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).
Bibliographical noteFunding Information:
The authors thank all patients and their caregivers who took part in the phase 3 rVWF prophylaxis study, as well as the study investigators and sites (NCT02973087, https://clinicaltrials.gov/ct2/show/NCT02973087 ). Under the direction of the authors, medical writing support was provided by Joanne Vaughan, an employee of Excel Medical Affairs (Fairfield, CT), and was funded by Takeda Development Center Americas, Inc (Lexington, MA).
This study was funded by Baxalta US Inc, a Takeda company (Lexington, MA), and Baxalta Innovations GmbH, a Takeda company (Vienna, Austria).
Conflict-of-interest disclosure: F.W.G.L. has received grants/research funding from CSL Behring, Sobi, Takeda, and uniQure; consultancy fees from BioMarin, CSL Behring, Takeda, and uniQure (all fees to university); and was a Data Safety Monitoring Board Member for Roche. F.P. has participated in advisory boards of BioMarin, Grifols, Roche, Sanofi, Sobi, Spark, and Takeda. M.E. has received consulting fees from BioMarin, CSL Behring, Genentech/Roche, Kedrion, NHF, Novo Nordisk, Pfizer, Sanofi, and Takeda; and received research funding from CSL Behring, Genentech, Novo Nordisk, Sanofi, Takeda, and uniQure. A.T. has received honoraria from Bayer, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, and Takeda. G.C. has served on advisory boards or been a consultant for Bayer, BioMarin, CSL Behring, Grifols, Kedrion, LFB, Novo Nordisk, Roche, Sanofi, Sobi, Takeda, and uniQure. M.W. has served on advisory boards or been a consultant for Bayer, BioMarin, Bioverativ, Catalyst Biosciences, CSL Behring, Genentech, Hema Biologics, Novo Nordisk, Takeda, and uniQure. T.W. has received research support from Sanofi, Takeda, and Genentech. J.B., Y.W., J.Z., B.M., and G.Ö. are employees of Takeda Development Center Americas Inc. and Takeda stockholders.
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