Methods of treating diseases associated with fibrosis using modified FGF-21 polypeptides and uses thereof

Patent metadata

Field	Value
Publication number	US-10377806-B2
Application number	US-201815979881-A
Country	US
Kind code	B2
Filing date	May 15, 2018
Priority date	Oct 24, 2014
Publication date	Aug 13, 2019
Grant date	Aug 13, 2019

Abstract

Modified FGF-21 polypeptides and uses thereof are provided, for example, for the treatment of diseases associated with fibrosis. Modified FGF-21 polypeptides are disclosed that contain an internal deletion and optionally replacement peptide, optionally modified with at least one non-naturally-encoded amino acid, and/or optionally fused to a fusion partner.

First claim

What is claimed is:

1. A method of treating a disease associated with fibrosis selected from non-alcoholic steatohepatitis (NASH), liver fibrosis, or cirrhosis comprising administering to a patient in need thereof an effective amount of a modified FGF-21 polypeptide comprising the polypeptide of SEQ ID NO:201, wherein the para-acetyl-phenylalanine residue thereof is linked to a poly(ethylene glycol) moiety.

2. The method of claim 1 , wherein said disease associated with fibrosis is NASH, wherein NASH is treated.

3. The method of claim 1 , wherein said disease associated with fibrosis is cirrhosis.

4. The method of claim 1 , wherein said disease associated with fibrosis is liver fibrosis.

5. The method of claim 1 , wherein said poly(ethylene glycol) has a molecular weight of between about 0.1 kDa and 100 kDa.

6. The method of claim 5 , wherein said poly(ethylene glycol) has a molecular weight of between about 10 kDa and about 40 kDa.

7. The method of claim 6 , wherein said poly(ethylene glycol) has a molecular weight of about 30 kDa.

8. The method of claim 1 , which results in one or more of decreased hepatic fat fraction and increased adiponectin levels in said patient.

9. The method of claim 1 , wherein prior to treatment the patient exhibits at least one of a fatty liver index of at least about 60, a a-hepatic fat fraction percentage of at least 10%, a body mass index greater than or equal to 25 kg/m 2 , and/or NASH Clinical Research Network (CRN) fibrosis stage 1-3.

10. The method of claim 9 , wherein said hepatic fat fraction is determined by magnetic resonance imaging and/or said NASH CRN fibrosis stage is determined by a liver biopsy.

11. The method of claim 1 , wherein said modified FGF-21 polypeptide is administered by subcutaneous injection.

12. The method of claim 1 , wherein said modified FGF-21 polypeptide is administered at a frequency of about once per day.

13. The method of claim 1 , wherein said modified FGF-21 polypeptide is administered at a frequency of about once per week.

14. The method of claim 1 , wherein said modified FGF-21 polypeptide is administered at a frequency of about twice per week, about once per two weeks, or about once per four weeks.

15. The method of claim 1 , wherein said modified FGF-21 polypeptide is administered in a dosage of between about 0.05 mg/kg and about 1 mg/kg of patient body weight.

16. The method of claim 1 , wherein said modified FGF-21 polypeptide is administered in a dosage of about 20 mg per week.

17. A method of treating NASH in a patient in need thereof, comprising administering to the patient an effective amount of a modified FGF-21 polypeptide comprising the polypeptide of SEQ ID NO:201, wherein the para-acetyl-phenylalanine residue thereof is linked to a poly(ethylene glycol) moiety having a molecular weight of between about 10 kDa and about 40 kDa.

18. The method of claim 17 , wherein NASH is treated.

19. The method of claim 17 , wherein said poly(ethylene glycol) has a molecular weight of about 30 kDa.

20. The method of claim 17 , which results in one or more of decreased hepatic fat fraction and increased adiponectin levels in said patient.

21. The method of claim 17 , wherein prior to treatment the patient exhibits at least one of a fatty liver index of at least about 60, a a-hepatic fat fraction percentage of at least 10%, a body mass index greater than or equal to 25 kg/m 2 , and/or NASH Clinical Research Network (CRN) fibrosis stage 1-3.

22. The method of claim 21 , wherein said hepatic fat fraction is determined by magnetic resonance imaging and/or said NASH CRN fibrosis stage is determined by a liver biopsy.

23. The method of claim 17 , wherein said modified FGF-21 polypeptide is administered by subcutaneous injection.

24. The method of claim 17 , wherein said modified FGF-21 polypeptide is administered at a frequency of about once per day.

25. The method of claim 17 , wherein said modified FGF-21 polypeptide is administered at a frequency of about once per week, about twice per week, or about once per two weeks.

26. The method of claim 17 , wherein said modified FGF-21 polypeptide is administered at a frequency of about once per three weeks or at a frequency of about once per four weeks.

27. The method of claim 17 , wherein said modified FGF-21 polypeptide is administered in a dosage of between about 0.05 mg/kg and about 1 mg/kg of patient body weight.

28. The method of claim 17 , wherein said modified FGF-21 polypeptide is administered in a dosage of about 20 mg per week.

29. A method of treating NASH in a patient in need thereof, comprising administering to the patient an effective amount of a modified FGF-21 polypeptide comprising the polypeptide of SEQ ID NO:201, wherein the para-acetyl-phenylalanine residue thereof is linked to a poly(ethylene glycol) moiety having a molecular weight of about 30 kDa, wherein said modified FGF-21 polypeptide is administered by subcutaneous injection about once per week at a dose of between about 0.05 mg/kg and about 1 mg/kg of patient body weight.

30. The method of claim 29 , wherein the modified FGF-21 polypeptide is administered by subcutaneous injection once per week at a dose of 20 mg.

Assignees

• Bristol Myers Squibb Co

Inventors

• Morin Paul E
• Cohen Daniel
• Mukherjee Ranjan
• Reilly Timothy P
• Christian Rose C
• Lipovsek Dasa
• Camphausen Ray
• Krupinski John

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/28

  Antiandrogens · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title