a run-in or Visit 1.1 assessment. Their last dose of SGLT2i occurred on the day before Visit 2 (i.e., Day -1).

[0561] Visit 2 (Randomization)

[0562] Participants will stop any previous SGLT2i therapy the day before visit 2 (i.e., day -1). All assessments and procedures will be carried out according to the active schedule (Table 7A is for SGLT2i first-time use participants, and Table 7B is for SGLT2i treatment participants). The researcher will review the eGFR values ​​obtained when visit 1 to determine the dosing distribution. The study intervention will be allocated to the participant by interactive response technology (IRT) / randomization and trial supply management (RTSM), and the participant will be instructed to receive the study intervention uninterruptedly according to the protocol, wherein the first dose is taken in the clinic after completing the assessment and procedure of visit 2.

[0563] Monthly urine pregnancy tests and contraceptive adherence checks (WOCBP only)

[0564] Female participants of childbearing potential will undergo monthly urine pregnancy testing and contraceptive adherence as described in the activity schedule from randomization until 1 month after the last dose. We will review the results of urine pregnancy tests with the participant, as well as a thorough review of their contraceptive adherence. In the event of suspected contraceptive failure or suspected or confirmed pregnancy, the procedures described herein will be followed to determine whether the participant will continue or withdraw from the study.

[0565] Early treatment discontinuation visit

[0566] 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 activity schedule (Table 7C). The PTDV visit will occur within 28 days of the last dose, after which the next visit will be conducted according to the activity schedule, based on the last visit before the study intervention was discontinued. Participants will continue in the study and receive open-label dapagliflozin 10 mg monotherapy until the end-of-term visit, unless the investigator determines that the participant cannot tolerate dapagliflozin. Dapagliflozin 10 mg monotherapy will be administered as an adjunctive medication, either prescribed by the investigator or purchased locally.

[0567] End-of-treatment visit

[0568] The EoT visit will occur after reaching CTED. CTED is defined as 2 years after the randomization date of the last participant in the study and will be used to determine when the EoT visit should be arranged. The EoT visit for all participants will preferably occur within 14 days and no more than 28 days after the announcement of CTED. At the EoT visit, all assessments and procedures will be performed as described in the activity plan (Table 7C). Participants will stop the blinded study intervention and start open-label dapagliflozin 10mg monotherapy until the safety follow-up visit (the last study visit). Open-label dapagliflozin 10mg monotherapy will be used as an adjunct medication prescribed by the investigator or purchased locally.

[0569] For participants who discontinue the study intervention prematurely but remain in the study according to their activity schedule, the EoT visit will be the final study visit. Following the final study visit, participants will resume usual care according to standard of care at the investigator's discretion. This includes treatment with an SGLT2i (including dapagliflozin) if deemed clinically indicated by the investigator or the participant's primary care physician.

[0570] Safety follow-up visits

[0571] The safety follow-up visit will be conducted 30 days after the EoT visit. At the safety follow-up visit, all assessments and procedures will be performed as described in the activity plan (Table 7C). This will be the last study visit for the study participants (except for the case of early termination as described above). After the last study visit, participants will resume conventional treatment at the discretion of the investigator. If the investigator or the participant's attending physician believes that there is a clinical indication, this includes treatment with SGLT2i (including dapagliflozin).

[0572] Statistical considerations

[0573] All personnel involved in the study analysis will remain blinded until database locks and protocol violations have been identified and documented. An independent Data Monitoring Committee (DMC) will monitor the data regularly (in an unblinded manner) during the study. The DMC's responsibilities will be detailed in the DMC charter.

[0574] Assume that the true difference in change from baseline eGFR between treatment groups is 2.0 mL / min / 1.73 m 2 , using a two-sided alpha level of 5%, assuming a standard deviation of 15.5, 1500 participants would provide 90% statistical power.

[0575] Key analysis:

[0576] The primary efficacy variable of change from baseline in eGFR at Month 24 will be assessed with an estimator defined by the following properties:

[0577] Population: Patients with CKD and hyperalbuminuria, with or without T2DM, who met the eligibility criteria defined by the inclusion and exclusion criteria.

[0578] Treatment: Zipotentan / dapagliflozin FDC QD or dapagliflozin (active comparator) QD.

[0579] Concurrent events:

[0580] • Proactively investigate treatment discontinuation, IMP dose changes, and concomitant medication changes: a treatment strategy implemented by including all available data.

[0581] • RRT or renal death: A comprehensive strategy was implemented by defining eGFR = 0 at the 24-month visit whenever RRT or renal death occurred at the earlier time point.

[0582] Non-renal mortality: hypothetical strategies implemented through a framework for handling missing data.

[0583] Group-level summary: Difference in mean change from baseline to treatment at Month 24 between treatment groups.

[0584] The primary estimator of the primary endpoint was obtained using a repeated measures mixed model (MMRM). The change in eGFR from baseline to the month 24 visit was the dependent variable; all intermediate visits were included in the MMRM analysis. Baseline was defined as the mean of two eGFR measurements taken at or before randomization. The model included baseline eGFR as a continuous variable and the stratification factors, treatment group, visit, and treatment-by-visit interaction as fixed-effect factors.

[0585] Measurements after the start of dialysis will not be included in the analysis. Missing post-baseline eGFR estimates are handled implicitly in the likelihood-based parameter estimation, assuming that the values ​​for subjects with missing data are similar to those for subjects with observed data with the same treatment assignment and covariate values ​​(ie, missing at random).

[0586] The analysis will focus on the treatment effect on irreversible disease progression. For this purpose, estimates of the change from baseline (the average of the last 2 values ​​obtained before randomization) to the average of the 2 values ​​obtained at Month 24 and subsequent visits will be used. The least squares mean estimates (with 95% confidence intervals) for each treatment group will be shown, as will the differences between the treatment groups (with 95% confidence intervals and p-values).

[0587] Secondary analyses

[0588] Secondary endpoints of change from baseline in UACR, UPCR, and systolic blood pressure will be analyzed using methods similar to those described for the primary endpoint.

[0589] The secondary endpoint of evaluating the renal composite endpoint of 40% sustained decline or ESKD or renal death will be analyzed as time to event using a Cox proportional hazards model with treatment factor, stratified by randomization factors, and adjusted for eGFR at baseline as a continuous variable.

[0590] Security Analysis

[0591] Safety and tolerability will be assessed based on AEs, vital signs, clinical laboratory variables, and ECG. Additionally, the following AESIs will be evaluated: HF; fluid retention; and hepatotoxicity.

[0592] The purpose of analyzing the safety data was to assess the overall safety objective, which would have been assessed in the absence of premature discontinuation of study treatment. Two analytical approaches were considered complementary to assess this hypothetical scenario for all safety endpoints:

[0593] · Access to treatment; maintain impartiality under the assumption that review after premature discontinuation of treatment is meaningless.

[0594] Acceptance of the study; maintaining impartiality under the assumption that the risk of the event is unrelated to continued treatment. Note that this approach can also be described as using a treatment policy approach to handle premature treatment discontinuation.

[0595] Therefore, the overall safety goal will be assessed by an estimator defined by the following properties:

[0596] Population: Patients with CKD and hyperalbuminuria, with or without T2DM, who met the eligibility criteria defined by the inclusion and exclusion criteria.

[0597] Treatment: Zipotentan / dapagliflozin FDC QD or dapagliflozin (active comparator) QD.

[0598] Concurrent Events (ICE):

[0599] Premature Study Treatment Discontinuation: Unless otherwise stated, all analyses will be presented using 2 complementary approaches:

[0600] o Assumption that ICE is unlikely to occur was achieved by using the on-treatment analysis period to exclude / censor data after premature study treatment discontinuation plus 28 days.

[0601] o This was achieved by including all available data, ignoring the ICE's treatment policy, and using the accepted study analysis period.

[0602] • Starting or changing concomitant medications, including rescue medications: These will be ignored in the ICE, i.e., managed using the management policy approach.

[0603] Death: This ICE will be treated in a hypothetical manner as if it could not have occurred by censoring the time of event data at the time of death and not entering any data after the death.

[0604] Group-level summaries and estimators for corresponding analyses:

[0605] The probability of an event (e.g., AE, laboratory abnormality) occurring before a predefined time point. These differences between treatment groups, as well as differences in HR (over the entire time period of interest). For repeated measurements (e.g., laboratory assessments performed at several time points), the distribution of measurements at the corresponding time points.

[0606] This estimator requires that randomized participants included in the analysis set for safety be followed as closely as possible, regardless of compliance with the study intervention and adherence to the study protocol (for the planned treatment period and safety follow-up).

[0607] Analysis: Hazard ratios comparing treatment groups will be estimated based on Cox proportional hazards regression models with treatment group as a factor, using the full defined analysis period (on-study and on-treatment, respectively). Cumulative distribution functions (CDFs) of the time to an event of interest in the respective treatment groups will be estimated by the Kaplan-Meier estimator. The probability of an event of interest occurring before a predefined time point will be estimated by the Kaplan-Meier estimator at one or more time points determined based on the extent of follow-up of the participant (updated in the statistical analysis plan, during the defined analysis period (on-study and on-treatment, respectively), before the clinical data lock (CDL) for the treatment groups, and treatment group differences will be estimated at one of the selected time points (the selected prior CDL).

[0608] Comparisons between treatment groups will be presented with their associated 95% confidence intervals. As all safety analyses were descriptive, p-values ​​will not be presented, and confidence intervals will be provided as an illustration of the precision of the estimates.

[0609] The analysis period began at the randomization visit date and ended at the last clinical event assessment date, unless the participant died during follow-up, in which case the date of death was used as the end date. If the participant withdrew consent to continue in the study, the analysis period ended at the latest on that date.

[0610] The on-treatment analysis period began on the date of the randomization visit and ended on the date of the last dose of IMP or 28 days after the end of the on-study analysis period, whichever came first.

[0611] Example 3

[0612] eGFR ≥ 20 mL / min / 1.73 m 2 The safety and efficacy of the combination of zilpotentan and dapagliflozin were evaluated in patients with chronic kidney disease (CKD) and a UACR ≥ 150 mg / g and ≤ 5000 mg / g. Two combinations of zilpotentan and dapagliflozin were evaluated: zilpotentan at a dose of 0.25 mg or 1.5 mg and dapagliflozin at a dose of 10 mg. The combination of zilpotentan and dapagliflozin was administered once daily for 12 weeks.

[0613] Figure 4 Depicted are changes in fluid-related events compared to baseline in study participants with a baseline UACR>700 mg / g who received dapagliflozin (10 mg; short dashed line), a low-dose combination of zilpotentan and dapagliflozin (0.25 mg / 10 mg, respectively; solid line), and a high-dose combination of zilpotentan and dapagliflozin (1.5 mg / 10 mg, respectively; long dashed line). Of the 39 subjects who received the low-dose combination of zilpotentan and dapagliflozin (0.25 mg / 10 mg), only 4 exhibited fluid-related events, for a relative event rate of 15.9%. The number and event rate of fluid-related events were comparable to and not significantly different from participants who received administration of dapagliflozin alone (8 / 80 events and a relative event rate of 17.0%). Study participants who received the high dose of zilpotentan and dapagliflozin (1.5 mg / 10 mg) showed an increased relative event rate of fluid-related events (47.0%), with 18 of 75 participants experiencing events, which was significantly increased compared to participants who received dapagliflozin alone (10 mg). These results suggest that the combination of zilpotentan and dapagliflozin is safe, at least up to a dose of 1.5 mg / 10 mg (zilpotentan / dapagliflozin).

[0614] Figure 5Depicted are the changes in UACR from baseline over a 12-week period for study participants with a UACR > 700 mg / g who received dapagliflozin (10 mg; green line with circle symbols), a low-dose combination of zilbotentan and dapagliflozin (0.25 mg / 10 mg, respectively; blue line with triangle symbols), and a high-dose combination of zilbotentan and dapagliflozin (1.5 mg / 10 mg, respectively; red line with square symbols). Over the 12-week period, participants receiving dapagliflozin alone showed a modest reduction in the mean percent change in UACR from baseline, with the percent change stabilizing at approximately a 20% reduction from baseline. Participants receiving the low-dose (0.25 mg zilbotentan and 10 mg dapagliflozin) and high-dose (1.5 mg zilbotentan and 10 mg dapagliflozin) combinations showed significant reductions in UACR levels from baseline, with both the low-dose and high-dose treatment groups showing changes in UACR levels of approximately 45% from baseline at the end of the 12-week period. These results demonstrate that both tested dose combinations of zilpotentan and dapagliflozin were effective in reducing UACR in individuals with high proteinuria (UACR>700 mg / g).

[0615] Figure 6 Depicted are the changes in systolic blood pressure relative to baseline levels during the 12-week administration period and the 2-week follow-up after administration for study participants with UACR <700 mg / g and study participants with UACR>700 mg / g. Over the 12-week period, participants who received dapagliflozin + placebo (short dashed line; dapagliflozin 10 mg and placebo (PBO)) showed a modest reduction in systolic blood pressure—a reduction of 3.4% (90% CI: -5.8, -1.0)—which remained consistent throughout the study. After administration of the final planned dose, systolic blood pressure returned to baseline levels for participants who received dapagliflozin + placebo, as measured at week 14. Participants who received either dose of the combination of dapagliflozin and zilpotentan showed a more significant reduction in blood pressure compared to baseline. Participants who received a lower dose of the combination of zilpotentan and dapagliflozin (long dashed line; 0.25 mg zilpotentan and 10 mg dapagliflozin) showed an average reduction of 7.1% (90% CI: -10, -4.1) in systolic blood pressure relative to baseline, and participants who received a higher dose of the combination of zilpotentan and dapagliflozin (solid line; 1.5 mg zilpotentan and 10 mg dapagliflozin) showed an average reduction of 11.0% (90% CI: -13.5, -8.4) in systolic blood pressure relative to baseline. Two weeks after the final planned dose was administered, the average systolic blood pressure levels of participants who received the combination of zilpotentan and dapagliflozin remained further below baseline levels. The results of this study on systolic blood pressure measurements are further detailed in Tables 10A and 10B.

[0616] Table 10A. Systolic blood pressure measurement parameters.

[0617]

[0618] Table 10B. Effect of the combination of zilpotentan and dapagliflozin on systolic blood pressure.

[0619]

[0620] Figure 7A and Figure 7B The changes in systolic and diastolic blood pressure relative to baseline levels over the 12-week administration period are depicted separately for study participants with UACR>700 mg / g. Over the 12-week period, study participants receiving dapagliflozin + placebo (short dashed line; dapagliflozin 10 mg and placebo) showed modest reductions in systolic and diastolic blood pressure at the end of the 12-week period, with an average reduction of just over 4% in systolic blood pressure relative to baseline and an average reduction of approximately 2% in diastolic blood pressure relative to baseline. Patients receiving a lower dose of the combination of zilpotentan and dapagliflozin (long dashed line; 0.25 mg zilpotentan and 10 mg dapagliflozin) showed a more significant reduction in systolic and diastolic blood pressure relative to baseline relative to patients receiving dapagliflozin + placebo. An average reduction of approximately 8% in systolic blood pressure relative to baseline was recorded in the group receiving the low-dose combination of zilpotentan and dapagliflozin, and an average reduction of approximately 6% in diastolic blood pressure relative to baseline was recorded at the end of the 12-week study. For the higher dose combination of zilpotentan and dapagliflozin (solid line; 1.25 mg zilpotentan and 10 mg dapagliflozin), an average reduction of more than 12% in systolic blood pressure relative to baseline was recorded, and an average reduction of approximately 6% in diastolic blood pressure was recorded. The mean reduction in diastolic blood pressure for both the lower and higher doses of zilpotentan and dapagliflozin was statistically significant relative to the dapagliflozin + placebo group (p = 0.052 and p = 0.024, respectively). The mean reduction in systolic blood pressure for the higher dose combination of zilpotentan and dapagliflozin was also statistically significant relative to the group receiving dapagliflozin + placebo (p < 0.001). The results from this study for systolic and diastolic blood pressure in patients with UACR> 700 mg / g are further detailed in Tables 11A and 11B, respectively.

[0621] Table 11A. Effect of the combination of zilpotentan and dapagliflozin on systolic blood pressure in participants with UACR > 700 mg / g.

[0622]

[0623]

[0624] *p=0.192, **p<0.001

[0625] Table 11B. Effect of the combination of zilpotentan and dapagliflozin on diastolic blood pressure in participants with UACR > 700 mg / g.

[0626]

[0627]

[0628] *p=0.052, **p=0.024

[0629] Example 4

[0630] Clinical trials of the fixed-dose combination of zilpotentan and dapagliflozin are ongoing, including an international, multicenter, randomized, double-blind, active-controlled, parallel-group study to evaluate the efficacy of the FDC of zilpotentan and dapagliflozin compared to dapagliflozin alone (i.e., dapagliflozin monotherapy) in study participants with IgAN.

[0631] Study Design

[0632] Figure 8 An overview of the study is provided. Approximately 500 participants will be randomized in a 1:1 ratio to one of two treatment groups: zilpotentan (dose described below) and dapagliflozin (10 mg) once daily; or dapagliflozin (10 mg) once daily. For participants receiving the FDC of zilpotentan and dapagliflozin, the zilpotentan dose will be determined by eGFR status at the first screening visit: toward eGFR < 45 mL / min / 1.72 m 2 Participants were given zilpotentan at a dose of 0.25 mg; eGFR ≥ 45 mL / min / 1.72 m 2 Participants with eGFR < 45 mL / min / 1.72 m 2 and ≥45 mL / min / 1.72 m 2 Study participants will be randomized in a 1:1 ratio to receive either FDC (zipotentan and dapagliflozin) or dapagliflozin monotherapy. Participants will receive blinded study interventions from Day 1 through Month 36. At the Month 36 visit, participants will begin open-label dapagliflozin therapy (10 mg). Participants who were not receiving an SGLT2i at the first screening visit will receive a continuous SGLT2i once daily for 28 days prior to study entry.

[0633] The objectives of the study were divided into two phases: Phase 1 (9 months) and Phase 2 (36 months) and are described in detail in Table 12.

[0634] Table 12. Study objectives.

[0635]

[0636]

[0637]

[0638] The key inclusion and exclusion criteria for the study are described in Table 13 below.

[0639] Table 13. Study inclusion and exclusion criteria.

[0640]

[0641] Screening and randomization of study participants into the study will be conducted according to the activity schedule shown in Tables 14A and 14B. Assessments during the study will be conducted according to the activity schedule shown in Table 15.

[0642] Table 14A. Screening and Randomization of SGLT2i-Naive Participants.

[0643]

[0644] a Individuals who do not meet the criteria for participation in this study (screening failure) may need to be re-screened. Re-screened participants should re-sign the informed consent form and be assigned the same participant number as the initial screening. If, during the screening period, the values ​​of the following studies are outside the participant's normal range based on the participant's medical history, up to 2 retests can be performed without re-screening: BP, eGFR, UACR and UPCR, ALT, AST, and random urine for bilirubin.

[0645] b The 10-day window (-34 [±5] days) for Visit 1 is to allow for turnaround time for central laboratory results before the 28-day run-in. Participants not already receiving a stable dose of an SGLT2i will enter a 28-day SGLT2i run-in from Day -28 to Day -1. During the run-in period, the SGLT2i will be provided as an adjunctive medication.

[0646] c Negative pregnancy test required for all women at enrollment / before the first dose of study intervention.

[0647] d At Visit 2, a negative urine pregnancy test must be performed before randomization. All WOCBP patients will require monthly pregnancy testing (urine) and contraceptive adherence monitoring from randomization until 1 month after the last dose. If the result is positive, treatment should be discontinued and the procedures for suspected contraceptive failure or suspected pregnancy should be followed. For months when no visit is scheduled, a home pregnancy test performed by a healthcare professional may be considered.

[0648] eWomen who meet one of the following criteria at screening are considered infertile: (a) postmenopausal, defined as amenorrhea for at least 12 months or longer after cessation of all exogenous hormone therapy, and an FSH level within the postmenopausal range (note: the postmenopausal range must be checked based on the specific FSH assay used). In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to define postmenopausal criteria. In the rare case of perimenopausal women or those with variable FSH levels, they should be considered fertile; or (b) documented irreversible surgical sterilization, including hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, excluding tubal ligation.

[0649] f These include fluid retention and signs of heart failure.

[0650] g Tests include: B-red blood cell count, B-hematocrit; B-hemoglobin, B-white blood cell differential 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, S-sodium.

[0651] h 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.

[0652] i Participation in the Genome Initiative research is optional and requires separate consent from the participant.

[0653] j At baseline, two samples of UPCR and UACR will be collected: one at home and one at the study center.

[0654] Table 14B. Screening and randomization of participants treated with SGLT2i.

[0655]

[0656] aIndividuals who do not meet the criteria for participation in this study (screening failure) may need to be re-screened. Re-screened participants should re-sign the informed consent form and be assigned the same participant number as the initial screening. If, during the screening period, the values ​​of the following studies are outside the participant's normal range based on the participant's medical history, up to 2 retests can be performed without re-screening: BP, eGFR, UACR and UPCR, ALT, AST, and random urine for bilirubin.

[0657] b Participants were already receiving a stable dose of an SGLT2i.

[0658] c Once the participant is confirmed to be of childbearing potential, this will be signed at the latest before randomization.

[0659] d Negative pregnancy test required for all women at enrollment / before the first dose of study intervention.

[0660] e At Visit 2, a negative urine pregnancy test must be performed before randomization. All WOCBP patients will require monthly pregnancy testing (urine) and contraceptive adherence monitoring from randomization until 1 month after the last dose. If the result is positive, treatment should be discontinued and the procedures for suspected contraceptive failure or suspected pregnancy should be followed. For months when no visit is scheduled, a home pregnancy test performed by a healthcare professional may be considered.

[0661] f Women who meet one of the following criteria at screening are considered infertile: (a) postmenopausal, defined as amenorrhea for at least 12 months or longer after cessation of all exogenous hormone therapy, and an FSH level within the postmenopausal range (note: the postmenopausal range must be checked based on the specific FSH assay used). In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to define postmenopausal criteria. In the rare case of perimenopausal women or those with variable FSH levels, they should be considered fertile; or (b) documented irreversible surgical sterilization, including hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, excluding tubal ligation.

[0662] g These include fluid retention and signs of heart failure.

[0663] hTests include: B-red blood cell count, B-hematocrit; B-hemoglobin, B-white blood cell differential 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, S-sodium.

[0664] i 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.

[0665] j Participation in the Genome Initiative research is optional and requires separate consent from the participant.

[0666] k At baseline, two samples of UACR and UACR will be collected: one at home and one at the study center.

[0667] Table 15. Activity schedule.

[0668]

[0669]

[0670] a At 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 prematurely but remain in the study per the SoA, Visit 14.1 will be the final study visit.

[0671] b Visit 4: Phone call to assess fluid retention and related conditions.

[0672] c All WOCBP patients will require monthly pregnancy testing (urine) and contraceptive adherence monitoring from randomization until 1 month after the last dose. If the result is positive, treatment should be discontinued and the procedures for suspected contraceptive failure or suspected pregnancy should be followed. The company may consider the option of having a healthcare professional perform a home pregnancy test in months when no visit is scheduled.

[0673] dWomen were diagnosed as infertile at screening if they met one of the following criteria: (a) postmenopausal, defined as amenorrhea for at least 12 months or longer after cessation of all exogenous hormone therapy, and FSH levels within the postmenopausal range (a single FSH measurement is insufficient to define postmenopausal criteria in the absence of 12 months of amenorrhea. In the rare case of perimenopausal women or those with variable FSH levels, they should be considered to be of fertile potential); or (b) documented irreversible surgical sterilization, including hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, excluding tubal ligation.

[0674] e These include fluid retention and signs of heart failure.

[0675] f Tests include: B-red blood cell count, B-hematocrit, B-hemoglobin, B-white blood cell differential 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, S-sodium.

[0676] g The mean eGFR value at Visit 14 will be calculated based on the eGFR values ​​at Visit 14 and Visit 14.1.

[0677] h PK samples will be collected pre-dose at Visits 3, 5, 6, and 12. For participants who have permanently discontinued the study intervention, PK samples should not be collected if more than 7 days have passed since the last dose.

[0678] i 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.

[0679] j If possible, the remaining (previously uncompleted) portion of the SPFQ should be completed at the PTDV only if the participant withdraws early from the study.

[0680] k Except for Visits 3, 5, 6, and 12, study interventions will be delivered at home.

[0681] lAt Visit 6 (6 months), a urine collection tube will be provided to obtain two samples of UACR and UACR at Visit 7 (9 months). One sample will be collected at home and one at the study center. At visits other than Screening, Randomization, and 9 months, only one urine sample will be collected at the study center.

[0682] m Except for Visit 14.

Claims

1. A method of treating chronic kidney disease in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to treat the patient's chronic kidney disease.

2. A method of slowing the decline of renal function in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to slow the decline of renal function in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

3. A method of reducing proteinuria in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce proteinuria in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

4. A method of reducing albuminuria in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the patient's albuminuria relative to a dosing regimen in which the patient receives dapagliflozin alone.

5. A method for reducing the incidence of a composite endpoint of a sustained 30% decline in eGFR or ESKD or renal death in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the incidence of the composite endpoint in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

6. A method for reducing the incidence of a composite endpoint of a sustained 40% decline in eGFR or ESKD or renal death in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the incidence of the composite endpoint in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

7. A method for reducing the incidence of a composite endpoint of a sustained 57% decline in eGFR or ESKD or renal death in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 g / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the incidence of the composite endpoint in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

8. A method of reducing the incidence of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the incidence of ANCA vasculitis in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

9. A method of reducing recurrence of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the recurrence of ANCA vasculitis in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

10. A method of treating Alport syndrome in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to treat Alport syndrome in the patient.

11. A method of reducing the progression of Alport syndrome in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the progression of Alport syndrome in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

12. A method of reducing the level of kidney inflammation (nephritis) associated with Alport syndrome in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the level of kidney inflammation (nephritis) associated with Alport syndrome in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

13. A method of reducing the incidence of hospitalization for heart failure in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the incidence of hospitalization for heart failure in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

14. A method of reducing the risk of hospitalization for heart failure in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the patient's risk of hospitalization for heart failure relative to a dosing regimen in which the patient receives dapagliflozin alone.

15. A method of lowering blood pressure in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to lower the patient's blood pressure relative to a dosing regimen in which the patient receives dapagliflozin alone.

16. A method of lowering blood pressure in a human patient having a urine albumin to creatine ratio (UACR) of less than 700 mg / g, the method comprising administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to lower the patient's blood pressure relative to a dosing regimen where the patient receives dapagliflozin alone.

17. A method of reducing the risk of elevated blood pressure in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the risk of elevated blood pressure in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

18. A method of preventing increased fluid retention in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to prevent increased fluid retention in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

19. A method of reducing the risk of increased fluid retention in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the risk of increased fluid retention in the patient relative to if the patient received a dosing regimen of dapagliflozin alone.

20. A method of preventing elevated levels of brain natriuretic peptide (BNP) in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to prevent an increase in the patient's BNP level relative to a dosing regimen in which the patient receives dapagliflozin alone.

21. A method of reducing the risk of elevated brain natriuretic peptide (BNP) levels in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the patient's risk of elevated BNP levels relative to if the patient received a dosing regimen of dapagliflozin alone.

22. A method of preventing total body water gain in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to prevent an increase in total body water in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

23. A method of reducing the risk of total body water gain in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to prevent an increase in total body water in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

24. A method of preventing weight gain in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to prevent weight gain in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

25. A method of reducing the risk of weight gain in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to prevent weight gain in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

26. A method of treating biopsy-confirmed IgA nephropathy (IgAN) in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to treat IgAN in the patient.

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

28. A method of reducing the rate of decline in renal function in a human patient with biopsy-confirmed IgA nephropathy, said human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the rate of decline in renal function in the patient.

29. A method of lowering cholesterol in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to lower the patient's cholesterol relative to a dosing regimen in which the patient receives dapagliflozin alone.

30. A method of reducing the risk of elevated cholesterol in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the patient's risk of elevated cholesterol relative to a dosing regimen in which the patient receives dapagliflozin alone.

31. A method of lowering hemoglobin A1c (HbA1c) in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to lower the patient's HbA1c relative to a dosing regimen in which the patient receives dapagliflozin alone.

32. A method of reducing the risk of elevated hemoglobin A1c (HbA1c) in a human patient having: a) a urine protein to creatine ratio (UPCR) greater than 1 g / g, or b) a urine albumin to creatine ratio (UACR) greater than 700 mg / g, The method comprises administering to the patient a fixed dose combination of zilpotentan and dapagliflozin in an amount effective to reduce the patient's risk of elevated HbA1c relative to a dosing regimen in which the patient receives dapagliflozin alone.

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

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

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

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

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

38. The method of any one of the preceding claims, comprising administering the fixed dose combination of zilpotentan and dapagliflozin to the patient once daily.

39. The method of any preceding claim, comprising administering zilpotentan at a dose of 0.25 mg to 1.5 mg.

40. The method of any preceding claim, comprising administering zilpotentan at a dose of 0.25 mg.

41. The method of any one of claims 1-39, comprising administering zilpotentan at a dose of 0.5 mg.

42. The method of any one of claims 1-39, comprising administering zilpotentan at a dose of 0.75 mg.

43. The method of any one of claims 1-39, comprising administering zilpotentan at a dose of 1.0 mg.

44. The method of any one of claims 1-39, comprising administering zilpotentan at a dose of 1.25 mg.

45. The method of any one of claims 1-39, comprising administering zilpotentan at a dose of 1.5 mg.

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

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

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

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

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

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

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

53. The method of any one of claims 1-38, comprising: 2 When the patient has an eGFR of ≥45 mL / min / 1.73 m 2 When the eGFR was ≥ 50%, zilpotentan was administered at a dose of 0.75 mg and dapagliflozin was administered at a dose of 10 mg.

54. The method of claim 53, wherein the patient's eGFR becomes <45 mL / min / 1.73 m 2 When the fixed dose combination of zilpotentan and dapagliflozin was adjusted from 0.75 mg zilpotentan and 10 mg dapagliflozin to 0.25 mg zilpotentan and 10 mg dapagliflozin.

55. The method of claim 53, wherein the patient's eGFR becomes ≥ 45 mL / min / 1.73 m 2 When the fixed dose combination of zilpotentan and dapagliflozin was adjusted from 0.25 mg zilpotentan and 10 mg dapagliflozin to 0.75 mg zilpotentan and 10 mg dapagliflozin.

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

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

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

59. The method of any one of the preceding claims, wherein the patient achieves partial remission or remission.

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

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

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

63. The method of any one of claims 1-9 and 11-62, wherein the fixed dose combination of zilpotentan and dapagliflozin is administered to treat Alport syndrome in the patient.

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

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

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

67. The method of any one of claims 1-13 and 15-66, wherein administering the fixed-dose combination of zilpotentan and dapagliflozin reduces the patient's risk of hospitalization for heart failure relative to a dosing regimen in which the patient receives dapagliflozin alone.

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

69. The method of any one of claims 1-14 and 17-68, wherein administration of the fixed-dose combination of zilpotentan and dapagliflozin lowers the patient's blood pressure relative to a dosing regimen in which the patient receives dapagliflozin alone, and wherein after discontinuation of administration of the fixed-dose combination of zilpotentan and dapagliflozin, the patient's blood pressure remains lowered for at least two weeks relative to a dosing regimen in which the patient receives dapagliflozin alone.

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

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

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

73. The method of any one of claims 1-19 and 21-72, wherein administering the fixed dose combination of zilpotentan and dapagliflozin does not increase the patient's brain natriuretic peptide (BNP) levels relative to a dosing regimen in which the patient receives dapagliflozin alone.

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

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

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

77. The method of any one of claims 1-23 and 25-76, wherein administration of the fixed dose combination of zilpotentan and dapagliflozin does not increase the patient's weight relative to a dosing regimen in which the patient receives dapagliflozin alone.

78. The method of any one of claims 1-24 and 26-77, wherein administering the fixed-dose combination of zilpotentan and dapagliflozin reduces the risk of weight gain in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.

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

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

81. The method of any one of claims 1-28 and 30-80, wherein administering the fixed dose combination of zilpotentan and dapagliflozin lowers the patient's cholesterol relative to a dosing regimen in which the patient receives dapagliflozin alone.

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

83. The method of any one of claims 1-30 and 32-82, wherein administering the fixed-dose combination of zilpotentan and dapagliflozin lowers the patient's HbA1c relative to a dosing regimen in which the patient receives dapagliflozin alone.

84. The method of any one of claims 1-31 and 33-83, wherein administering the fixed-dose combination of zilpotentan and dapagliflozin reduces the patient's risk of elevated HbA1c relative to a patient receiving a dosing regimen of dapagliflozin alone.

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