Recombinant von willebrand factor for perioperative management of bleeding in pediatric patients with severe von willebrand disease: Interim results from a phase 3 multicenter study and a phase 3b continuation study

Abstract Introduction: Von Willebrand disease (VWD) is the most common bleeding disorder in children. Recombinant von Willebrand factor (rVWF, Takeda Pharmaceuticals U.S.A., Inc.) has demonstrated efficacy and safety in adults with VWD. We present data from the ongoing Phase 3 (NCT02932618) and Phase 3b continuation (NCT03879135) studies of rVWF evaluating the hemostatic efficacy and safety of rVWF, with or without recombinant factor VIII (rFVIII), in pediatric patients with severe VWD undergoing surgery. Methods: In this open-label, prospective, multicenter Phase 3 study, patients aged <18 years with severe VWD were enrolled into one of three arms: on-demand treatment (12–18 months), elective surgery, or emergency surgery. After completing the Phase 3 study, participants could enter the Phase 3b continuation study, which also enrolled new non-rollover pediatric patients. Patients had an initial pharmacokinetic (PK)-pharmacodynamic evaluation at baseline, and results were used to guide perioperative dosing. Perioperative rVWF dosage depended on the type of surgery and PK results and was tailored to raise the VWF:ristocetin cofactor activity to 100 IU/dL for major surgeries and 50–60 IU/dL for minor and oral surgeries. rFVIII was infused if target FVIII levels (40–50 IU/dL for minor/oral surgery or 80–100 IU/dL for major surgery) were not achieved with rVWF only. Assessment of actual versus predicted blood loss and intraoperative hemostatic efficacy was made immediately post-surgery. Overall hemostatic efficacy of rVWF with/without rFVIII was assessed 24 h after the last perioperative infusion or at postoperative Day 14, whichever came first, using a 4-point rating scale (1 = excellent, 2 = good, 3 = moderate, 4 = none). Adverse events (AEs) were assessed for safety evaluation. Written informed consent was obtained for all patients. Results: This interim analysis (cutoff: January 3, 2025) includes 8 pediatric patients who received rVWF for 9 surgical procedures in either the Phase 3 study (4 patients: elective surgery, n=3; emergency surgery, n=1) or Phase 3b continuation study (4 patients: elective surgery, n=5). All were minor procedures: 5 minimally invasive surgeries, 3 endoscopic procedures and 1 dental surgery. The mean age of the eight patients was 10.4 years (standard deviation 2.8; range 6-13 years) (≥6–<12 years, n=4; ≥12–<18 years, n=4). All eight patients were White, and seven were male. Four patients had VWD Type 3, three had Type 1, and one patient had Type 2B. Overall perioperative hemostatic efficacy and intraoperative efficacy were rated “Excellent” for all 8 surgeries with available data (95% confidence interval of 63.1 to 100.0% for both). Overall efficacy was missing for one minor surgery, for which the intraoperative efficacy rating was “Excellent”. The blood loss rating was also “Excellent” for 8 surgeries with non-missing data. A total of 62 perioperative rVWF infusions were administered, with a median (range) of 2.0 (1-2) preoperative and 2.0 (1-4) postoperative infusions of rVWF per surgery. The median (range) preoperative rVWF dose was 79.4 (48.2-116.6) IU/kg per surgery; the postoperative dose was 106.5 (50.0-248.3) IU/kg per surgery. Most patients (6/8) did not receive rFVIII for perioperative management. A total of 6 infusions of rFVIII were administered for two surgeries: one elective surgery in a VWD Type 1 patient (37.0 IU/kg, 1 preoperative infusion) and one emergency surgery in a VWD Type 3 patient (46.6 IU/kg, 1 preoperative infusion; 186.2 IU/kg, 4 postoperative infusions). Four treatment-emergent adverse events (TEAEs) (otitis media, viral upper respiratory tract infection, road traffic accident, and presyncope) were reported in 3 patients (37.5%; three TEAEs in two patients aged ≥6–<12 years and one TEAE in one patient aged ≥12–<18 years) during the perioperative assessment period. None of these events were severe, serious, or fatal, or considered to be related to study drug. No thromboembolic events or severe hypersensitivity reactions were reported, and no VWF or FVIII inhibitors (neutralizing antibodies) were reported in either study.Conclusions:rVWF, with or without rFVIII, was effective for perioperative bleeding management in pediatric patients with severe VWD undergoing minor surgical procedures, and rFVIII was not required in most surgeries (7/9). No new safety concerns were identified with perioperative rVWF treatment.