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

Patent metadata

Field	Value
Publication number	US-11248031-B2
Application number	US-201916455990-A
Country	US
Kind code	B2
Filing date	Jun 28, 2019
Priority date	Oct 24, 2014
Publication date	Feb 15, 2022
Grant date	Feb 15, 2022

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 having a molecular weight of about 30 kDa, wherein said modified FGF-21 polypeptide is administered by subcutaneous injection.

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 , which results in one or more of decreased hepatic fat fraction and increased adiponectin levels in said patient.

6. 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 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.

7. The method of claim 6 , wherein said hepatic fat fraction is determined by magnetic resonance imaging and/or said NASH CRN fibrosis stage is determined by a liver biopsy.

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

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

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

11. The method of claim 1 , wherein said modified FGF-21 polypeptide is administered in a dosage of about 40 mg per week.

12. 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.

13. The method of claim 12 , which results in one or more of decreased hepatic fat fraction and increased adiponectin levels in said patient.

14. The method of claim 12 , wherein prior to treatment the patient exhibits at least one of a fatty liver index of at least about 60, 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.

15. The method of claim 14 , wherein said hepatic fat fraction is determined by magnetic resonance imaging and/or said NASH CRN fibrosis stage is determined by a liver biopsy.

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

17. The method of claim 12 , wherein said modified FGF-21 polypeptide is administered at a frequency of about once per day, about twice per week, or about once per two weeks, about once per three weeks, or about once per four weeks.

18. The method of claim 12 , wherein said modified FGF-21 polypeptide is administered in a dosage of about 20 mg per week.

19. The method of claim 12 , wherein said modified FGF-21 polypeptide is administered in a dosage of about 40 mg per week.

20. 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.

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

22. The method of claim 20 , wherein said modified FGF-21 polypeptide is administered in a dosage of about 40 mg per week.

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

• A61P13/12

  of the kidneys · CPC title

• A61K38/1825

  Fibroblast growth factor [FGF] · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P27/12

  for cataracts · CPC title