Factor IX polypeptide formulations

1. A pharmaceutical composition comprising:

(a) a rFIXFc polypeptide comprising human FIX fused to a Fc domain of a human antibody;

(b) between about 10 mg/ml and about 20 mg/ml of sucrose;

(c) between about 20 mg/ml and about 40 mg/ml of mannitol

(d) between about 3 mg/ml and about 4 mg/ml of sodium chloride (NaCl);

(e) between about 3 mg/ml and about 6 mg/ml of L-histidine; and

(f) between about 0.08 mg/ml and about 0.2 mg/ml of polysorbate 20 or polysorbate 80.

2. The pharmaceutical composition of claim 1 , comprising about 11.9 mg/ml of sucrose.

3. The pharmaceutical composition of claim 1 , comprising about 16.7 mg/ml of sucrose.

4. The pharmaceutical composition of claim 1 , comprising about 23.8 mg/ml of mannitol.

5. The pharmaceutical composition of claim 1 , comprising about 33.3 mg/ml of mannitol.

6. The pharmaceutical composition of claim 1 , comprising about 3.25 mg/ml of NaCl.

7. The pharmaceutical composition of claim 1 , comprising about 3.88 mg/ml of L-histidine.

8. The pharmaceutical composition of claim 1 , comprising about 5.43 mg/ml of L-histidine.

9. The pharmaceutical composition of claim 1 , comprising 0.10 mg/ml of polysorbate 20 or polysorbate 80.

10. The pharmaceutical composition of claim 1 , comprising about 0.14 mg/ml of polysorbate 20 or polysorbate 80.

11. The pharmaceutical composition of claim 1 , comprising:

(a) about 50 IU/ml of the rFIXFc polypeptide;

(b) about 11.9 mg/ml of sucrose;

(c) about 23.8 mg/ml of mannitol;

(d) about 3.25 mg/ml of NaCl;

(e) about 3.88 mg/ml of L-histidine; and

(f) about 0.10 mg/ml of polysorbate 20 or polysorbate 80.

12. The pharmaceutical composition of claim 1 , comprising:

(a) about 100 IU/ml of the rFIXFc polypeptide;

(b) about 11.9 mg/ml of sucrose;

(c) about 23.8 mg/ml of mannitol;

(d) about 3.25 mg/ml of NaCl;

(e) about 3.88 mg/ml of L-histidine; and

(f) about 0.10 mg/ml of polysorbate 20 or polysorbate 80.

13. The pharmaceutical composition of claim 1 , comprising:

(a) about 200 IU/ml of the rFIXFc polypeptide;

(b) about 11.9 mg/ml of sucrose;

(c) about 23.8 mg/ml of mannitol;

(d) about 3.25 mg/ml of NaCl;

(e) about 3.88 mg/ml of L-histidine; and

(f) about 0.10 mg/ml of polysorbate 20 or polysorbate 80.

14. The pharmaceutical composition of claim 1 , comprising:

(a) about 400 IU/ml of the rFIXFc polypeptide;

(b) about 11.9 mg/ml of sucrose;

(c) about 23.8 mg/ml of mannitol;

(d) about 3.25 mg/ml of NaCl;

(e) about 3.88 mg/ml of L-histidine; and

(f) about 0.10 mg/ml of polysorbate 20 or polysorbate 80.

15. The pharmaceutical composition of claim 1 , comprising:

(a) about 600 IU/ml of the rFIXFc polypeptide;

(b) about 16.7 mg/ml of sucrose;

(c) about 33.3 mg/ml of mannitol;

(d) about 3.25 mg/ml of NaCl;

(e) about 5.43 mg/ml of L-histidine; and

(f) about 0.14 mg/ml of polysorbate 20 or polysorbate 80.

16. A pharmaceutical kit comprising:

(a) a first container comprising a lyophilized powder, where the powder comprises

(i) about 200 IU to about 4000 IU of a rFIXFc polypeptide comprising human Factor IX fused to a Fc domain of a human antibody;

(ii) about 59.5 mg or about 83.3 mg of sucrose;

(iii) about 119 mg or about 167 mg of mannitol;

(iv) about 19.4 mg or about 27.2 mg of L-histidine; and

(v) about 0.50 mg or about 0.7 mg of polysorbate 20 or polysorbate 80; and

(b) a second container comprising 0.325% (w/v) NaCl to be combined with the lyophilized powder of the first container.

17. A pharmaceutical composition comprising:

(a) between about 25 IU/ml and about 700 IU/ml of a rFIXFc polypeptide comprising human Factor IX fused to a Fc domain of a human antibody;

(b) between about 10 mg/ml and about 20 mg/ml of sucrose;

(c) between about 20 mg/ml and about 40 mg/ml of mannitol;

(d) between about 3 mg/ml and about 4 mg/ml of NaCl;

(e) between about 3 mg/ml and about 6 mg/ml of L-histidine; and

(f) between about 0.08 mg/ml and about 0.15 mg/ml of polysorbate-20 or polysorbate-80.

18. The pharmaceutical composition of claim 17 , comprising:

(a) about 50 IU/ml, about 100 IU/ml, about 200 IU/ml, or about 400 IU/ml of the rFIXFc polypeptide;

(b) about 11.9 mg/ml of sucrose;

(c) about 23.8 mg/ml of mannitol;

(d) about 3.25 mg/ml of NaCl;

(e) about 3.88 mg/ml of L-histidine; and

(f) about 0.10 mg/ml of polysorbate-20 or polysorbate-80.

19. The pharmaceutical composition of claim 17 , comprising:

(a) about 600 IU/ml of the rFIXFc polypeptide;

(b) about 16.7 mg/ml of sucrose;

(c) about 33.3 mg/ml of mannitol;

(d) about 3.25 mg/ml of NaCl;

(e) about 5.43 mg/ml of L-histidine; and

(f) about 0.14 mg/ml of polysorbate-20 or polysorbate-80.

20. The pharmaceutical composition of claim 1 , which is a liquid formulation.

21. A vial comprising the pharmaceutical composition of claim 20 .

22. The pharmaceutical kit of claim 16 , wherein the rFIXFc polypeptide comprises a first subunit comprising an amino acid sequence at least 90% identical to amino acids 1 to 642 of SEQ ID NO:2, and a second subunit comprising an amino acid sequence at least 90% identical to amino acids 1 to 227 of SEQ ID NO:4.

23. The pharmaceutical kit of claim 16 , wherein the rFIXFc polypeptide is a rFIXFc polypeptide comprises a first subunit comprising amino acids 1 to 642 of SEQ ID NO:2, and a second subunit comprising amino acids 1 to 227 of SEQ ID NO:4.

24. The pharmaceutical kit of claim 22 , wherein the powder comprises

(i) about 250 IU of the rFIXFc polypeptide,

(ii) about 59.5 mg of sucrose;

(iii) about 119 mg of mannitol;

(iv) about 19.4 mg of L-histidine; and

(v) about 0.50 mg of polysorbate 20 or polysorbate 80.

25. The pharmaceutical kit of claim 22 , wherein the powder comprises

(i) about 500 IU of the rFIXFc polypeptide,

(ii) about 59.5 mg of sucrose;

(iii) about 119 mg of mannitol;

(iv) about 19.4 mg of L-histidine; and

(v) about 0.50 mg of polysorbate 20 or polysorbate 80.

26. The pharmaceutical kit of claim 22 , wherein the powder comprises

(i) about 1000 IU of the rFIXFc polypeptide,

(ii) about 59.5 mg of sucrose;

(iii) about 119 mg of mannitol;

(iv) about 19.4 mg of L-histidine; and

(v) about 0.50 mg of polysorbate 20 or polysorbate 80.

27. The pharmaceutical kit of claim 22 , wherein the powder comprises

(i) about 2000 IU of the rFIXFc polypeptide,

(ii) about 59.5 mg of sucrose;

(iii) about 119 mg of mannitol;

(iv) about 19.4 mg of L-histidine; and

(v) about 0.50 mg of polysorbate 20 or polysorbate 80.

28. The pharmaceutical kit of claim 22 , wherein the powder comprises

(i) about 3000 IU of the rFIXFc polypeptide,

(ii) about 83.3 mg of sucrose;

(iii) about 167 mg of mannitol;

(iv) about 27.2 mg of L-histidine; and

(v) about 0.7 mg of polysorbate 20 or polysorbate 80.

29. The pharmaceutical composition of claim 16 , wherein the rFIXFc polypeptide comprises a first subunit comprising an amino acid sequence at least 90% identical to amino acids 1 to 642 of SEQ ID NO:2, and a second subunit comprising an amino acid sequence at least 90% identical to amino acids 1 to 227 of SEQ ID NO:4.

30. The pharmaceutical composition of claim 16 , wherein the rFIXFc polypeptide comprises a first subunit comprising amino acids 1 to 642 of SEQ ID NO:2, and a second subunit comprising amino acids 1 to 227 of SEQ ID NO:4.

31. A pharmaceutical kit comprising:

(a) a first container comprising a lyophilized powder, where the powder comprises

(i) 200 IU to 4000 IU of a rFIXFc protein comprising human coagulation Factor IX (FIX) and a Fc domain of a human antibody,

wherein the rFIXFc protein comprises a first subunit comprising amino acids 1 to 642 of SEQ ID NO:2 and a second subunit comprising amino acids 1 to 227 of SEQ ID NO:4,

(ii) 59.5 mg or 83.3 mg of sucrose,

(iii) 119 mg or 167 mg of mannitol,

(iv) 19.4 mg or 27.2 mg of L-histidine, and

(v) 0.50 mg or 0.7 mg of polysorbate 20; and

(b) a second container comprising 0.325% (w/v) NaCl to be combined with the lyophilized powder of the first container.

32. The pharmaceutical kit of claim 31 , wherein the powder comprises

(i) 250 IU of the rFIXFc protein;

(ii) 59.5 mg of sucrose;

(iii) 119 mg of mannitol;

(iv) 19.4 mg of L-histidine; and

(v) 0.50 mg of polysorbate 20.

33. The pharmaceutical kit of claim 31 , wherein the powder comprises

(i) 500 IU of the rFIXFc protein;

(ii) 59.5 mg of sucrose;

(iii) 119 mg of mannitol;

(iv) 19.4 mg of L-histidine; and

(v) 0.50 mg of polysorbate 20.

34. The pharmaceutical kit of claim 31 , wherein the powder comprises

(i) 1000 IU of the rFIXFc protein;

(ii) 59.5 mg of sucrose;

(iii) 119 mg of mannitol;

(iv) 19.4 mg of L-histidine; and

(v) 0.50 mg of polysorbate 20.

35. The pharmaceutical kit of claim 31 , wherein the powder comprises

(i) 2000 IU of the rFIXFc protein;

(ii) 59.5 mg of sucrose;

(iii) 119 mg of mannitol;

(iv) 19.4 mg of L-histidine; and

(v) 0.50 mg of polysorbate 20.

36. The pharmaceutical kit of claim 31 , wherein the powder comprises

(i) 3000 IU of the rFIXFc protein;

(ii) 83.3 mg of sucrose;

(iii) 167 mg of mannitol;

(iv) 27.2 mg of L-histidine; and

(v) 0.7 mg of polysorbate 20.

37. A pharmaceutical composition comprising:

(a) 25 IU/ml to 700 IU/ml of a rFIXFc protein comprising human coagulation Factor IX (FIX) and a Fc domain of a human antibody,

wherein the rFIXFc protein comprises a first subunit comprising amino acids 1 to 642 of SEQ ID NO:2 and a second subunit comprising amino acids 1 to 227 of SEQ ID NO:4;

(b) 10 mg/ml to 20 mg/ml of sucrose;

(c) 20 mg/ml to 40 mg/ml of mannitol;

(d) 3 mg/ml to 4 mg/ml of NaCl;

(e) 3 mg/ml to 6 mg/ml of L-histidine; and

(f) 0.08 mg/ml to 0.15 mg/ml of polysorbate 20.

38. The pharmaceutical composition of claim 37 , comprising:

(a) 50 IU/ml of the rFIXFc protein;

(b) 11.9 mg/ml of sucrose;

(c) 23.8 mg/ml of mannitol;

(d) 3.25 mg/ml of NaCl;

(e) 3.88 mg/ml of L-histidine; and

(f) 0.10 mg/ml of polysorbate 20.

39. The pharmaceutical composition of claim 37 , comprising:

(a) 100 IU/ml of the rFIXFc protein;

(b) 11.9 mg/ml of sucrose;

(c) 23.8 mg/ml of mannitol;

(d) 3.25 mg/ml of NaCl;

(e) 3.88 mg/ml of L-histidine; and

(f) 0.10 mg/ml of polysorbate 20.

40. The pharmaceutical composition of claim 37 , comprising:

(a) 200 IU/ml of the rFIXFc protein;

(b) 11.9 mg/ml of sucrose;

(c) 23.8 mg/ml of mannitol;

(d) 3.25 mg/ml of NaCl;

(e) 3.88 mg/ml of L-histidine; and

(f) 0.10 mg/ml of polysorbate 20.

41. The pharmaceutical composition of claim 37 , comprising:

(a) 400 IU/ml of the rFIXFc protein;

(b) 11.9 mg/ml of sucrose;

(c) 23.8 mg/ml of mannitol;

(d) 3.25 mg/ml of NaCl;

(e) 3.88 mg/ml of L-histidine; and

(f) 0.10 mg/ml of polysorbate 20.

42. The pharmaceutical composition of claim 37 , comprising:

(a) 600 IU/m 1 of the rFIXFc protein;

(b) 16.7 mg/ml of sucrose;

(c) 33.3 mg/ml of mannitol;

(d) 3.25 mg/ml of NaCl;

(e) 5.43 mg/ml of L-histidine; and

(f) 0.14 mg/ml of polysorbate 20.