Combination of zibotentan and dapagliflozin for the treatment of endothelin related diseases
The present disclosure relates to the endothelin receptor antagonist (ERA) zibotentan in combination with the sodium-dependent glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin for use in the treatment of certain endothelin related diseases.
1. A method of reducing blood pressure in a human patient with chronic kidney disease and in need thereof, the method comprising administering to the patient a combination of zibotentan, N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide,
or a pharmaceutically acceptable salt thereof, and dapagliflozin, in amounts effective for reducing blood pressure in the patient.
2. The method according to claim 1 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered once daily in combination with dapagliflozin.
3. The method according to claim 2 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5 mg and dapagliflozin is administered at a dose of 10 mg.
4. The method according to claim 2 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1.5 mg and dapagliflozin is administered at a dose of 10 mg.
5. The method according to claim 2 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.25 mg and dapagliflozin is administered at a dose of 10 mg.
6. The method according to claim 2 , wherein the patient is a chronic kidney disease patient classified as a stage 1-4 patient having an eGFR 20-60 ml/min/1.73 m 2 .
7. The method according to claim 6 , wherein the patient is a chronic kidney disease patient classified as a stage 3-4 patient.
8. A method of reducing risk of blood pressure elevation in a human patient with chronic kidney disease and in need thereof, the method comprising administering to the patient a combination of zibotentan, N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide,
or a pharmaceutically acceptable salt thereof, and dapagliflozin, in amounts effective for reducing risk of blood pressure elevation in the patient.
9. The method according to claim 8 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered once daily in combination with dapagliflozin.
10. The method according to claim 9 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5 mg and dapagliflozin is administered at a dose of 10 mg.
11. The method according to claim 9 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1.5 mg and dapagliflozin is administered at a dose of 10 mg.
12. The method according to claim 9 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.25 mg and dapagliflozin is administered at a dose of 10 mg.
13. The method according to claim 9 , wherein the patient is a chronic kidney disease patient classified as a stage 1-4 patient having an eGFR 20-60 ml/min/1.73 m 2 .
14. The method according to claim 13 , wherein the patient is a chronic kidney disease patient classified as a stage 3-4 patient.
15. A method of reducing incidence of a composite endpoint of ≥40% decline in eGFR, reaching end-stage kidney disease (ESKD), and renal death in a human patient with chronic kidney disease and in need thereof, the method comprising administering to the patient a combination of zibotentan, N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide,
or a pharmaceutically acceptable salt thereof, and dapagliflozin, in amounts effective for reducing incidence of a composite endpoint of ≥40% decline in eGFR, reaching end-stage kidney disease (ESKD), and renal death in the human patient.
16. The method according to claim 15 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered once daily in combination with dapagliflozin.
17. The method according to claim 16 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5 mg and dapagliflozin is administered at a dose of 10 mg.
18. The method according to claim 16 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1.5 mg and dapagliflozin is administered at a dose of 10 mg.
19. The method according to claim 16 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.25 mg and dapagliflozin is administered at a dose of 10 mg.
20. The method according to claim 16 , wherein the patient is a chronic kidney disease patient classified as a stage 1-4 patient having an eGFR 20-60 ml/min/1.73 m 2 .
21. The method according to claim 20 , wherein the patient is a chronic kidney disease patient classified as a stage 3-4 patient.
22. A method of reducing the incidence of reaching end-stage kidney disease (ESKD) in a human patient with chronic kidney disease and in need thereof, the method comprising administering to the patient a combination of zibotentan, N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide,
or a pharmaceutically acceptable salt thereof, and dapagliflozin, in amounts effective for reducing the incidence of the patient reaching ESKD.
23. The method according to claim 22 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered once daily in combination with dapagliflozin.
24. The method according to claim 23 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5 mg and dapagliflozin is administered at a dose of 10 mg.
25. The method according to claim 23 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1.5 mg and dapagliflozin is administered at a dose of 10 mg.
26. The method according to claim 23 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.25 mg and dapagliflozin is administered at a dose of 10 mg.
27. The method according to claim 23 , wherein the patient is a chronic kidney disease patient classified as a stage 1-4 patient having an eGFR 20-60 ml/min/1.73 m 2 .
28. The method according to claim 27 , wherein the patient is a chronic kidney disease patient classified as a stage 3-4 patient.
29. A method of reducing the incidence of renal death in a human patient with chronic kidney disease and in need thereof, the method comprising administering to the patient a combination of zibotentan, N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide,
or a pharmaceutically acceptable salt thereof, and dapagliflozin, in amounts effective for reducing the incidence of renal death in the patient.
30. The method according to claim 29 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered once daily in combination with dapagliflozin.
31. The method according to claim 30 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5 mg and dapagliflozin is administered at a dose of 10 mg.
32. The method according to claim 30 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1.5 mg and dapagliflozin is administered at a dose of 10 mg.
33. The method according to claim 30 , wherein zibotentan, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.25 mg and dapagliflozin is administered at a dose of 10 mg.
34. The method according to claim 30 , wherein the patient is a chronic kidney disease patient classified as a stage 1-4 patient having an eGFR 20-60 ml/min/1.73 m 2 .
35. The method according to claim 34 , wherein the patient is a chronic kidney disease patient classified as a stage 3-4 patient.