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 and 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. The planned duration of rVWF prophylaxis was 12 months; starting rVWF dose was 50 ± 10 VWF: ristocetin cofactor (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 (ABR) of treated spontaneous BEs (sABR) during rVWF prophylaxis. Over the 12-month study period, treated sABR decreased by 91.5% on-study vs historical sABR in 13 patients in the prior on-demand group, and by 45.0% in 10 patients in the switch group (model-based analysis ratio, 0.085; 95% confidence interval [CI], 0.021-0.346 and 0.550; 95% CI, 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. This trial was registered at www.clinicaltrials.gov (#NCT02973087) and www.clinicaltrialsregister.eu (#EudraCT 2016-001478-14).

© 2022 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Patient disposition. *Primary reason: platelet count <100 000/mL at screening (n = 1), scheduled for surgical intervention (n = 1), history or presence of a VWF inhibitor at screening (n = 1), patient not willing or able to comply with protocol requirements (n = 2), VWD inclusion criteria not met (n = 1). †Patients who were treated on-demand with any VWF during the 12-month period before enrolling in this study. ‡Patients who were treated prophylactically with a pdVWF for ≥12 months before enrolling in this study. §Nonserious headache (moderate intensity), which was considered by the investigator to be possibly related to rVWF and began during an rVWF infusion. ‖One patient in each group withdrew consent for reasons unrelated to efficacy/bleeding, and 1 patient in the prior on-demand group was lost to follow-up. ¶Scheduled for extended treatment with hydrocortisone >10 mg per day (not permitted during the study). **Required treatment with high corticosteroid doses for rheumatoid arthritis (not permitted during the study). ††All patients who were enrolled and received any amount of rVWF. ‡‡All patients who received rVWF prophylaxis. §§All patients who received ≥1 rVWF infusion and provided ≥1 quantifiable PK/PD postdose measurement. FAS, full analysis set; PKFAS, pharmacokinetic full analysis set; SAS, safety analysis set.

Figure 2.

Treated spontaneous ABRs. sABRs for (A) the prior on-demand group and (B) the switch group (FAS). Figures show the proportion of patients in each bleeding category, historically and on-study, as well as mean (SD) and median (range) change from historical to on-study sABR (on-study through month 12). Historically (ie, within the past 12 months), none of the patients in the prior on-demand group had a 0 or >0 to 2 sABR.