Factor VIII polypeptide formulations

Patent metadata

Field	Value
Publication number	US-10786554-B2
Application number	US-201715455043-A
Country	US
Kind code	B2
Filing date	Mar 9, 2017
Priority date	Mar 15, 2013
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

Abstract

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.

First claim

What is claimed is:

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

Assignees

• Bioverativ Therapeutics Inc

Inventors

• Maloney Kevin
• Gage Daniel
• Abdul-Fattah Ahmad

Classifications

• C07K16/2833

  against MHC-molecules, e.g. HLA-molecules · CPC title

• A61K38/37 Primary

  Factors VIII · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• C07K14/755

  Factors VIII {, e.g. factor VIII C (AHF), factor VIII Ag (VWF)} · CPC title