Factor VIII polypeptide formulations
The present invention provides a formulation of a Factor VIII polypeptide, e.g., FVIII-Fc, and methods of using the same. The FVIII polypeptide can be a recombinant FVIII protein, a short-acting FVIII protein, or a long-acting FVIII protein. The pharmaceutical formulation comprising a FVIII polypeptide can be used for individual prophylaxis, weekly prophylaxis, episodic (on-demand) treatment, or perioperative management of hemophilia.
1. A method of reducing the annualized bleeding rate in a subject having Hemophilia A, comprising administering to the subject an effective amount of a pharmaceutical composition at a dosing interval of about once every three to five days, wherein the pharmaceutical composition comprises:
(a) about 50 IU/ml to about 2500 IU/ml of a long-acting chimeric Factor VIII-Fc (rFVIIIFc) polypeptide;
(b) about 13 mg/ml to about 20 mg/ml sucrose;
(c) about 10 mg/ml to about 13 mg/ml sodium chloride (NaCl);
(d) about 0.75 mg/ml to about 2.25 mg/ml L-histidine;
(e) about 5 mM to about 10 mM calcium chloride; and
(f) about 0.08 mg/ml to about 0.25 mg/ml polysorbate 20 or polysorbate 80,
wherein the long-acting rFVIIIFc polypeptide comprises a first subunit and a second subunit, wherein the first subunit comprises an amino acid sequence at least 95% identical to amino acids 20 to 1684 of SEQ ID NO: 2, and wherein the second subunit comprises an FcRn binding partner, wherein the FcRn binding partner comprises an amino acid sequence at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4, and
wherein the effective amount is between about 20 IU/kg to about 90 IU/kg of the long-acting rFVIIIFc polypeptide.
2. The method of claim 1 , wherein the administration is prophylactic and individualized for the subject.
3. The method of claim 1 , wherein the administering is on-demand or episodic.
4. The method of claim 1 , wherein the administration is prophylactic and individualized at an effective dose of about 25 IU/kg to about 65 IU/kg twice weekly or every three days or about 50 IU/kg to about 65 IU/kg every 4 or 5 days.
5. The method of claim 1 , wherein the subject is in need of long-term treatment.
6. The method of claim 1 , wherein the long-acting rFVIIIFc polypeptide is administered intravenously.
7. A method of treating Hemophilia A in a subject having Hemophilia A, the method comprising administering to the subject an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises:
(a) about 50 IU/ml to about 2500 IU/ml of a long-acting chimeric Factor VIII-Fc (rFVIIIFc) polypeptide;
(b) about 13 mg/ml to about 20 mg/ml sucrose;
(c) about 10 mg/ml to about 13 mg/ml sodium chloride (NaCl);
(d) about 0.75 mg/ml to about 2.25 mg/ml L-histidine;
(e) about 5 mM to about 10 mM calcium chloride; and
(f) about 0.08 mg/ml to about 0.25 mg/ml polysorbate 20 or polysorbate 80,
wherein the long-acting rFVIIIFc polypeptide comprises a first subunit and a second subunit, wherein the first subunit comprises an amino acid sequence at least 95% identical to amino acids 20 to 1684 of SEQ ID NO: 2, and
wherein the second subunit comprises an FcRn binding partner, wherein the FcRn binding partner comprises an amino acid sequence at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4,
thereby treating Hemophilia A in the subject.
8. The method of claim 1 , wherein the pharmaceutical composition comprises about 13.3 mg/ml sucrose.
9. The method of claim 1 , wherein the pharmaceutical composition comprises about 12.0 mg/ml NaCl.
10. The method of claim 1 , wherein the pharmaceutical composition comprises about 1.03 mg/ml L-histidine.
11. The method of claim 1 , wherein the pharmaceutical composition comprises about 5.4 mM calcium chloride.
12. The method of claim 1 , wherein the pharmaceutical composition comprises about 0.13 mg/ml polysorbate 20 or polysorbate 80.
13. The method of claim 1 , wherein the rFVIIIFc polypeptide comprises a first subunit comprising an amino acid sequence identical to amino acids 20 to 1683 of SEQ ID NO: 2, and a second subunit comprising an amino acid sequence identical to amino acids 21 to 246 of SEQ ID NO: 4.
14. The method of claim 1 , wherein mannitol, glycine, alanine, or hydroxyethyl starch is not included as a bulking agent in the pharmaceutical composition.
15. The method of claim 1 , wherein NaCl is the only bulking agent in the pharmaceutical composition.
16. The method of claim 7 , wherein the pharmaceutical composition comprises about 12.0 mg/ml NaCl.
17. The method of claim 7 , wherein the pharmaceutical composition comprises about 1.03 mg/ml L-histidine.
18. The method of claim 7 , wherein the pharmaceutical composition comprises about 5.4 mM calcium chloride.
19. The method of claim 8 , wherein the pharmaceutical composition comprises about 0.13 mg/ml polysorbate 20 or polysorbate 80.
20. The method of claim 7 , wherein the rFVIIIFc polypeptide comprises a first subunit comprising an amino acid sequence identical to amino acids 20 to 1683 of SEQ ID NO: 2, and a second subunit comprising an amino acid sequence identical to amino acids 21 to 246 of SEQ ID NO: 4.
21. The method of claim 7 , wherein mannitol, glycine, alanine, or hydroxyethyl starch is not included as a bulking agent in the pharmaceutical composition.
22. The method of claim 7 , wherein NaCl is the only bulking agent in the pharmaceutical composition.
23. The method of claim 7 , wherein the FcRn binding partner comprises an amino acid sequence identical to amino acids 21 to 246 of SEQ ID NO: 4.
24. The method of claim 1 , wherein the FcRn binding partner comprises an amino acid sequence identical to amino acids 21 to 246 of SEQ ID NO: 4.
25. A method of reducing the annualized bleeding rate in a subject having Hemophilia A, the method comprising administering to the subject an effective amount of a pharmaceutical composition at a dosing interval of about three days or longer,
wherein the pharmaceutical composition comprises a lyophilized powder,
wherein upon reconstitution with about 3 ml sterile water for injection the pharmaceutical composition produces a solution comprising:
(a) a long-acting FVIII polypeptide;
(b) about 13.3 mg/ml sucrose;
(c) about 12.0 mg/ml sodium chloride (NaCl);
(d) about 1.03 mg/ml L-histidine;
(e) about 5.4 mM calcium chloride hydrate; and
(f) about 0.13 mg/ml polysorbate 20 or polysorbate 80.
26. The method of claim 1 , wherein the long-acting rFVIIIFc polypeptide is administered subcutaneously.
27. The method of claim 7 , wherein the long-acting rFVIIIFc polypeptide is administered intravenously.
28. The method of claim 7 , wherein the long-acting rFVIIIFc polypeptide is administered subcutaneously.
29. A method of reducing the annualized bleeding rate in a subject having Hemophilia A, comprising administering to the subject an effective amount of a pharmaceutical composition at a dosing interval of about once every three to five days, wherein the pharmaceutical composition comprises:
(a) about 50 IU/ml to about 2500 IU/ml of a long-acting chimeric Factor VIII polypeptide comprising a FVIII polypeptide and an Fc region;
(b) about 13 mg/ml to about 20 mg/ml sucrose;
(c) about 10 mg/ml to about 13 mg/ml sodium chloride (NaCl);
(d) about 0.75 mg/ml to about 2.25 mg/ml L-histidine;
(e) about 5 mM to about 10mM calcium chloride; and
(f) about 0.08 mg/ml to about 0.25 mg/ml polysorbate 20 or polysorbate 80,
wherein the effective amount is between about 20 IU/kg to about 90 IU/kg of the long- acting rFVIIIFc polypeptide.
30. The method of claim 29 , wherein the long-acting chimeric Factor VIII polypeptide comprises a first subunit comprising an amino acid sequence at least 95% identical to amino acids 20 to 1684 of SEQ ID NO: 2, and a second subunit comprising an amino acid sequence at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.
31. The method of claim 29 , wherein the long-acting chimeric Factor VIII polypeptide comprises a first subunit comprising an amino acid sequence at least 99% identical to amino acids 20 to 1684 of SEQ ID NO: 2, and a second subunit comprising an amino acid sequence at least 99% identical to amino acids 21 to 247 of SEQ ID NO: 4.
32. The method of claim 29 , wherein the long-acting chimeric Factor VIII polypeptide comprises a first subunit comprising an amino acid sequence identical to amino acids 20 to 1683 of SEQ ID NO: 2, and a second subunit comprising an amino acid sequence identical to amino acids 21 to 246 of SEQ ID NO: 4.
33. The method of claim 32 , wherein first subunit and the second subunit are associated by a disulfide bond.
34. The method of claim 29 , wherein the Factor VIII polypeptide and the Fc region are joined by a linker.
35. The method of claim 29 , wherein the Factor VIII polypeptide is fused directly to the N-terminus of the Fc region with no intervening linker.
36. A method of treating Hemophilia A in a subject having Hemophilia A, the method comprising administering to the subject an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises:
(a) about 50 IU/ml to about 2500 IU/ml of a long-acting chimeric Factor VIII polypeptide comprising a FVIII polypeptide and an Fc region;
(b) about 13 mg/ml to about 20 mg/ml sucrose;
(c) about 10 mg/ml to about 13 mg/ml sodium chloride (NaCl);
(d) about 0.75 mg/ml to about 2.25 mg/ml L-histidine;
(e) about 5 mM to about 10 mM calcium chloride; and
(f) about 0.08 mg/ml to about 0.25 mg/ml polysorbate 20 or polysorbate 80 , thereby treating Hemophilia A in the subject.
37. The method of claim 36 , wherein the long-acting chimeric Factor VIII polypeptide comprises a first subunit comprising an amino acid sequence at least 95% identical to amino acids 20 to 1684 of SEQ ID NO: 2, and a second subunit comprising an amino acid sequence at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.
38. The method of claim 36 , wherein the long-acting chimeric Factor VIII polypeptide comprises a first subunit comprising an amino acid sequence at least 99% identical to amino acids 20 to 1684 of SEQ ID NO: 2, and a second subunit comprising an amino acid sequence at least 99% identical to amino acids 21 to 247 of SEQ ID NO: 4.
39. The method of claim 36 , wherein the long-acting chimeric Factor VIII polypeptide comprises a first subunit comprising an amino acid sequence identical to amino acids 20 to 1683 of SEQ ID NO: 2, and a second subunit comprising an amino acid sequence identical to amino acids 21 to 246 of SEQ ID NO: 4.
40. The method of claim 39 , wherein first subunit and the second subunit are associated by a disulfide bond.
41. The method of claim 36 , wherein the Factor VIII polypeptide and the Fc region are joined by a linker.
42. The method of claim 36 , wherein the Factor VIII polypeptide is fused directly to the N-terminus of the Fc region with no intervening linker.