Quantitative Evaluation of Factor VIII in Factor VIII Products.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4012-4012
Author(s):  
Saulius Butenas ◽  
Behnaz Parhami-Seren ◽  
Matthew T. Gissel ◽  
Edward D. Gomperts ◽  
Kenneth G. Mann
Keyword(s):  
Factor Viii ◽  
Protein Content ◽  
Quantitative Evaluation ◽  
Hemophilia A ◽  
Specific Activity ◽  
Full Length ◽  
Recombinant Factor Viii ◽  
Factor Viii Activity

Abstract Several factor VIII products, recombinant and natural, have been used for hemophilia A treatment worldwide. Typically, two activity-based assays (factor Xase and aPTT) are used for the assessment of factor VIII concentration in these products. Frequently, the results are dependent upon the assay and its modifications in different laboratories. In this study, we evaluated five pharmacologic factor VIII products (three lots of each) in three activity-based assays and in two immunoassays for the concentration and activity of factor VIII protein. Two factor VIII products were plasma-derived (Immunate and Hemofil M) and three were recombinant; two of these contained full-length factor VIII (Recombinate and Kogenate) and one was B-domainless (ReFacto). Albumin-free full-length recombinant factor VIII was used as a standard in all assays. In the factor Xase assay, all recombinant factor VIII products and Immunate at 1U/ml (indicated by manufacturer) showed activity similar to that of 0.7nM (1U/ml) standard, whereas activity of Hemofil M was 64–68% of the standard. In the aPTT assay both full-length recombinant products and Hemofil M displayed activity similar to the standard, whereas Immunate had increased (142% of standard) and ReFacto decreased (83% of standard) activity. In synthetic plasma, all three recombinant products had standard-like activity, whereas Hemofil M and Immunate were slightly more active than standard. The ELISA immunoassay revealed that the factor VIII protein content in Recombinate, Kogenate and Hemofil M corresponded to the units assigned by manufacturers (1.4–1.6x1012U/mol vs1.4x1012U/mol calculated for standard), whereas the specific activity of Immunate was 50% of that expected (0.7x1012U/mol). In contrast, the specific activity of ReFacto was almost 3-fold that of full-length factor VIII (4.0x1012U/mol). The data of this study indicate that: 1) factor VIII activity estimated in different assays gives dissimilar results; 2) the specific activity of factor VIII in various factor VIII products is different and, as a consequence, administration of an equal factor VIII activity in U/ml means the administration of different amounts of factor VIII protein.

Perioperative Efficacy of an Extended Half-Life, Pegylated, Full-Length, Recombinant Factor VIII (BAX 855) in Individual Procedures

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2299-2299
Author(s):  
Brigitte Brand ◽  
Ralph A. Gruppo ◽  
Tung T. Wynn ◽  
Laimonas Griskevicius ◽  
Maria Fernanda Lopez Fernandez ◽  
...  
Keyword(s):  
Blood Loss ◽  
Factor Viii ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Full Length ◽  
Recombinant Factor Viii ◽  
Employment Equity ◽  
Major Procedure ◽  
Equity Ownership

Abstract BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on rFVIII (ADVATE) with an extended half-life and is intended for prophylaxis and the treatment of bleeding in patients with hemophilia A.1 This phase 3 surgery study is evaluating the efficacy and safety of BAX 855 for the perioperative control of hemostasis. Patients' informed consent and appropriate ethics committee approvals were obtained. Elective procedures were prospectively classified (major or minor) by the investigator/surgeon and major emergency surgeries were excluded. The target trough FVIII levels for major and minor surgeries were to be ≥80% and 30-60%, respectively. Each patient's pharmacokinetic (PK) profile was used to guide the BAX 855 dose and infusion frequency. BAX 855 PK were consistent with previous PK assessments with terminal half-life ranging from 8.81 to 18.06 hours for the 15 patients in this study. In this interim analysis, 15 male previously treated patients (PTPs) ranging from 19 to 52 years of age have undergone 15 procedures in 7 countries. Individual procedure profiles are compiled to evaluate the control of hemostasis for BAX 855. There were 11 major procedures: 6 orthopedic (3 knee replacements, 2 arthroscopic synovectomies, 1 elbow cyst extirpation) and 5 non-orthopedic procedures (3 dental [root canals for 2 teeth, 2 extractions of ≥4 teeth, 1 radicular cyst removal], 1 cardiovascular [mediport placement], 1 abdominal [gastric band insertion]). The 4 minor surgeries comprised 1 synoviorthesis, 1 dental, 1 dermatological and 1 endoscopy (radiosynovectomy) procedure. Efficacy was evaluated by the surgeon or investigator's rating of hemostatic control using 4-point scale which was based on blood loss and by comparing actual blood loss with predicted blood loss which was specified by the surgeon for non-hemophilia patients prior to the procedure. For all procedures, the hemostatic control of BAX 855 was rated "excellent" for the intraoperative (during the procedure), postoperative (24 hours after completion of the procedure), and perioperative (from start of the procedure until discharge or day 14) periods, except for 1 minor dental procedure in which postoperative efficacy was rated "good" and 1 minor procedure in which a postoperative rating was not provided (for both of these procedures intra- and perioperative ratings were "excellent"). Actual blood loss (ABL) for the intraoperative and postoperative periods were compared with predicted average and maximum values. Intraoperative ABL for all minor and major procedures was less than or equal to predicted averages and maximums, except for 1 minor procedure in which the ABL was greater than the predicted average and maximum and 1 major procedure which did not have ABL recorded. Postoperative ABL was less than or equal to predicted averages and maximums for 4/4 minor procedures and 5 major procedures. For 4 major procedures, postoperative ABL was greater than or equal to predicted average, but less than predicted maximums. For the remaining major procedure (synovectomy with general anesthesia) with reported ABL, postoperative ABL was greater than the predicted the average and maximum - the efficacy assessments at all periods for this procedure were considered "excellent". These results demonstrate the efficacy of BAX 855 for the perioperative control of hemostasis in patients with severe hemophilia A. 1 Konkle BA, Stasyshyn O, Chowdary P et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015; Link to Publisher's site: http://www.bloodjournal.org/content/bloodjournal/early/2015/07/08/blood-2015-03-630897.full.pdf Disclosures Brand: CSL Behring: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Baxalta: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biotest: Consultancy. Gruppo:Baxalta: Consultancy, Research Funding; Novo Nordisk: Consultancy; Pfizer: Consultancy; Alexion: Speakers Bureau. Wynn:Baxalta: Research Funding. Griskevicius:Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Fernanda Lopez Fernandez:Baxalta: Research Funding. Dvorak:Baxalta: Employment, Equity Ownership. Patrone:Baxalta: Employment, Equity Ownership. Abbuehl:Baxalta: Employment, Equity Ownership.

scholarly journals Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs

Blood ◽  
2012 ◽  
Vol 119 (13) ◽  
pp. 3024-3030 ◽  
Author(s):  
Jennifer A. Dumont ◽  
Tongyao Liu ◽  
Susan C. Low ◽  
Xin Zhang ◽  
George Kamphaus ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Specific Activity ◽  
Recombinant Factor Viii ◽  
Prophylactic Efficacy ◽  
Reduced Frequency ◽  
Fc Fusion Protein ◽  
Partial Correction

Abstract Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ∼ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation.

Target Joint Status in Patients with Hemophilia a during 18 Consecutive Months of Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2592-2592
Author(s):  
Werner Engl ◽  
Lisa Patrone ◽  
Brigitt E. Abbuehl
Keyword(s):  
Factor Viii ◽  
Treatment Period ◽  
Half Life ◽  
Hemophilia A ◽  
Full Length ◽  
Adult Patients ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Equity Ownership

Abstract Introduction and Objective: Patients with severe hemophilia A repeatedly bleed into joints and subsequently develop target joints and arthropathy. BAX 855, a polyethylene glycol pegylated, full-length, recombinant factor VIII built on ADVATE, demonstrates an extended half-life, efficacy, and safety for prophylaxis and the treatment of bleeding in patients with severe hemophilia A. Target joint status was evaluated in an ad-hocanalysis of integrated efficacy data from previously treated adolescent and adult patients who participated in the pivotal (completed) and continuation (ongoing) studies. Methods: The number of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, were analyzed over 3 consecutive 6-month periods in patients who received twice weekly BAX 855 prophylaxis at 40-50 IU/kg. Results: After approximately 6 months of twice weekly prophylaxis during the pivotal study, 101 adolescent and adult patients continued treatment in the continuation study, 51 of whom were treated with twice weekly prophylaxis for 18 consecutive months. At screening 29.4% (15/51) of these patients had no target joints, 19.6% (10) had 1 target joint, 21.6% (11) had 2, and the remaining 29.4% (15) had 3 or more. After the first 6-month treatment period, the percent of patients with no target joints increased to 66.7% (34 patients), including 19 patients in whom 1 or more target joints had resolved and 15 patients who remained target joint-free from screening. Of note, for the 15 patients with 3 or more target joints at screening, all of their target joints resolved after the first 6 months of treatment with BAX 855. This trend was maintained after the second 6-month treatment period. After the third 6-month period of twice weekly prophylaxis, the percent of patients with no target joints further increased to 82.4% (42), which included the 15 patients who remained target joint-free from screening. Nine patients had 1 or more unresolved target joint after 18 months of twice weekly prophylaxis, and in 6 of these patients, 1 to 3 other target joints had resolved. Overall, there were 89 target joints at screening which reduced to 14 after 18 months of twice weekly prophylaxis. Of those, 10 target joints changed status (eg, were present, resolved, and then re-appeared) and only 4 target joints (in 4 patients) persisted as unresolved through each of the 3 consecutive 6-month treatment periods. Conclusions: These results demonstrate the efficacy of continuous twice weekly prophylaxis with BAX 855 for preventing and resolving the majority of target joints. Disclosures Engl: Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Patrone:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Abbuehl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership.

scholarly journals BAY 81-8973, a full-length recombinant factor VIII for the treatment of hemophilia A: product review

2018 ◽  
Vol 9 (7) ◽  
pp. 191-205 ◽  
Author(s):  
Johnny N. Mahlangu ◽  
Sanjay P. Ahuja ◽  
Jerzy Windyga ◽  
Nikki Church ◽  
Anita Shah ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Treated Patient ◽  
Age Groups ◽  
Development Program ◽  
Pharmacokinetic Profile ◽  
Full Length ◽  
Recombinant Factor Viii ◽  
Clinical Development Program ◽  
Chromogenic Assay

BAY 81-8973 (Kovaltry®) is an unmodified, full-length recombinant factor VIII (rFVIII) approved for the prevention and treatment of bleeding episodes in patients with hemophilia A. The amino acid sequence for BAY 81-8973 is identical to that of sucrose-formulated rFVIII (rFVIII-FS; Kogenate® FS/KOGENATE®, Bayer), but the two products differ in their manufacturing approaches. The manufacture of BAY 81-8973 includes several modifications and enhancements, such as the introduction of the gene for human heat shock protein 70, a molecular chaperone protein that facilitates folding of proteins; no addition of human- or animal-derived proteins in the cell culture, purification process, or final formulation; and use of a 20-nm filter to remove any potential aggregates and pathogens. BAY 81-8973 was extensively studied in the LEOPOLD clinical development program, which enrolled participants of all age groups (children, adolescents, and adults) with severe hemophilia A. The pharmacokinetic profile of BAY 81-8973 was shown to be noninferior to, and for some variables more favorable than, rFVIII-FS and another commercial full-length rFVIII product. BAY 81-8973 was shown to be efficacious when used for prophylaxis, on-demand treatment, and perioperative hemostasis. The efficacious prophylaxis dose of BAY 81-8973 was approximately 20–40 IU/kg given two or three times per week, which achieved low annualized bleeding rates. Either the one-stage or the chromogenic assay provides accurate measurements for postinfusion monitoring of BAY 81-8973 levels, with no product-specific calibration standard needed. The incidence of treatment-related adverse events was ⩽7% across all LEOPOLD studies, and no previously treated patient developed anti-BAY 81-8973 inhibitors in the completed primary studies.

Measurement of factor VIII activity of B-domain deleted recombinant factor VIII

2001 ◽  
Vol 38 (2, Suppl 4) ◽  
pp. 13-23 ◽  
Author(s):  
M. Mikaelsson ◽  
U. Oswaldsson ◽  
M. A. Jankowski
Keyword(s):  
Factor Viii ◽  
Recombinant Factor Viii ◽  
Factor Viii Activity

A Multicenter Pharmacosurveillance Study for the Evaluation of the Efficacy and Safety of Recombinant Factor VIII in the Treatment of Patients with Hemophilia A

1997 ◽  
Vol 78 (05) ◽  
pp. 1352-1356 ◽  
Author(s):  
Emel Aygören-Pürsün ◽  
Inge Scharrer ◽  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Parvovirus B19 ◽  
Subjective Evaluation ◽  
Recombinant Factor Viii ◽  
Fviii Inhibitor ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Bleeding Episodes ◽  
Recombinant Fviii

SummaryIn this open multicenter study the safety and efficacy of recombinant factor VIII (rFVIII) was assessed in 39 previously treated patients with hemophilia A (factor VIII basal activity ≤15%).Recombinant FVIII was administered for prophylaxis and treatment of bleeding episodes and for surgical procedures. A total of 3679 infusions of rFVIII were given. Efficacy of rFVIII as assessed by subjective evaluation of response to infusion and mean annual consumption of rFVIII was comparable to that of plasma derived FVIII concentrates. The incremental recovery of FVIII (2.4 ± 0,83%/IU/kg, 2.12 ± 0.61%/IU/kg, resp.) was within the expected range. No clinical significant FVIII inhibitor was detected in this trial. Five of 16 susceptible patients showed a seroconversion for parvovirus B19. However, the results are ambiguous in two cases and might be explained otherwise in one further case. Thus, in two patients a reliable seroconversion for parvovirus B19 was observed.

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