Methods of using variants of FGF19 polypeptides for the treatment of pruritus

Patent metadata

Field	Value
Publication number	US-10744185-B2
Application number	US-201615773120-A
Country	US
Kind code	B2
Filing date	Nov 8, 2016
Priority date	Nov 9, 2015
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

Abstract

Provided herein are variants of fibroblast growth factor 19 (FGF19) proteins and peptide sequences (and peptidomimetics) and fusions of FGF19 and/or fibroblast growth factor 21 (FGF21) proteins and peptide sequences (and peptidomimetics), and variants of fusions of FG-F19 and/or FGF21 proteins and peptide sequences (and peptidomimetics). In some embodiments, these variants and fusions modulate bile acid homeostasis, and are useful in treatment of bile acid related and associated disorders. In some embodiments, these variants and fusions have glucose lowering activity, and are useful in treatment of hyperglycemia and other disorders.

First claim

What is claimed is:

1. A method of treating pruritus associated with a cholestatic liver disease in a subject in need thereof, comprising administering to the subject an effective amount of a peptide, wherein the peptide has an amino acid sequence comprising:

(SEQ ID NO: 70)

MRDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSA

HSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEI

RPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEP

EDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK.

2. The method of claim 1 , wherein the effective amount of the peptide is 0.3 mg.

3. The method of claim 1 , wherein the effective amount of the peptide is 1 mg.

4. The method of claim 1 , wherein the effective amount of the peptide is 2 mg.

5. The method of claim 1 , wherein the effective amount of the peptide is 3 mg.

6. The method of claim 1 , wherein the effective amount of the peptide is 5 mg.

7. The method of claim 1 , wherein the effective amount of the peptide is 10 mg.

8. The method of claim 1 , wherein the peptide is administered once a day.

9. The method of claim 1 , wherein the peptide is administered twice a day.

10. The method of claim 1 , wherein the peptide is administrated subcutaneously.

11. The method of claim 1 , wherein the peptide is administered for 7 days or longer.

12. The method of claim 1 , wherein the peptide is administered for 14 days or longer.

13. The method of claim 1 , wherein the peptide is administered for 21 days or longer.

14. The method of claim 1 , wherein the peptide is administered for 28 days or longer.

15. The method of claim 1 , wherein the peptide is administered for 1 to 12 months.

16. The method of claim 1 , wherein the peptide is administered for 12 months.

17. The method of claim 1 , wherein the peptide is administered for more than 12 months.

18. The method of claim 1 , wherein the peptide is administered in combination with ursodeoxycholic acid (UDCA).

19. The method of claim 1 , wherein the subject has a cholestatic liver disease.

20. The method of claim 19 , wherein the cholestatic liver disease is primary sclerosing cholangitis (PSC).

21. The method of claim 19 , wherein the cholestatic liver disease is primary biliary cirrhosis (PBC).

22. The method of claim 19 , wherein the cholestatic liver disease is intrahepatic cholestasis of pregnancy.

23. The method of claim 19 , wherein the cholestatic liver disease is alcoholic hepatitis.

24. The method of claim 19 , wherein the cholestatic liver disease is drug-induced cholestasis.

25. The method of claim 1 , wherein the subject is human.

26. A method of treating pruritus associated with a cholestatic liver disease in a subject in need thereof, comprising administering to the subject an effective amount of a peptide, wherein the peptide has an amino acid sequence consisting of:

(SEQ ID NO: 70)

MRDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSA

HSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEI

RPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEP

EDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK.

27. The method of claim 26 , wherein the effective amount of the peptide is 0.3 mg.

28. The method of claim 26 , wherein the effective amount of the peptide is 1 mg.

29. The method of claim 26 , wherein the effective amount of the peptide is 2 mg.

30. The method of claim 26 , wherein the effective amount of the peptide is 3 mg.

31. The method of claim 26 , wherein the effective amount of the peptide is 5 mg.

32. The method of claim 26 , wherein the effective amount of the peptide is 10 mg.

33. The method of claim 26 , wherein the peptide is administered once a day.

34. The method of claim 26 , wherein the peptide is administered twice a day.

35. The method of claim 26 , wherein the peptide is administrated subcutaneously.

36. The method of claim 26 , wherein the peptide is administered for 7 days or longer.

37. The method of claim 26 , wherein the peptide is administered for 14 days or longer.

38. The method of claim 26 , wherein the peptide is administered for 21 days or longer.

39. The method of claim 26 , wherein the peptide is administered for 28 days or longer.

40. The method of claim 26 , wherein the peptide is administered for 1 to 12 months.

41. The method of claim 26 , wherein the peptide is administered for 12 months.

42. The method of claim 26 , wherein the peptide is administered for more than 12 months.

43. The method of claim 26 , wherein the peptide is administered in combination with UDCA.

44. The method of claim 26 , wherein the subject has a cholestatic liver disease.

45. The method of claim 44 , wherein the cholestatic liver disease is PSC.

46. The method of claim 44 , wherein the cholestatic liver disease is PBC.

47. The method of claim 44 , wherein the cholestatic liver disease is intrahepatic cholestasis of pregnancy.

48. The method of claim 44 , wherein the cholestatic liver disease is alcoholic hepatitis.

49. The method of claim 44 , wherein the cholestatic liver disease is drug-induced cholestasis.

50. The method of claim 26 , wherein the subject is human.

51. A method of preventing the induction or exacerbation of pruritus associated with a cholestatic liver disease in a subject being treated for the cholestatic liver disease, comprising administering to the subject an effective amount of a peptide, wherein the peptide has an amino acid sequence comprising:

(SEQ ID NO: 70)

MRDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSA

HSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEI

RPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEP

Assignees

• Ngm Biopharmaceuticals Inc

Inventors

• Ling Lei
• Luo Jian
• Tian Hui

Classifications

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K38/1825 Primary

  Fibroblast growth factor [FGF] · CPC title

• C07K14/50

  Fibroblast growth factor [FGF] · CPC title

• A61K31/575

  substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol · CPC title