Activin-actrii antagonists and uses for treating anemia

Patent metadata

Field	Value
Publication number	US-2017360887-A1
Application number	US-201515532329-A
Country	US
Kind code	A1
Filing date	Dec 3, 2015
Priority date	Dec 3, 2014
Publication date	Dec 21, 2017
Grant date	—

Abstract

Provided herein are methods for the treatment in a subject of anemia, anemia requiring RBC transfusion, low or intermediate-1-risk myelodysplastic syndromes (MDS), and/or non-proliferative chronic myelomonocytic leukemia (CMML) in any mammals wherein the methods comprise administration of Activin-ActRII signaling inhibitors to a subject in need of the treatment.

First claim

What is claimed:

1 . A method of treating a blood-related disorder in a subject, comprising
(a) determining a percentage of erythroblasts in the subject that are ring sideroblasts; and (b) administering a pharmaceutically effective dose of an ActRII signaling inhibitor of between 0.1 mg/kg and 2.0 mg/kg to the subject if at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of erythroblasts in the subject are ring sideroblasts.

2 . The method of claim 1 , wherein the blood-related disorder is anemia, anemia requiring transfusion, myelodysplastic syndromes (MDS), or non-proliferative chronic myelomonocytic leukemia (CMML).

3 . The method of claim 1 or 2 , wherein the percentage of erythroblasts in the subject that are ring sideroblasts is determined at a first time.

4 . The method of claim 3 , wherein the first time is a within 1 day, 2 days, 3, days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, or 6 months of administering the pharmaceutically effective dose of the ActRII signaling inhibitor to the subject.

5 . A method of treating a blood-related disorder in a subject, comprising administering to the subject an activin receptor type II (ActRII) signaling inhibitor at a pharmaceutically effective dose and for a period of time to achieve (i) a long-term reduction in a percentage of erythroblasts in the subject that are ring sideroblasts as compared to an initial percentage of erythroblasts in the subject that are ring sideroblasts; and/or (ii) a long-term increase in hemoglobin level in the subject as compared to the hemoglobin level in the subject a period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor; wherein the pharmaceutically effective dose is between 0.1 mg/kg and 2.0 mg/kg, and wherein the initial percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%.

6 . The method of claim 5 , wherein the blood-related disorder is anemia, MDS, or non-proliferative CMML.

7 . A method of treating anemia in a subject, comprising administering to the subject an activin receptor type II (ActRII) signaling inhibitor at a pharmaceutically effective dose and for a period of time to achieve (i) a long-term reduction in a percentage of erythroblasts in the subject that are ring sideroblasts as compared to an initial percentage of erythroblasts in the subject that are ring sideroblasts; and/or (ii) a long-term increase in hemoglobin level in the subject as compared to the hemoglobin level in the subject a period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor; wherein the pharmaceutically effective dose is between 0.1 mg/kg and 2.0 mg/kg, and wherein the initial percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%.

8 . The method of claim 7 , wherein the subject is a subject requiring RBC transfusion.

9 . A method for treating MDS in a subject, comprising administering to the subject an ActRII signaling inhibitor at a pharmaceutically effective dose and for a period of time to achieve (i) a long-term reduction in a percentage of erythroblasts in the subject that are ring sideroblasts as compared to an initial percentage of erythroblasts in the subject that are ring sideroblasts; and/or (ii) a long-term increase in hemoglobin level in the subject as compared to the hemoglobin level in the subject a period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor; wherein the pharmaceutically effective dose is between 0.1 mg/kg and 2.0 mg/kg, and wherein the initial percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%.

10 . A method for treating non-proliferative CMML in a subject, comprising administering to the subject an ActRII signaling inhibitor at a pharmaceutically effective dose and for a period of time to achieve (i) a long-term reduction in a percentage of erythroblasts in the subject that are ring sideroblasts as compared to an initial percentage of erythroblasts in the subject that are ring sideroblasts; and/or (ii) a long-term increase in hemoglobin level in the subject as compared to the hemoglobin level in the subject a period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor; wherein the pharmaceutically effective dose is between 0.1 mg/kg and 2.0 mg/kg, and wherein the initial percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%.

11 . The method any one of claims 5 - 10 , wherein the period of time of ActRII signaling inhibitor administration is 1, 2, 3, 4, 5, or 6 months.

12 . The method of any one of claims 5 - 11 , wherein the initial percentage of erythroblasts in the subject that are ring sideroblasts is a percentage of erythroblasts in the subject that are ring sideroblasts a period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor.

13 . The method of any one of claims 5 - 12 , wherein the long-term reduction in the percentage of erythroblasts in the subject that are ring sideroblasts is maintained for at least 1, 2, 3, 4, 5, 6, 12, 18, or 24 months after the period of time of ActRII signaling inhibitor administration.

14 . The method of any one of claims 5 - 13 , wherein the long-term reduction in the percentage of erythroblasts in the subject that are ring sideroblasts is at least 1.5, 2.5, 5.0, 7.5, or 10.0 fold below the initial percentage of erythroblasts in the subject that are ring sideroblasts for at least 6, 12, 18, or 24 months after the period of time of ActRII signaling inhibitor administration.

15 . The method of any one of claims 5 - 14 , wherein the initial hemoglobin level in the subject is the hemoglobin level in the subject a period of time period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor.

16 . The method of any one of claims 5 - 15 , wherein the initial hemoglobin level in said subject is less than about 11 g/dL.

17 . The method of any one of claims 5 - 16 , wherein the long-term increase in the hemoglobin level in the subject is maintained for at least 3, 4, 5, 6, 12, 18, or 24 months after the period of time of ActRII signaling inhibitor administration.

18 . The method of any one of claims 5 - 17 , wherein the long-term increase in the hemoglobin level in the subject is a hemoglobin level of between about 11 g/dL and 18 g/dL in the subject for at least 3, 4, 5, 6, 12, 18, or 24 months after the period of time of ActRII signaling inhibitor administration.

19 . The method of any one of claims 5 - 17 , wherein the subject does not require red blood cell transfusion for at least 3, 4, 5, 6, 12, 18, or 24 months after the period of time of ActRII signaling inhibitor administration.

20 . The method of any one of the preceding claims, wherein the ActRII signaling inhibitor is administered once every three weeks.

21 . The method of any one of claims 1 - 19 , wherein the ActRII signaling inhibitor is administered (i) once every 28 days; or (ii) once every 42 days.

22 . The method of any one of the precedin

Assignees

• Celgene Corp
• Acceleron Pharma Inc

Inventors

• Attie Kenneth M
• Rovaldi Christopher
• Laadem Abderrahmane

Classifications

• A61K38/179 Primary

  for growth factors; for growth regulators · CPC title

• 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

• G01N33/49

  Blood {(chemical methods for determining blood cell populations G01N33/5094; chemical analysis of blood groups or blood types G01N33/80)} · CPC title

• A61P35/02

  specific for leukemia · CPC title