Combination of zibotentan and dapagliflozin for the treatment of high proteinuria chronic kidney disease
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- ASTRAZENECA AB
- Filing Date
- 2026-06-02
- Publication Date
- 2026-07-10
Smart Images
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Abstract
Description
This paper discloses a method for treating patients with chronic kidney disease with high proteinuria and / or at least one related disease, condition, or symptom using a fixed-dose combination of zipotentan and dapagliflozin. (Abstract)
Claims
CLAIMSWhat is claimed is:1 . A method of treating chronic kidney disease in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to treat the patient’s chronic kidney disease.
2. A method of slowing decline in renal function in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to slow the patient’s decline in renal function relative to a dosing regimen in which the patient receives dapagliflozin alone.
3. A method of reducing proteinuria in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the patient’sproteinuria relative to a dosing regimen in which the patient receives dapagliflozin alone.
4. A method of reducing albuminuria in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan 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 30% sustained decline in eGFR or ESKD or renal death in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the incidence of the composite endpoint in the patient reduced relative to a dosing regimen in which the patient receives dapagliflozin alone.
6. A method for reducing the incidence of a composite endpoint of 40% sustained decline in eGFR or ESKD or renal death in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, orb) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan 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 57% sustained decline in eGFR or ESKD or renal death in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 g / g, the method comprising administering to the patient a fixed-dose combination of zibotentan 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-neutrophilic cytoplasmic autoantibody (ANCA) vasculitis in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan 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 the recurrence of anti-neutrophilic cytoplasmic autoantibody (ANCA) vasculitis in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan 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 who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan 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 who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the progression ofAlport syndrome in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
12. A method of reducing the levels of kidney inflammation (nephritis) associated with Alport syndrome in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the levels 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 who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan 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 who has:a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the risk of hospitalization for heart failure in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
15. A method of reducing blood pressure in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the blood pressure in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
16. A method of reducing blood pressure in a human patient who has a urinary albumin to creatine ratio (UACR) of less than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the blood pressure in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
17. A method of reducing the risk of blood pressure elevation in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the risk of blood pressure elevation 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 who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan 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 who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the risk of increasedfluid retention in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
20. A method of preventing an increase in levels of brain natriuretic peptide (BNP) in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to prevent increased levels of BNP in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
21. A method of reducing the risk of increased in levels of brain natriuretic peptide (BNP) in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the risk of increased levels of BNP in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
22. A method of preventing an increase in total body water in a human patient who has:a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to prevent increased 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 increased total body water in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to prevent increased total body water in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
24. A method of preventing an increase in body weight in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to prevent increased body weight in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
25. A method of reducing the risk of increased body weight in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to prevent increased body weight in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
26. A method of treating IgA nephropathy (IgAN) in a human patient having biopsy- confirmed IgAN who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to treat IgAN in the patient.
27. A method of reducing proteinuria in a human patient having biopsy-confirmed IgA nephropathy who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g,the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce proteinuria in the patient.
28. A method of reducing the rate of kidney function decline in a human patient having biopsy-confirmed IgA nephropathy who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the rate of kidney function decline in the patient.
29. A method of reducing cholesterol in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce cholesterol in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
30. A method of reducing the risk of cholesterol elevation in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g,the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the risk of cholesterol elevation in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.31 . A method of reducing hemoglobin A1 c (HbA1 c) in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce HbA1c in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
32. A method of reducing the risk of hemoglobin A1c (HbA1c) elevation in a human patient who has: a) a urinary protein to creatine ratio (UPCR) of greater than 1 g / g, or b) a urinary albumin to creatine ratio (UACR) of greater than 700 mg / g, the method comprising administering to the patient a fixed-dose combination of zibotentan and dapagliflozin in an amount effective to reduce the risk of HbA1c elevation in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
33. The method according to any one of the preceding claims, wherein the patient is naive to a sodium-glucose cotransporter-2 (SGLT2) inhibitor.
34. The method according to any one of the preceding claims, wherein the patient has an estimated glomerular filtration rate (eGFR) of 20-90 mL / min / 1.73 m2.
35. The method according to any one of the preceding claims, wherein the patient has a UPCR of 1-1.3 g / g.
36. The method according to any one of the preceding claims, wherein the patient has a UACR of 700-900 mg / g.
37. The method according to any one of the preceding claims, wherein the patient has a UPCR of 1-1.3 g / g and a UACR of 700-900 mg / g.
38. The method according to any one of the preceding claims, comprising administering the fixed-dose combination of zibotentan and dapagliflozin to the patient once per day.
39. The method according to any one of the preceding claims, comprising administering zibotentan at a dose of 0.25 mg to 1 .5 mg.
40. The method according to any one of the preceding claims, comprising administering zibotentan at a dose of 0.25 mg.
41. The method according to any one of claims 1-39 comprising administering zibotentan at a dose of 0.5 mg.
42. The method according to any one of claims 1-39, comprising administering zibotentan at a dose of 0.75 mg.
43. The method according to any one of claims 1-39, comprising administering zibotentan at a dose of 1 .0 mg.
44. The method according to any one of claims 1-39, comprising administering zibotentan at a dose of 1 .25 mg.
45. The method according to any one of claims 1-39, comprising administering zibotentan at a dose of 1 .5 mg.
46. The method according to any one of the preceding claims, comprising administering dapagliflozin at a dose of 2.5 mg to 10 mg.
47. The method according to any one of the preceding claims, comprising administering dapagliflozin at a dose of 2.5 mg.
48. The method according to any one of claims 1-46, comprising administering dapagliflozin at a dose of 5.0 mg.
49. The method according to any one of claims 1-46, comprising administering dapagliflozin at a dose of 10.0 mg.
50. The method according to any one of claims 1-38, comprising administering zibotentan at a dose of 0.75 mg and dapagliflozin at a dose of 10 mg.
51. The method according to any one of claims 1-38, comprising administering zibotentan at a dose of 0.5 mg and dapagliflozin at a dose of 10 mg.
52. The method according to any one of claims 1-38, comprising administering zibotentan at a dose of 0.25 mg and dapagliflozin at a dose of 10 mg.
53. The method according to any one of claims 1-38, comprising administering zibotentan at a dose of 0.25 mg and dapagliflozin at a dose of 10 mg when the patient has an eGFR that is < 45 mL / min / 1.73 m2, and administering zibotentan at a dose of 0.75 mg and dapagliflozin at a dose of 10 mg when the patient has an eGFR that is > 45 mL / min / 1 .73 m2.
54. The method according to claim 53, wherein the fixed dose combination of zibotentan and dapagliflozin is adjusted from 0.75 mg of zibotentan and 10 mg of dapagliflozin to 0.25 mg of zibotentan and 10 mg of dapagliflozin when the patient’s eGFR changes to < 45 mL / min / 1.73 m2.
55. The method according to claim 53, wherein the fixed dose combination of zibotentan and dapagliflozin is adjusted from 0.25 mg of zibotentan and 10 mg of dapagliflozin to 0.75 mg of zibotentan and 10 mg of dapagliflozin when the patient’s eGFR changes to > 45 mL / min / 1 .73 m2.
56. The method according to any one of the preceding claims, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the patient’s UACR to below 300 mg / g.
57. The method according to any one of the preceding claims, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the patient’s UPCR to below 1 g / g.
58. The method according to any one of the preceding claims, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the patient’s UACR to below 300 mg / g and the patient’s UPCR to below 1 g / g.
59. The method according to any one of the preceding claims, wherein the patient achieves partial remission or remission.
60. The method according to any one of the preceding claims, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces incidence ofstroke and / or acute coronary syndrome in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
61. The method according to any one of claims 1-7 and 9-60, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the incidence of anti-neutrophilic cytoplasmic autoantibody (ANCA) vasculitis in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
62. The method according to any one of claims 1-8 and 9-61 , wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the recurrence of anti-neutrophilic cytoplasmic autoantibody (ANCA) vasculitis in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
63. The method according to any one of claims 1 -9 and 11 -62, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin treats Alport syndrome in the patient.
64. The method according to any one of claims 1 -10 and 12-63, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the progression of Alport syndrome in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
65. The method according to any one of claims 1 -11 and 13-64, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces levels of kidney inflammation (nephritis) associated with Alport syndrome in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
66. The method according to any one of claims 1 -12 and 14-65, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin does not lead to hospitalization of heart failure for the patient.
67. The method according to any one of claims 1-13 and 15-66, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of hospitalization of heart failure in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
68. The method according to any one of claims 1 -14 and 17-67, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the patient’s blood pressure relative to a dosing regimen in which the patient receives dapagliflozin alone.
69. The method according to any one of claims 1 -14 and 17-68, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the patient’s blood pressure relative to a dosing regimen in which the patient receivesdapagliflozin alone, and wherein the patient’s blood pressure remains reduced relative to the dosing regimen in which the patient receives dapagliflozin alone for at least two weeks after administration of the fixed-dose combination of zibotentan and dapagliflozin is stopped.
70. The method according to any one of claims 1 -16 and 18-69, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of blood pressure elevation in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.71 . The method according to any one of claims 1-17 and 19-70, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin does not increase the patient’s fluid retention relative to a dosing regimen in which the patient receives dapagliflozin alone.
72. The method according to any one of claims 1 -18 and 20-71 , wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of increased fluid retention in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
73. The method according to any one of claims 1 -19 and 21-72, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin does not increasethe patient’s levels of brain natriuretic peptide (BNP) relative to a dosing regimen in which the patient receives dapagliflozin alone.
74. The method according to any one of claims 1 -20 and 22-73, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of increased levels of brain natriuretic peptide (BNP) in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
75. The method according to any one of claims 1 -21 and 23-74, wherein administration of the fixed-dose combination of zibotentan 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 according to any one of claims 1 -22 and 24-75, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of increased total body water in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
77. The method according to any one of claims 1 -23 and 25-76, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin does not increase the patient’s body weight relative to a dosing regimen in which the patient receives dapagliflozin alone.
78. The method according to any one of claims 1 -24 and 26-77, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of increased body weight in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
79. The method according to any one of claims 1 -26 and 28-78, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces proteinuria in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
80. The method according to any one of claims 1 -27 and 29-79, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the rate of kidney function decline in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.81 . The method according to any one of claims 1 -28 and 30-80, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces cholesterol in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
82. The method according to any one of claims 1 -29 and 31 -81 , wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk ofcholesterol elevation in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
83. The method according to any one of claims 1 -30 and 32-82, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces HbA1c in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.
84. The method according to any one of claims 1 -31 and 33-83, wherein administration of the fixed-dose combination of zibotentan and dapagliflozin reduces the risk of HbA1c elevation in the patient relative to a dosing regimen in which the patient receives dapagliflozin alone.