Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results

Abstract

International guidelines conditionally recommend long-term prophylaxis in patients with von Willebrand disease (VWD) and severe/frequent bleeding. As recombinant von Willebrand factor (rVWF, vonicog alfa) may reduce the frequency of treated spontaneous bleeding events (BEs), we investigated the efficacy and safety of rVWF prophylaxis in adults with severe VWD. Patients with BEs requiring VWF therapy in the past year (on-demand VWF therapy [Prior On-Demand group] or plasma-derived VWF prophylaxis [pdVWF; Switch group]) were enrolled in a prospective, open-label, nonrandomized, phase 3 study. Planned duration of rVWF prophylaxis was 12 months; starting rVWF dose was 50±10 VWF:RCo IU/kg twice weekly (Prior On-Demand group) or based on prior pdVWF weekly dose/dosing frequency (Switch group). The primary endpoint was annualized bleeding rate of treated spontaneous BEs (sABR) during rVWF prophylaxis. Over the 12-month study period, treated sABR decreased by 91.5% on-study versus historical sABR in 13 patients in Prior On-Demand group, and by 45.0% in 10 patients in Switch group (model-based analysis ratio [95% CI]: 0.085 [0.021-0.346] and 0.550 [0.086-3.523], respectively). No treated spontaneous BEs were recorded in 84.6% (11/13) and 70.0% (7/10) of patients, respectively. The safety profile of rVWF was consistent with the previously established profile, with no new adverse drug reactions identified. Findings suggest that rVWF prophylaxis can reduce treated spontaneous BEs in patients previously receiving on-demand VWF therapy and maintains at least the same level of hemostatic control in patients who switch from prophylaxis with pdVWF to rVWF, with a favorable safety profile. Trial registration: www.clinicaltrials.gov (#NCT02973087) and www.clinicaltrialsregister.eu (#EudraCT 2016-001478-14).

Prophylaxis with recombinant von Willebrand factor in patients with type 3 von Willebrand disease: Results of a post hoc analysis from a phase 3 trial

“…In the Switch group, the model‐based mean ABR for treated spontaneous BEs was reduced by 47% (ratio, 0.53; 95% CI, 0.08–3.62), from 0.95 (95% CI, 0.08–10.69) to 0.50 (95% CI, 0.04–6.02). Findings from the model‐based analysis were supported by descriptive statistics (Table 2) and the results were in line with outcomes of the overall study population reported previously 18 …”

“…The safety profile of rVWF prophylaxis in patients with type 3 VWD was consistent with the previously reported safety profile for all patients in this study, 18 with only one nonserious AE considered possibly related to treatment, and no cases of hypersensitivity, severe allergic reactions, anaphylactic reactions, or development of inhibitors to VWF or FVIII. The efficacy and PK/PD results in this post hoc analysis were also consistent with those seen in the overall population with severe VWD from the phase 3 rVWF prophylaxis study 18 . This was not unexpected because 18/23 patients in the study had type 3 VWD, and all on‐study treated BEs were reported in patients with type 3 VWD.…”

“…Further details of the entry criteria have been published previously 18 . This post hoc analysis focused on patients with type 3 VWD from the overall study population of patients with severe VWD (defined as a baseline VWF:RCo of <20 IU/dL 21 ).…”

“…PK/PD parameters (including trough FVIII levels and VWF:RCo incremental recovery) after a single rVWF prophylactic dose in the Prior OD group, and after multiple rVWF prophylactic doses in both groups, were derived using noncompartmental methods, as previously described 18 …”

“…In a recent phase 3 study, prophylaxis with rVWF (vonicog alfa, VONVENDI® [US, Japan]/VEYVONDI™ [Europe, Australia], Takeda Pharmaceuticals USA, Lexington, Massachusetts) was shown to reduce treated spontaneous bleeding rates in patients with severe VWD who were previously receiving OD VWF therapy 18 . In the same study, patients switching to rVWF prophylaxis from prophylactic pdVWF concentrates maintained at least the same level of hemostatic control.…”