Efficacy and Safety of Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate Among Von Willebrand Disease Patients across All ABO Antigen Blood Groups

Introduction: von Willebrand disease (VWD) is caused by quantitative or qualitative defects in von Willebrand factor (VWF). VWF levels are also affected by a person’s ABO antigen blood group. Generally, individuals with blood group O have lower VWF plasma levels than individuals with blood groups A, B or AB. Prophylaxis with a VWF concentrate is the recommended treatment for VWD patients with frequent and severe bleeding. The WIL-31 study (NCT04052698) is the largest prospective prophylaxis study in VWD with an on-demand run-in study as an intra-individual comparator. The results of the WIL-31 study showed that a plasma-derived VWF/factor VIII concentrate containing VWF and FVIII in a 1:1 activity ratio (pdVWF/FVIII; wilate^®) is highly effective at preventing bleeding in adults and children, males and females, with VWD of all types. There are limited data on the impact of ABO blood group on the efficacy of VWF prophylaxis.

Aim: To investigate the efficacy of regular prophylaxis with pdVWF/FVIII compared with prior on-demand treatment in VWD patients with different ABO blood groups.

Methods: WIL-31 was a prospective, non-controlled, international, multicenter Phase 3 trial that enrolled male and female patients, aged ≥6 years with VWD type 1 (VWF:RCo <30 IU/dL), type 2 (except 2N), or type 3. All patients had previously received on-demand treatment with a VWF concentrate during a 6-month prospective, observational, run-in study (WIL-29; NCT04053699). Patients who had experienced at least 6 bleeding episodes during WIL-29, excluding menstrual bleeds, of which at least 2 were treated with a VWF concentrate, were able to be enrolled in WIL-31. In WIL-31 patients received prophylaxis with pdVWF/FVIII 2–3× per week at 20–40 IU/kg for 12 months. Mean total and spontaneous annualized bleed rate (ABR) were compared, and the number and site of breakthrough bleeds were described. VWF and FVIII activity were measured at baseline and throughout the study. Safety and tolerability were assessed throughout the study.

Results: The overall study population included 33 patients: 18 with blood group A (4 VWD type 1, 4 type 2A, 10 type 3), 5 with blood group B (1 type 2A, 4 type 3), 1 with blood group AB (type 1) and 9 with blood group O (1 type 1, 8 type 3). The mean total ABRs during on-demand treatment vs prophylaxis were 25.4 vs 5.5 (-78%), 57.7 vs 4.6 (-92%), 60.6 vs 13.9 (-77%), and 32.7 vs 4.2 (-87%) among patients with blood groups A, B, AB, and O, respectively. Of these bleeds, the most common site was the nose: 39/98 (40%) in patients with blood group A, 18/23 (78%) in patients with blood group B, 14/14 (100%) in the patient with blood group AB, and 18/38 (47%) in patients with blood group O. During the 12 months of prophylaxis, 44%, 60%, 0% and 44% of patients with blood groups A, B, AB, and O, respectively, experienced no spontaneous bleeds. Among patients with VWD type 3 (n = 22), mean spontaneous ABRs during on-demand vs prophylaxis were 21.7 vs 3.2 (-85%), 50.4 vs 5.0 (-90%), and 20.5 vs 1.3 (-94%), among blood group A, B and O patients, respectively. There were no significant differences in the baseline FVIII and VWF activity levels. FVIII levels were slightly higher in patients with blood group A; potentially due to the lower proportion of patients with type 3 VWD. FVIII and VWF activity levels increased 60 minutes after VWF infusion in patients with no appreciable differences between patients with different blood groups. No serious adverse events related to study treatment and no thrombotic events were observed.

Conclusion: wilate^® prophylaxis was efficacious at reducing bleeding in patients with VWD regardless of ABO blood group.