Phase 3 study of the efficacy, pharmacokinetics, immunogenicity and safety of von Willebrand Factor/Factor VIII concentrate in patients with severe von Willebrand Disease under 6 years of age

Introduction Von Willebrand disease (VWD) is a common congenital haemorrhagic disorder affecting around 1 in every 100 individuals. Prophylactic von Willebrand factor (VWF) replacement therapy in patients with severe VWD, including paediatric patients, is associated with reduced mucosal and joint bleeding rates, decreased median annual bleeding rate (ABR), a reduced incidence of major bleeding events (BEs) and good tolerability. WIL-33 will investigate the efficacy, pharmacokinetics (PK) and safety of a plasma-derived, stable, highly purified, double virus inactivated VWF/factor VIII (FVIII) concentrate (Octapharma) in paediatric patients with severe VWD.

Method WIL-33 is anopen-label, prospective, non-controlled, international, multicentre Phase 3 study of VWF/FVIII concentrate efficacy as prophylactic treatment of patients aged <6 years with severe VWD (defined as screening von Willebrand factor ristocetin cofactor activity [VWF:RCo] <20%). WIL-33 plans to enrol 12 patients regardless of prior treatment, of which eight should be evaluable for the primary endpoint; at least four should have hereditary type 3 VWD. Remaining patients can be diagnosed with severe type 2 (except 2N) or severe type 1 VWD ([Fig. 1]).

Fig. 1 WIL-33 Study Outline.

The primary endpoint is ABR under prophylaxis over the 12-month prophylactic treatment period. Secondary objectives include determination of the VWF/FVIII concentrate PK for VWF activity (VWF:RCo) and FVIII:C (one-stage assay) and incremental in vivo recovery (IVR); data on VWF/FVIII concentrate consumption for prophylaxis, on-demand treatment and surgeries; immunogenic potential; and safety/tolerability. WIL-33 will also examine VWF multimer composition in paediatric patients with type 3 VWD with ≥14.5 kg bodyweight (BW). PK will be determined following a single 80 IU/kg/BW dose. Blood samples will be taken pre-dose (baseline), and 15 minutes, 3, 9, 24, 48 and 72 hours after VWF/FVIII concentrate administration. For prophylactic treatment, VWF/FVIII concentrate will be administered 2–3 times per week at 30–50 IU/kg/BW over 12 months. Patients will record BEs in a diary, which will be used to calculate ABR. Treatment for BEs or surgeries will be performed according to pre-established dosing guidelines.

Results To date, 5 patients have been recruited at 5 study sites in 4 countries. Clinical end is expected early 2024, with results anticipated by end of 2024.

Conclusion Prophylactic treatment in other congenital bleeding disorders is widely accepted as standard of care to prevent bleeding in patients, but to date this treatment in patients with VWD is not well characterised. WIL-33 will provide data on the efficacy of prophylactic treatment in paediatric patients with severe VWD below 6 years of age.