COMPOSITIONS AND METHODS TO TREAT NON-ALCOHOLIC FATTY LIVER DISEASES (NAFLD)

1 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (c) together are effective in treating NAFLD.

2 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (c) together are effective in treating NAFLD.

3 . A method of treating a subject, the method comprising:

identifying a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof

wherein the amounts of (a), (b), and (c) together are effective in treating NAFLD.

4 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject:

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt thereof, and

(b) a therapeutically effective amount of an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a therapeutically effective amount of a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof.

5 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt thereof, and

(b) a therapeutically effective amount of an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a therapeutically effective amount of a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, to the selected subject.

6 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, to the selected subject;

wherein the amounts of (a), (b), and (c) together are effective in treating NAFLD.

7 . A method of treating a subject, the method comprising:

identifying a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, to the subject;

wherein the amounts of (a), (b), and (c) together are effective in treating NAFLD.

8 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject:

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) a therapeutically effective amount of an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a therapeutically effective amount of a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof.

9 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) a therapeutically effective amount of an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a therapeutically effective amount of a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, to the selected subject.

10 . The method of any one of claims 1 - 9 , wherein (a), (b), and (c) are administered concurrently.

11 . The method of any one of claims 1 - 9 , wherein (a), (b), and (c) are administered sequentially in any order.

12 . The method of any one of claims 1 - 11 , wherein the treatment of NAFLD comprises a reduction in hepatic steatosis.

13 . The method of any one of claims 1 - 12 , wherein the treatment of NAFLD comprises a reduction in hepatic inflammation.

14 . The method of any one of claims 1 - 13 , wherein the NAFLD activity score (NAS) following administration is 7 or less.

15 . The method of any one of claims 1 - 14 , wherein the NAS is 5 or less.

16 . The method of any one of claims 1 - 15 , wherein the NAS is 3 or less.

17 . The method of any one of claims 1 - 16 , wherein the treatment of the NAFLD comprises treatment of liver cirrhosis.

18 . The method of any one of claims 1 - 17 , wherein the adiponectin level in the subject is increased by at least about 30%, at least about 68%, at least about 175%, or at least about 200%.

19 . The method of any one of claims 1 - 18 , wherein the level of one or more biomarkers indicative of one or more of liver damage, inflammation, fibrosis, and/or cirrhosis is decreased.

20 . The method of claim 19 , wherein the increase is by at least about 175%.

21 . The method of any one of claims 1 - 20 , wherein the treatment of NAFLD comprises treatment of pruritus.

22 . The method of any one of claims 1 - 21 , wherein the subject has hepatic cirrhosis associated with the NAFLD.

23 . The method of any one of claims 1 - 22 , wherein the subject has hepatic cirrhosis as a comorbidity.

24 . The method of any one of claims 1 - 22 , wherein the subject has hepatic cirrhosis caused by the NAFLD.

25 . The method of any one of claims 1 - 22 , wherein the NAFLD is NAFL with attendant liver cirrhosis.

26 . The method of any one of claims 1 - 25 , wherein the treatment of NAFL decreases the level of serum bile acids in the subject.

27 . The method of any one of claims 1 - 26 , wherein the NAFLD is nonalcoholic steatohepatitis (NASH).

28 . The method of any one of claims 1 - 27 , wherein the NAFLD is NASH with attendant liver cirrhosis.

29 . The method of any one of claims 27 - 28 , wherein the treatment of NASH decreases the level of serum bile acids in the subject.

30 . The method of any one of claims 27 - 29 , wherein the treatment of NASH comprises treatment of pruritus.

31 . The method of any one of claims 1 - 27 , wherein the NAFLD is simple nonalcoholic fatty liver (NAFL).

32 . The method of any one of claims 1 - 31 , wherein the method further comprises performing a liver biopsy to determine the NAFLD activity score of the biopsy sample obtained from the subject.

33 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject:

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (c) together are effective in treating fibrosis.

34 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject:

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) a therapeutically effective amount of an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a therapeutically effective amount of a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof.

35 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject:

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) a therapeutically effective amount of an SGLT inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a therapeutically effective amount of a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (c) together are effective in treating fibrosis.

36 . The method of any one of claims 33 - 35 , wherein the fibrosis is cirrhosis.

37 . The method of any one of claims 33 - 36 , wherein the fibrosis is associated with NAFLD.

38 . The method of any one of claims 33 - 37 , wherein the fibrosis is caused by NAFLD.

39 . The method of claim 37 or 38 , wherein the NAFLD is NASH.

40 . The method of any one of claims 37 - 39 , wherein the method further comprises performing a liver biopsy to determine the NAFLD activity score of the biopsy sample obtained from the subject.

41 . The method of any one of claims 33 - 40 , wherein the treatment of fibrosis comprises a decrease in the stage of fibrosis, a lack of progression of the fibrosis, or a slowing in the progression of the fibrosis.

42 . The method of any one of claims 33 - 41 , wherein the treatment of fibrosis comprises a decrease in the stage of fibrosis.

43 . The method of any one of claims 33 - 42 , wherein the decrease in the stage of fibrosis is from stage 4 to stage 3, from stage 4 to stage 2, from stage 4 to stage 1, from stage 4 to stage 0, from stage 3 to stage 2, from stage 3 to stage 1, from stage 3 to stage 0, from stage 2 to stage 1, from stage 2 to stage 0, or from stage 1 to stage 0.

44 . The method of any one of claims 1 - 43 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, serfliflozin etabonate, sotagliflozin, tofogliflozin, or a pharmaceutically acceptable salt or solvate of any of the foregoing.

45 . The method of any one of claims 1 to 44 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is empagliflozin.

46 . The method of any one of claims 1 to 45 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 1 to about 350 mg.

47 . The method of any one of claims 1 to 46 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 85 to about 325 mg.

48 . The method of any one of claims 1 to 47 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 5 to about 15 mg.

49 . The method of any one of claims 1 to 48 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 10 mg.

50 . The method of any one of claims 1 to 48 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 8 mg.

51 . The method of any one of claims 1 to 48 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 5 mg.

52 . The method of any one of claims 1 to 51 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject twice a day, daily, every other day, three times a week, twice a week, weekly, every other week, twice a month, or monthly.

53 . The method of any one of claims 1 to 52 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject daily.

54 . The method of any one of claims 1 - 53 , wherein the DPP-4 inhibitor is selected from the group consisting of: sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, and dutogliptin, or a pharmaceutically acceptable salt of any of the foregoing.

55 . The method of any one of claims 1 - 54 , wherein the DPP-4 inhibitor is sitagliptin.

56 . The method of any one of claims 1 - 55 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg to about 100 mg.

57 . The method of any one of claims 1 - 56 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5 mg to about 50 mg.

58 . The method of any one of claims 1 - 57 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg to about 25 mg.

59 . The method of any one of claims 1 - 56 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 25 mg to about 75 mg.

60 . The method of any one of claims 1 - 56 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg to about 100 mg.

61 . The method of any one of claims 1 to 60 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject twice a day, daily, every other day, three times a week, twice a week, weekly, every other week, twice a month, or monthly.

62 . The method of any one of claims 1 to 61 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject daily.

63 . The method of any one of claims 1 - 62 , wherein the compound of Formula (I), a pharmaceutically acceptable salt thereof, is administered prophylactically.

64 . The method of any one of claims 1 - 63 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose from about 0.1 to about 15 mg.

65 . The method of any one of claims 1 - 64 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose from about 1 to about 10 mg.

66 . The method of any one of claims 1 - 65 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose from about 2 to about 6 mg.

67 . The method of any one of claims 1 - 65 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose from about 0.5 to about 3 mg.

68 . The method of any one of claims 1 - 67 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 3 mg.

69 . The method of any one of claims 1 - 67 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 2 mg.

70 . The method of any one of claims 1 - 67 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg.

71 . The method of any one of claims 1 - 70 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject twice a day, daily, every other day, three times a week, twice a week, weekly, every other week, twice a month, or monthly.

72 . The method of any one of claims 1 - 71 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject daily.

73 . The method of any one of claims 1 - 68 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject daily and the dose of the compound of Formula (I) is about 3 mg.

74 . The method of any one of claims 1 - 63 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose from about 0.1-about 10.0 mg per day.

75 . The method of any one of claims 1 - 63 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose from about 0.1-about 3 mg per day.

76 . The method of any one of claims 1 - 63 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.5 milligram per day.

77 . The method of any one of claims 1 - 63 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 milligram per day.

78 . The method of any one of claims 1 - 63 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 2 mg per day.

79 . The method of any one of claims 1 - 78 , wherein the compound of Formula (I) is in the form of a besylate salt.

80 . A pharmaceutical composition comprising

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, and

one or more pharmaceutical excipients,

wherein the amounts of (a), (b), and (c) together are effective in treating NAFLD.

81 . The pharmaceutical composition of claim 80 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, serfliflozin etabonate, sotagliflozin, tofogliflozin, or a pharmaceutically acceptable salt or solvate of any of the foregoing.

82 . The pharmaceutical composition of claim 80 or 81 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, and dutogliptin, or a pharmaceutically acceptable salt of any of the foregoing.

83 . The pharmaceutical composition of any one of claims 80 - 82 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided in the form of a besylate salt.

84 . The pharmaceutical composition of any one of claims 80 - 83 , wherein the composition comprises:

from about 1 mg to about 5 mg of the besylate salt of the compound of Formula (I);

from about 5 mg to about 25 mg of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of: empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin, or a pharmaceutically acceptable salt or solvate of any of the foregoing;

from about 1 mg to about 50 mg of a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: sitagliptin, saxagliptin, linagliptin, and alogliptin, or a pharmaceutically acceptable salt of any of the foregoing; and

one or more pharmaceutical excipients.

85 . A pharmaceutical combination comprising

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof;

for concurrent or sequential administration for use in the treatment of non-alcoholic fatty liver disease (NAFLD).

86 . The pharmaceutical combination of claim 85 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, serfliflozin etabonate, sotagliflozin, tofogliflozin, or a pharmaceutically acceptable salt or solvate of any of the foregoing.

87 . The pharmaceutical combination of claim 85 or 86 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, and dutogliptin, or a pharmaceutically acceptable salt of any of the foregoing.

88 . The pharmaceutical combination of any one of claims 85 - 87 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided in the form of a besylate salt.

89 . The pharmaceutical combination of any one of claims 85 - 88 , further comprising at least one pharmaceutically acceptable carrier.

90 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof consisting essentially of administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

(c) a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (c) together are effective in treating NAFLD.

91 . The method of claim 90 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, serfliflozin etabonate, sotagliflozin, tofogliflozin, or a pharmaceutically acceptable salt or solvate of any of the foregoing.

92 . The method of claim 90 or 91 , wherein the DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, and dutogliptin, or a pharmaceutically acceptable salt of any of the foregoing.

93 . The method of any one of claims 90 - 92 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided in the form of a besylate salt.