Discussion

In the final analysis of data from the on-demand arm of the phase 3 study, the primary end point of treatment success was met in all 18 (100%) pediatric patients who experienced a BE treated with rVWF (without or with rFVIII), during ∼12 to 17 months of the on-demand treatment period. A hemostatic efficacy rating of excellent or good was achieved in 100% of assessed treated BEs, with excellent being reported for the majority (99.0%) of BEs. Consistent efficacy was demonstrated by pediatric age group, VWD type, bleeding severity, and bleeding location. Most BEs (82%) resolved with 1 infusion of rVWF, and most (73%) did not require an rFVIII infusion in addition to rVWF for bleeding treatment. The mean (SD) rVWF dose per infusion per bleed was 48.4 (8.1) IU/kg, consistent with the recommended initial dose for adult on-demand treatment (40-80 IU/kg) [19,20]. In the phase 3b continuation study, rVWF continued to show similar efficacy for on-demand treatment in 16 patients for an additional treatment period of up to 3 years, with all rated BEs having a hemostatic efficacy rating of excellent or good. BEs resolved with a mean 1.1 rVWF infusions, and the majority of these bleeds did not require rFVIII.

The results for children and adolescents in our study align with those previously reported in adults receiving on-demand therapy. For example, in a pivotal phase 3 study in 22 patients with severe VWD, on-demand treatment with 1 infusion of rVWF (and with rFVIII in 94% of these treatments) was effective in 82% of bleeds, with treatment success achieved in 100% of patients [25]. The present studies also demonstrate hemostatic efficacy with rVWF without the use of rFVIII in pediatric patients, consistent with findings in adults [25,31] and in agreement with its role in stabilizing endogenous FVIII. This is also aligned with the current dosing recommendation that rVWF may be given without rFVIII when an immediate rise in FVIII is not required or when baseline FVIII levels are adequate to achieve hemostasis [19,20]. In the phase 3 study, 7 patients received rFVIII along with rVWF. Patients were treated according to the protocol dosing guidance, so would have received rFVIII at the investigator’s discretion to maintain hemostasis due to low baseline FVIII levels, as 6 of the 7 patients had type 3 VWD with low baseline FVIII. It is also possible that some investigators may have dosed rFVIII based on their clinical practice. The observation that many cases of rFVIII coadministration in our phase 3 study were for BEs of mild severity indicates that a cautious approach was being taken. Overall, data support the flexibility of dosing FVIII while treating BEs with rVWF. In contrast to the varying concentrations of VWF/FVIII ratios in plasma-derived VWF products, rVWF contains no FVIII, thus allowing the physician to optimize the therapy without or with rFVIII for each patient. This reduces the risk of excessive FVIII plasma levels and the associated risk of thrombosis, especially when used for the repeated dosing that is required to treat major and difficult-to-manage BEs.

The PK/PD profile of on-demand rVWF showed a response pattern similar to the known rVWF PK/PD profile in adults [25,29]. The levels of FVIII:C in our study peaked at a later time than VWF activity, which is expected based on the disposition and PK/PD relationship of rVWF. However, due to the limitations of a small sample size and a sparse sampling approach, additional population PK analyses are warranted to characterize the PK/PD of rVWF in the pediatric population.

Overall, no new safety concerns were identified during up to 4 years of rVWF treatment, compared with reports of rVWF safety in adults [25,29,31,32]. The only TEAE considered to be related to rVWF in the present studies was a case of moderate nausea in the phase 3 study. Nausea is an existing serious adverse event of rVWF identified from the adult trials.

The studies recruited a sample of pediatric patients that was well distributed across 3 types of VWD and 3 age groups, including 5 young children aged <6 years, among whom 2 were infants aged <2 years, adding a considerable amount of safety and efficacy data in support of the evaluation of the rVWF benefit–risk profile in pediatric patients with VWD. In addition, the continuation study allowed the long-term safety and efficacy of rVWF to be assessed for up to a total of 4 years across 2 studies. Limitations of this study included the open-label, uncontrolled design, and the limited patient sample, although it is justified and acceptable according to regulatory guidelines for this rare disease. In addition, investigator-rated hemostatic efficacy is inherently subjective and may be influenced by expectation bias. However, hemostatic efficacy often requires real-time clinical assessment and was evaluated using an accepted approach common to bleeding disorder studies.

In conclusion, rVWF without and with rFVIII was demonstrated to be efficacious for the treatment of nonsurgical BEs in pediatric patients with VWD, with consistent efficacy across all pediatric age groups, VWD types, bleeding severities, and bleeding locations. Most BEs resolved after 1 infusion of rVWF, and the majority of bleeds did not require additional rFVIII. It remains of interest to model FVIII levels without and with additional FVIII treatment. Across the phase 3 and phase 3b studies, efficacy was maintained for up to 4 years of the on-demand rVWF treatment period. rVWF was well tolerated, and no new adverse drug reactions were identified in the pediatric population of the studies. Although the single-arm, open-label design of this trial precludes benchmarking of outcomes against plasma-derived VWF products, the findings support the use of rVWF as an efficacious treatment option, with no new safety concerns, for nonsurgical BEs in pediatric patients with VWD.