Efficacy and Safety of Prophylaxis with a Plasma-Derived Von Willebrand Factor/ Factor VIII Concentrate in Previously Treated Patients with Von Willebrand Disease

Introduction: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in von Willebrand disease (VWD) patients with a history of severe and frequent bleeds, regardless of age or VWD type. Data on the efficacy and safety of prophylaxis with a human plasma-derived VWF/factor VIII concentrate (pdVWF/FVIII; wilate®) that contains the two factors in a physiological 1:1 activity ratio have been collected previously from 19 VWD patients in four prospective, multicenter phase 2 and 3 trials. In these patients, bleeding rates were significantly reduced compared with previous treatment.

Aims: To investigate the efficacy and safety of regular prophylaxis with a pdVWF/FVIII concentratein previously treated patients with VWD.

Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled patients of any gender with VWD type 1 (VWF:RCo <30 IU/dL), type 2 (except 2N) or type 3, who were at least 6 years old. Prior to entering the WIL-31 study, all patients had received on-demand treatment with pdVWF/FVIII during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 bleeding episodes (BEs), excluding menstrual bleeds, with at least 2 of these BEs treated with a VWF-containing product, were eligible to enter WIL-31. Patients in WIL-31 received regular pdVWF/FVIIIprophylaxis, 2-3 times per week at a dose of 20-40 IU/kg, for 12 months. The primary endpoint of the study was to demonstrate that prophylaxis with pdVWF/FVIII lowered the mean total annualized bleeding rate (ABR) compared with that during 6 months of on-demand treatment by more than 50%. Secondary outcomes included spontaneous ABR and treatment-emergent adverse events.

Results: Thirty-three patients were included in the modified full analysis set, with a median (range) age of 18 years (7-61). Fourteen (42.4%) patients were female, 9 (27.3%) patients were <12 years old. Six (18.2%) patients had severe Type 1 VWD, 7 (21.2%) had type 2, and 20 (60.6%) patients had type 3 VWD.

Mean (median, range) total ABR in the on-demand run-in period and during pdVWF/FVIII prophylaxis was 33.4 (24.5, 11-115) and 5.2 (1.9, 0-35.8), respectively (Figure 1), meeting the primary endpoint of a ≥50% reduction in mean ABR. Mean (median, range) spontaneous ABR in the on-demand run-in period and during pdVWF/FVIII prophylaxis was 24.4 (18.7, 5-93) and 3.2 (1.0, 0-24.6), respectively. Of the 33 patients, 10 (30.3%) and 15 (45.5%) patients had zero total or spontaneous BEs during the study period, respectively. A total of 173 BEs occurred, the majority of which (146 BEs; 84.4%) were classified as minor. Of the 173 BEs, 121 (69.9%) were treated with pdVWF/FVIII. The overall efficacy of treatment was assessed as "excellent” or "good” for 120 (99.2%) BEs and "moderate” for 1 (0.8%) BE.

Five serious adverse events were reported, none of which were assessed as related to the study treatment. Two patients had adverse events assessed as probably or possibly related to the study treatment by the investigator, and both patients discontinued from the study. One patient developed mild chest tightness (3 events), the other had hypersensitivity reactions of moderate severity (2 events). No thrombotic events occurred.

Conclusions: Prophylaxis with a pdVWF/FVIII containing VWF and FVIII in a 1:1 activity ratio was effective in pediatric and adult patients with VWD of all types.

Sidonio, Jr.:Biomarin: Honoraria; UniQure: Honoraria; Guardian Therapeutics: Honoraria; Bayer: Honoraria; Novo Nordisk: Honoraria; Octapharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Spark: Honoraria; Pfizer: Honoraria. Boban:Octapharma: Honoraria, Speakers Bureau; CSL Behring: Honoraria, Speakers Bureau. Inati:Octapharma: Research Funding; Roche: Consultancy; Novo Nordisk: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Research Funding; Agios Pharmaceuticals: Research Funding; Imara: Research Funding; AstraZeneca: Research Funding; Vifor Pharma: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Kiss:Octapharma: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria. Lissitchkov:Sobi: Consultancy, Other: lecturer, Research Funding; Novo Nordisk: Other: lecturer. Novik:Octapharma: Research Funding. Taher:Ionis Pharmaceuticals: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Vifor Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Imara: Consultancy, Research Funding. Werner:Octapharma USA: Current Employment. Knaub:Octapharma AG: Current Employment. Khayat:Octapharma: Other: Principal Investigator, Speakers Bureau; CSL Behring: Other: Principal Investigator, Speakers Bureau.

This study is investigating the use of a VWF/FVIII concentrate for the prevention of bleeds in patients with von Willebrand disease of any type