ACTIVIN-ACTRII ANTAGONISTS AND USES FOR TREATING BONE AND OTHER DISORDERS

• US 20150283209A1
• Filed: 11/01/2013
• Published: 10/08/2015
• Est. Priority Date: 11/02/2012
• Status: Active Grant

• Current Assignee: Celgene Corporation (Bristol-Myers Squibb Company), Washington University In St Louis
• Original Assignee: Celgene Corporation (Bristol-Myers Squibb Company), Washington University In St Louis
• Inventors: Sung, Victoria, Stevens, Randall, Hruska, Keith, Smith, William, Schorr Sloan, Victor, Fang, Yifu
• Granted Patent: US 10,195,249 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 38/1796 for hormones for neuromediators A61K38/1787
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

Provided herein are methods for the treatment of bone disorders that are associated with kidney disease wherein the methods comprise administration of Activin-ActRIIA inhibitors to a subject in need of the treatment. Also provided herein are methods and compositions for the treatment of low turnover bone disorders wherein the methods comprise administration of Activin-ActRIIA inhibitors to a subject in need of the treatment. Further provided herein are compositions for the treatment of bone disorders that are associated with kidney disease and compositions for the treatment of low turnover bone disorders and vascular calcification.

Claims

1. A method for treating an adynamic bone disorder in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the adynamic bone disorder.

3. The method of claim 1 or 2, wherein the adynamic bone disorder is characterized by absence of tetracycline incorporation into mineralized bone.

11. The method of claim 1, 2, 4, 6, 7, 8, or 10 wherein the ActRII inhibitor is a polypeptide comprising an amino acid sequence selected from the group consisting of:

a. 90% identical to SEQ ID NO;

2;

b. 95% identical to SEQ ID NO;

2;

c. 98% identical to SEQ ID NO;

2;

d. SEQ ID NO;

2;

e. 90% identical to SEQ ID NO;

3;

f. 95% identical to SEQ ID NO;

3;

g. 98% identical to SEQ ID NO;

3;

h. SEQ ID NO;

3;

i. 90% identical to SEQ ID NO;

6;

j. 95% identical to SEQ ID NO;

6;

k. 98% identical to SEQ ID NO;

6;

l. SEQ ID NO;

6;

m. 90% identical to SEQ ID NO;

7;

n. 95% identical to SEQ ID NO;

7;

o. 98% identical to SEQ ID NO;

7;

p. SEQ ID NO;

7;

q. 90% identical to SEQ ID NO;

12;

r. 95% identical to SEQ ID NO;

12;

s. 98% identical to SEQ ID NO;

12;

t. SEQ ID NO;

12;

u. 90% identical to SEQ ID NO;

17;

v. 95% identical to SEQ ID NO;

17;

w. 98% identical to SEQ ID NO;

17;

x. SEQ ID NO;

17;

y. 90% identical to SEQ ID NO;

20;

z. 95% identical to SEQ ID NO;

20;

aa. 98% identical to SEQ ID NO;

20;

bb. SEQ ID NO;

20;

cc. 90% identical to SEQ ID NO;

21;

dd. 95% identical to SEQ ID NO;

21;

ee. 98% identical to SEQ ID NO;

21;

ff. SEQ ID NO;

21

gg. 90% identical to SEQ ID NO;

23;

hh. 95% identical to SEQ ID NO;

23;

ii. 98% identical to SEQ ID NO;

23;

jj. SEQ ID NO;

23

kk. 90% identical to SEQ ID NO;

25;

ll. 95% identical to SEQ ID NO;

25;

mm. 98% identical to SEQ ID NO;

25; and

nn. SEQ ID NO;

25.

12. The method of claim 1, 2, 4, 6, 7, 8, or 10, wherein the ActRII inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:

7.

13. The method of claim 1, 2, 4, 6, 7, 8, or 10, wherein the ActRII inhibitor is administered parentally.

14. The method of claim 1, 2, 4, 6, 7, 8, or 10, wherein the subject is less than 18 years old.

15. The method of claim 1, 2, 4, 6, 7, 8, or 10, wherein the method increases the height of the subject.

16. The method of claim 1, 2, 4, 6, 7, 8, or 10, wherein the subject has end stage renal disease.

17. The method of claim 1, 2, 4, 6, 7, 8, or 10, wherein the subject undergoes dialysis.

2. A method for treating an adynamic bone disorder form of CKD-MBD in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the adynamic bone disorder form of CKD-MBD.

4. A method for treating a low bone turnover form of CKD-MBD in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the low bone turnover form of CKD-MBD.

5. The method of claim 4, wherein the low bone turnover form of CKD-MBD is osteomalacia.

6. A method for treating a bone disorder characterized by hyperphosphatemia in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the bone disorder characterized by hyperphosphatemia.

7. A method for treating vascular calcification in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of atherosclerotic calcification.

8. A method for treating a renal disease in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the renal disease.

9. The method of claim 8, wherein the renal disease is renal fibrosis.

10. A method for reducing vascular calcium levels in a subject diagnosed with vascular calcification, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to the subject.