Methods for the treatment of non-alcoholic steatohepatitis

1. A method of treating NASH or slowing the progression of NAFLD to NASH, the method comprising administering a therapeutically effective dose of ubenimex and a therapeutically effective dose of a second therapeutic agent to a subject in need thereof, wherein the second therapeutic agent is a FXR agonist, a PPAR agonist, aramchol, a caspase inhibitor, a galectin 3 inhibitor, a MAPK5 inhibitor, a FGF19 agonist, a FGF21 agonist, a LTD4 receptor antagonist, a niacin analog, an ASBT inhibitor, an ASK1 inhibitor, an ACE inhibitor, an angiotensin receptor blocker, a chemokine receptor inhibitor, a thiozolidinedione, a GLP-1 analog, a biguanide, or an NSAID, wherein the ubenimex is administered for at least 4 weeks.

2. The method of claim 1 , wherein the ubenimex is administered for at least 12 weeks.

3. The method of claim 2 , wherein the ubenimex is administered for at least 24 weeks.

4. A method of treating non-alcoholic steatohepatitis (NASH), the method comprising administering to a subject in need of treatment a therapeutically effective amount of ubenimex, wherein the ubenimex is administered at a daily dose of about 20 mg to about 450 mg QD.

5. The method of claim 4 , wherein the ubenimex is administered orally, intranasally, rectally, topically, intraperitoneally, intravenously, intramuscularly, subcutaneously, subdermally, transdermally, or intrathecally.

6. A method of treating non-alcoholic steatohepatitis (NASH), the method comprising administering to a subject in need of treatment a therapeutically effective amount of ubenimex, wherein the ubenimex is administered at a daily dose of about 10 mg to about 200 mg BID.

7. The method of claim 6 , wherein the ubenimex is administered at a dose of about 10 mg to about 150 mg TID.

8. The method of claim 6 , wherein the ubenimex is administered orally, intranasally, rectally, topically, intraperitoneally, intravenously, intramuscularly, subcutaneously, subdermally, transdermally, or intrathecally.

9. The method of claim 4 or 6 , wherein the ubenimex is administered once daily, twice daily, or three times daily.

10. A method of treating non-alcoholic steatohepatitis (NASH), the method comprising administering to a subject in need of treatment a therapeutically effective amount of ubenimex, wherein the ubenimex is administered until a therapeutic improvement is observed for the subject, and wherein the therapeutic improvement comprises a reduction of at least 10% in at least one of fibrosis, hepatocyte ballooning, inflammation, steatosis, or lobular inflammation in the subject.

11. The method of claim 10 , wherein the therapeutic improvement is measured using at least one of a non-alcoholic fatty liver disease (NAFLD) activity score, a fatty liver index, a hepatic steatosis index, a NAFLD liver fat score, a steatosis, activity, and fibrosis (SAF) score, a NAFLD fibrosis score, or a serum biomarker.

12. The method of claim 11 , wherein the serum biomarker comprises at least one of plasma CK-18, alanine aminotransferase (ALT), or liver triglycerides.

13. The method of claim 10 , wherein the therapeutic improvement comprises a reduction in hepatocyte ballooning in the subject.

14. The method of claim 10 , wherein the ubenimex is administered in combination with a second therapeutic agent.

15. The method of claim 14 , wherein the second therapeutic agent is a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activator receptor (PPAR) agonist, aramchol, a caspase inhibitor, a galectin 3 inhibitor, a mitogen-activated protein kinase 5 (MAPK5) inhibitor, a fibroblast growth factor 19 (FGF19) agonist, a FGF21 agonist, a leukotriene D4 (LTD4) receptor antagonist, a niacin analog, an apical sodium bile acid cotransporter (ASBT) inhibitor, an apoptosis signal regulating kinase 1 (ASK1) inhibitor, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker, a chemokine receptor inhibitor, a thiozolidinedione, a GLP-1 analog, a biguanide, or a non-steroidal anti-inflammatory drug (NSAID).

16. The method of claim 14 , wherein the method results in an improvement in at least one of insulin sensitivity, insulin resistance, steatosis, inflammation, or fibrosis.

17. The method of claim 10 , wherein the ubenimex is administered at a dose of about 5 mg to about 450 mg.

18. The method of claim 10 , wherein the ubenimex is administered orally, intranasally, rectally, topically, intraperitoneally, intravenously, intramuscularly, subcutaneously, subdermally, transdermally, or intrathecally.

19. The method of claim 10 , wherein the ubenimex is administered once daily, twice daily, or three times daily.

20. A method of delaying or preventing the progression of non-alcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) in a subject having NASH, the method comprising administering to the subject a therapeutically effective amount of ubenimex.

21. The method of claim 20 , wherein the method results in a reduction in hepatocyte ballooning in the subject.

22. The method of claim 20 , wherein the ubenimex is administered at a daily dose in the range of 5 mg to 1000 mg.

23. The method of claim 20 , wherein the ubenimex is administered at a daily dose of about 5 mg to about 450 mg.

24. The method of claim 23 , wherein the ubenimex is administered at a dose of about 20 mg to about 450 mg QD.

25. The method of claim 23 , wherein the ubenimex is administered at a dose of about 10 mg to about 200 mg BID.

26. The method of claim 23 , wherein the ubenimex is administered at a dose of about 10 mg to about 150 mg TID.

27. The method of claim 20 , wherein the ubenimex is administered for at least 4 weeks.

28. The method of claim 27 , wherein the ubenimex is administered for at least 12 weeks.

29. The method of claim 20 , wherein the ubenimex is administered orally, intranasally, rectally, topically, intraperitoneally, intravenously, intramuscularly, subcutaneously, subdermally, transdermally, or intrathecally.

30. The method of claim 20 , wherein the ubenimex is administered once daily, twice daily, or three times daily.

31. A method of treating non-alcoholic steatohepatitis (NASH), the method comprising administering to a subject in need of treatment a therapeutically effective amount of ubenimex, wherein the ubenimex is administered orally, intranasally, rectally, topically, intraperitoneally, intravenously, intramuscularly, subcutaneously, subdermally, transdermally, or intrathecally.

32. The method of claim 31 , wherein the subject has early-stage or middle-stage NASH.

33. The method of claim 31 , wherein the ubenimex is administered for at least 12 weeks.

34. The method of claim 31 , wherein the ubenimex is administered for at least 24 weeks.

35. The method of claim 31 , wherein the ubenimex is administered at a total daily dose in the range of 5 mg to 1000 mg.

36. The method of claim 31 , wherein treatment results in a reduction in plasma CK-18 levels in the subject.

37. The method of claim 31 , wherein treatment results in a reduction in hepatocyte ballooning in the subject.

38. The method of claim 31 , wherein the ubenimex is administered in combination with a second therapeutic agent.

39. The method of claim 31 , wherein the ubenimex is administered once daily, twice daily, or three times daily.

40. A method of treating non-alcoholic steatohepatitis (NASH), the method comprising administering to a subject in need of treatment a therapeutically effective amount of ubenimex, wherein the ubenimex is administered once daily, twice daily, or three times daily.

41. The method of claim 40 , wherein the subject has early-stage or middle-stage NASH.

42. The method of claim 40 , wherein the ubenimex is administered for at least 12 weeks.

43. The method of claim 40 , wherein the ubenimex is administered for at least 24 weeks.

44. The method of claim 40 , wherein the ubenimex is administered at a total daily dose in the range of 5 mg to 1000 mg.

45. The method of claim 40 , wherein treatment results in a reduction in plasma CK-18 levels in the subject.

46. The method of claim 40 , wherein treatment results in a reduction in hepatocyte ballooning in the subject.

47. The method of claim 40 , wherein the ubenimex is administered in combination with a second therapeutic agent.

48. The method of claim 40 , wherein the ubenimex is administered orally, intranasally, rectally, topically, intraperitoneally, intravenously, intramuscularly, subcutaneously, subdermally, transdermally, or intrathecally.