Increased Prophylactic Dosing Frequency Effectively Improve Bleeding Rates in Von Willebrand Disease Patients Who Require Higher Hemostatic Coverage - a Sub-Analysis of Data from the Wil-31 Study

Introduction: Prophylaxis with a von Willebrand factor (VWF) is the recommended treatment for von Willebrand disease (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 prophylaxis with a plasma-derived VWF/factor VIII (FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (pdVWF/FVIII; wilate®) was highly efficacious in adults and children, males and females, with VWD of all types.

Aims: To investigate bleeding outcomes in VWD patients in whom the dosing frequency was increased from 2 to 3 infusions weekly during the WIL-31 study.

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 over 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. Patients in WIL-31 received prophylaxis with 20-40 IU/kg pdVWF/FVIII 2 to 3× weekly for 12 months. Each patient's initial dose was determined based on clinical condition, and dosage was to be increased by ~5 IU/kg in the case of >2 spontaneous bleed events or 1 major bleed event within a 30-day period. If a patient still experienced >2 spontaneous bleed events following a dose increase, then the dosing regimen was to be changed from 2× to 3× weekly.

Results: Of the 33 patients in WIL-31, 91% (30 patients) initiated prophylaxis on a 2× weekly dosing regimen and 9% (3 patients) on 3× weekly. Of these 30 patients, 7 changed from 2× to 3× weekly dosing during the study. The 7 patients included 4 with VWD type 3, 2 with type 1, and 1 with type 2A. Four of the 7 (57%) patients had circumstances that led to the regimen change: allergic rhinitis resulting in nosebleeds; gingivitis; first menstrual period which required hospitalisation; and prior left and right ankle arthropathy. During the prior on-demand 6-month period, the 7 patients experienced 215 bleeds (72% spontaneous) with a median spontaneous annualized bleeding rate (SABR) of 32.2 (range: 16.3-77.0). During 2× weekly prophylaxis there were 54 breakthrough bleeds (72% spontaneous), with a median SABR of 5.8 (0.0-53.4), corresponding to a reduction of 82% compared with the on-demand period. During 3× weekly dosing, the patients experienced 25 total breakthrough bleeds (68% spontaneous) with a median SABR of 2.4 (0.0-14.5), a reduction of a further 59%. Nosebleeds represented 64% of all spontaneous bleeds. The median nosebleed SABR in these 7 patients was reduced by 71% from 16.4 (0.0-73.1) during on-demand treatment to 4.8 (0.0-49.0) during 2× weekly prophylaxis and by a further 54% to 2.2 (0.0-5.7) on 3× weekly prophylaxis. Mean baseline levels of FVIII and VWF in patients who changed dosing frequency compared with those who did not were slightly lower (not statistically significant).

Conclusion: Prophylaxis with pdVWF/FVIII is effective for decreasing bleeding rates in VWD patients. Twice weekly dosing was sufficient to control bleeding in the majority (70%) of patients. Of those who required an increase in the dosing frequency, most had underlying circumstances that precipitated the change. Patients have diverse needs that must be considered when deciding on the dosing regimen for an individual.

Sidonio:Biomarin: Consultancy; Vega: Consultancy; Genentech: Consultancy, Research Funding; Sobi/Sanofi: Consultancy; Bayer: Consultancy; Guardian Therapeutics: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy, Research Funding; Uniqure: Honoraria; CSL Behring: Honoraria; Hema Biologics: Consultancy; Takeda: Consultancy, Research Funding; Novo Nordisk: Consultancy; LFB/Hema Biologics: Research Funding; ISTH: Membership on an entity's Board of Directors or advisory committees; HFA: Membership on an entity's Board of Directors or advisory committees; NHF: Membership on an entity's Board of Directors or advisory committees; ATHN: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Other: expert testimony; HEMAB: Consultancy.