# US 2024/0197902 A1 · Actrii-alk4 antagonists and methods of treating heart failure

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- Number: US 2024/0197902 A1
- Document ID: US20240197902A1
- Status: Published application
- Kind: A1
- Application number: 18/549,461
- Filed: 2022-03-09
- Published: 2024-06-20
- Earliest claimed: 2021-03-10
- Assignees: Acceleron Pharma Inc.
- Applicants: Acceleron Pharma Inc.
- Inventors: Rajasekhar Naga Venkata Sai Suragani; Jia Li; Patrick Andre; Ravindra Kumar
- Web page: https://patentgrep.com/patent/US20240197902A1

## CPC

- A61K 47/6811: {the drug being a protein or peptide, e.g. transferrin or bleomycin}
- A61K 38/1796: {for hormones (for neuromediators A61K38/1787)}
- A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- C07K 14/71: for growth factors; for growth regulators
- C07K 2319/02: containing a signal sequence
- 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
- 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)

## Abstract

In some aspects, the disclosure relates to ActRII-ALK4 antagonists and methods of using ActRII-ALK4 antagonists to treat, prevent, or reduce the progression rate and/or severity of heart failure (HF), particularly treating, preventing or reducing the progression rate and/or severity of one or more HF-associated comorbidities. The disclosure also provides methods of using an ActRII-ALK4 antagonist to treat, prevent, or reduce the progression rate and/or severity of heart failure associated with a variety of conditions including, but not limited to, heart failure associated with aging.

## Claims

### Claim 1

A method of treating heart failure associated with aging, comprising administering to a patient in need thereof an effective amount of an ActRII-ALK4 antagonist.

### Claim 2 (depends on 1)

The method of claim 1, wherein the heart failure is heart failure associated with preserved ejection fraction (HFpEF).

### Claim 3 (depends on 1)

The method of claim 1, wherein the patient has left ventricular (LV) hypertrophy, a diastolic dysfunction, or an elevated brain natriuretic peptide (BNP) level as compared to a healthy patient.

### Claim 4 (depends on 1)

The method of claim 1, wherein the method decreases LV hypertrophy in the patient; increases ventricular relaxation and decreases filling pressures in the patient; improves the patient's diastolic dysfunction; or decreases BNP levels in the patient.

### Claim 5

(canceled)

### Claim 6 (depends on 3)

The method of claim 3, wherein the patient's ratio of early diastolic transmitral flow to early diastolic mitral annular tissue velocity (E/e′ ratio) is increased in comparison to healthy people of similar age and sex.

### Claim at position 7

7-10. (canceled)

### Claim 11 (depends on 1)

The method of claim 1, wherein the ActRII-ALK4 antagonist comprises an ActRIIA polypeptide.

### Claim 12 (depends on 11)

The method of claim 11, wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 90% identical to an amino acid sequence that begins at any one of amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 of SEQ ID NO: 366 and ends at any one of amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135 of SEQ ID NO: 366.

### Claim 13 (depends on 11)

The method of claim 11, wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 90% identical to an amino acid sequence of SEQ ID NO: 367 or SEQ ID NO: 368.

### Claim 14

(canceled)

### Claim 15 (depends on 11)

The method of claim 11, wherein the ActRIIA polypeptide is a fusion polypeptide comprising an ActRIIA polypeptide domain and one or more heterologous domains.

### Claim 16 (depends on 15)

The method of claim 15, wherein the fusion polypeptide is an ActRIIA-Fc fusion polypeptide.

### Claim 17 (depends on 15)

The method of claim 15, wherein the fusion polypeptide further comprises a linker domain positioned between the ActRIIA polypeptide domain and i) the one or more heterologous domains.

### Claim 18

(canceled)

### Claim 19 (depends on 16)

The method of claim 16, wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 380 or SEQ ID NO:378.

### Claim at position 17

20-22. (canceled)

### Claim 23 (depends on 1)

The method of claim 1, wherein the ActRII-ALK4 antagonist is a heteromultimer polypeptide.

### Claim 24 (depends on 23)

The method of claim 23, wherein the heteromultimer polypeptide comprises an ActRIIB polypeptide, and an ALK4 polypeptide or an ALK7 polypeptide.

### Claim 25

(canceled)

### Claim 26 (depends on 24)

The method of claim 24, wherein the heteromultimer polypeptide comprises an ALK4 polypeptide comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 84, 85, 86, 87, 88, 89, 92, 93, 247, 249, 421, and 422.

### Claim 27 (depends on 24)

The method of claim 24, wherein the heteromultimer polypeptide comprises an ALK7 polypeptide comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 133, and 134.

### Claim 28 (depends on 24)

The method of claim 24, wherein the heteromultimer polypeptide comprises an ALK4 polypeptide that is a fusion polypeptide comprising an ALK4 polypeptide domain and one or more heterologous domains.

### Claim 29 (depends on 24)

The method of claim 24, wherein the heteromultimer polypeptide comprises an ALK7 polypeptide that is a fusion polypeptide comprising an ALK7 polypeptide domain and one or more heterologous domains.

### Claim 30 (depends on 28)

The method of claim 28, wherein the fusion polypeptide is an ALK4-Fc fusion polypeptide, and wherein the ALK4-Fc fusion polypeptide optionally further comprises a linker domain positioned between the ALK4 polypeptide domain and the Fc domain.

### Claim 31 (depends on 29)

The method of claim 29, wherein the fusion polypeptide is an ALK7-Fc fusion polypeptide, and wherein the ALK7-Fc fusion polypeptide further comprises a linker domain positioned between the ALK7 polypeptide domain and the Fc domain.

### Claim at position 27

32-35. (canceled)

### Claim 36 (depends on 23)

The method of claim 23, wherein the ActRII-ALK4 heteromultimer comprises an ActRIIB polypeptide.

### Claim 37 (depends on 36)

The method of claim 36, wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 90% identical to an amino acid sequence that begins at any one of amino acid residues 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 of SEQ ID NO: 2 and ends at any one of amino acid residues 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, or 134 of SEQ ID NO: 2.

### Claim 38 (depends on 36)

The method of claim 36, wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 90% identical to amino acids 29-109, 25-131, or 20-134 of SEQ ID NO: 2: or at least 90% identical to the amino acid sequence of SEQ ID NO: 53, SEQ ID NO: 388, or SEQ ID NO: 380.

### Claim at position 31

39-43. (canceled)

### Claim 44 (depends on 36)

The method of claim 36, wherein the ActRIIB polypeptide is a fusion polypeptide comprising an ActRIIB polypeptide domain and one or more heterologous domains.

### Claim 45 (depends on 44)

The method of claim 44, wherein the fusion polypeptide is an ActRIIB-Fc fusion polypeptide, and wherein the fusion polypeptide optionally further comprises a linker domain positioned between the ActRIIB polypeptide domain and the Fc domain.

### Claim at position 34

46-47. (canceled)

### Claim 48 (depends on 45)

The method of claim 45, wherein the fusion polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 12.

### Claim 49

(canceled)

### Claim 50 (depends on 36)

The method of claim 36, wherein the ActRIIB polypeptide comprises one or more amino acid substitutions with respect to the amino acid sequence of SEQ ID NO: 2 selected from the group consisting of: A24N, S26T, N35E, E37A, E37D, L38N, R40A, R40K, S44T, L46V, L46I, L46F, L46A, E50K, E50P, E50L, E52A, E52D, E52G, E52H, E52K, E52N, E52P, E52R, E52S, E52T, E52Y, Q53R, Q53K, Q53N, Q53H, D54A, K55A, K55D, K55E, K55R, R56A, L57E, L57I, L57R, L57T, L57V, Y60D, Y60F, Y60K, Y60P, R64A, R64H, R64K, R64N, N65A, S67N, S67T, G68R, K74A, K74E, K74F, K74I, K74R, K74Y, W78A, W78Y, L79A, L79D, L79E, L79F, L79H, L79K, L79P, L79R, L79S, L79T, L79W, D80A, D80F, D80G, D80I, D80K, D80M, D80N, D80R, F82A, F82D, F82E, F82I, F82K, F82L, F82S, F82T, F82W, F82Y, N83A, N83R, T93D, T93E, T93G, T93H, T93K, T93P, T93R, T93S, T93Y, E94K, Q98D, Q98E, Q98K, Q98R, V99E, V99G, V99K, E105N, F108I, F108L, F108V, F108Y, E111D, E111H, E111K, 111N, E111Q, E111R, R112H, R112K, R112N, R112S, R112T, A119P, A119V, G120N, E123N, P129N, P129S, P130A, P130R, and A132N.

### Claim 51 (depends on 36)

The method of claim 36, wherein the ActRIIB polypeptide comprises one or more amino acid substitutions with respect to the amino acid sequence of SEQ ID NO: 2 selected from the group consisting of: L38N, E50L, E52D, E52N, E52Y, L57E, L57I, L57R, L57T, L57V, Y60D, G68R, K74E, W78Y, L79E, L79F, L79H, L79R, L79S, L79T, L79W, F82D, F82E, F82I, F82K, F82L, F82S, F82T, F82Y, N83R, E94K, and V99G.