Long acting glucagon like polypeptide-1 (GLP-1) receptor agonists and methods of use

Patent metadata

Field	Value
Publication number	US-12084485-B2
Application number	US-202117553381-A
Country	US
Kind code	B2
Filing date	Dec 16, 2021
Priority date	Dec 17, 2020
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

This invention relates to isolated polypeptides that are long acting analogs of human GLP-1. The disclosed GLP-1 receptor agonist polypeptides have beneficial physicochemical properties relative to endogenous GLP-1 and known synthetic GLP-1 receptor agonist polypeptides, such as longer (i.e., “long-acting”) elimination half-lives (t 1/2 ), and improved solubility and thermal stability. This invention also relates to methods of using presently disclosed GLP-1 receptor agonist polypeptides in a variety of therapeutic indications, as well as methods of producing the same. The disclosed GLP-1 receptor agonist polypeptides are particularly useful in methods of treating metabolic diseases or disorders, such as type 2 diabetes, treating obesity, and providing weight loss, and in methods of treating nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH).

First claim

What is claimed is:

1. An isolated polypeptide, comprising the amino acid sequence HX 2 X 3 GTX 6 X 7 X 8 X 9 X 10 SX 12 X 13 X 14 EX 16 X 17 X 18 X 19 X 20 X 21 FIX 24 WLKX 28 GGPX 32 SGAPPPS-(OH/N H 2 ) (SEQ ID NO: 200) or a pharmaceutically acceptable salt thereof, wherein:
X 2 is A, 2-aminoisobutyric acid (Aib), or G;
X 3 is E or N-methyl Glu;
X 6 is For Y;
X 7 is S or T;
X 8 is diaminopimelic acid (Dap), E, K, N, N-methyl Ser, Q, S, s, or Y;
X 9 is D or E;
X 10 is I, L, N-methyl Leu, or V;
X 12 is E, K, Q, or S;
X 13 is Aib, E, K, Q, S, W, or Y;
X 14 is Y;
X 16 is 2,4-diaminobutanoic acid (Dab), Dap, E, K, k, or ornithine (Orn);
X 17 is E, K, or Q;
X 18 is A, K, S, or Y;
X 19 is A, K, or V;
X 20 is E, K, or R;
X 21 is Aib, E, H, K, L, Q, or Y;
X 24 is A, Aib, E, K, Q, S, or Y;
X 28 is D, E, K, N, Q, S, or Y; and
X 32 is Dap, H, K, R, or S;
wherein when X 16 is Dab, Dap, K, or Orn, it is covalently bound to a lipophilic substituent, optionally via a spacer;
wherein when X 16 is E, at least one of X 17 , X 18 , X 19 , X 20 , or X 21 is K and covalently bound to a lipophilic substituent, optionally via a spacer; and
wherein the peptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of K and E at positions X 17 and X 21 ; at positions X 21 and X 17 ; at positions X 21 and X 28 ; at positions X 28 and X 21 ; at positions X 20 and X 24 ; at positions X 24 and X 20 ; or at positions X 12 and X 16 .

2. The isolated polypeptide of claim 1 , comprising the amino acid sequence: HX 2 EGTFTX 8 DX 10 SX 12 QX 14 EX 16 X 17 X 18 X 19 X 20 X 21 FIX 24 WLKX 28 GGPX 32 SGAPPPS-(OH/NH 2 ) (SEQ ID NO: 204), or a pharmaceutically acceptable salt thereof, wherein:
X 2 is 2-aminoisobutyric acid (Aib) or G;
X 8 is N or S;
X 10 is I, L, or V;
X 12 is E, K, or Q;
X 14 is Y;
X 16 is (Dap) covalently bound to a lipophilic substituent, optionally via a spacer, or K covalently bound to a lipophilic substituent, optionally via a spacer;
X 17 is E or K;
X 18 is A or Y;
X 19 is A or V;
X 20 is E, K, or R;
X 21 is E, K, L, or Q;
X 24 is E, K, or S;
X 28 is N or Q; and
X 32 is H or S;
wherein the peptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of K and E at positions X 17 and X 21 ; at positions X 21 and X 17 ; at positions X 20 and X 24 ; or at positions X 24 and X 20 .

3. The isolated polypeptide of claim 1 , comprising the amino acid sequence: HAibEGTFTSDX 10 SKQYEX 16 EAX 19 X 20 X 21 FIX 24 WLKNGGPSSGAPPPS-(OH/NH 2 ) (SEQ ID NO: 208), or a pharmaceutically acceptable salt thereof, wherein:
X 10 is L or V;
X 16 is K covalently bound to a lipophilic substituent, optionally via a spacer;
X 19 is A or V;
X 20 is E, K, or R;
X 21 is K or Q;
X 24 is E, K, or S; and
wherein the peptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of K and E at positions X 21 and X 17 ; at positions X 20 and X 24 ; or at positions X 24 and X 20 .

4. The isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein if X 16 is E, then X 21 is K or E.

5. The isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 16 is K covalently bound to a lipophilic substituent, optionally via a spacer.

6. The isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein if X 24 is S, then X 10 is V.

7. The isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the peptide further comprises a lactam bridge formed via an amide bond between the side chains of K and E at positions X 20 and X 24 .

8. The isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2 is Aib.

9. The isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the lipophilic substituent is covalently bound to the isolated polypeptide via a spacer, and wherein the lipophilic substituent and spacer are of Formula II:
—(Y) n —CO—(CH 2 ) m —Z  Formula II

or of Formula IV:
-(Y1) n1 -(dpeg) r -(Y2) n2 -CO—(CH 2 ) m —Z   Formula IV

wherein,
dpeg is —[CO(CH 2 )O(CH 2 ) 2 O(CH 2 )NH]—;
Y is selected from the group consisting of γGlu, D, K, and G;
Y1 is selected from the group consisting of γGlu, D and G;
Y2 is selected from the group consisting of γGlu, D and G;
Z is —CH 3 or —CO 2 H;
m is from 4 to 24;
n is from 1 to 10
n1 is from 0 to 10;
n2 is from 0 to 10; and
r is from 1 to 8.

10. The isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence of any one of SEQ ID NOs: 15, 27-32, 39-121, and 126-162.

11. The isolated polypeptide of claim 10 , comprising the amino acid sequence of any one of SEQ ID NOs: 55, 115, 120, and 132, or a pharmaceutically acceptable salt thereof.

12. The isolated polypeptide of claim 11 , comprising the amino acid sequence of SEQ ID NO: 115, or a pharmaceutically acceptable salt thereof.

13. The isolated polypeptide of claim 11 , comprising the amino acid sequence of SEQ ID NO: 120, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

15. An osmotic delivery device, comprising the isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof.

16. A method of treating obesity, providing weight loss, or suppressing appetite in a human subject, comprising administering to the subject in need thereof a pharmaceutical composition comprising the isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 , wherein said pharmaceutical composition is administered via injection.

18. The method of claim 16 , wherein said pharmaceutical composition is administered orally.

19. A method of treating diabetes in a human subject, comprising administering to the subject in need thereof a pharmaceutical composition comprising the isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof.

20. The method of claim 19 , wherein said pharmaceutical composition is administered via injection.

21. The method of claim 19 , wherein said pharmaceutical composition is administered orally.

22. A method of treating nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH) in a human subject, comprising administering to the subject in need thereof a pharmaceutical composition comprising the isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof.

23. The method of claim 22 , wherein said pharmaceutical composition is administered via injection.

24. The method of claim 22 , wherein said pharmaceutical composition is administered orally.

25. The method of claim 16 , wherein said isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 115, or a pharmaceutically acceptable salt thereof.

26. The method of claim 19 , wherein said isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 115, or a pharmaceutically acceptable salt thereof.

27. The method of claim 16 , wherein said isolated polype

Assignees

• Intarcia Therapeutics Inc
• I2O Therapeutics Inc

Inventors

• Blackwell William
• Srivastava Ved P
• Paulik Mark

Classifications

• A61K38/26

  Glucagons · CPC title

• A61K9/0004

  Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K38/00

  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 title