Abstract
Introduction: In patients with von Willebrand disease (VWD) and a history of severe and recurrent bleeding, long-term prophylaxis with von Willebrand factor (VWF) concentrate is recommended as standard of care. Efficacy and safety of prophylaxis with a plasma-derived (pd)VWF/factor VIII (FVIII) concentrate in a 1:1 activity ratio (wilate®) has been demonstrated in WIL-31, the largest study in VWD to date. WIL-31 included adults, adolescents and children aged 6 years or older with VWD of all types. Currently, limited data are available for prophylaxis with VWF in pediatric patients under 6 years of age with severe VWD.
Aims: To assess the efficacy and safety of prophylaxis with pdVWF/FVIII prophylaxis in children under 6 years old through the first prospective global clinical study.
Methods: WIL-33 (NCT04953884) was an open-label, prospective, non-controlled, international, multicenter phase 3 study investigating the efficacy, immunogenicity, and safety of pdVWF/FVIII prophylaxis and pharmacokinetics in pediatric patients under 6 years old with severe VWD (VWF ristocetin cofactor activity [VWF:RCo] <20%). pdVWF/FVIII was administered 2–3 times per week at a recommended dose of 30–50 international units (IU)/kg over 12 months. The primary endpoint was the total annualized bleeding rate (TABR) during prophylaxis. Safety and tolerability were assessed throughout the study.
Results: A total of 12 patients were enrolled and treated in this global study. At baseline the median (range) age was 2.0 (1.0–5.0), there were 6 male patients (50%), 4 patients (33.3%) had VWD type 2, and 8 patients (66.7%) had VWD type 3. The per-protocol robustness (PPR) set, a subset of the full analysis set (FAS), excluded three patients with deviations mainly from the recommended dosing. The mean (standard deviation [SD]) TABR in the FAS and PPR set was 4.6 (6.1) and 2.7 (1.8), respectively. The mean (SD) TABR was 2.1 (1.0) and 5.8 (7.2) in patients with VWD type 2 and VWD type 3, respectively in the FAS (PPR: 2.0 [1.1] vs 3.4 [2.2], respectively). Over one third of the total bleeds (22/56; 39%) during prophylaxis in the FAS set were due to allergic rhinitis in one patient. The mean (SD) spontaneous ABR was 0.9 (1.2) in the FAS and 1.0 (1.3) in the PPR set. The median (range) weekly prophylactic dose was 100 (63–311) and 92 (63–130) IU/kg in the FAS and PPR set, respectively. Pharmacokinetic parameters were within the expected ranges. The mean VWF:RCo half-life was 11.7 h. All 45 bleeds treated with pdVWF/FVIII during the prophylaxis period in 10/12 patients in the FAS were successfully managed and rated “excellent”. Most bleeds (95.6%) required only one infusion. Epistaxis was the most frequent bleed type across patients, while joint bleeds were the rarest, with only one bleeding observed in the study. One patient also received wilate® for major surgery during the study, with an overall rating of “excellent” by the hematologist and surgeon. No serious adverse events related to study treatment and no thrombotic events were observed.
Conclusion(s): pdVWF/FVIII prophylaxis was efficacious and well tolerated in children under 6 years with severe VWD. WIL-33 is the only prospective clinical trial to specifically investigate prophylaxis in this population.
