Optivate

Von Willebrand disease (VWD) is the commonest congenital bleeding disorder, which is caused by a deficiency in a glycoprotein, von Willebrand factor (VWF). VWF is a large, multimeric protein that circulates in the blood at a wide range of molecular weights; the larger high-molecular weight (HMW) multimers are essential for platelet adhesion 1. VWF replacement therapy with plasma-derived concentrates is used to treat patients with severe VWD or those in whom desmopressin is not effective or contraindicated. The composition of these VWF-containing factor concentrates is variable, and the quantity of the VWF ristocetin cofactor activity (VWF:RCo) and factor VIII (FVIII) differs between products 1. Subjects with VWD are usually dosed on the basis of VWF:RCo, so postinfusion FVIII levels are closely monitored, as high FVIII plasma levels have been associated with an increased risk of thrombosis 1, 2. Optivate is a dual viral inactivated plasma-derived FVIII and VWF concentrate; of which approximately 94% of the total protein (by weight) is VWF and about 0.9% is FVIII 3. Other plasma proteins are detected; the most abundant are fibrinogen and fibronectin, which are well below the normal levels found in plasma 3. No extraneous proteins, such as albumin, are added to Optivate as stabilizers. In vitro, Optivate had the highest antigen (VWF:Ag) 4 and was as effective as other FVIII/VWF concentrates in platelet capture 5, including Haemate P, Fanhdi, 8Y and Wilate. Across 50 consecutive manufacturing batches, Optivate has a mean FVIII/VWF:RCo ratio of 1:1.9. Optivate is licensed in several countries worldwide for the treatment of Haemophilia A in both adults and children 6-9. This letter reviews data from a BPL sponsored single centre, randomized pharmacokinetic (PK) study comparing Optivate and Haemate P (also known as Humate P) in VWD patients. Kessler et al. 10 conducted similar investigations, except they compared Wilate and Humate P in 20 patients, administered a lower VWF:RCo dose (40 IU kg−1), and collected PK and multimer samples up until 72 h postinfusion. This letter also compares the data obtained from the Kessler group and the BPL study (Table 1). Ethics approval and written informed consent were obtained before any patients were enrolled into the BPL study. Patients were eligible if they were >12 years and with VWD, without inhibitors to FVIII or VWF, and had a poor response to desmopressin or it was contraindicated. Exclusion criteria included active bleeding, INR >1.5 or PT >3 s above the upper limit of the reference range; thrombocytopenia; clinically significant renal disease; and liver disease; taking protease inhibitors. Laboratory normal ranges for VWF:RCo were set according to blood type. For blood type O (40–130%) and non-O (50–160%). Classification of VWD phenotypes were set as defined in the European guidelines 1. Each patient was randomized to receive a single intravenous dose of one of the two concentrates (Optivate or Haemate P) for the first PK assessment (60 IU kg−1 of VWF:RCo 1). Blood samples for PK analysis were drawn prebolus and at 30 min, then at 1, 2, 5, 8, 24 and 48 h postinfusion, and for VWF multimer, analysis were taken predose and then at 30 min, and 5 h postinfusion. After a 12-day washout period, the alternative concentrate was administered and blood samples were taken at identical time points as for the first assessment. Bethesda FVIII inhibitor tests were conducted prior to each PK assessment and at the end-of-study. Twelve patients with VWD were enrolled in the study: type 3 (four subjects, VWF:RCo range 0–5 IU dL−1); type 2A (5, VWF:RCo range 5–16 IU dL−1); type 2B (1, VWF:RCo 10 IU dL−1) and type 1 (2, VWF:RCo range 36–55 IU dL−1). All the patients were Caucasian, and the male/female ratio was evenly split (6:6). The median age was 33 years (range 20 to 68 years). Similar VWF multimer profiles were seen for Optivate and Haemate P, both had proportionately less HMW multimers than normal plasma. In type 3 patients, the multimer profiles at 30 min postinfusion samples were very similar to those of the products. In the 5 h postinfusion samples, the clearance of HMW multimers was higher in the Haemate P sample compared to Optivate. Postinfusion VWF results were virtually identical for Optivate and Haemate P (Table 1). In the BPL study for the primary surrogate efficacy variable, VWF:RCo AUC0–48, the treatment difference between Optivate and Haemate P was not statistically significant (P = 0.66). Likewise, the between-treatment differences were not statistically significant for any of the other VWF:RCo pharmacokinetic parameters. Bioequivalence was concluded for VWF:RCo AUC0–48, AUC0–inf, recovery and clearance, but not for half-life. The mean VWF:RCo AUC0–48 for type 3 patients (Haemate P 813.1 IU h−1 dL−1; Optivate 859.6 IU h−1 dL−1) were lower than for other phenotypes (1094.0 and 1100.6 IU h−1 dL−1 respectively), but the 95% CI were wide with extensive overlap, so these differences are not statistically different. Similarly, the mean VWF:RCo elimination half-lives in the type 3 subset (Haemate P 11.6 h; Optivate 9.5 h) were slightly shorter than in the other subsets (13.1 and 10.0 h respectively), but again there was wide overlap of 95% CI for both products. Mean VWF:RCo recoveries in type 3 patients were 1.4 and 1.2 IU dL−1 per IU kg−1 respectively. In this study, the two products showed similar VWF:RCo pharmacokinetic profiles in type 3 subjects, with no marked difference from the aggregated data from the other types of VWD. In contrast, there was a difference in the mean FVIII AUC0–48 (95% CI) between type 3 subjects and those with other types of VWD for both products: Haemate P type 3 3284.4 (2892.3, 3676.5) IU h−1 dL−1; other VWD types 1506.6 (1109.1, 1904.1) IU h−1 dL−1 and for Optivate type 3 2772.7 (2381.9, 3163.5) IU h−1 dL−1; other VWD types Optivate 1167.7 (933.9, 1401.5) IU h−1 dL−1. The Kessler group reported higher VWF:RCo recoveries and half-lives for Wilate and Humate P in the all patient set (Table 1), however, the SEM values were high, which suggests a wide range of values. This could be due to the fact that only 7/20 patients were type 3 patients. The VWF:RCo half-live values in the type 3 subsets are similar to those reported in the BPL study: Wilate 9.1 and Humate P 10.2 h. For the BPL study, mean FVIII recovery was 2.4 and 3.4 IU dL−1 per IU kg−1 for Optivate and Haemate P respectively (Table 1). Bioequivalence was not concluded, however, the treatment difference was not statistically significant. The mean FVIII recoveries for each product were similar for subjects with type 3 and those with other types of VWD: Haemate P 3.4 and 3.5 IU dL−1 per IU kg−1 respectively; Optivate 2.7 and 2.3 IU dL−1 per IU kg−1 respectively. For FVIII recovery, the 95% CIs for these products only just overlapped for type 3 subjects. The Kessler group reported comparable FVIII recovery values in type 3 patients for Wilate and Humate P, 2.5 and 2.7 IU dL−1 per IU kg−1 respectively. Baseline adjusted, postinfusion FVIII levels for the BPL study are displayed in Fig. 1. Lower FVIII levels were maintained with Optivate than with Haemate P. Kessler et al. 10 also noted a plateau in the FVIII decay curve over the first 12 to 24 h with Humate P. This was not observed with Wilate. In the BPL study, only one Adverse Event (AE) was reported. A 29-year-old Caucasian female was noted to have raised alkaline phosphatase 29 days after her second PK assessment, when she had received Haemate P. However, at the screening visit, this patient had a raised alkaline phosphatase level: 118 U L−1. Her alaine aminotransferase (ALT) levels were within the normal range (screening, 17 U L−1; end-of-study, 83 U L−1). Extensive follow-up viral evaluations were conducted and all were negative. The event was considered unlikely to be related to Optivate or Haemate P. No other clinically significant safety concern was reported in this study. All the FVIII inhibitor tests remained negative throughout the study. In conclusion, the composition of Optivate has been shown to be comparable to other VWF/FVIII concentrates 4, 5, 10. PK profile of Optivate is similar to Haemate P/Humate P and Wilate 4, 5, 10. Bioequivalence between Optivate and Haemate P was confirmed for VWF:RCo AUC0–48, AUC0–inf, Recovery and clearance. Overall Optivate was well tolerated. There have been no reports of inhibitor development to FVIII and/or VWF with Optivate in this study or any of the other clinical studies 2, 6-9 or from postmarketing experience to date. Postinfusion FVIII levels and FVIII recovery values were slightly lower with Optivate than with Haemate P. A slower FVIII decay for Humate P was also observed by Kessler et al. 10. High FVIII plasma levels have been associated with an increased risk of thrombosis, which increases during surgery 1, 2, 10. Subjects with VWD are usually dosed on the basis of VWF:RCo. Therefore, maintaining lower postinfusion FVIII levels could possibly lower the risk of thrombosis. To date, there have been no adverse reactions with a thrombotic aetiology from either formal clinical trials or reporting of spontaneous adverse drug reactions with Optivate 2, 6-9. In addition, thrombogenicity data gathered from a separate Optivate study in 11 VWD patients (unpublished data) concluded there was no clinical evidence of thrombosis. Therefore, the data presented suggests that Optivate would be as safe and effective as other VWF/FVIII products in treating patients with VWD. We are grateful to investigator and staff at Haematology Dept., Institute of Thrombosis and Hemostasis, Sheba Medical Centre, Israel for enrolling and managing the patients into the cross-over clinical PK study. In addition, BPL thanks all the staff at this centre for processing the study coagulation samples. CD and RS-Z were involved the management and oversight of the clinical trial. All the authors were involved in the preparation of this article. This article presents data from trials funded by Bio Products Laboratory Ltd (BPL). AI (Principal Investigator) and AL (Co-Investigator) participated in the clinical study funded by BPL. CD has worked as an independent Medical Director for BPL. RS-Z has been contracted by BPL to work as a Clinical Research Consultant. All the authors have no other potential conflicts of interest and have been involved in the preparation of this article.

Summary.  Optivate® is a high‐purity FVIII/VWF product. Its safety, tolerability and efficacy in subjects ≥12 years have been demonstrated. This study was undertaken to assess Optivate® in children with haemophilia A. Twenty‐five children, including one PUP (previously untreated patient), aged 1–6 years (mean 4.67 years) were treated with Optivate® for 26 weeks. Inhibitors were assessed every 3 months and viral status at the study start and end. Prophylaxis was used by five boys and on demand by twenty. The mean number of bleeds in the study was lower compared to the same period pre‐study (12.0/child vs. 16.2/child), with fewer bleeds (P < 0.05) in the prophylactic subgroup (8.0/child) compared with the on‐demand sub‐group (13.4/child). Fourteen major bleeds were reported, all by the on‐demand sub‐group. Children on prophylaxis were administered a mean of 59.4 infusions; on‐demand group 35.1 infusions. A total of 998 infusions were used with a mean dose of 29.1 IU kg−1, and a mean of 38.6 exposure days (ED). Children <4 years used higher doses, and reported fewer bleeds than older children. Children’s Parents/Guardians rated Optivate® as helpful or very helpful in controlling 97.5% of bleeds by the prophylactic group, and in 98.5% of the bleeds in the on‐demand group. Only 5 of 101 ADRs were treatment‐related events (5%), all were mild and non‐serious. There were no clinically significant changes in vital signs, viral transmissions or inhibitors. In young children Optivate® was well tolerated, safe and efficacious.