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CC BY 4.0 · TH Open 2024; 08(02): e243-e251
DOI: 10.1055/s-0044-1787815
Original Article

Exposure–Response Relationship between VWF/FVIII Activity and Spontaneous Bleeding Events Following Recombinant VWF Prophylaxis in Severe VWD

Frank W.G. Leebeek
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
,
Giancarlo Castaman
2   Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Florence, Italy
,
Jean François Marier
3   Certara Strategic Consulting, Princeton, New Jersey, United States
,
Gülden Özen   *
4   Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States
,
Indranil Bhattacharya
4   Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States
,
Jingmei Zhang
4   Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States
,
Scarlett Wang
4   Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States
,
Yi Wang 
4   Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States
› Author Affiliations Funding This study was supported by Takeda Development Center Americas, Inc., Lexington, Massachusetts, United States.
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Abstract

Background Recombinant von Willebrand factor (rVWF, vonicog alfa, Takeda Pharmaceuticals USA) is indicated in adults diagnosed with von Willebrand disease (VWD). In this study, the exposure–response (ER) relationship between VWF activity (VWF:RCo) or factor VIII activity (FVIII:C) and spontaneous bleeding events (BEs) was evaluated in adults with severe VWD receiving rVWF prophylaxis for up to 1 year.

Methods This secondary analysis included 23 patients receiving rVWF prophylaxis in the open-label, phase 3 prophylaxis trial (NCT02973087). Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were used to characterize VWF activity and endogenous FVIII:C, and PK/PD simulations were linked to spontaneous BEs to develop an ER model.

Results None of the five patients with VWD types 1 or 2A/B experienced spontaneous BEs. Five of 18 patients with VWD type 3 experienced ≥1 spontaneous BEs. An ER relationship was observed whereby higher VWF:RCo levels were associated with a numerically lower spontaneous BE risk (p < 0.10). This relationship was independent of patients' pretrial VWF treatment. A statistically significant ER relationship was observed after accounting for relevant data (average ± standard error exposure estimate for VWF:RCo over 24 hours prior to the spontaneous BE: −0.043 ± 0.021, p = 0.041). The model-generated hazard ratio for a 10 IU/dL increment in the average exposure of VWF:RCo 24 hours before a spontaneous BE was 0.651 (95% confidence interval: 0.431–0.982).

Conclusions This ER analysis suggests a causal association between VWF:RCo and spontaneous BEs, with an increase of VWF:RCo exposure leading to a decrease in spontaneous BE risk.

Keywords

bleeding - prophylaxis - recombinant VWF - vonicog alfa - von Willebrand disease - factor VIII

Data Sharing Statement

The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results reported in this article, will be made available within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after their de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.


Authors' Contribution

F.W.G. Leebeek, G. Castaman, G. Özen, Y. Wang, and I. Bhattacharya made substantial contributions to the conception and design of the study. All authors made substantial contributions to the analysis or interpretation of the data, drafted or critically reviewed the manuscript, provided final approval, and agreed to be accountable for all aspects of the work.


* Affiliation at the time of the study.


Supplementary Material



Publication History

Received: 05 December 2023

Accepted: 21 May 2024

Article published online:
27 June 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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