Methods for glucagon suppression

• US 6,872,700 B1
• Filed: 01/14/2000
• Issued: 03/29/2005
• Est. Priority Date: 01/14/1999
• Status: Expired due to Term

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Young, Andrew A., Gedulin, Bronislava
• Primary Examiner(s): Carlson, Karen Cochrane
• Assistant Examiner(s): LIU, SAMUEL W
• Application Number:
  US09/889,331
• Time in Patent Office: 1,901 Days
• Field of Search: 514/2, 530/308, 530/322, 530/33, 530/402, 530/421, 530/333, 530/344, 424/278.1
• US Class Current: 514/6.9
• 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 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides

Abstract

Methods for use of an exendin, an exendin agonist, or a modified exendin or exendin agonist having an exendin or exendin agonist linked to one or more polyethylene glycol polymers, for example, for lowering glucagon levels and/or suppressing glucagon secretion in a subject are provide. These methods are useful in treating hyperglucagonemia and other conditions that would be benefited by lowering plasma glucagon or suppressing glucagon secretion.

Claims

1. A method of lowering plasma glucagon in a subject in need thereof, comprising:

identifying a subject in need of therapeutic lowering of plasma glucagon levels; and

administering to said subject a composition comprising a therapeutically effective glucagon lowering amount of an exendin, an exendin analog or combinations thereof;

wherein said exendin and exendin analog each have amino acid sequence that is more than 30 amino acid residues in length.

2. The method of claim 1, wherein said subject is suffering from nocrolytic migratory erythema.

3. The method of claim 1, wherein said subject has a glucagonoma.

4. The method of claim 1, wherein the subject has a diabetes-related disorder.

5. The method of claim 4, wherein the subject has type 2 diabetes.

6. The method of any of claims 1-5, wherein said subject is a human.

7. The method of claim 1, wherein said composition is provided in a dosage unit form and further comprises another anti-glucagon agent.

8. The method of claim 1, wherein said composition comprises an exendin analog having an amino acid sequence selected from the sequences of SEQ ID NO:

47 and SEQ ID NO;

48.

9. The method of claim 8, wherein said amino acid sequence has a sequence of SEQ ID NO:

47, wherein the Xaa in position 1 is His;

the Xaa in position 2 is Gly, the Xaa in position 6 is Phe or naphthylalanine;

the Xaa in position 14 is Leu, pentylglycine or Met;

the Xaa in position 22 is Phe or naphthylalanine;

the Xaa in position 23 is Ile or Val;

the Xaa in position 25 is Phe, Tyr, or naphthylalanine;

the Xaa in positions 31, 36, 37, and 38 are independently selected from Pro, homoproline, thioproline, and N-alkylalanine; and

the Xaa in position 39 is Ser or Tyr.

10. The method of claim 8, wherein said amino acid sequence has a sequence of SEQ ID NO:

47, wherein the Xaa in position 14 is Leu or pentylglycine; and

the Xaa in position 22 is Phe or naphthylalanine.

11. The method of claim 8, wherein said amino acid sequence has a sequence of SEQ ID NO:

48, wherein the Xaa in positions 6 and 22 are independently selected from Phe and naphthylalanine;

the Xaa in position 23 is Ile or Val; and

the Xaa in positions 30, 36, 37, and 38 are independently selected from Pro, homoproline, thioproline, and N-alkylalanine.

12. The method of claim 1, wherein said composition comprises exendin-4.

17. The method of claim 7, wherein said anti-glucagon agent comprises amylin.

13. A method of lowering plasma glucagon in a subject, comprising:

identifying a subject in need of therapeutic lowering of plasma glucagon levels; and

administering to said subject a composition consisting essentially of a therapeutically glucagon lowering amount of an exendin, an exendin analog or combinations thereof;

wherein said exendin and exendin analog each have an amino acid sequence that is more than 30 amino acid residues in length.

14. The method of claim 13, wherein said subject is suffering from necrolytic migratory erythema.

15. The method of claim 13, wherein said subject has a glucaganoma.

16. The method of claim 13, wherein said composition consists essentially of exendin-4.

18. The method of claim 13, wherein the subject has a diabetes-related disorder.

19. The method of claim 18, wherein the subject has type 2 diabetes.

20. The method of any of claims 13-19, wherein said subject is a human.

21. The method of claim 13, wherein said composition consists essentially of an exendin analog having an amino acid sequence selected from the sequences of SEQ ID NO:

47 and SEQ ID NO;

48.

22. The method of claim 21, wherein said amino acid sequence has a sequence of SEQ ID NO:

47, wherein the Xaa in position 1 is His;

the Xaa in position 2 is Gly;

the Xaa in position 6 is Phe or naphthylalanine;

the Xaa in position 14 is Leu, pentylglycine or Met;

the Xaa in position 22 is Phe or naphthylalanine;

the Xaa in position 23 is Ile or Val;

the Xaa in position 25 is Phe, Tyr, or naphthylalanine;

the Xaa in positions 31, 36, 37, and 38 are independently selected from Pro, homoproline, thioproline, and N-alkylalanine; and

the Xaa in position 39 is Ser or Tyr.

23. The method of claim 21, wherein said amino acid sequence has a sequence of SEQ ID NO:

47, wherein the Xaa in position 14 is Leu pentylglycine, and the Xaa in position 22 is Phe or naphthylalanine.

24. The method of claim 21, wherein said amino acid sequence has a sequence of SEQ ID NO:

48, wherein the Xaa in positions 6 and 22 are independently selected from Phe and naphthylalanine;

the Xaa in position 23 is Ile or Val; and

the Xaa in positions 30, 36, 37, and 38 are independently selected from Pro, homoproline, thioproline, and N-alkylalanine.