Results of Prophylactic Treatment of Severe von Willebrand Disease with Recombinant vWF

Purpose of the Study

Von Willebrand disease is a congenital autosomal inherited bleeding disorder characterized by a deficiency of vWF—a plasma glycoprotein that mediates platelet adhesion and aggregation and stabilizes coagulation factor VIII (FVIII). The disease is associated with various bleeding phenotypes, particularly in patients with type 2 or type 3 vWD, who are at higher risk of bleeding that may be life-threatening (e.g., gastrointestinal bleeding) or lead to long-term complications (e.g., arthropathy). Bleeding episodes require immediate administration of vWF on-demand or long-term prophylaxis, which induces and maintains hemostatic levels of vWF and FVIII. Long-term prophylaxis also prevents bleeding recurrences, improves health-related quality of life, and reduces the risk of long-term complications.

Recombinant vWF has previously demonstrated efficacy and a consistent safety profile when used on-demand or in the management of perioperative bleeding in patients with vWD. This study evaluated the efficacy, safety, and pharmacokinetics of rvWF prophylaxis in adults with severe vWD.

Study Methodology, Patient Population

This was a prospective open-label non-randomized phase III study. Severe vWD was defined as a baseline vWF (ristocetin cofactor activity) of 20 IU/dL. Enrolled patients were divided into two cohorts: A) those previously treated with on-demand vWF with ≥ 3 spontaneous bleeding episodes in the last 12 months, and B) those previously treated with prophylactic pdvWF for at least 12 months. In total, 23 patients were enrolled (13 in cohort A and 10 in cohort B), of whom 17 completed the study. The mean age was 40.6 ± 19.3 years, approximately half were male, and 78% had type 3 vWD. All patients received rvWF infusions during the study. Patients in cohort A received an initial dose of 50 ± 10 vWF IU/kg twice weekly, while those in cohort B received doses based on their previous weekly dose and frequency of pdvWF administration (equivalent to the weekly dose ± 10%, divided into 1–3 weekly doses, with a maximum of 80 vWFIU/kg in a single infusion). The planned prophylaxis duration was 12 months. The primary endpoint was the annualized bleeding rate (sABR) of spontaneous treated bleeding episodes during prophylaxis.

Results

During the 12-month prophylaxis, the sABR in cohort A decreased by 91.5% compared to baseline (ratio 0.085; 95% confidence interval [CI] 0.021–0.346), from 6.54 to 0.56. In cohort B, the sABR decreased by 45% (ratio 0.550; 95% CI 0.086–3.523), from 0.51 to 0.28. During rvWF prophylaxis, 84.6% (11/13) of patients in cohort A and 70.0% (7/10) in cohort B experienced no spontaneous bleeding.

A total of 31 bleeding episodes occurred during the prophylaxis period, most of which were spontaneous, mild to moderate in severity, and required only one rvWF infusion.

Pharmacokinetic parameters for vWF were comparable at both the initial and final assessments in cohort A, and remained stable in cohort B. The safety profile of rvWF was consistent with previous findings, and no new safety signals were identified. Only one reported adverse event was deemed potentially related to rvWF administration (a non-severe moderate headache in one patient).

Conclusion

The results of this study indicate that rvWF prophylaxis can reduce the frequency of treated bleeding episodes in adult patients with severe vWD who were previously treated on-demand, or maintain at least the same level of hemostatic control in those switched from pdvWF prophylaxis to rvWF, all while demonstrating a very favorable safety profile.

(Author initials: zza)

Source:

Leebeek F. W. G., Peyvandi F., Escobar M. et al. Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results. Blood 2022; 140 (2): 89−98, doi: 10.1182/blood.2021014810.