Objectives:
This trial evaluated the hemostatic efficacy, pharmacokinetics, and safety of a recombinant VWF (rVWF) in adults with severe von Willebrand disease (VWD) (type 3 [VWF:Ag ≤ 3 IU/dL], severe type 1 [VWF:RCo< 20 IU/dL], 2A [VWF:RCo< 20 IU/dL], 2N [FVIII:C<10% ], 2B, or 2M).
Methods:
Bleeds were to be treated initially with rVWF and rFVIII (1.3:1 ratio), followed by rVWF alone (as long as FVIII:C >40%). Hemostatic efficacy was evaluated using a pre- defined 4-point rating scale (none=4, moderate=3, good=2, excellent=1). PK parameters for rVWF vs. rVWF:rFVIII were assessed in a randomized crossover design, and a 6-month repeated PK evaluation for rVWF alone.
Summary:
Of 31 subjects assigned to bleed treatment, 22 (17 type 3, 4 type 2A and 1 type 2N) experienced 192 bleeding episodes (several in multiple locations) that were treated with rVWF: 106 occurred in mucosal tissue (including 32 menorrhagic, 42 nasopharyngeal, 26 mouth/oral bleeds), 59 joint bleeds, 6 gastrointestinal bleeds, and 37 in other locations. Treatment success (mean efficacy rating <2.5) was achieved in all 22 subjects (100%; Clopper-Pearson exact 90% confidence interval: 87.3 to 100.0). ‘Excellent’ ratings were given for 186/192 (96.9%) bleeds (119/122 minor, 59/61 moderate, 6/7 severe, 2/2 unknown severity) and the remaining 3.1% were ‘good’. One infusion was effective in 81.8% of bleeds (median [range]: 1 [1-4] overall; 2 [1-3] for severe bleeds). The subject’s own assessment of treatment efficacy (an exploratory endpoint), was ‘excellent’ within 8 hours after the first infusion for 125/134 (93.3%), ‘good’ for 8/134 (6.0%) and ‘moderate’ for 1/134 (0.7%) bleeding episodes. A substantial increase in FVIII:C and sustained stabilization (> 40% by 6 hours, rising to >80% 24 hours post-infusion) was observed after infusion with rVWF. PK parameters for VWF Ristocetin cofactor (VWF:RCo, a surrogate for the platelet-dependent function of rVWF) were similar when rVWF was infused alone (mean T1/2 21.9 h vs. 19.6 h with rVWF:rFVIII). Eight adverse events (tachycardia, infusion site paraesthesia, ECG t wave inversion, dysgeusia, generalized pruritis, hot flush, chest discomfort and increased heart rate) in 5 subjects were assessed as related to rVWF. No inhibitor or anti-VWF binding antibody development was observed, and there were no thrombotic events or severe allergic reactions.
Conclusions:
rVWF was safe, well-tolerated and effective in the treatment of a variety of bleeding presentations in severe VWD. The sustained stabilization in FVIII:C after the initial infusion enables subsequent infusion of rVWF without rFVIII, when multiple infusions are required.