Pharmacokinetics, Efficacy and Safety of a Plasma-Derived VWF/FVIII Concentrate (Formulation V) in Pediatric Patients with von Willebrand Disease (SWIFTLY-VWD Study)

Abstract

Purpose: Formulation V (VONCENTO^®) is a plasma-derived high-concentration/low-volume, high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate, originally indicated for von Willebrand disease (VWD) in adults and adolescents. This multicenter, open-label study (SWIFTLY-VWD) evaluated the pharmacokinetics (PK), as well as hemostatic efficacy and safety, of Formulation V in pediatric patients (<12 years) with severe VWD requiring treatment or prophylaxis of bleedings.

Methods: PK investigations were performed following one dose of Formulation V at Day 1 and 180. Nonsurgical bleeds were analyzed, while hemostatic efficacy was graded as excellent/good/moderate/none. Safety assessments included adverse events, and presence of VWF and/or FVIII inhibitors.

Results: Formulation V was administered as on-demand (N=13) or prophylaxis therapy (N=4) for 12 months (<6 years, N=9; 6 to <12 years, N=8). PK parameters for VWF markers were generally comparable to adults but showed lower VWF:ristocetin cofactor (RCo) exposure. Incidence of major bleeds was lower for prophylaxis (3.3%) than on-demand therapy (27.1%); joint bleeds were also lower (3.3% vs 11.5%, respectively). Investigator-reported excellent/good hemostatic efficacy against nonsurgical bleeds was 100%. No clinically relevant differences in PK, hemostatic efficacy, or safety were observed between age-groups (<6 years and 6 to <12 years). Formulation V was well tolerated. Adverse events were mild-moderate and consistent with the adult safety profile. No cases of anaphylactic reactions or angioedema, development of FVIII/VWF inhibitors, thromboembolic events, or viral infections were reported.

Conclusion: This study provides evidence for use of Formulation V to treat and prevent bleeding in pediatric patients with severe VWD, and led to the European approval of Formulation V in children.

Keywords: clinical trial; pediatrics; prophylaxis; von Willebrand disease; von Willebrand factor-factor VIII concentrate.

Figure 1

Patient disposition. Notes: ^a14 subjects eligible for analysis. ^b5 subjects eligible for analysis. Abbreviations: PK, pharmacokinetics; VWD, von Willebrand disease.

Figure 2

Mean (SD) concentration profiles (IU/mL) of baseline-adjusted VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C in patients below the age of 12 (initial PK [N=14], repeat PK [N=8]). Red dashed line: lower limit of quantitation (VWF:RCo: 0.1 IU/mL; VWF:Ag, VWF:CB: 0.025 IU/mL; FVIII:C: 0.008 IU/mL). Abbreviations: FVIII:C, factor VIII:coagulant activity; PK, pharmacokinetics; SD, standard deviation; VWF:Ag, von Willebrand factor: antigen; VWF:CB, von Willebrand factor: collagen binding; VWF:RCo, von Willebrand factor: ristocetin cofactor.

Figure 3

Investigator’s efficacy assessment of treated bleeding events (A), minor and major bleeding events (including bleeding events without treatment) (B), and locations of bleeds (including bleeding events without treatment) (C) in both treatment arms.