Real-world study of population pharmacokinetic-guided pdVWF/FVIII (1:1) prophylaxis in people with severe von Willebrand disease: The PopPK-WILPROPHY study

Abstract Introduction: Prophylaxis with a von Willebrand factor (VWF)-containing concentrate is recommended for individuals with von Willebrand disease (VWD) with severe and recurrent bleeds. Tailoring of prophylaxis to individual patients has been shown to increase the net clinical benefit of treatments in people with hemophilia and is the standard of care. There is a paucity of data regarding individualization of VWF dosing according to patient characteristics in people with VWD. While the efficacy and safety of prophylaxis with a plasma-derived VWF/factor VIII concentrate (pdVWF/FVIII) in a 1:1 activity ratio (wilate®) has been demonstrated in adults, adolescents and children with severe VWD prophylaxis, data on pharmacokinetic (PK)-guided prophylaxis in persons with VWD are lacking and individualized prophylaxis has not yet been implemented or operationalized. Aims: To investigate the impact of PK-guided prophylaxis with a 1:1 pdVWF/FVIII concentrate on clinical outcomes in people with clinically severe VWD during routine clinical practice. Methods: The PopPK-WILPROPHY study will be a prospective, observational, single-arm, multicenter study enrolling 70 patients with clinically severe VWD. The study will enroll patients with severe VWD, of any age in accordance with locally approved prescribing information, who are either a) already receiving any VWF concentrate prophylaxis or b) receiving on-demand VWF treatment (for whom prophylactic treatment is recommended by the Investigator) and intend to start 1:1 pdVWF/FVIII prophylaxis. Patients will be treated in accordance with standard clinical practice at their local center at the discretion of the treating physician. Following a screening visit, prior to switching to a PK-guided prophylaxis dosing regimen, patients will be treated with a 1:1 pdVWF/FVIII concentrate prophylactically for 6 months. The dose and dosing interval will be at the discretion of the treating physician and per the locally approved package insert. During this 6-month period, patients will undergo a PK assessment. PK data will be analyzed using a population PK (PopPK) model, developed by the Amsterdam University Medical Center in the Netherlands. The model will be used to propose a tailored dosing regimen for subsequent PopPK-guided prophylaxis over 12 months optimized according to VWD subtype and patient characteristics. The total study duration per patient is 18 months. The use of a 1:1 pdVWF/FVIII concentrate for the treatment of bleeds or surgical prophylaxis will be in accordance with the prescribing information. The primary endpoint will be the annualized bleeding rate (ABR) during PopPK-guided 1:1 pdVWF/FVIII prophylaxis compared with the ABR during the 6 months period prior to starting PopPK-guided 1:1 pdVWF/FVIII prophylaxis. Secondary endpoints will include quality of life, efficacy in the treatment of bleeding episodes, efficacy of surgical prophylaxis, pdVWF/FVIII consumption, and adverse events (AEs) and serious AEs, including AEs of special interest (e.g. thrombotic events and inhibitor development). Results: This study is planned to start in Q1 2026 and aims to enroll 70 patients at approximately 20 centers in the USA, Canada, Europe, Asia and Latin America. Conclusion(s): The PopPK-WILPROPHY study will provide important evidence on the clinical utility of PopPK-guided 1:1 pdVWF/FVIII prophylaxis, supporting personalized treatment strategies in patients with severe VWD.