Efficacy, PK, Immunogenicity and Safety of Wilate in Severe Von Willebrand Disease (VWD) Patients <6 Years of Age

TABR is defined as the total number of bleeding episodes (BEs) including spontaneous, traumatic, and other bleeds, occurring during the period from the first prophylactic dose of wilate to the study completion visit, divided by the duration (in years) between these two time points. Bleeding episodes that occurred during surgery periods were excluded from the calculation of TABR.

Total BEs refers to all bleeding episodes that occurred during the study period, regardless of whether they were treated with wilate or not. Treated BEs are a subset of total BEs comprising of bleeding episodes that were treated with wilate.

Mean AUC of VWF:Ac after PK injection of wilate as measured by chromogenic assay.

Mean AUC of FVIII after PK injection of wilate as measured by chromogenic assay.

Mean AUC of VWF:Ac after PK injection of wilate, normalised for the actual administered dose (IU/kg), over time. AUC norm was measured and reported as [h*kg/IU]/(dL/IU) which could also be reported as h*kg/dL.

Mean AUC of FVIII after PK injection of wilate, normalised for the actual administered dose (IU/kg), over time. AUC norm was measured and reported as [h*kg/IU]/(dL/IU) which could also be reported as h*kg/dL.

Mean clearance (CL) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as the ratio of dose administered to the area under the plasma concentration-time curve (AUC), over time. Clearance was defined as the rate of drug elimination divided by plasma concentration, giving a volume of plasma from which drug is completely removed per unit of time.

Mean clearance (CL) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as the ratio of dose administered to the area under the plasma concentration-time curve (AUC), over time.

Mean maximum plasma concentration (Cmax) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, as determined from the observed peak value in the plasma concentration-time profile.

Mean maximum plasma concentration (Cmax) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, as determined from the observed peak value in the plasma concentration-time profile.

Mean residence time (MRT) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as the average time a VWF:Ac molecule remains in the body, derived from the ratio of area under the first moment curve (AUMC) to AUC.

Mean residence time (MRT) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as the average time a FVIII:C molecule remains in the body, derived from the ratio of area under the first moment curve (AUMC) to AUC.

Mean in vivo half-life (T1/2) VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as the time required for the plasma concentration to decrease by half during the terminal elimination phase.

Mean in vivo half-life (T1/2) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as the time required for the plasma concentration to decrease by half during the terminal elimination phase.

Mean time to reach maximum plasma concentration (Tmax) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, defined as the time from dosing to the observed peak plasma concentration.

Mean time to reach maximum plasma concentration (Tmax) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, defined as the time from dosing to the observed peak plasma concentration.

Mean volume of distribution at steady state (Vd) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as clearance (CL) multiplied by mean residence time (MRT).

Mean volume of distribution at steady state (Vd) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as clearance (CL) multiplied by mean residence time (MRT).

Mean incremental in vivo recovery (IVR) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as the increase in plasma VWF:Ac concentration per IU/kg of wilate administered.

Mean incremental in vivo recovery (IVR) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as the increase in plasma FVIII:C concentration per IU/kg of wilate administered.

Proportion of BEs successfully treated with wilate, as assessed using a predefined 4-point ordinal haemostatic efficacy scale. Each BE was rated at the end of treatment as "excellent", "good", "moderate", or "none" based on the time to bleeding cessation and the dose required. A BE is considered successfully treated if the efficacy rating is "excellent" (bleeding stopped within 3 days for minor bleeds, within 7 days for major bleeds, or within 10 days for gastrointestinal bleeds) or "good" (bleeding stopped, but time and/or dose slightly exceeded expectations). The outcome is reported as the percentage of BEs with a rating of "excellent" or "good" out of all treated BEs

Overall efficacy of wilate in perioperative prophylaxis against excessive bleeding, as assessed at the end of the postoperative period by the responsible treating investigator using a predefined 4-point ordinal haemostatic efficacy scale. The assessment is based on the presence or absence of postoperative bleeding or oozing, the need for additional dosing, and the ability to control bleeding with wilate.

Excellent: No postoperative bleeding or oozing not due to surgical complications; all postoperative bleeding due to complications controlled with wilate as anticipated for the procedure.

Good: No postoperative bleeding or oozing not due to surgical complications; control of postoperative bleeding due to complications required increased dosing or additional injections of wilate not originally anticipated.

Moderate: Some postoperative bleeding or oozing not due to surgical complications; control required increased dosing or additional injections of wilate not originally anticipated

Mean dose of wilate administered for routine prophylactic treatment, reported as (a) mean dose per injection (IU/kg) and (b) mean dose per week (IU/kg). Dose per injection is calculated as the total amount of wilate (IU) administered per injection divided by the patient's body weight (kg). Dose per week was calculated as the total amount of wilate (IU) administered for prophylaxis in a week, divided by the patient's body weight (kg). Both measures were averaged across all prophylactic infusions during the study period

Mean dose of wilate administered for the on-demand treatment of BEs, reported as (a) mean dose per BE (IU/kg) and (b) mean dose per injection (IU/kg). Dose per BE is calculated as the total amount of wilate (IU) administered per BE treatment divided by the patient's body weight (kg). Dose per injection is calculated as the total amount of wilate (IU) administered for BE treatment in a week, divided by the patient's body weight (kg). Both measures are averaged across all treated BEs during the study period

Mean dose of wilate administered for surgical prophylaxis, reported as dose per exposure day (ED) in IU/kg. Dose per exposure day is calculated as the total amount of wilate (IU) administered for surgical prophylaxis on each day, divided by the patient's body weight (kg). The measure is averaged across all exposure days during the perioperative period

Number of patients with detectable inhibitory antibodies to von Willebrand factor (VWF) and factor VIII (FVIII) during the study testing. Inhibitor testing is performed at baseline, every 3 months, and at any time if inhibitor development is suspected.

Incidence of thromboembolic events, defined as the proportion of patients who experience one or more thromboembolic events (such as deep vein thrombosis, pulmonary embolism, or other clinically relevant thromboses) during the study period. Thromboembolic events are monitored and recorded as adverse events throughout the study, and are confirmed by clinical assessment and/or diagnostic imaging as appropriate. The outcome is reported as the number and percentage of patients with at least one thromboembolic event during the study

Change from baseline in the Haemophilia Joint Health Score (HJHS) total score, assessed at baseline and at the end of the study (12 months). The HJHS is a validated clinical tool used to evaluate joint health in patients with bleeding disorders, measured over a scale of 0-124, with higher scores indicating worse joint health. This score is comprised of the assessments of 6 joints according to 8 criteria (each joint is scored from 0 to 20, giving a possible assessment range for all joints of 0 to 120) plus the Global Gait Score (measured from 0 to 4). The outcome is reported as the mean change in total HJHS score from baseline to study completion for each participant. An increase (positive value) indicates an increase in HJHS over the course of the study and worsening of joint health. A decrease (negative value) reflects a reduction in HJHS over the study duration and improvements in joint health. Assessments are performed by trained investigators using the standard HJHS protocol.