Methods of treating fgf21-associated disorders

Patent metadata

Field	Value
Publication number	US-2016051628-A1
Application number	US-201514676863-A
Country	US
Kind code	A1
Filing date	Apr 2, 2015
Priority date	Nov 19, 2010
Publication date	Feb 25, 2016
Grant date	—

Abstract

The invention relates to the identification of new polypeptide and protein variants of fibroblast growth factor 21 (FGF21) that have improved pharmaceutical properties. Also disclosed are methods for treating FGF21-associated disorders, including metabolic conditions.

First claim

1 . A polypeptide variant having a sequence selected from SEQ ID NO:5-49.

2 . The variant of claim 1 , wherein the variant further comprises one or more of the following modifications: (a) an amino-terminal truncation of no more than 8 amino acid residues; and (b) a carboxyl-terminal truncation of no more than 12 amino acid residues.

3 . The variant of claim 1 , wherein the variant is covalently linked to polyethylene glycol (PEG) or polysialic acid.

4 . The variant of claim 3 , wherein the variant further comprises a branched, 40 kDa PEG group, covalently linked to a cysteine of the variant.

5 . The variant of claim 1 , wherein the variant is fused to a heterologous amino acid sequence consisting of one of the following: an IgG constant domain or fragment thereof; Human Serum Albumin (HSA); and albumin-binding polypeptides.

6 . The variant of claim 5 , wherein the heterologous amino acid sequence is fused to the amino-terminal of the variant.

7 . The variant of claim 5 , wherein the heterologous amino acid sequence is fused to the carboxy-terminal of the variant.

8 . (canceled)

9 . The multimer of claim 1 , wherein the multimer is a homodimer.

10 - 14 . (canceled)

15 . A method for treating a patient comprising administering to said patient a therapeutically effective amount of a polypeptide variant having a sequence selected from SEQ ID NO:5-49, wherein said patient exhibits one or more of FGF21-associated disorders

16 . The method of claim 15 , wherein the FGF21-associated disorders consist of one or more of the following: obesity, type 1 and type 2 diabetes mellitus, pancreatitis, dyslipidemia, nonalcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, metabolic syndrome, and other metabolic disorders

17 . The method of claim 16 , wherein the FGF21-associated disorder consists of type 1 diabetes mellitus.

18 . The method of claim 16 , wherein the FGF21-associated disorder consists of type 2 diabetes mellitus.

19 . A method for treating a patient comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of the polypeptide variant of claim 1 , wherein said patient exhibits one or more of FGF21-associated disorders.

20 . The method of claim 19 , wherein said variant further comprises SEQ ID NO:39, with PEGylation at the cysteine residue at position 154.

21 . The method of claim 20 , wherein the FGF21-associated disorders consist of one or more of the following: obesity, type 1 and type 2 diabetes mellitus, pancreatitis, dyslipidemia, nonalcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, metabolic syndrome, and other metabolic disorders

22 . The method of claim 21 , wherein the FGF21-associated disorder consists of type 1 diabetes mellitus.

23 . The method of claim 21 , wherein the FGF21-associated disorder consists of type 2 diabetes mellitus.

24 . A method for reducing one or more of hyperglycemia, hyperinsulinemia, liver lipids, and weight gain in a patient in need, comprising administering to said patient a therapeutically effective amount of polypeptide variant having a sequence selected from SEQ ID NO:5-49.

25 . The method of claim 24 , wherein the variant further comprises SEQ ID NO:39, with PEGylation at the cysteine residue at position 154.

Assignees

• Boettcher Brian R
• Loew Andreas
• Caplan Shari L
• Daniels Douglas S
• Geierstanger Bernhard H
• Hamamatsu Norio
• Licht Stuart
• Weldon Stephen Craig
• Irm Llc
• Novartis Ag

Inventors

• Boettcher Brian R
• Loew Andreas
• Caplan Shari L
• Daniels Douglas S
• Geierstanger Bernhard H
• Hamamatsu Norio
• Licht Stuart
• Weldon Stephen Craig

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title