Introduction Surgical procedures in von Willebrand disease (VWD) patients may require prophylactic treatment with exogenous von Willebrand factor (VWF) and coagulation factor VIII (FVIII) to prevent excessive bleeding. Wilate® is a plasma‐derived, double virus‐inactivated, highly purified, freeze‐dried VWF/FVIII concentrate, containing both factors in a physiological activity ratio of 1:1. Aim To investigate the efficacy and safety of wilate® in maintaining haemostasis in VWD patients undergoing surgical procedures. Methods This prospective, open‐label multinational clinical study documents 28 individuals who underwent 30 surgical procedures managed with wilate®. Twenty‐one patients had VWD Type 3, and 21 surgeries were major. Efficacy was assessed intra‐ and postoperatively by the surgeon and investigator, respectively, and adjudicated by an Independent Data Monitoring Committee, using an objective scale based on blood loss, transfusion requirements and postoperative bleeding and oozing. Treatment success (primary endpoint) was determined using a composite assessment algorithm and was formally assessed. Results Surgical prophylaxis with wilate® was successful in 29 of 30 procedures. The overall rate of success was 96.7% (98.75% CI: 0.784, 1.000). All 21 surgeries in patients with VWD Type 3 were managed successfully. There was no accumulation of VWF or FVIII after multiple dosing, and no thromboembolic events or inhibitors to VWF or FVIII were observed. Conclusions Wilate® demonstrated effective prevention and treatment of bleeding in inherited VWD patients undergoing surgery, with no clinically significant safety concerns.

Background The efficacy and safety of wilate (human von Willebrand factor/coagulation factor VIII) in patients with von Willebrand disease (VWD) has been demonstrated in clinical trials. Here, we present real-world data on the use of wilate for the routine care of patients with VWD. Objectives The objectives of this observational, prospective, phase 4 study were to evaluate the safety, tolerability, and effectiveness of wilate in on-demand treatment of bleeding episodes (BEs), long-term prophylaxis, and surgical prophylaxis among patients with any type of VWD. Methods Patients were enrolled at 31 study centers in 11 countries and followed for up to 2 years. Safety endpoints included adverse drug reactions (ADRs) and drug tolerability. Effectiveness was assessed using annualized bleeding rates (ABRs) during prophylaxis and predefined criteria for the treatment of BEs and surgical prophylaxis. Results A total of 111 patients (76 [68%] female) including 41 (37%) children were treated with wilate. Twenty-five patients received prophylaxis, 29 on-demand treatment, and 62 surgical prophylaxis. Tolerability was rated by patients as “excellent” for 96.2% of 6,497 infusions. No unexpected ADRs or thrombotic events were reported. Median ABR during prophylaxis was 1.9. Effectiveness was assessed as “excellent” or “good” by patients and investigators for 100% of BEs treated on-demand, 98% (patient rating) and 99% (investigator rating) of breakthrough BEs, and 99% of surgical procedures (investigator rating). Conclusion wilate was safe, well tolerated, and effective for the prevention and treatment of bleeding in pediatric and adult VWD patients in a real-world setting.

This novel plasma derived, double viral attenuated VWF/FVIII concentrate with a ratio of 1:1 between both coagulant proteins (Wilate) was utilized in a pivotal clinical study conducted to further investigate its clinical efficacy and safety in VWD patients requiring surgery. This was a prospective, open-label, uncontrolled, multi-center, phase III clinical study. The primary objective was to evaluate the overall hemostatic efficacy of Wilate in preventing excessive intra- and post-operative bleeding in pediatric and adult patients with VWD. Forty–one patients, 20 major and 10 with Type 3 VWD, were planned to be enrolled to document 41 surgical procedures. During the planned interim analysis after 30 procedures, a pre-specified success rate for study termination was reached and the study was stopped early as determined by an independent data and safety monitoring board (IDMC). In vivo recovery (IVR) was investigated in all patients at the beginning of the study for pre- and post-surgical dosing. Hemostaticefficacy was assessed for each case intra- and post-operatively by the surgeons and hematologists independently, utilizing objective 4-point ordinal efficacy scales. This assessment was additionally adjudicated by the IDMC. Safety and immunogenicity were monitored throughout the study. Twenty-eight individual patients, who underwent 30 surgeries, were enrolled from 14 sites in 8 countries in Europe, Asia, and the USA. Of the 30 procedures (2 patients had more than 1 procedure), 7 had VWD Type 1 unresponsive to DDAVP (23.3%); 2 had VWD Type 2 (6.7%, one with Type 2A and one with Type 2B), and 21 had severe VWD Type 3 (70.0%). Age at baseline ranged from 12 to 74 years (median 36 years), with 3 adolescents (younger than 18 years of age) included in the study. Most surgeries were either orthopedic (10 surgeries) or dental (7 surgeries). Five surgeries were obstetric/gynecological; 4 were gastrointestinal; 3 of the ear, nose or throat; and one was ophthalmologic. In total 21 major surgeries and 9 minor surgeries were performed. Of the 21 severe VWD Type 3 patients, 17 underwent major surgery and 4 underwent minor surgery. The mean loading dose of VWF/FVIII concentrate (Wilate) per infusion (measured in VWF:RCo units) was 55.5 IU/kg for major surgeries and 37.5 IU/kg for minor surgeries. The mean maintenance dose was 30 IU/kg for major and 20.6 IU/kg for minor surgeries. Mean FVIII:C and VWF:RCo peak plasma activity levels of each patient during the maintenance infusions (infusion 1 post surgery to infusion 7), ranged from 119 IU/dL – 138 IU/dL and 66 IU/dL - 92 IU/dL, respectively, and were stable over time with no accumulation of FVIII:C (Figure 1). In the 30 procedures patients received a mean total dose (VWF:RCo) of Wilate of 434.2 ± 271.2 IU/kg (29,086 ± 17,932 IU). The overall treatment with Wilate was successful in 29 out of 30 surgeries (rate 0.967; 98.75 CI: 0.784, 1.000). Nine of 9 minor surgeries (success rate 1.000; 98.75% CI: 0.569, 1.000), and 20 of 21 major surgeries (success rate 0.952; 98.75% CI: 0.704, 1.000), were successful, as were all 21 surgeries in patients with Type 3 VWD (success rate 1.000; 98.75% CI: 0.785, 1.000). None of the patients experienced excessive intra- or post-operatively bleeding that was uncontrolled or required an alternate VWF/FVIII concentrate. No incidences of thrombotic events were reported despite 1/3 of the surgeries being orthopedic and high risk for such in non-coagulopathic populations. No FVIII or VWF neutralizing inhibitors or study drug related serious adverse events (SAEs) were observed. Figure 1 Mean Course of Peak Values by Maintenance Dose for VWF:RCo, VWF:Ag and FVIII:C Concentrations (IU/dL) (Population, N=30) Figure 1. Mean Course of Peak Values by Maintenance Dose for VWF:RCo, VWF:Ag and FVIII:C Concentrations (IU/dL) (Population, N=30) Numbers above the graph indicate the number of observations at each dosing point Conclusion: Results of this study showed that more than 96% of the study’s surgeries treated prophylactically with Wilate were rated as having excellent or good hemostatic efficacy, as adjudicated by the IDMC. The study was terminated early because of clear and robust demonstration of efficacy, as pre-specified in the protocol. There was no accumulation of FVIII:C activity after repeat dosing. No cases of VWF or FVIII:C inhibitors, thrombotic events, or related SAEs were observed. Disclosures Srivastava: Octapharma: Consultancy, Other. Off Label Use: Wilate is a Human VWF/FVIII product licensed in the US for treatment of acute bleeding in VWD patients but not licensed for prophylactic treatment in surgical procedures. Werner:Octapharma: Employment. Schwartz:Octapharma: Employment. Knaub:Octapharma: Employment.

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