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

• US 10,377,806 B2
• Filed: 05/15/2018
• Issued: 08/13/2019
• Est. Priority Date: 10/24/2014
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Morin, Paul E., Cohen, Daniel, Mukherjee, Ranjan, Reilly, Timothy P., Christian, Rose C., Lipovsek, Dasa, Camphausen, Ray, Krupinski, John
• Primary Examiner(s): Saoud, Christine J
• Application Number:
  US15/979,881
• Publication Number:
  US 20180243375A1
• Time in Patent Office: 455 Days
• Field of Search: None
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/28 Antiandrogens
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/50 : Fibroblast growth factor [FGF]
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

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.

Claims

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/m², 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/m², 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.