# US 10,946,067 B2 · Compositions and methods for treating pulmonary hypertension

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- Number: US 10,946,067 B2
- Document ID: US10946067B2
- Status: Granted
- Kind: B2
- Application number: 17/002,553
- Filed: 2020-08-25
- Published: 2020-12-17
- Granted: 2021-03-16
- Earliest claimed: 2016-07-15
- Assignees: Acceleron Pharma Inc.
- Applicants: Acceleron Pharma Inc.
- Inventors: Ravindra Kumar; John Knopf
- Web page: https://patentgrep.com/patent/US10946067B2

## CPC

- A61K 38/1875: {Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor}
- A61K 38/179: {for growth factors; for growth regulators}
- A61K 38/1796: {for hormones (for neuromediators A61K38/1787)}
- A61K 38/45: Transferases (2)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 11/00: Drugs for disorders of the respiratory system
- C07K 14/71: for growth factors; for growth regulators
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

In some aspects, the disclosure relates to GDF/BMP antagonists and methods of using GDF/BMP antagonists to treat, prevent, or reduce the progression rate and/or severity of pulmonary hypertension (PH), particularly treating, preventing or reducing the progression rate and/or severity of one or more PH-associated complications. The disclosure also provides methods of using a GDF/BMP antagonist to treat, prevent, or reduce the progression rate and/or severity of a variety of conditions including, but not limited to, pulmonary vascular remodeling, pulmonary fibrosis, and right ventricular hypertrophy. The disclosure further provides methods of using a GDF/BMP antagonist to reduce right ventricular systolic pressure in a subject in need thereof.

## Claims

### Claim 1

A method of treating pulmonary arterial hypertension, comprising administering to a patient in need thereof an effective amount of a fusion protein comprising:
a) an ActRIIA polypeptide domain comprising the amino acid sequence of SEQ ID NO: 10;
b) an Fc domain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 14; and
c) a linker domain.

### Claim 2 (depends on 1)

The method of claim 1, wherein the linker domain is positioned between the ActRIIA polypeptide domain and the Fc domain.

### Claim 3 (depends on 1)

The method of claim 1, wherein the linker domain comprises TGGG (SEQ ID NO: 23).

### Claim 4 (depends on 1)

The method of claim 1, wherein the fusion protein binds to one or more ligands selected from the group consisting of: activin A, activin B, and GDF11.

### Claim 5 (depends on 4)

The method of claim 4, wherein the fusion protein further binds to one or more ligands selected from the group consisting of: BMP10, GDF8, and BMP6.

### Claim 6 (depends on 1)

The method of claim 1, wherein the patient has resting pulmonary arterial pressure of at least 25 mmHg.

### Claim 7 (depends on 1)

The method of claim 1, wherein the method decreases pulmonary arterial pressure in the patient.

### Claim 8 (depends on 7)

The method of claim 7, wherein the method decreases the pulmonary arterial pressure by at least 3 mmHg.

### Claim 9 (depends on 7)

The method of claim 7, wherein the method decreases the pulmonary arterial pressure by at least 7 mmHg.

### Claim 10 (depends on 1)

The method of claim 1, wherein the method increases the patient's 6-minute walk distance.

### Claim 11 (depends on 10)

The method of claim 10, wherein the method increases the patient's 6-minute walk distance by at least 50 meters.

### Claim 12 (depends on 1)

The method of claim 1, wherein the method decreases ventricle hypertrophy in the patient.

### Claim 13 (depends on 1)

The method of claim 1, wherein the method decreases smooth muscle hypertrophy in the patient.

### Claim 14 (depends on 1)

The method of claim 1, wherein the method decreases pulmonary arteriole muscularity in the patient.

### Claim 15 (depends on 1)

The method of claim 1, wherein the method decreases pulmonary vascular resistance in the patient.

### Claim 16 (depends on 15)

The method of claim 15, wherein the method decreases pulmonary vascular resistance in the patient by at least 20%.

### Claim 17 (depends on 1)

The method of claim 1, wherein the patient has been treated with one or more vasodilators.

### Claim 18 (depends on 1)

The method of claim 1, wherein the patient has been treated with one or more agents selected from the group consisting of: phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin receptor agonist, and endothelin receptor antagonists.

### Claim 19 (depends on 18)

The method of claim 18, wherein the one or more agents is selected from the group consisting of: bosentan, sildenafil, beraprost, macitentan, selexipag, epoprostenol, treprostinil, iloprost, ambrisentan, and tadalafil.

### Claim 20 (depends on 1)

The method of claim 1, wherein the patient has pulmonary arterial hypertension and has Functional Class II or Class III pulmonary hypertension in accordance with the World Health Organization's functional classification system for pulmonary hypertension.

### Claim 21 (depends on 1)

The method of claim 1, wherein the method delays clinical worsening of pulmonary arterial hypertension.

### Claim 22 (depends on 21)

The method of claim 21, wherein the method delays clinical worsening of pulmonary arterial hypertension in accordance with the World Health Organization's functional classification system for pulmonary hypertension.

### Claim 23 (depends on 22)

The method of claim 22, wherein the method delays clinical worsening of pulmonary hypertension by delaying the progression from Functional Class II to Class III as recognized by the World Health Organization.

### Claim 24 (depends on 1)

The method of claim 1, wherein the fusion protein is administered using subcutaneous injection.

### Claim 25 (depends on 1)

The method of claim 1, wherein the fusion protein is formulated into a pharmaceutical composition.

### Claim 26 (depends on 1)

The method of claim 1, wherein the Fc domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 14.

### Claim 27 (depends on 1)

The method of claim 1, wherein the Fc domain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 14.

### Claim 28 (depends on 1)

The method of claim 1, wherein the Fc domain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 14.

### Claim 29 (depends on 1)

The method of claim 1, wherein the Fc domain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 14.

### Claim 30 (depends on 1)

The method of claim 1, wherein the Fc domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 14.