Abstract Number: LPB0128
Meeting: ISTH 2021 Congress
Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » VWF and von Willebrand Factor Disorders - Clinical Conditions
Background: Patients with severe von Willebrand disease (VWD) may benefit from prophylaxis with recombinant von Willebrand factor (rVWF, vonicog alfa; Baxalta US Inc., a Takeda company, Lexington, MA, USA) to reduce frequency of spontaneous bleeding events (BEs) requiring VWF treatment.
Aims: Investigate efficacy and safety of rVWF prophylaxis.
Methods: Prospective, open-label, non-randomized, multicenter, phase 3 study (NCT02973087, EudraCT 2016-001478-14). Eligible patients were aged ≥18 years, had severe VWD (VWF ristocetin cofactor activity <20 IU/dL) requiring VWF therapy to manage BEs in past year (on-demand [prior OD arm] or plasma-derived VWF [pdVWF] prophylaxis [switch arm]), and no VWF or factor VIII inhibitors or history of thromboembolic events. Planned prophylactic rVWF treatment duration was ≥1 year: prior OD patients started with 50±10 IU/kg twice weekly; starting dose for switch patients was based on prior pdVWF weekly VWF dose and dosing frequency (1-3 times weekly; maximum 80 IU/kg/infusion). Primary endpoint was annualized bleeding rates (ABRs) for treated, spontaneous BEs during rVWF prophylaxis. Informed consent and ethics approval were obtained.
Results: 23 enrolled patients received rVWF prophylaxis (prior OD arm: n=13; switch arm: n=10); 18/23 (78.3%) patients had type 3 VWD. Over the 12-month study period, 11/13 (84.6%) prior OD patients and 7/10 (70.0%) switch patients had a treated, spontaneous ABR (sABR) of zero, whereas, historically, 13/13 prior OD and 1/10 switch patients had an sABR >2. The sABR was reduced by 91.5% on study compared with historical sABR in prior OD patients, and by 45.0% in switch patients (model-based analysis; Table 1). Benefit-risk profile was maintained, with no newly identified risks (Table 2).
Time period Statistic |
Prior OD arm* (n=13) |
Switch arm† (n=10) |
Historical Number of treated spontaneous BEs sABR (95% CI) |
201 6.54 (2.52, 17.00) |
50 0.51 (0.04, 6.31) |
On-study (while receiving prophylactic rVWF) Number of treated spontaneous BEs sABR (95% CI) |
9 0.56 (0.15, 2.05) |
18 0.28 (0.02, 3.85) |
Comparison (on-study vs historical sABR) sABR on-study:historical ratio (95% CI) sABR percentage change from historical |
0.09 (0.02, 0.35) 91.5% reduction |
0.55 (0.09, 3.52) 45.0% reduction |
BE, bleeding episode; OD, on-demand; rVWF, recombinant von Willebrand factor; sABR, spontaneous annualized bleeding rate (ABR for spontaneous bleeds). sABR was the number of spontaneous bleeds divided by the observation period in years. Only BEs treated with VWF infusions are included. Six BEs of unknown cause (4 historical [all in prior OD group] and 2 on-study [switch group]) were counted as spontaneous bleeds for this analysis. Percentage change in sABR was calculated directly from the sABR ratio (RR): 100×(RR-1). *Patients who were treated on-demand with any VWF during the 12-month period prior to enrolling into this study to receive prophylaxis with rVWF. †Patients who were treated prophylactically with a plasma-derived VWF during the 12-month period prior to enrolling into this study to receive prophylaxis with rVWF. |
Prior OD arm (n=13) |
Switch arm (n=10) |
|
All AEs | 10 (76.9) / 26 | 7 (70.0) / 15 |
Serious AEs | 1 (7.7) / 1 | 2 (20.0) / 2 |
AEs related to rVWF* | 1 (7.7) / 1 | 0 |
Serious AEs related to rVWF | 0 | 0 |
AEs leading to rVWF discontinuation* | 1 (7.7) / 1 | 0 |
Severe AEs | 2 (15.4) / 3 | 1 (10.0) / 1 |
AEs of special interest† | 1 (7.7) / 1 | 1 (10.0) / 1 |
AE, adverse event; OD, on-demand. Values are number (%) of patients with events / number of events. *Headache of moderate severity, considered possibly related to rVWF by investigator (the only AE considered related to study treatment), led to rVWF discontinuation and study withdrawal. †AE of special interest (hypersensitivity reactions, thromboembolic events, development of inhibitors) were identified by broad standardized MedDRA queries (SMQ) search and immunogenicity laboratory results. 1 event of non-serious, non-severe purpura was attributed to trauma and considered unrelated to rVWF, and 1 event of non-serious, non-severe rash pruritic was considered unrelated to rVWF; no inhibitors to VWF or FVIII were developed. Overall number of exposure days (ED) for rVWF in Takeda-sponsored clinical trials increased from ~450 days in previously completed trials to >2200 days upon completion of this study. |
Conclusions: These findings suggest that rVWF prophylaxis can effectively reduce sABR in patients previously treated OD with VWF products 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.
To cite this abstract in AMA style:
WG Leebeek F, Peyvandi F, Escobar M, Tiede A, Castaman G, Gu J, Mellgård B, Ewenstein B, Özen G. Phase 3 Trial Results: Prophylaxis with Recombinant von Willebrand Factor in Patients with Severe von Willebrand Disease [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/phase-3-trial-results-prophylaxis-with-recombinant-von-willebrand-factor-in-patients-with-severe-von-willebrand-disease/. Accessed March 21, 2024.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/phase-3-trial-results-prophylaxis-with-recombinant-von-willebrand-factor-in-patients-with-severe-von-willebrand-disease/