Methods and uses for modulating bile acid homeostasis and treatment of bile acid disorders and diseases

Patent metadata

Field	Value
Publication number	US-10456449-B2
Application number	US-201515316108-A
Country	US
Kind code	B2
Filing date	Jun 15, 2015
Priority date	Jun 16, 2014
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

Provided herein are methods of modulating bile acid homeostasis or treating a bile-acid related or associated disorder, comprising using variants and fusions of fibroblast growth factor 19 (FGF19), variants and fusions of fibroblast growth factor 21 (FGF21), fusions of FGF19 and/or FGF21, and variants or fusions of FGF19 and/or FGF21 proteins and peptide sequences (and peptidomimetics), in combination with agents effective in modulating bile acid homeostasis or treating a bile-acid related or associated disorder.

First claim

What is claimed is:

1. A method of reducing bile acid synthesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of
(i) a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:70, and
(ii) at least one additional agent, wherein the additional agent is an anti-CD20 agent, an anti-CD80 agent, an anti-cytokine antibody, an anti-retroviral therapy, an apical sodium bile acid transporter (ASBT) inhibitor, an autoimmune agent, azathioprine, cochicine, a CSCL10 neutralizing antibody, a CXCR3 ligand, cyclosporine, a cytokine anti-inflammatory drug (CSAID), a cytokine, a growth factor, a fibrate, a fish oil, an immune checkpoint inhibitor, or a non-steroidal anti-inflammatory drug (NSAID);
thereby reducing bile acid synthesis in the subject without inducing HGG hepatocellular carcinoma (HCC) formation.

2. The method of claim 1 , wherein the additional agent is an anti-CD20 agent.

3. The method of claim 1 , wherein the additional agent is an anti-CD80 agent.

4. The method of claim 1 , wherein the additional agent is an anti-cytokine antibody.

5. The method of claim 1 , wherein the additional agent is an anti-retroviral therapy.

6. The method of claim 1 , wherein the additional agent is an ASBT inhibitor.

7. The method of claim 1 , wherein the additional agent is an autoimmune agent.

8. The method of claim 1 , wherein the additional agent is azathioprine.

9. The method of claim 1 , wherein the additional agent is cochicine.

10. The method of claim 1 , wherein the additional agent is a CSCL10 neutralizing antibody.

11. The method of claim 1 , wherein the additional agent is a CXCR3 ligand.

12. The method of claim 1 , wherein the additional agent is cyclosporine.

13. The method of claim 1 , wherein the additional agent is a CSAID.

14. The method of claim 1 , wherein the additional agent is a cytokine.

15. The method of claim 14 , wherein the cytokine is IL-12.

16. The method of claim 1 , wherein the additional agent is a growth factor.

17. The method of claim 1 , wherein the additional agent is a fibrate.

18. The method of claim 1 , wherein the additional agent is a fish oil.

19. The method of claim 1 , wherein the additional agent is an immune checkpoint inhibitor.

20. The method of claim 1 , wherein the additional agent is a NSAID.

21. The method of claim 1 , wherein the subject has nonalcoholic steatohepatitis (NASH).

22. The method of claim 1 , wherein the subject has primary biliary cirrhosis (PBC).

23. The method of claim 1 , wherein the subject has cholestasis.

24. The method of claim 1 , wherein the subject has primary sclerosing cholangitis (PSC).

25. The method of claim 1 , wherein the subject has bile acid diarrhea (BAD) or bile acid malabsorption.

26. The method of claim 1 , wherein the subject has pregnancy intrahepatic cholestasis (PIC).

27. The method of claim 1 , wherein the subject has liver fibrosis.

28. The method of claim 1 , wherein the subject has nonalcoholic fatty liver disease (NAFLD).

29. The method of claim 1 , wherein the subject has cirrhosis.

30. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:70.

31. The method of claim 1 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:70.

32. A method of reducing bile acid synthesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of
(i) a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:70, and
(ii) at least one additional agent, wherein the additional agent is a farnesoid X receptor (FXR) agonist or a steroid;
thereby reducing bile acid synthesis in the subject without inducing HCC formation.

33. The method of claim 32 , wherein the additional agent is a FXR agonist.

34. The method of claim 32 , wherein the additional agent is a steroid.

35. The method of claim 32 , wherein the steroid is a glucocorticoid.

36. The method of claim 32 , wherein the subject has NASH.

37. The method of claim 32 , wherein the subject has PBC.

38. The method of claim 32 , wherein the subject has cholestasis.

39. The method of claim 32 , wherein the subject has PSC.

40. The method of claim 32 , wherein the subject has an error of bile acid synthesis.

41. The method of claim 32 , wherein the subject has BAD or bile acid malabsorption.

42. The method of claim 32 , wherein the subject has PIC.

43. The method of claim 32 , wherein the subject has liver fibrosis.

44. The method of claim 32 , wherein the subject has NAFLD.

45. The method of claim 32 , wherein the subject has cirrhosis.

46. The method of claim 32 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:70.

47. The method of claim 32 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:70.

48. A method of reducing bile acid synthesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of
(i) a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:70, and
(ii) at least one additional agent, wherein the additional agent is chenodeoxycholic acid (CDCA), obeticholic acid (OCA), or ursodeoxycholic acid (UDCA);
thereby reducing bile acid synthesis in the subject without inducing HCC formation.

49. The method of claim 48 , wherein the additional agent is CDCA.

50. The method of claim 48 , wherein the additional agent is OCA.

51. The method of claim 48 , wherein the additional agent is UDCA.

52. The method of claim 48 , wherein the subject has NASH.

53. The method of claim 48 , wherein the subject has PBC.

54. The method of claim 48 , wherein the subject has cholestasis.

55. The method of claim 48 , wherein the subject has PSC.

56. The method of claim 48 , wherein the subject has an error of bile acid synthesis.

57. The method of claim 48 , wherein the subject has BAD or bile acid malabsorption.

58. The method of claim 48 , wherein the subject has PIC.

59. The method of claim 48 , wherein the subject has liver fibrosis.

60. The method of claim 48 , wherein the subject has NAFLD.

61. The method of claim 48 , wherein the subject has cirrhosis.

62. The method of claim 48 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:70.

63. The method of claim 48 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:70.

Assignees

• Ngm Biopharmaceuticals Inc

Inventors

• Ling Lei
• Tian Hui

Classifications

• A61K31/64

  Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• C07K14/50

  Fibroblast growth factor [FGF] · CPC title

• A61K38/13

  Cyclosporins · CPC title

• A61K31/165

  having aromatic rings, e.g. colchicine, atenolol, progabide · CPC title