Introduction

von Willebrand disease (VWD) has an estimated incidence ranging between 109 and 1300 per 100,000 in pediatric populations [[1], [2], [3]]. It is caused by quantitative and/or qualitative defects of von Willebrand factor (VWF), which mediates platelet adhesion and stabilizes coagulation factor (F)VIII [4,5]. The disease is classified into 3 types: type 1 (partial deficiency of VWF); type 2 (qualitative defects of VWF classified into 2A, 2B, 2M, and 2N subtypes); and type 3 (complete or almost complete absence of VWF) [4].

Diagnosing VWD in children can be challenging because younger patients may not yet have encountered major hemostatic challenges such as surgery or dental extraction, and mild cases often show borderline findings [6,7]. In addition, bleeding symptoms are frequently nonspecific and may overlap with normal childhood bruising or nosebleeds [7]. Diagnosis is further complicated by individual fluctuations in VWF levels related to age, stress, exercise, and illness [4]. Therefore, delayed diagnosis or misdiagnosis of VWD is common, even in symptomatic patients, prolonging the time before children with the condition receive appropriate treatment [8,9]. However, symptoms due to VWD in childhood, from severe to nuisance bleeding, may place a considerable burden on parents and caregivers [10,11]. VWD negatively affects health-related quality of life in children, impacting physical, behavioral, and emotional functioning compared with those without VWD [12]. First bleeds in children with VWD commonly include epistaxis, oropharyngeal bleeding, or cutaneous bleeding [7,13]. Furthermore, joint bleeds in patients with moderate and severe VWD have been reported to mostly start before 16 years of age [14].

Patients with VWD, particularly those with a more severe bleeding phenotype, have an increased risk of bleeding; this includes serious and potentially life-threatening bleeding events (BEs) and milder BEs requiring on-demand medication [15,16]. Treatment options for pediatric patients with VWD include hormonal therapy in adolescent girls, antifibrinolytics, desmopressin (DDAVP; when DDAVP response is expected and sufficient and the child is aged ≥2 to 4 years [17]), and replacement therapy with VWF concentrates [18]. A recent real-world study of 117 pediatric patients with VWD in a French registry reported that 50% of the children received antifibrinolytics, 11% received DDAVP, 26% of girls received hormonal therapy, and 4% of all patients received long-term prophylaxis with VWF [18].

Recombinant VWF (rVWF; vonicog alfa; VEYVONDI/VONVENDI) is approved for the management of VWD in adults [19,20]; rVWF was also recently approved for on-demand treatment (in the United States, European Union, United Kingdom, and Japan [[19], [20], [21], [22]]) and perioperative management (in the United States and Japan [20,21]) of pediatric patients with VWD. The properties and characteristics of rVWF make it a valuable treatment option for patients with VWD, including children. rVWF is produced using recombinant DNA technology, eliminating the risk of blood-borne pathogen transmission [23]. Compared with plasma-derived VWF products, rVWF also has a longer half-life and exhibits higher specific activity [[24], [25], [26]]. Unlike plasma-derived VWF, rVWF contains the full spectrum of multimers, including ultralarge multimers with higher biological activity [23,27]. In addition, rVWF does not contain FVIII, allowing more flexibility of dosing and reducing concerns relating to excessive FVIII levels in specific patient groups [23,28,29].

To assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of rVWF as an on-demand therapy to control BEs, and for elective and emergency surgery coverage, in pediatric patients with severe VWD, a prospective, open-label, phase 3 study is being conducted at 45 sites in 13 countries in Europe and the United States (ClinicalTrials.gov, NCT02932618). In this study, we present final data from the completed on-demand treatment arm following a planned interim analysis of the phase 3 study (results from the surgery arms will be reported separately once completed). Data are also presented from pediatric patients who completed the phase 3 study and continued on-demand treatment in a phase 3b continuation study (ClinicalTrials.gov, NCT03879135).