Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof
The present invention provides methods of treating or preventing Alport syndrome in a patients in need thereof using bardoxolone methyl or analogs thereof, and/or improving the kidney function of patients who have been diagnosed with Alport syndrome.
1. A method of treating or preventing Alport syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the patient does not have a cardiovascular disease.
3. The method of claim 1 , wherein the patient does not have Stage 4 or higher chronic kidney disease.
4. The method of claim 1 , wherein the patient does not have an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m 2 .
5. The method of claim 1 , wherein the patient does not have an elevated albumin/creatinine ratio (ACR) greater than 2000 mg/g.
6. The method of claim 1 , wherein the patient does not have diabetes, a complication associated with diabetes, or insulin resistance.
7. The method of claim 1 , wherein the patient does not have cancer.
8. The method of claim 1 , wherein the patient has impaired renal function or elevated levels of at least one biomarker associated with renal disease.
9. The method of claim 8 , wherein the biomarker is serum creatinine, cystatin C, or uric acid.
10. The method of claim 1 , wherein the patient further exhibits microhematuria or microalbuminuria.
11. The method of claim 1 , wherein the patient further exhibits proteinuria.
12. The method of claim 1 , wherein the patient does not have any of the following characteristics:
(A) a cardiovascular disease;
(B) an elevated baseline B-type natriuretic peptide (BNP) level;
(C) an estimated glomerular filtration rate (eGFR)<45 mL/min/1.73 m 2 ; and
(D) an elevated albumin/creatinine ratio (ACR)>2000 mg/g.
13. The method of claim 1 , further defined as a method of improving the kidney function of a patient who has been diagnosed with Alport syndrome.
14. The method of claim 1 , wherein at least a portion of the compound is present as a crystalline form having an X-ray diffraction pattern (CuKα) comprising significant diffraction peaks at about 8.8, 12.9, 13.4, 14.2 and 17.4° 2θ.
15. The method of claim 1 , wherein at least a portion of the compound is present as an amorphous form having an X-ray diffraction pattern (CuKα) with a peak at approximately 13.5° 2θ, substantially as shown in FIG. 1C , and a transition glass temperature (T g ), wherein the T g value is in the range of about 120° C. to about 135° C.
16. The method of claim 1 , wherein the therapeutically effective amount is a daily dose from about 0.1 mg to about 300 mg of the compound.
17. The method of claim 1 , wherein the compound is administered orally, intraarterially or intravenously.
18. The method of claim 1 , wherein the compound is formulated as a hard or soft capsule or a tablet.
19. The method of claim 1 , wherein the compound is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient.
20. The method of claim 19 , wherein the excipient is a methacrylic acid ethyl acrylate copolymer.
21. The method of claim 1 , wherein the patient has a B-type natriuretic peptide (BNP) level that is not elevated.
22. The method of claim 1 , wherein the patient has a BNP level that is less than or equal to 200 pg/mL.
23. The method of claim 1 , wherein the patient does not have an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m 2 .
24. The method of claim 1 , further defined as a method of treating chronic kidney disease in a patient who has been diagnosed with Alport syndrome.