FGF21 compound / GLP-1R agonist combinations with optimized activity ratio

Patent metadata

Field	Value
Publication number	US-10583174-B2
Application number	US-201715851963-A
Country	US
Kind code	B2
Filing date	Dec 22, 2017
Priority date	Dec 22, 2016
Publication date	Mar 10, 2020
Grant date	Mar 10, 2020

Abstract

The present invention relates to combinations, pharmaceutical compositions and fusion molecules comprising an FGF21 (fibroblast growth factor 21) compound and a GLP-1R (glucagon-like peptide-1 receptor) agonist with optimized GLP-1R agonist/FGF21 compound activity ratio. It further relates to their use as medicaments, in particular for the treatment of obesity, being overweight, metabolic syndrome, diabetes mellitus, diabetic retinopathy, hyperglycemia, dyslipidemia, Non-Alcoholic SteatoHepatitis (NASH) and/or atherosclerosis.

First claim

The invention claimed is:

1. A combination comprising a fibroblast growth factor 21 (FGF21) compound and a glucagon-like peptide-1 receptor (GLP-1R) agonist,
wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as the FGF21 activity of native FGF21, and
wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36), and wherein the GLP-1R agonist comprises or consists of the amino acid sequence H-G-E-G-T-F-T-S-D-X 10 -S-X 12 -Q-X 14 -X 15 -E-E-X 18 -V-X 20 -X 21 -F-I-E-W-L-X 27 -X 28 -X 29 -X 30 (SEQ ID NO: 37), wherein
X 10 is L or K;
X 12 is K or I;
X 14 is L;
X 15 is E or D;
X 15 is A or R;
X 20 is R or Q;
X 21 is L or E;
X 27 is L, E, K or V;
X 28 is A;
X 29 is T or G; and
X 30 is G or R.

2. The combination according to claim 1 , wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 482-fold or 9- to 319-fold or 9- to 121-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36).

3. The combination according to claim 1 , wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 18- to 501-fold or 18- to 469-fold or 18- to 313-fold or 18- to 123-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36).

4. The combination according to claim 1 , wherein the FGF21 compound is native FGF21 or an FGF21 variant having at least 80% or at least 90% or at least 95% amino acid sequence identity to the amino acid sequence of native FGF21.

5. The combination according to claim 1 , wherein the GLP-1R agonist comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 10, 12, 14, 16, 17, 19 and 20.

6. The combination according to claim 1 , wherein the amino acid sequence comprises at least one additional amino acid residue at its N-terminus.

7. The combination according to claim 1 , wherein the amino acid sequence comprises a peptide extension consisting of up to 12, 11 or 10 amino acid residues at its C-terminus.

8. The combination according to claim 1 , wherein the amino acid sequence comprises at least one additional amino acid residue at its N-terminus and a peptide extension consisting of up to 12, 11 or 10 amino acid residues at its C-terminus.

9. A method for treating a disease or disorder selected from the group consisting of obesity, being overweight, metabolic syndrome, diabetes mellitus, diabetic retinopathy, hyperglycemia, dyslipidemia, Non-Alcoholic SteatoHepatitis (NASH) and atherosclerosis, the method comprising administering the combination according to claim 1 to a subject in need thereof.

10. The method according to claim 9 , wherein the diabetes mellitus is type 1 diabetes mellitus or type 2 diabetes mellitus.

11. The method according to claim 9 , wherein the diabetes mellitus is type 2 diabetes mellitus.

12. A pharmaceutical composition comprising a fibroblast growth factor 21 (FGF21) compound and a glucagon-like peptide-1 receptor (GLP-1R) agonist together with a pharmaceutically acceptable carrier and/or excipient,
wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as the FGF21 activity of native FGF21, and
wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36), and wherein the GLP-1R agonist comprises or consists of the amino acid sequence H-G-E-G-T-F-T-S-D-X 10 -S-X 12 -Q-X 14 -X 15 -E-E-X 18 -V-X 20 -X 21 -F-I-E-W-L-X 27 -X 28 -X 29 -X 30 (SEQ ID NO: 37), wherein
X 10 is L or K;
X 12 is K or I;
X 14 is L;
X 15 is E or D;
X 18 is A or R;
X 20 is R or Q;
X 21 is L or E;
X 27 is L, E, K or V;
X 28 is A;
X 29 is T or G; and
X 30 is G or R.

13. The pharmaceutical composition according to claim 12 , wherein the amino acid sequence comprises at least one additional amino acid residue at its N-terminus.

14. The pharmaceutical composition according to claim 12 , wherein the amino acid sequence comprises a peptide extension consisting of up to 12, 11 or 10 amino acid residues at its C-terminus.

15. The pharmaceutical composition according to claim 12 , wherein the amino acid sequence comprises at least one additional amino acid residue at its N-terminus and a peptide extension consisting of up to 12, 11 or 10 amino acid residues at its C-terminus.

16. A method of treating a disease or disorder selected from the group consisting of obesity, being overweight, metabolic syndrome, diabetes mellitus, diabetic retinopathy, hyperglycemia, dyslipidemia, Non-Alcoholic SteatoHepatitis (NASH) and atherosclerosis, the method comprising administering the pharmaceutical composition according to claim 12 to a subject in need thereof.

17. The method according to claim 16 , wherein the diabetes mellitus is type 2 diabetes mellitus.

18. A glucagon-like peptide-1 receptor (GLP-1R) agonist having a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36), wherein the GLP-1R agonist comprises or consists of the amino acid sequence H-G-E-G-T-F-T-S-D-X 10 -S-X 12 -Q-X 14 -X 15 -E-E-X 18 -V-X 20 -X 21 -F-I-E-W-L-X 27 -X 28 -X 29 -X 30 (SEQ ID NO: 37), wherein
X 10 is L or K;
X 12 is K or I;
X 14 is L;
X 15 is E or D;
X 18 is A or R;
X 20 is R or Q,
X 21 is L or E;
X 27 is L, E, K or V;
X 28 is A;
X 29 is T or G; and
X 30 is G or R.

19. The GLP-1R agonist according to claim 18 , comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 10, 12, 14, 16, 17, 19 and 20.

20. The GLP-1R agonist according to claim 18 , wherein the amino acid sequence comprises at least one additional amino acid residue at its N-terminus.

21. The GLP-1R agonist according to claim 18 , wherein the amino acid sequence comprises a peptide extension consisting of up to 12, 11 or 10 amino acid residues at its C-terminus.

22. The GLP-1R agonist according to claim 18 , wherein the amino acid sequence comprises at least one additional amino acid residue at its N-terminus and a peptide extension consisting of up to 12, 11 or 10 amino acid residues at its C-terminus.

Assignees

• Sanofi Sa

Inventors

• Göbel Britta
• Sommerfeld Mark
• Boscheinen Oliver
• Langer Thomas
• Rudolph Christine
• Evers Andreas

Classifications

• A61K38/18

  Growth factors; Growth regulators · CPC title

• C07K14/605

  Glucagons · CPC title

• A61K38/26 Primary

  Glucagons · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K38/1825

  Fibroblast growth factor [FGF] · CPC title