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Von Willebrand Disease (VWD) is an autosomally-inherited congenital bleeding disorder in which there is a deficiency or dysfunction of VWF. A reduction in VWF concentration in the bloodstream results in low FVIII activity and abnormal platelet function, which may result in excessive bleeding.
The VWF activity in Aleviate exists in a 2:1 ratio with FVIII:C activity. Aleviate has been demonstrated to contain the high molecular weight (HMW) multimers of VWF. HMW multimers are considered to be important for correcting the haemostatic defect in patients with VWD as they are important for platelet adhesion.
Haemophilia A is an X-linked recessive blood coagulation disorder. It is caused by reduced FVIII activity through either insufficient or abnormal synthesis of the FVIII protein, which is required for the formation of blood clots. Activated FVIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.
Clinical Trials: A total of 221 subjects were exposed in the prospective clinical studies, including 147 subjects with haemophilia A and 74 subjects with VWD. Among these exposed subjects, 5 subjects with haemophilia A and 3 subjects with VWD were adolescents, (aged 12 to <18 years), 36 subjects with haemophilia A (1 with high titre FVIII inhibitors was <1 year old) and 18 subjects with VWD were paediatrics aged <12 years.
In addition, efficacy and safety data in VWD subjects were collected in 2 published investigator-led studies that included 43 adult VWD subjects (Shortt 2007) and 43 adolescents and children (Howman 2011). Fifteen paediatric haemophilia A subjects, with FVIII inhibitors, treated for immune tolerance induction are reported in a published investigator-led retrospective chart review (Robertson 2014).
Von Willebrand Disease: Efficacy in the control of non-surgical and surgical bleeding was assessed in 3 open-label non-controlled trials. A 4-point rating scale was used in all trials: None - no control of bleeding; Moderate - moderate control of bleeding, other treatment also required; Good - slight oozing, partial but adequate control of bleeding; Excellent - haemostasis achieved.
In the first trial, with a focus on non-surgical bleeds (NSB), the haemostatic efficacy for 98.2% of 407 evaluable NSB were assessed by the investigator as excellent or good and 1.7% as moderate. During the study 8 subjects experienced 125 major NSBs, of which 7 were mucosal bleeds. The investigator's overall assessment was excellent for 1 and moderate for the other 6 major mucosal bleeds which were uterine bleeds; although for 4 of the later 6 bleeds the investigator had assessed efficacy as good on at least 1 day. Eight subjects in this trial were treated on-demand for 12 months before being switched to a prophylaxis regimen. The total number of NSB events decreased from 306 (ranging from 18 to 82 per subject, on-demand) to 10 in 5 of the subjects during prophylaxis. The haemostatic efficacy of all events treated with Aleviate was assessed by the investigator as excellent.
In the second trial the focus was on surgery. In 9 subjects undergoing 10 major surgical procedures, the efficacy was excellent or good in 10 (100%). In 11 patients undergoing 15 minor surgical procedures, haemostatic efficacy was excellent in 14 (93%) and good in 1 (7%).
The mean dose to achieve haemostasis was 27 IU FVIII:C/kg/day for a median 2 days in non-surgical bleeding, 33 IU FVIII:C/kg/day for a median 2 days in minor surgery and 41 IU FVIII:C/kg/day for a median 7.5 days in major surgery.
In the third trial 12 paediatric subjects treated on-demand experienced 96 NSB events which included 26 major events, 13 of which were mucosal bleeds. Haemostatic efficacy was assessed as excellent (45%) and good (55%) by the investigator for all of the NSB events evaluated. Three subjects in this group underwent 8 minor surgical procedures (all were dental). For a group of 4 paediatric subjects receiving prophylaxis treatment, 73 NSB events required treatment, however the haemostatic efficacy for these events was assessed by the investigator as excellent for 81% and good for the remaining 19% of events.
In a retrospective review of surgical bleeding in 43 adult patients undergoing 58 procedures, the haemostatic efficacy was excellent or good in 100% of procedures. Efficacy in the VWD Type 3 patients (n=5) was rated as excellent in 55%. The mean dose to achieve haemostasis was 29 IU FVIII:C/kg/day for a mean 2 days (range 1-4) in minor dental procedures and 5 days (range 1-13) in major surgery. There was some concomitant use of tranexamic acid and desmopressin.
In a second retrospective review in children and adolescents, 42 surgical events were treated: 10 major events in 10 subjects and 32 minor surgical events in 21 subjects. Four episodes of post-surgical bleeding events were also treated in 4 subjects, who had not received the product to prevent bleeding during the procedure. A total of 72 NSB events were treated: 46 mucocutaneous in 11 subjects and 26 musculoskeletal or soft tissue bleedings in 13 subjects. Only tranexamic acid was used as an adjunctive therapy in these subjects.
The haemostatic efficacy for all surgical events was excellent or good in approximately 90% of events (90% major and 91% of minor surgical events). Haemostatic efficacy for all NSB events was rated as excellent or good in 94% of events, and within Type 3 VWD subjects in 98% of NSB events.
The mean daily dose was 51 IU FVIII/kg (range 13-151) for major surgery with a median treatment duration of 7 days (range 1-24) and 45 IU FVIII/kg (range 14-76) for minor surgery with a median treatment duration of 3 days (range 1-8). For NSB events, the mean daily dose was 45 IU FVIII/kg (range 16-192) with a median treatment duration of 1 day (range 1-13).
Efficacy and safety in acquired VWD has not been established.
Adverse reactions encountered during the clinical trials in VWD patients are included under Adverse Reactions.
Haemophilia A: Efficacy in haemophilia A was assessed in 2 open-label, non-controlled trials.
In the first study in adult and adolescent subjects with haemophilia A, 81 subjects were treated with 77 subjects completing 6 months of treatment. Patients were treated either on-demand (including the prevention of bleeding in relation to surgery) or as prophylaxis. Of 656 evaluable bleeding events, 96.4% were assessed as excellent or good, 3.5% as moderate and 0.2% as none (one event, no efficacy).
During the study, a total of 37 surgical events occurred in 20 subjects; 12 events were major and 25 minor. Investigator's assessment of haemostatic efficacy at discharge was reported as excellent for 8 major and 10 minor surgical events, and as good for 2 major surgical events.
In the second study in paediatric subjects <12 years of age, 35 subjects were treated either on-demand or as prophylaxis, with 21 subjects completing at least 50 exposure days. In the on-demand group, all 318 evaluable bleeding events were assessed as excellent or good (24.2 and 75.8% respectively), including 98 (30.6%) major bleeds, 7 of which were mucosal. In the prophylaxis group 99.4% of the evaluable bleeding events (172) were assessed as excellent or good (1 event was moderate). Of the 85 major bleeding events (49.1%), none were mucosal. Five subjects in the prophylaxis group did not experience any bleeding event during treatment.
A total of 5 surgeries, 2 major and 3 minor, occurred during the study. The investigator's assessment of these events was reported as excellent for 2 (minor) surgeries and good for the remaining 3 surgeries.
The retrospective chart review of haemophilia A subjects with FVIII inhibitors describes exposure to high doses of Aleviate.
Adverse reactions encountered during the clinical trials in haemophilia A patients are included under Adverse Reactions.
Efficacy and safety have not been studied in previously untreated patients.
Pharmacokinetics: Clinical trials have been conducted with Biostate. Biostate is the tradename for the purified human coagulation FVIII product manufactured by CSL for distribution in Australia. The process used for the manufacture of Biostate is the same as that used for the manufacture of Aleviate.
Von Willebrand Factor: The pharmacokinetics (PK) of the product have been evaluated in VWD patients in the non-bleeding state.
Based on a PK study with 12 subjects with VWD, the PK characteristics for VWF:RCo, VWF antigen (VWF:Ag) and VWF collagen binding (VWF:CB) in Table 2 were observed following a single intravenous infusion of 80 IU VWF:RCo/kg. (See Table 2.)
Click on icon to see table/diagram/imagePeak plasma levels of VWF usually occur within a mean time of 18 minutes (median 15 minutes) after injection.
Similar results for both VWF and FVIII PK parameters were found when assessed after 6 months of treatment.
A population PK analysis which included PK data from both the adult subjects and a trial in paediatric subjects, indicated that dosing both populations on a 80 IU/kg basis provides similar concentrations for each of the VWF markers measured and found only body weight influences the PK of Aleviate which supports the dosing of Aleviate on an IU/kg basis.
Factor VIII: The pharmacokinetics of the product have been evaluated in haemophilia A patients in the non-bleeding state.
Based on a PK study with 16 subjects with haemophilia A, the PK characteristics for FVIII:C in Table 3 were observed following a single intravenous infusion of 50 IU/kg. (See Table 3.)
Click on icon to see table/diagram/imagePeak plasma levels of FVIII usually occur within a mean time of 49 minutes (median 30 minutes) after injection.
Similar PK results, including FVIII half-life, were found when PK parameters were assessed 6 months after the initial PK study. VWF PK parameters were not measured in the initial assessment or the repeat assessment after 6 months.
Paediatric population: There were small differences in PK parameters, reduced exposure and increased clearance, observed between the paediatric age groups (<6 years and 6-12 years) in both VWD and haemophilia A studies. The differences when compared with inherent subject variability are not expected to be clinically important.
The PK data in paediatric subjects are comparable to those observed in adult subjects.
