Von Willebrand factor

Recombinant human von Willebrand factor (rVWF) behaves in the same way as endogenous von Willebrand factor.

Administration of recombinant human von Willebrand factor allows correction of the haemostatic abnormalities exhibited by patients who suffer from von Willebrand factor deficiency (von Willebrand's disease) at two levels:

• Recombinant human von Willebrand factor (rVWF) re-establishes platelet adhesion to the vascular sub-endothelium at the site of vascular damage (as it binds both to the vascular sub-endothelium matrix (e.g. collagen) and to the platelet membrane), providing primary haemostasis as shown by the shortening of the bleeding time. This effect occurs immediately and is known to depend to a large extent on the level of polymerisation of the protein.
• Recombinant human von Willebrand factor (rVWF) produces delayed correction of the associated factor VIII deficiency. Administered intravenously, von Willebrand factor binds to endogenous factor VIII (which is produced normally by the patient), and by stabilising this factor, avoids its rapid degradation. Because of this, administration of von Willebrand factor restores the FVIII:C level to normal as a secondary effect. After the first infusion, the FVIII:C level is expected to rise above 40% within 6 hours and to peak within 24 hours in most patients, depending on the baseline FVIII:C level.

Recombinant human von Willebrand factor (rVWF) contains ultra-large multimers in addition to all of the multimers found in plasma as it is not exposed to proteolysis by ADAMTS13 during the manufacturing process.

The pharmacokinetics (PK) of von Willebrand factor were determined in three clinical trials in adults by assessing the plasma levels of VWF:RCo, von Willebrand Factor Antigen (VWF:Ag), and von Willebrand Collagen Binding Activity (VWF:CB). In all three studies, subjects were evaluated in the non-bleeding state. Sustained increase of FVIII:C was observed by six hours after a single infusion of von Willebrand factor.

Table 1 summarizes the PK of von Willebrand factor in adults after 50 IU/kg VWR:RCo (PK₅₀) or 80 IU/kg VWF:RCo (PK₈₀) infusions. The mean duration of infusion was 16.5 minutes (SD ± 3.51 minutes) for 50 IU/kg (PK₅₀) and 11.8 minutes (± 2.86 minutes) for 80 IU/kg VWF:RCo (PK₈₀).

Table 1. Pharmacokinetic assessment of VWF:RCo^a in adults:

^a [VWF:RCo assays with different sensitivity and working ranges were used: Phase 1: automated assay 0.08–1.50 IU/mL and sensitive manual assay 0.01–0.08 IU/mL; Phase 3: automated assay 0.08–1.50 IU/mL.
^b [hours]
^c [dL/kg/hours]
^d [(IU/dL)/(IU VWF:RCo/kg)]
^e [(h*IU/dL)]
^f [(h*IU/dL)/(IU VWF:RCo/kg)]
^g This trial was done using ADVATE, a recombinant factor VIII.

An exploratory analysis of combined data from studies 070701 and 071001 indicated a statistically significantly (at the 5% level) longer mean residence time, a statistically significantly (at the 5% level) longer terminal half-life and statistically significantly (at the 5% level) larger AUC_0-inf regarding VWF:RCo following administration with von Willebrand factor (50 IU/kg VWF:RCo) and combined administration of von Willebrand factor and octocog alfa (50 IU/kg VWF:RCo and 38.5 IU/kg rFVIII) than after administration of pdVWF and plasma derived factor VIII (pdFVIII) (50 IU/kg pdVWF:RCo and 38.5 IU/kg pdFVIII).

In addition, full PK assessments of von Willebrand factor were performed following single and multiple dosing in study 071301, which investigated long-term prophylactic treatment in a total of 23 adult subjects with severe VWD (N=3 type 1, N=1 type 2A, N=1 type 2B, N=18 type 3). PK parameters derived from these assessment confirmed the results of previous trials (see Table 5 above) and a statistical comparison of key VWF PK parameters between initiation and month 12 of prophylactic treatment did not reveal any significant differences.

PK data of VWF (N=134) across 6 studies were evaluated using a population PK modelling and simulation approach. These results confirmed that the PK of VWF:RCo is both dose-independent (range: 2.0 to 80 IU/kg) and time-independent (up to 4.3 years). Covariate evaluations indicated no clinically meaningful effect of gender, race or VWD type on VWF:RCo PK; body weight and age were identified as significant covariates.

Paediatric population

PK of VWF in 24 paediatric patients with VWD were estimated based on population PK modelling using sparse PK samples collected during a paediatric study across three age groups (less than 6 years old [N=5], 6 years to less than 12 years old [N=10], and 12 years to less than 18 years old [N=9]) after receiving a single infusion of 50 ± 5 IU/kg rVWF:RCo (see Table 2).

Table 2. Pharmacokinetic assessment of VWF:RCo in paediatric subjects^a:

^a Data represent 4 sparse PK samples collected in each subject during paediatric study 071102 and population PK modeling results
^b [hours]
^c [dL/kg/hours]
^d [(IU/dL)/(IU VWF:RCo/kg)]
^e [(h*IU/dL)]
^f [(h*IU/dL)/(IU VWF:RCo/kg)]

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

No investigations on carcinogenicity, fertility impairment and fetal development have been conducted. In a human ex vivo placenta perfusion model, it has been demonstrated that von Willebrand factor does not cross the human placenta barrier.