Search

US-12622950-B2 - Treatment of patients with severe von Willebrand disease undergoing elective surgery by administration of recombinant VWF

US12622950B2US 12622950 B2US12622950 B2US 12622950B2US-12622950-B2

Abstract

The present invention relates to method for pretreating a subject with severe von Willebrand disease prior to a surgical procedure comprising administering to the subject a dose ranging from about 20 IU/kg to about 60 IU/kg rVWF between about 12 hours and about 24 hours prior to the surgical procedure, and wherein Factor VIII is not administered with the rVWF prior to the surgical procedure.

Inventors

  • Miranda Chapman
  • Bruce Ewenstein
  • Bettina Ploder

Assignees

  • TAKEDA PHARMACEUTICAL COMPANY LIMITED

Dates

Publication Date
20260512
Application Date
20211208

Claims (20)

  1. 1 . A method for pre-treatment of a subject with severe von Willebrand disease (VWD) prior to a surgical procedure, wherein said pre-treatment comprises the following steps: (i) administering 40-60 IU/kg of recombinant Von Willebrand Factor (rVWF) to said subject between 12 hours and 24 hours prior to said surgical procedure, wherein Factor VIII (FVIII) is not administered with the rVWF prior to the surgical procedure, wherein the rVWF comprises ultra-large multimers (ULMs), wherein the ULMs comprise over 40 subunits and are at least 10,000 kDa; (ii) measuring the subject's FVIII: C level within 3 hours prior to said procedure; and (iii) administering 5-90 IU/kg rVWF to said subject within 1 hour prior to said surgical procedure.
  2. 2 . The method of claim 1 , wherein FVIII is not administered after said surgical procedure.
  3. 3 . The method of claim 1 , wherein said surgical procedure is selected from the group consisting of major surgery, minor surgery, and oral surgery.
  4. 4 . The method of claim 1 , wherein said subject is administered 50-60 IU/kg rVWF between 12 hours and 24 hours prior to said surgical procedure and said surgical procedure is a minor surgical procedure.
  5. 5 . The method of claim 1 , wherein said subject is administered 45-60 IU/kg rVWF between 12 hours and 24 hours prior to said surgical procedure and said surgical procedure is a major surgical procedure.
  6. 6 . The method of claim 1 , wherein said subject is administered 5-50 IU/kg rVWF 1 hour prior to the surgical procedure and said surgical procedure is a minor surgical procedure.
  7. 7 . The method of claim 1 , wherein said subject is administered 15-90 IU/kg rVWF 1 hour prior to said surgical procedure and said surgical procedure is a major surgical procedure.
  8. 8 . The method of claim 1 , wherein said subject is administered 20-50 IU/kg rVWF 1 hour prior to said surgical procedure and said surgical procedure is an oral surgical procedure.
  9. 9 . The method of claim 1 , wherein said subject is administered 10-50 IU/kg rVWF during said surgical procedure and said surgical procedure is an oral surgical procedure.
  10. 10 . The method of claim 1 , wherein said subject is administered 70-220 IU/kg rVWF after said surgical procedure.
  11. 11 . The method of claim 1 , wherein said subject is administered 70-150 IU/kg rVWF after said surgical procedure and said surgical procedure is a minor surgical procedure.
  12. 12 . The method of claim 1 , wherein said subject is administered 150-220 IU/kg rVWF after said surgical procedure and said surgical procedure is a major surgical procedure.
  13. 13 . The method of claim 1 , wherein said subject is administered 20-50 IU/kg rVWF after said surgical procedure and said surgical procedure is an oral surgical procedure.
  14. 14 . The method of claim 1 , wherein said subject is administered a total dosage of 100-220 IU/kg rVWF and said surgical procedure is a minor surgical procedure.
  15. 15 . The method of claim 1 , wherein said subject is administered a total dosage of 220-320 IU/kg rVWF and said surgical procedure is a major surgical procedure.
  16. 16 . The method of claim 1 , wherein said subject is administered a total dosage of 70-190 IU/kg rVWF and said surgical procedure is an oral surgical procedure.
  17. 17 . The method of claim 1 , wherein said surgical procedure is a major surgical procedure and said pre-treatment comprises administering at least two approximately equal doses of rVWF prior to the surgical procedure.
  18. 18 . The method of claim 1 , wherein said surgical procedure is a minor surgical procedure and said pre-treatment comprises administering at least two doses of rVWF prior to the surgical procedure, wherein the first dose is larger than the second dose.
  19. 19 . The method of claim 1 , wherein said surgical procedure is an oral surgical procedure and said pre-treatment comprises administering at least two approximately equal doses of rVWF prior to the surgical procedure.
  20. 20 . The method of claim 1 , wherein said surgical procedure further comprises step (iv) administering recombinant factor VIII immediately after said administration of 5-90 IU/kg of rVWF if the subject's measured FVIII: C level is below 30 IU/dL for a minor/oral surgical procedure or below 60 IU/dL for a major surgical procedure.

Description

CROSS REFERENCE TO RELATED APPLICATION This application is a continuation of U.S. application Ser. No. 16/030,653, filed on Jul. 9, 2018, which claims priority to U.S. Provisional Patent Application No. 62/546,999, filed on Aug. 17, 2017, and U.S. Provisional Patent Application No. 62/530,024, filed on Jul. 7, 2017, which are hereby incorporated by reference in their entirety. REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM, LISTING APPENDIX SUBMITTED ON A COMPACT DISK This disclosure incorporates by reference the Sequence Listing text copy submitted herewith, which was created on Oct. 1, 2018, entitled 008073_5186_US_ST25.txt which is 53 kilobytes in size. BACKGROUND OF THE INVENTION Coagulation diseases, such as von Willebrand Disease (VWD) generally result from a deficiency in the coagulation cascade. von Willebrand Disease (VWD) refers to the group of diseases caused by a deficiency of von Willebrand factor. Von Willebrand factor helps blood platelets clump together and stick to the blood vessel wall, which is necessary for normal blood clotting. von Willebrand disease (VWD) is the most common inherited bleeding disorder, with an estimated prevalence rate of 1% (Veyradier A, et al., Medicine (Baltimore). 2016, 95(11):e3038). However, excluding milder forms of the disease, only about 1/10,000 patients actually require treatment. Current treatment for these coagulopathies includes a replacement therapy using pharmaceutical preparations comprising the normal coagulation factor. VWF is a glycoprotein circulating in plasma as a series of multimers ranging in size from about 500 to 20,000 kD. The full length of cDNA of VWF has been cloned; the propolypeptide corresponds to amino acid residues 23 to 764 of the full length prepro-VWF (Eikenboom et al (1995) Haemophilia 1, 77 90). Multimeric forms of VWF are composed of 250 kD polypeptide subunits linked together by disulfide bonds. VWF mediates the initial platelet adhesion to the sub-endothelium of the damaged vessel wall, with the larger multimers exhibiting enhanced hemostatic activity. Multimerized VWF binds to the platelet surface glycoprotein Gp1bα, through an interaction in the A1 domain of VWF, facilitating platelet adhesion. Other sites on VWF mediate binding to the blood vessel wall. Thus, VWF forms a bridge between the platelet and the vessel wall that is essential to platelet adhesion and primary hemostasis under conditions of high shear stress. Normally, endothelial cells secrete large polymeric forms of VWF and those forms of VWF that have a lower molecular weight arise from proteolytic cleavage. The multimers of exceptionally large molecular masses are stored in the Weibel-Pallade bodies of the endothelial cells and liberated upon stimulation by agonists such as thrombin and histamine. For patients with VWD, it is recommended that they be treated with von Willebrand factor (VWF) replacement given the need for prolonged hemostasis, particularly in major surgery (Mannucci P M and Franchini M., Haemophilia, 2017, 23(2):182-187; National Institutes of Health. National Heart, Lung, and Blood Institute. The Diagnosis, Evaluation, and Management of von Willebrand Disease NIH Publication No. 08-5832; December, 2007). Plasma-derived VWF therapies contain factor VIII (FVIII) and have the potential for FVIII accumulation with repeated dosing. VONVENDI® (von Willebrand factor [recombinant], Shire, Westlake Village, CA) is the first and only recombinant VWF (rVWF) concentrate (Turecek P L, et al. Hamostaseologie. 2009; 29(suppl 1):532-38; Mannucci P M, et al. Blood, 2013; 122(5):648-657; Gill J C, et al. Blood, 2015; 126(17):2038-2046). BRIEF SUMMARY OF THE INVENTION The present invention provides methods of pre-treatment for a patient with severe von Willebrand disease prior to surgery by administering 20-60 IU/kg recombinant von Willebrand Factor (rVWF) to the patient between 12 hours and 24 hours, e.g., 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 12 hours and 24 hours, 14 hours and 24 hours, 16 and 24 hours, 18 hours and 24 hours, or 20 hours and 24 hours prior to the surgical procedure, and not administering Factor VIII (FVIII) with the rVWF prior to the surgical procedure. In some embodiments, the method of pre-treating further comprises administering to the subject 5-90 IU/kg rVWF 1 hour prior to surgery. In some embodiments, the subject is administered 70-200 IU rVWF after the surgery, either with or without the pre-treatment described above. In some cases, the surgical procedure is selected from a group consisting of major surgery, minor surgery, and oral surgery. In some embodiments, the subject is administered 35-60 IU/kg rVWF between 12 hours and 24 hours prior to a major surgical procedure. In other embodiments, the subject is administered 15-90 IU/kg rVWF 1 hour prior to major surgical procedure. In another embodiment, the subject is administer