General Information

Vonvendi is a recombinant von Willebrand factor (VWF).

Vonvendi is specifically indicated for:

on-demand treatment and control of bleeding episodes in adults (age 18 and older) diagnosed with von Willebrand disease.

routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 von Willebrand disease receiving on-demand therapy

Vonvendi is supplied as a powder for intravenous use after reconstitution only.

On-Demand Treatment and Control of Bleeding Episodes:

For each bleeding episode, administer the first dose of Vonvendi with an approved recombinant (non-von Willebrand factor containing) factor VIII if factor VIII baseline levels are below 40% or are unknown. The initial dose is 40 to 80 international units (IU) per kg body weight. Adjust the dosage based on the extent and location of bleeding. Please see the drug label for specific dosing recommendations.

Routine Prophylaxis:

Initial dosage of Vonvendi is 40 to 60 IU/kg body weight to be administered twice weekly. The dose may be adjusted up to 60 IU/kg twice weekly based on frequency of bleeding episodes.

Mechanism of Action

Vonvendi acts 1) to promote hemostasis by mediating platelet adhesion to damaged vascular sub-endothelial matrix (e.g. collagen) and platelet aggregation, and 2) as a carrier protein for factor VIII, protecting it from rapid proteolysis. The adhesive activity of VWF depends on the size of its multimers, with large multimers being the most effective in supporting interactions with collagen and platelet receptors. The binding capacity and affinity of Vonvendi to factor VIII in plasma is comparable to that of endogenous VWF, allowing for Vonvendi to reduce factor VIII clearance.

Clinical Trial Results

On-Demand Treatment and Control of Bleeding Episodes

The hemostatic efficacy of Vonvendi was assessed in a multicenter, open label trial investigating different dosing strategies with and without recombinant factor VIII for on-demand treatment and control of bleeding episodes in adults (age 18 years and older) diagnosed with von Willebrand disease. In this trial, all subjects requiring recombinant factor VIII received Advate [Antihemophilic factor (Recombinant)]. Bleeding episodes were treated initially with an infusion of Vonvendi and Advate at a ratio of 1.3:1 respectively, and subsequently with Vonvendi with or without Advate, based on FVIII:C levels. The aim of the initial dose of Vonvendi with Advate was to achieve target plasma levels of greater than 0.6 IU/mL (60%) VWF:RCo and greater than 0.4 IU/mL (40%) of FVIII:C. A total of 193 bleeding episodes were reported in 22/37 subjects exposed to Vonvendi. The primary efficacy endpoint was the number of subjects with treatment success for control of bleeding episodes. Treatment success was defined as a mean efficacy rating score of less than 2.5 for all bleeding episodes in a subject treated with Vonvendi (with or without Advate) during the trial period. The efficacy rating was assessed using a pre-specified 4 point rating scale comparing the prospectively estimated number of infusions needed to treat the bleeding episodes as assessed by the investigator to the actual number of infusions administered. The rate of subjects (n=18) with treatment success was 100% (95% CI 81.5 to 100). Sensitivity analyses of treatment success for bleeding episodes including GI bleeds and those bleeding episodes for which the investigator had to make retrospective assessment of the number of infusions required (n=22: 17 with type 3 VWD, 4 with type 2A VWD and 1 with type 2N VWD) confirmed the primary analysis, with a 100% treatment success rate for each scenario. All bleeding episodes treated with Vonvendi and Advate or Vonvendi alone were controlled with an efficacy rating of excellent (96.9%) or good (3.1%). Control of bleeding episodes was consistent across all degrees of severity.

Routine Prophylaxis

The approval is based on data from a prospective, open-label, international multicenter study to evaluate efficacy and safety of prophylactic treatment in reducing the frequency of bleeding episodes in 10 adult patients diagnosed with severe Type 3 VWD who were previously treated on-demand. Based on descriptive statistics, the median annualized bleeding rates (ABR) for all bleeds (treated and untreated spontaneous and traumatic bleeding events) was reduced from historical median ABR 5.0 to an on-study median ABR of 2.3, which is a 54.7% reduction.