# US 2025/0084142 A1 · Long acting peptide tyrosine tyrosine (pyy) analogs and methods of use

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- Number: US 2025/0084142 A1
- Document ID: US20250084142A1
- Status: Published application
- Kind: A1
- Application number: 18/889,043
- Filed: 2024-09-18
- Published: 2025-03-13
- Earliest claimed: 2020-04-17
- Assignees: I2O Therapeutics, Inc.
- Applicants: i2o Therapeutics, Inc.
- Inventors: William Blackwell; Ved P. Srivastava; James M. Way
- Web page: https://patentgrep.com/patent/US20250084142A1

## CPC

- C07K 14/575: Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695)
- A61K 9/0004: {Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas}
- A61K 38/26: Glucagons
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention relates to isolated polypeptides that are long acting analogs of human PYY. The disclosed PYY analog polypeptides have beneficial physicochemical properties relative to endogenous PYY and known synthetic PYY analog polypeptides, such as longer (i.e., “long-acting”) elimination half-lives (t1/2), and improved solubility and thermal stability. This invention also relates to methods of using presently disclosed PYY analog polypeptides in a variety of therapeutic indications, as well as methods of producing the same. The disclosed PYY analog 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).

## Claims

### Claim 1

A method of treating obesity in a human subject, providing weight loss to the human subject, or suppressing appetite in the human subject comprising administering to the subject in need thereof:
(i) an isolated polypeptide, comprising the amino acid sequence of SEQ ID NO: 90: X0PX2PX4X5PX7X8X9X10SPX13X14X15X16RX18X19X20DX22X23HX25X26X27WLTRX32RX34-(OH/NH2) (SEQ ID NO: 90), or a pharmaceutically acceptable salt thereof, wherein:
X0 is absent or K;
X2 is K;
X4 is E or K;
X5 is A or K;
X7 is G or K
X8 is E, K, or k;
X9 is D or K;
X10 is A or K;
X13 is E or K;
X14 is E or K;
X15 is L or W;
X16 is D, E, K, N, Q, S, T, α-methylserine, or homoserine;
X18 is K or Y;
X19 is K or Y;
X20 is A, D, E, K, k, or Dap,
X22 is A, D, K, or L;
X23 is K or R;
X25 is K or Y;
X26 is E, K, or L;
X27 is K or N;
X32 is K or Q;
X34 is F, y, 3-pyridinylalanine, 4-pyridinylalanine, 4-carboxyphenylalanine, 4-fluorophenylalanine, 4-methylphenylalanine, N-methylphenylalanine, homophenylalanine, β-homotyrosine, homotyrosine, or N-methyltyrosine;
wherein when X0, X2, X4, X5, X7, X8, X13, X20, X23, X25, X27, or X32 are K, the lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer, and
wherein when X8 or X20 are k, the D-lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer,
provided that the polypeptide comprises at least one residue covalently bound to lipophilic substituent, optionally via a spacer; and
wherein the polypeptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of a lysine and an aspartic acid or between the side chains of a lysine and a glutamic acid, wherein the residues that form the lactam bridge are located at positions X9 and X13 or at positions X16 and X20 or at positions X22 and X26; and
(ii) a GLP-1 receptor agonist.

### Claim 2 (depends on 1)

The method of claim 1, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 91 PKPEX5PX7X8DASPX13EX15X16RYYX20DX22RHYLNWLTRQRX34-(OH/NH2) (SEQ ID NO: 91), or a pharmaceutically acceptable salt thereof, wherein:
X5 is A or K;
X7 is G or K;
X8 is E, K, or k;
X13 is E or K;
X15 is L or W;
X16 is D, E, K, N, S, α-methylserine, or homoserine;
X20 is A, D, E, K, or k,
X22 is A or L;
X34 is F, 3-pyridinylalanine, 4-pyridinylalanine, 4-carboxyphenylalanine, 4-fluorophenylalanine, 4-methylphenylalanine, N-methylphenylalanine, homophenylalanine, β-homotyrosine, homotyrosine, or N-methyltyrosine;
wherein when X5, X7, X8, X13, or X20 are K, the lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer, and
wherein when X8 or X20 are k, the D-lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer,
provided that the polypeptide comprises at least one residue covalently bound to lipophilic substituent, optionally via a spacer; and
wherein the polypeptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of a lysine and an aspartic acid or between the side chains of a lysine and a glutamic acid, wherein the residues that form the lactam bridge are located at positions X16 and X20.

### Claim 3 (depends on 1)

The method of claim 1, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 92: PKPEX5PX7X8DASPX13EX15X16RYYX20DX22RHYLNWLTRQRX34-(OH/NH2) (SEQ ID NO: 92), or a pharmaceutically acceptable salt thereof, wherein:
X5 is A or K;
X7 is G or K;
X8 is E, K, or k;
X13 is E or K;
X15 is L or W;
X16 is D, E, K, S, α-methylserine, or homoserine;
X20 is A, D, E, K, or k,
X22 is A or L;
X34 is F, 3-pyridinylalanine, 4-pyridinylalanine, 4-carboxyphenylalanine, 4-fluorophenylalanine, 4-methylphenylalanine, N-methylphenylalanine, homophenylalanine, β-homotyrosine, homotyrosine, or N-methyltyrosine;
wherein when X5, X7, X8, X13, or X20 are K, the lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer, and
wherein when X8 or X20 are k, the D-lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer,
provided that the polypeptide comprises at least one residue covalently bound to lipophilic substituent, optionally via a spacer; and
wherein the polypeptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of a lysine and an aspartic acid or between the side chains of a lysine and a glutamic acid, wherein the residues that form the lactam bridge are located at positions X16 and X20.

### Claim 4 (depends on 1)

The method of claim 1, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 93: PKPEX5PX7X8DASPX13EX15X16RYYX20DX22RHYLNWLTRQRX34-(OH/NH2) (SEQ ID NO: 93), or a pharmaceutically acceptable salt thereof, wherein:
X5 is A or K;
X7 is G or K;
X8 is E, K, or k;
X13 is E or K;
X15 is L or W;
X16 is D, E, K, N, S, α-methylserine, or homoserine;
X20 is D, E, K, or k,
X22 is A or L;
X34 is F, 3-pyridinylalanine, 4-pyridinylalanine, 4-carboxyphenylalanine, 4-fluorophenylalanine, 4-methylphenylalanine, N-methylphenylalanine, homophenylalanine, β-homotyrosine, homotyrosine, or N-methyltyrosine;
wherein when X5, X7, X8, X13, or X20 are K, the lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer, and
wherein when X8 or X20 are k, the D-lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer,
provided that the polypeptide comprises at least one residue covalently bound to lipophilic substituent, optionally via a spacer; and
wherein the polypeptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of a lysine and an aspartic acid or between the side chains of a lysine and a glutamic acid, wherein the residues that form the lactam bridge are located at positions X16 and X20.

### Claim 5 (depends on 1)

The method of claim 1, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 94: PKPEX5PGX8DASPX13EWX16RYYX20DX22RHYLNWLTRQRX34-(OH/NH2) (SEQ ID NO: 94), or a pharmaceutically acceptable salt thereof, wherein:
X5 is A or K;
X8 is E, K, or k;
X13 is E or K;
X16 is D, E, K, or N;
X20 is A, D, E, K, or k,
X22 is A or L;
X34 is F or N-methyltyrosine;
wherein when X5, X8, X13, or X20 are K, the lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer, and
wherein when X8 or X20 are k, the D-lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer,
provided that the polypeptide comprises at least one residue covalently bound to lipophilic substituent, optionally via a spacer; and
wherein the polypeptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of a lysine and an aspartic acid or between the side chains of a lysine and a glutamic acid, wherein the residues that form the lactam bridge are located at positions X16 and X20.

### Claim 6 (depends on 1)

The method of claim 1, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 95: PKPEX5PGK8DASPX13EWX16RYYX20DLRHYLNWLTRQRF-(OH/NH2) (SEQ ID NO: 95), or a pharmaceutically acceptable salt thereof, wherein:
X5 is A or K;
X13 is E or K;
X16 is D, E, K, or N;
X20 is A, D, E, K, or k; and
wherein when X5, X13, or X20 are K, the lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer,
wherein K8 is optionally covalently bound to a lipophilic substituent, optionally via a spacer, and
wherein when X20 is k, the D-lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer,
provided that the polypeptide comprises at least one residue covalently bound to lipophilic substituent, optionally via a spacer; and
wherein the polypeptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of a lysine and an aspartic acid or between the side chains of a lysine and a glutamic acid, wherein the residues that form the lactam bridge are located at positions X16 and X20.

### Claim at position 7

7-21. (canceled)

### Claim 22 (depends on 1)

The method of claim 1, wherein the lipophilic substituent is covalently bound to the isolated peptide via a spacer, and wherein the lipophilic substituent and spacer are of Formula II:
—(Y)n—CO—(CH2)m—Z Formula II
wherein,
Y is selected from the group consisting of γGlu, Asp, Lys and Gly;
Z is —CH3 or —CO2H;
m is from 4 to 24; and
n is from 1 to 10.

### Claim at position 9

23-25. (canceled)

### Claim 26 (depends on 22)

The method of claim 22, wherein Y is γGlu, and n is 2.

### Claim at position 11

27-38. (canceled)

### Claim 39

A method of treating obesity in a human subject, providing weight loss to the human subject, or suppressing appetite in the human subject comprising administering to the subject in need thereof:
(i) an isolated polypeptide comprising the amino acid sequence of any of SEQ ID NOs: 1 to 78, or a pharmaceutically acceptable salt thereof; and
(ii) a GLP-1 receptor agonist.

### Claim 40 (depends on 39)

The method of claim 39, wherein the isolated polypeptide comprises an amino acid sequence selected from the group consisting of those represented by SEQ ID NOs: 13, 24, 42, and 43.

### Claim 41 (depends on 39)

The method of claim 39, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 13, or a pharmaceutically acceptable salt thereof.

### Claim 42 (depends on 39)

The method of claim 39, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 24, or a pharmaceutically acceptable salt thereof.

### Claim 43 (depends on 39)

The method of claim 39, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 42, or a pharmaceutically acceptable salt thereof.

### Claim 44 (depends on 39)

The method of claim 39, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO: 43, or a pharmaceutically acceptable salt thereof.

### Claim at position 18

45-53. (canceled)

### Claim 54 (depends on 1)

The method of claim 1, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, and semaglutide.

### Claim 55 (depends on 1)

The method of claim 1, wherein the GLP-1 receptor agonist is semaglutide.

### Claim 56 (depends on 41)

The method of claim 41, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, and semaglutide.

### Claim 57 (depends on 41)

The method of claim 41, wherein the GLP-1 receptor agonist is semaglutide.

### Claim 58 (depends on 42)

The method of claim 42, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, and semaglutide.

### Claim 59 (depends on 42)

The method of claim 42, wherein the GLP-1 receptor agonist is semaglutide.

### Claim 60 (depends on 43)

The method of claim 43, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, and semaglutide.

### Claim 61 (depends on 43)

The method of claim 43, wherein the GLP-1 receptor agonist is semaglutide.

### Claim 62 (depends on 44)

The method of claim 44, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, and semaglutide.

### Claim 63 (depends on 44)

The method of claim 44, wherein the GLP-1 receptor agonist is semaglutide.