VEYVONDI Powder and solvent for solution for injection Ref.[27668] Active ingredients: Von Willebrand factor

Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Baxalta Innovations GmbH, Industriestraße 67, 1221 Vienna, Austria

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Antihaemorrhagics: blood coagulation factor von Willebrand factor
ATC code: B02BD10

Mechanism of action

VEYVONDI is a recombinant human von Willebrand factor (rVWF). VEYVONDI behaves in the same way as endogenous von Willebrand factor.

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

VEYVONDI 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.
VEYVONDI produces delayed correction of the associated factor VIII deficiency. Administered intravenously, VEYVONDI 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 VEYVONDI restores the FVIII:C level to normal as a secondary effect after the first infusion Administration of the FVIII:C rises above 40% within 6 hours and peaks within 24 hours in a majority of patients, depending on the baseline FVIII:C level.

VEYVONDI is a rVWF that 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.

Clinical efficacy and safety

The clinical safety, efficacy and PK data were assessed in 3 completed trials, (070701, 071001 and 071101) which enrolled patients with VWD. A total of 92 unique subjects (80 unique subjects with VWD in studies 070701, 071001 and 071101 and 12 subjects with Haemophilia A in study 071104) were exposed to VEYVONDI during clinical development.

The European Medicines Agency has deferred the obligation to submit the results of studies with VEYVONDI in all subsets of the paediatric population in the treatment of von Willebrand Disease (see section 4.2 for information on paediatric use).

5.2. Pharmacokinetic properties

The pharmacokinetics (PK) of VEYVONDI were determined in three clinical studies 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 VEYVONDI.

Table 6 summarizes the PK of VEYVONDI 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 5. Pharmacokinetic Assessment of VWF:RCo^f :

Parameter	Phase 1 PK₅₀ VEYVONDI with octocog alfa^g (Study 070701) Mean (95% CI) SD	Phase 3 PK₅₀ VEYVONDI (Study 071001) Mean (95% CI) SD	Phase 3 PK₈₀ VEYVONDI (Study 071001) Mean (95% CI) SD	Surgery PK₅₀ VEYVONDI (Study 071101) Mean (95% CI) SD
T_1/2^a	19.3 (14.3; 24.3) 10.99	22.6 (19.5; 25.7) 5.34	19.1 (16.7; 21.5) 4.32	17.8 (12.9; 22.8) 7.34
Cl_b	0.04 (0.03; 0.05) 0.028	0.02 (0.02; 0.03) 0.005	0.03 (0.02; 0.03) 0.009	0.03 (0.02; 0.04) 0.011
IR at C_max^c	1.7 (1.4; 2.0) 0.62	1.9 (1.6; 2.1) 0.41	2.0 (1.7; 2.2) 0.39	2.0 (1.7; 2.3) 0.45
AUC_0-inf^d	1541.4 (1295.7; 1787.2) 554.31	2105.4 (1858.6; 2352.3) 427.51	2939.0 (2533.2; 3344.8) 732.72	1834.4 (1259.0; 2409.7) 856.45
AUC_0-inf/Dose^e	33.4 (27.2; 39.5) 13.87	42.1 (37.3; 46.9) 8.31	36.8 (31.8; 41.8) 8.97	37.5 (25.3; 49.7) 18.14

^a [hours]
^b [dL/kg/hours]
^c [(IU/dL)/(U VWF:RCo/kg)]
^d [(h*IU/dL)]
^e [(h*IU/dL)/(IU VWF:RCo/kg)]
^f [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
^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 AUC0-inf regarding VWF:RCo following administration with VEYVONDI (50 IU/kg VWF:RCo) and combined administration of VEYVONDI and octocog alfa (50 IU/kg VWF:RCo and 38.5 IU/kg rFVIII) than after administration of pdVWF and pdFVIII (50 IU/kg pdVWF:RCo and 38.5 IU/kg pdFVIII).

5.3. Preclinical safety data

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 VEYVONDI does not cross the human placenta barrier.

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