Final Results from a Non-Interventional Safety and Efficacy Study of a VWF/FVIII Concentrate (wilate®) in Patients with Von Willebrand Disease

Abstract Introduction: Post-marketing studies provide important insight into the consistency of data from clinical studies and routine clinical use. This non-interventional, prospective, multicentre study (WIL-20) collected real-life data on the use of a human VWF/FVIII concentrate with the native VWF/FVIII complex in a physiological 1:1 ratio (wilate®; pdVWF/FVIII) in routine clinical practice. Here, we report the final results from this study. Methods: The primary objective was to document the safety and tolerability of pdVWF/FVIII in routine clinical practice, with a planned observation period per patient of 2 years. Secondary objectives were to document the efficacy in on-demand treatment of acute bleeding, long-term prophylaxis, and surgical prophylaxis. Male and female patients of any age and with any type of VWD who were prescribed pdVWF/FVIII were eligible for the study. pdVWF/FVIII was administered at the investigator's discretion. Data recorded included patient demographics, laboratory parameters, treatment details, and occurrence of adverse drug reactions (ADRs), including immunogenicity and thrombogenicity. Tolerability was assessed using a verbal rating scale; efficacy of on-demand treatment and surgical prophylaxis using a haemostatic scale; and prophylactic efficacy based on the frequency of spontaneous breakthrough bleeds. Results: The study enrolled 120 patients from 11 countries. Within the safety population (111 patients who received at least one dose of pdVWF/FVIII), 45% of patients had type 1 VWD, 29% type 2 and 18% type 3; disease type was unavailable for 8 patients, and 1 patient was diagnosed with haemophilia A during the study. Of the 111 patients, 33% were previously untreated with a FVIII/VWF product. A total of 7024 infusions were administered to the safety population over a median observation time of 2 years; median dose was 320.5 IU/kg. A total of 26 ADRs were reported in 8 patients; 4 were mild, 3 moderate and 1 severe. Three patients discontinued treatment and 1 stopped treatment temporarily due to adverse events. Using an experimental assay, 3 cases of VWF inhibitors were identified, with no impact on clinical outcome. No thromboembolic events were reported. Tolerability was rated for 6497 infusions, with 96.2% rated 'excellent', 3.7% 'satisfactory', and 0.1% 'unsatisfactory'. Of the 29 patients treated on-demand, 150 bleeding events (BEs), excluding menstrual bleeds, were reported in 25 patients; 18% of BEs were mild, 71.3% were moderate, and 10% were severe. 94% of treated bleeds (130/138) resolved with 1 or 2 infusions, with a median dose per BE of 33 IU/kg. The efficacy of treatment was rated as 'excellent' or 'good' for 100% of BEs. Of the 25 patients treated with pdVWF/FVIII for prophylaxis, 18 patients had a total of 233 breakthrough BEs; 37% mild, 44% moderate, and 9% severe (severity information was unavailable for 11% of bleeds). Of the breakthrough BEs that required treatment, 85% (149/175) were treated with 1 or 2 infusions of pdVWF/FVIII, with a median dose per BE of 55.4 IU/kg. Efficacy of pdVWF/FVIII was rated as 'excellent' or 'good' by investigators for 99% of 139 evaluable breakthrough BEs. For patients on prophylaxis (n = 25), the median annualised bleeding rate for spontaneous BEs was 1.5 (range 0.0-19.7). The efficacy of prophylaxis for prevention of spontaneous breakthrough bleeds was rated as 'excellent' or 'good' in 96% (24/25) of these patients. A total of 99 surgical procedures were performed in 62 patients; 56% with type 1 VWD, 29% type 2 and 13% type 3 (2% were type unknown). Of the procedures, 46 were major and 53 minor. All but one of the surgeries were managed with pdVWF/FVIII prophylaxis, and the efficacy was rated as 'excellent' or 'good' in 99% (96/97) of surgeries with assessments available. Conclusions: The final results of this non-interventional study indicate that pdVWF/FVIII is well tolerated and effective for on-demand treatment, prophylaxis, and surgical prophylaxis in patients with all types of VWD treated as part of routine clinical practice. The data are consistent with those from previous clinical studies and provide real-life evidence from around the world on the use of pdVWF/FVIIIfor management of VWD in all clinical settings. Disclosures Werner: Octapharma USA Inc.: Employment. Hashimoto:Octapharma USA Inc.: Employment. Knaub:Octapharma AG: Employment. Rodgers:Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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