Regulatory Decision Summary for Vonvendi

Vonvendi (von Willebrand factor [Recombinant]) is a new active substance for the treatment and control of bleeding episodes and for the perioperative management of bleeding in adult patients with von Willebrand disease. Dosage recommendations also include the concomitant administration of a recombinant Factor VIII product (e.g. Advate), as endogenous levels are dependent on levels of functional von Willebrand factor (VWF). In contrast to current available treatment with plasma-derived concentrates having fixed ratio in VWF and FVIII which may lead to an overdose in FVIII in some VWD patients, the administration of Vonvendi with or without Advate allows individualized dosing based on patients pharmacokinetics for rVWF:RCo and rFVIII:C activity levels, which are to be monitored at suitable intervals.

The safety, efficacy and pharmacokinetics of Vonvendi were established in 80 adult patients with severe VWD in a Phase I dose escalation study (070701) and in the two Phase III studies (071001 and 071101). Most patients were White (89%) and the remaining were Asian (11%). The main exclusion criteria were history of hypersensitivity, neutralizing antibodies (inhibitors) against VWF or FVIII and thromboembolic events.

The efficacy of Vonvendi was shown to be comparable to expected number of infusions required using a plasma-derived concentrate for the treatment of bleeding episodes, or in achieving intra- and postoperative hemostasis as expected for minor or major surgical procedures performed in hemostatically normal subjects. The mean half-life of Vonvendi across three clinical studies was 19.7 h, which allows repeated infusions at a frequency of 8 to 24 h (comparatively 8 to 12 h for plasma-derived products).

Adverse drug reactions reported in the clinical trials were assessed by the investigator or sponsor as related to Vonvendi. A temporal association with an infusion (i.e. during or within 24 hours after infusion) was observed for 28% (53/187) of the overall number of adverse events (AEs). A total of 3 serious AEs (increased heart rate with chest discomfort, and deep venous thrombosis) reported in 2 patients in the safety population were of moderate severity and resolved without sequelae. All non-serious AEs were of mild or moderate severity, although several were related to allergic reactions (e.g., generalized pruritus, nausea and chest discomfort) or associated with too rapid rates of infusions (i.e. hypersensitivity reactions). Neutralizing antibodies against either rVWF or rFVIII were not observed, nor for binding antibodies against VWF, Furin, Chinese hamster ovary (CHO) protein and mouse immunoglobulin G (IgG). One patients who received Vonvendi during a major total knee replacement surgery developed treatment-emergent non-neutralizing binding antibodies against VWF following a transfusion of packed red blood cells.

The main risks identified with the use of Vonvendi correspond to the occurrence of thrombotic events in patients with at risk factors for thrombosis and with major surgical procedures (e.g., orthopedic or cardiac surgery), as well as hypersensitivity reactions which may occur with rVWF and rFVIII. The risk in thrombotic events is particularly associated with low endogenous levels of ADAMTS13 levels, a plasma proteinase involved in the proteolysis of ultra-large VWF multimers into smaller multimers that are less procoagulant. One patient with ADAMTS13 at 37% of the normal plasma levels and who undergone major surgery (total hip replacement) developed proximal deep venous thrombosis in the perioperative period while receiving Vonvendi. Risk mitigation was addressed in the proposed Product Monograph.

The benefit in the use of Vonvendi is considered favorable over the risks as described in the Product Monograph, along with commitments in providing educational and training material for the prescriber and patient, and to file for a pediatric indication when data become available.