Use of GLP-1 analogs and derivative adminstered peripherally in regulation of obesity

• US 6,583,111 B1
• Filed: 06/01/2000
• Issued: 06/24/2003
• Est. Priority Date: 11/05/1996
• Status: Expired due to Term

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: DiMarchi, Richard, Efendic, Suad
• Primary Examiner(s): Saoud, Christine J.
• Application Number:
  US09/585,186
• Time in Patent Office: 1,118 Days
• Field of Search: 514/2, 514/12, 514/866, 530/300
• US Class Current: 514/4.8
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

This invention relates the use of glucagon-like peptides such as GLP-1, a GLP-1 analog, or a GLP-1 derivative in methods and compositions for reducing body weight.

Claims

1. A method of reducing body weight in a subject in need of body weight reduction by administering to the subject a composition comprising a glucagon-like peptide-1 (GLP-1), a glucagon-like peptide analog (GLP-1 analog), a glucagon-like peptide derivative (GLP-1 derivative) or a pharmaceutically acceptable salt thereof in a dose sufficient to cause reduction in body weight for a period of time effective to produce weight loss.

2. The method of claim 1, wherein the composition administered comprises GLP-1 (7-36) amide having an amino acid sequence shown in SEQ ID NO:

5, or a pharmaceutically-acceptable salt thereof.

3. The method of claim 1, wherein the administering of the composition is by a peripheral parenteral route.

4. The method of claim 1, wherein the administering of the composition is intravenously.

5. The method of claim 4, wherein the intravenous administration is intermittent.

6. The method of claim 1, wherein the administering of the composition is subcutaneously.

7. The method of claim 1, wherein the administering of the composition is continuous.

8. The method of claim 7, wherein the administering of the composition is at a rate of between 0.25 and 6 pmol/kg/min.

9. The method of claim 7 wherein the administering of the composition is at a rate of between 0.6 and 2.4 pmol/kg/min.

10. The method of claim 1 wherein the composition comprises a GLP-1 analog comprising at least one modification selected from the group consisting of:

a. substitution of a neutral amino acid, arginine, or a D form of lysine for lysine at position 26 and/or 34 and/or a neutral amino acid, lysine, or a D form of arginine for arginine at position 36;

b. substitution of an oxidation-resistant amino acid for tryptophan at position 31;

c. substitution according to at least one of;

Y for V at position 16;

K for S at position 18;

D for E at position 21;

S for G at position 22;

R for Q at position 23;

R for A at position 24;

or

Q for K at position 26;

d. substitution comprising at least one of;

(i) an alternative small neutral amino acid for A at position 8;

(ii) an alternative acidic amino acid or neutral amino acid for E at position 9;

(iii) an alternative neutral amino acid for G at position 10;

or (iv) an alternative acidic amino acid for D at position 15; and

e. substitution of an alternative neutral amino acid or the D or N-acylated or alkylated form of histidine for histidine at position 7.

11. The method of claim 10 wherein the GLP-1 analog is acylated.

12. The method of claim 1 wherein the GLP-1 analog comprises at least one modification selected from the group consisting of:

a. substitution of an arginine for lysine at position 26;

b. substitution of lysine for serine at position 18; and

c. substitution of at least one of glycine, serine, or cysteine for alanine at position 8.

13. The method of claim 1 wherein the GLP-1 analog comprises the substitution of glycine, serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, arginine, or D-lysine for lysine at position 34.

14. The method of claim 13 wherein the GLP-1 analog is acylated.

15. The method of claim 1 wherein the composition comprises an acylated GLP-1 derivative.

16. The method of claim 15 wherein the acylated GLP-1 derivative is acylated at the ε

-amino group of a lysine residue.

17. A method of reducing body weight in a subject in need of body weight reduction by administering to the subject a composition comprising Val⁸-GLP-1(7-37)OH having an amino acid sequence shown in SEQ ID NO:

6, or a pharmaceutically-acceptable salt thereof, in a dose sufficient to cause reduction in body weight for a period of time effective to produce weight loss.

18. A method of reducing body weight in a subject in need of body weight reduction by administering to the subject a composition comprising an agonist of the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof in a dose sufficient to cause reduction in body weight for a period of time effective to produce weight loss.

19. A method of reducing body weight in a non-diabetic subject in need of body weight reduction by administering to the subject a composition comprising a glucagon-like peptide-1 (GLP-1), a glucagon-like peptide analog (GLP-1 analog), a glucagon-like peptide derivative (GLP-1 derivative) or a pharmaceutically acceptable salt thereof in a dose sufficient to cause reduction in body weight for a period of time effective to produce weight loss.

20. The method of claim 19, wherein the composition administered comprises GLP-1 (7-36) amide having an amino acid sequence shown in SEQ ID NO:

5, or a pharmaceutically-acceptable salt thereof.

21. The method of claim 19, wherein the administering of the composition is by a peripheral parenteral route.

22. The method of claim 19, wherein the administering of the composition is intravenously.

23. The method of claim 22, wherein the intravenous administration is intermittent.

24. The method of claim 19, wherein the administering of the composition is subcutaneously.

25. The method of claim 19, wherein the administering of the composition is continuous.

26. A method of reducing body weight in a non-diabetic subject in need of body weight reduction by administering to the subject a composition comprising Val⁸-GLP-1(7-37)OH having an amino acid sequence shown in SEQ ID NO:

6, or a pharmaceutically-acceptable salt thereof in a dose sufficient to cause reduction in body weight for a period of time effective to produce weight loss.

27. A method of reducing body weight in a non-diabetic subject in need of body weight reduction by administering to the subject a composition comprising an agonist of the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof in a dose sufficient to cause reduction in body weight for a period of time effective to produce weight loss.

28. A method of treating obesity in a subject by administering to the subject a composition comprising a glucagon-like peptide-1 (GLP-1), a glucagons-like peptide-1 analog (GLP-1 analog), or a glucagon-like peptide derivative (GLP-1 derivative) or a pharmaceutically acceptable salt thereof in a dose sufficient to cause a reduction in body weight for a period of time effective to produce weight loss.

29. The method of claim 28, wherein the administering of the composition is by a peripheral parenteral route.

30. A method of treating obesity in a subject by administering to the subject a composition comprising an agonist of the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof in a dose sufficient to cause reduction in body weight for a period of time effective to produce weight loss.

31. The method of claim 30, wherein the administering of the composition is subcutaneously.