Compositions and methods for treating pulmonary hypertension

Patent metadata

Field	Value
Publication number	US-12343378-B2
Application number	US-202217960911-A
Country	US
Kind code	B2
Filing date	Oct 6, 2022
Priority date	Jul 15, 2016
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

In some aspects, the disclosure relates to GDF/BMP antagonists and methods of using GDF3/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.

First claim

We claim:

1. A method of treating pulmonary arterial hypertension, comprising administering to a patient in need thereof a fusion protein comprising:
a) an ActRIIA polypeptide comprising the amino acid sequence of SEQ ID NO: 10;
b) an Fc domain of an IgG1 immunoglobulin; and
c) a linker domain,

wherein the linker domain is positioned between the ActRIIA polypeptide and the Fc domain of the IgG1 immunoglobulin.

2. The method of claim 1 , wherein proliferation of smooth muscle and endothelial cells in the pulmonary artery is inhibited.

3. The method of claim 1 , wherein the method increases the exercise capacity of the patient.

4. The method of claim 3 , wherein the method increases the patient's 6-minute walk distance (6MWD).

5. The method of claim 4 , wherein the patient's 6MWD is increased by at least 10 meters.

6. The method of claim 4 , wherein the patient's 6MWD is increased by at least 50 meters.

7. The method of claim 1 , wherein the method reduces the patient's Borg dyspnea index (BDI).

8. The method of claim 7 , wherein the method reduces the patient's BDI by at least 0.5 index points.

9. The method of claim 7 , wherein the method reduces the patient's BDI by at least 5 index points.

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

11. The method of claim 1 , wherein the method increases pulmonary capillary wedge pressure.

12. The method of claim 1 , wherein the method increases left ventricular end-diastolic pressure.

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

14. The method of claim 13 , wherein the method decreases pulmonary arterial pressure in the patient by at least 10%.

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

16. The method of claim 15 , wherein the method decreases ventricle hypertrophy in the patient by at least 10%.

17. The method of claim 2 , wherein the method decreases smooth muscle hypertrophy in the patient.

18. The method of claim 17 , wherein the method decreases smooth muscle hypertrophy in the patient by at least 10%.

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

20. The method of claim 19 , wherein the method decreases pulmonary arteriole muscularity in the patient by at least 10%.

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

22. The method of claim 21 , wherein the method decreases pulmonary vascular resistance in the patient by at least 10%.

23. The method of claim 1 , wherein the patient has a hemoglobin level from greater than 8 and less than 15 g/dl.

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

25. The method of claim 1 , wherein the method reduces the risk of hospitalization for one or more complications associated with pulmonary arterial hypertension.

26. A method of treating pulmonary arterial hypertension, comprising administering to a patient in need thereof a fusion protein comprising:
a) an ActRIIA polypeptide comprising the amino acid sequence of SEQ ID NO: 10;
b) an Fc domain of an IgG1 immunoglobulin; and
c) a linker domain,

wherein the linker domain is positioned between the ActRIIA polypeptide and the Fc domain of the IgG1 immunoglobulin, and wherein the method increases exercise capacity of the patient.

27. The method of claim 1 , wherein the linker domain comprises an amino acid sequence of SEQ ID NO: 23.

28. The method of claim 26 , wherein the linker domain comprises an amino acid sequence of SEQ ID NO: 23.

29. 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.

30. The method of claim 26 , wherein the Fc domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 14.

31. 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.

32. The method of claim 26 , wherein the Fc domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 14.

33. The method of claim 1 , wherein the Fc domain comprises an amino acid sequence of SEQ ID NO: 14.

34. The method of claim 26 , wherein the Fc domain comprises an amino acid sequence of SEQ ID NO: 14.

35. A method of treating pulmonary arterial hypertension in a human patient in need thereof, comprising administering to the human patient 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 of an IgG1 immunoglobulin; and
c) a linker domain comprising the amino acid sequence of SEQ ID NO: 23;

wherein the linker domain is positioned between the ActRIIA polypeptide domain and the Fc domain.

36. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 14.

37. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 14.

38. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 14.

39. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 14.

40. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 14.

41. The method of claim 35 , wherein the Fc domain comprises the amino acid sequence of SEQ ID NO: 14.

42. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 32.

43. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 32.

44. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 32.

45. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 32.

46. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 32.

47. The method of claim 35 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 32.

48. The method of claim 35 , wherein the fusion protein is a homodimer.

49. The method of claim 46 , wherein the fusion protein is a homodimer.

50. The method of claim 35 , wherein the human patient has Functional Class II or Class III pulmonary hypertension in accordance with the World Health Organization's functional classification system for pulmonary hypertension.

51. The method of claim 49 , wherein the human patient has Function

Assignees

• Acceleron Pharma Inc

Inventors

• Kumar Ravindra
• Knopf John

Classifications

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• C07K14/71

  for growth factors; for growth regulators · CPC title

• A61K38/45

  Transferases (2) · CPC title

• A61K38/179

  for growth factors; for growth regulators · CPC title

• A61K38/1796 Primary

  for hormones (for neuromediators A61K38/1787) · CPC title