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EP-4740963-A2 - FORMULATIONS OF FACTOR VIII CHIMERIC PROTEINS AND USES THEREOF

EP4740963A2EP 4740963 A2EP4740963 A2EP 4740963A2EP-4740963-A2

Abstract

The present disclosure provides pharmaceutical compositions of a chimeric protein comprising a factor VIII (FVIII) polypeptide and a von Willebrand factor (VWF) polypeptide. Also disclosed are pharmaceutical kits and methods of using the disclosed pharmaceutical compositions to treat hemophilia A.

Inventors

  • CARLAGE, Tyler
  • MAULDIN, RANDALL
  • MCCOY, Timothy R.
  • TAZI, Loubna Mzaalak

Assignees

  • Bioverativ Therapeutics Inc.

Dates

Publication Date
20260513
Application Date
20221014

Claims (15)

  1. A pharmaceutical kit comprising: (i) a first container comprising a lyophilized pharmaceutical composition comprising: (a) a chimeric protein comprising a first polypeptide chain which comprises the amino acid sequence set forth as SEQ ID NO: 1, and a second polypeptide chain which comprises the amino acid sequence set forth as SEQ ID NO: 2, wherein the first polypeptide chain and the second polypeptide chain are covalently linked by two disulfide bonds between Fc domains in the first and second polypeptide chains; (b) sucrose; (c) histidine; (d) arginine; (e) calcium chloride; and (f) a poloxamer, (ii) a second container comprising sterile water; wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises: (a) the chimeric protein (b) sucrose; (c) histidine; (d) at least about 150 mM arginine; (e) calcium chloride; and (f) a poloxamer, wherein about means ± 10%.
  2. The pharmaceutical kit of claim 1, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises about 200 mM to 300 mM arginine, wherein about means ± 10%, preferably wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises 200 mM to 300 mM arginine.
  3. The pharmaceutical kit of claim 1 or 2, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises 1% (w/v) to 7.5% (w/v) sucrose.
  4. The pharmaceutical kit of any one of claims 1 to 3, wherein the poloxamer is poloxamer 188 (P188).
  5. The pharmaceutical kit of any one of claims 1 to 4, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises 5 mM to 15 mM histidine.
  6. The pharmaceutical kit of any one of claims 1 to 5, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises about 250 mM arginine, wherein about means ± 10%, preferably wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises 250 mM arginine.
  7. The pharmaceutical kit of any one of claims 1 to 6, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises 2.5 mM to 10 mM calcium chloride.
  8. The pharmaceutical kit of any one of claims 1 to 7, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises 0.01 % (w/v) to 1.0% (w/v) poloxamer 188 (P188).
  9. The pharmaceutical kit of any one of claims 1 to 8, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises: (a) about 5% (w/v) sucrose; (b) about 10 mM histidine; (c) about 250 mM arginine; (d) about 5 mM calcium chloride; and (e) about 0.1% (w/v) poloxamer 188, wherein about means ± 10%, preferably wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises: (a) 5% (w/v) sucrose; (b) 10 mM histidine; (c) 250 mM arginine; (d) 5 mM calcium chloride; and (e) 0.1% (w/v) poloxamer 188.
  10. The pharmaceutical kit of any one of claims 1 to 9, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises has a pH of 6.5 to 7.5, or wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises has a pH of about 7.0, wherein about means ± 10%.
  11. The pharmaceutical kit of any one of claims 1 to 10, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition has a pH of 7.0.
  12. The pharmaceutical kit of any one of claims 1 to 11, wherein upon reconstitution with the sterile water the reconstituted pharmaceutical composition comprises less than 8.8 mg/mL sodium chloride (NaCl).
  13. The pharmaceutical kit of any one of claims 1 to 12, wherein the histidine is L-histidine, and/or wherein the arginine is L-arginine, and/or wherein the chimeric protein is efanesoctocog alfa.
  14. The pharmaceutical kit of any one of claims 1 to 13, wherein the lyophilized pharmaceutical composition comprises 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU, or 4,000 IU of the chimeric protein.
  15. The pharmaceutical kit of any one of claims 1 to 14, wherein the reconstituted pharmaceutical composition is suitable for intravenous infusion.

Description

RELATED APPLICATION This application claims priority to U.S. provisional application no. 63/256,432, filed October 15, 2021, the contents of which are incorporated herein in their entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY The content of the electronically submitted sequence listing in XML file format (Name: SA9-483PC_SL_ST26.xml; Size: 55,697 bytes; Created: October 4, 2022) is incorporated herein by reference in its entirety. BACKGROUND OF THE DISCLOSURE Hemophilia A is a bleeding disorder caused by defects in the gene encoding coagulation factor VIII (FVIII) and affects 1-2 in 10,000 male births. Graw et al., Nat. Rev. Genet. 6(6): 488-501 (2005). Patients affected with hemophilia A can be treated with infusions of purified plasma FVIII or recombinantly produced FVIII. Many commercially available FVIII products are known to have a half-life of about 8-12 hours, requiring frequent intravenous administration to the patients. See Weiner M.A. and Cairo, M.S., Pediatric Hematology Secrets, Lee, M.T., 12. Disorders of Coagulation, Elsevier Health Sciences, 2001; Lillicrap, D. Thromb. Res. 122 Suppl 4:S2-8 (2008). In addition, a number of approaches have been tried in order to extend the FVIII half-life. For example, the approaches in development to extend the half-life of clotting factors include pegylation, glycopegylation, and conjugation with albumin. See Dumont et al., Blood. 119(13): 3024-3030 (2012). Consistent results have been demonstrated in humans, for example, rFVIllFc was reported to improve half-life up to ~1.7-fold compared with ADVATE® in hemophilia A patients. See Powell et al., Blood. 119(13): 3031-3037 (2012). Therefore, the half-life increases, despite minor improvements, indicate the presence of other half-life limiting factors, such as clearance by VWF. Pipe et al., Blood. 128(16):2007-2016 (2016)). Efanesoctocog alfa (also known as Efa and BIVV001) is a fusion protein that is designed to uncouple recombinant clotting factor VIII from VWF in circulation. The chimeric protein comprises a single recombinant factor VIII protein fused to dimeric Fc, a D'D3 domain of VWF, and two ELNN Polypeptides. Chhabra et al. Blood 135(17): 1484-1496 (2020). In one early study involving patients with severe hemophilia A, a single intravenous injection of efanesoctocog alfa resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII. See Konkle et al., NEJM. 383:1018-27 (2020). However, there remains a need for improved pharmaceutical compositions. SUMMARY OF THE DISCLOSURE The present disclosure is directed to, inter alia, pharmaceutical compositions comprising a Factor VIII ("FVIII") protein, kits comprising such pharmaceutical compositions, and therapeutic methods and uses of the pharmaceutical compositions. In some embodiments, the pharmaceutical composition comprises a chimeric protein or protein which comprises a first polypeptide chain which comprises a FVIII protein or a portion thereof and a first immunoglobulin ("Ig") constant region or a portion thereof, and a second polypeptide chain which comprises a von Willebrand Factor ("VWF") protein and a second Ig constant region or a portion thereof. In some embodiments, the chimeric protein comprises (i) a FVIII protein comprising a FVIII polypeptide, an ELNN Polypeptide inserted within the B domain (e.g., replacing at least a portion of the B domain) of the FVIII polypeptide, and a first Fc region; and (ii) a VWF protein comprising a VWF fragment (e.g., a fragment comprising the D'D3 domains of VWF, which fragment may comprise mutations), a second ELNN Polypeptide, a thrombin-cleavable linker (such as an a2 linker), and a second Fc region. In some embodiments, the chimeric protein disclosed herein is a FVIII-ELNN-Fc/D'D3-ELNN-Fc heterodimer. In some embodiments, the pharmaceutical composition comprises: (a) a FVIII protein; (b) about 1% (w/v) to about 7.5% (w/v) sucrose; (c) about 5 mM to about 15 mM histidine; (d) about 200 mM to about 300 mM arginine; (e) about 2.5 mM to about 10 mM calcium chloride; and (f) about 0.01% (w/v) to about 1.0% (w/v) of a poloxamer. In some embodiments, the pharmaceutical composition comprises: (a) a FVIII protein; (b) about 1% (w/v) to about 7.5% (w/v) sucrose; (c) about 5 mM to about 15 mM L-histidine; (d) about 200 mM to about 300 mM L-arginine; (e) about 2.5 mM to about 10 mM calcium chloride; and (f) about 0.01% (w/v) to about 1.0% (w/v) of a poloxamer. In some embodiments, the pharmaceutical composition comprising: (a) a Factor VIII ("FVIII") protein; (b) about 1% (w/v) to about 7.5% (w/v) sucrose; (c) about 5 mM to about 15 mM L-histidine; (d) about 200 mM to about 300 mM L-arginine-HCI; (e) about 2.5 mM to about 10 mM calcium chloride dihydrate; and (f) about 0.008% (w/v) to about 0.1% (w/v) of a poloxamer. In some embodiments, the composition comprises about 250 mM L-arginine. In some embodiments, the