Sucrose Formulated Recombinant Human Antihemophilic Factor VIII Is Safe and Efficacious for Treatment of Hemophilia A in Home Therapy

2000 ◽  
Vol 83 (06) ◽  
pp. 811-816 ◽  
Author(s):  
E. Gorina ◽  
E. Kellermann ◽  
E. Vosburgh ◽  
T. C. Abshire ◽  
H.-H. Brackmann ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
De Novo ◽  
Pharmacokinetic Profile ◽  
Full Length ◽  
Home Therapy ◽  
Safety And Efficacy ◽  
Previously Treated Patients ◽  
New Formulation ◽  
Antihemophilic Factor

SummaryTo add an increased level of safety to antihemophilic factor replacement therapy, a full-length, recombinant Factor VIII (rFVIII) product has been developed without human-derived plasma proteins during purification and formulation and using an additional solvent/detergent viral inactivation step. This first clinical trial of a sucrose-formulated full-length rFVIII (rFVIII-FS) was conducted in previously treated patients (≥100 prior exposure days) with severe (<2% FVIII) hemophilia A in North America (NA) and Europe (EU). Pharmacokinetic profiles for rFVIII-FS were compared with those of currently licensed rFVIII product (Kogenate®) in 35 patients. Safety and efficacy during home therapy were evaluated in 71 patients. The new formulation displayed a pharmacokinetic profile similar to that of rFVIII. Patients on home therapy received a cumulative total of 11,867 exposure days, 12,546 infusions, and 22,443,694 IU of rFVIII-FS. Of 2585 bleeds, 93.5% were treated with 1-2 infusions and 80.5% of responses were rated as excellent or good. No evidence of de novo inhibitor formation was observed. Only 0.27% of infusions were associated with any drugrelated adverse event. Except for an episode of intermittent chest pain with palpitations which ceased after treatment with analgesics, associated adverse events were mild or moderate. Overall, rFVIII-FS provided excellent hemostatic control, was well-tolerated, and caused no significant adverse effects, thus demonstrating safety and efficacy for treatment of bleeds in patients with hemophilia A.

Safety and efficacy of sucrose-formulated full-length recombinant factor VIII: Experience in the standard clinical setting

2008 ◽  
Vol 99 (01) ◽  
pp. 52-58 ◽  
Author(s):  
Elena Santagostino ◽  
Albert Faradji ◽  
Alfonso Iorio ◽  
Jan van der Meer ◽  
Jørgen Ingerslev ◽  
...  
Keyword(s):  
Observational Study ◽  
Factor Viii ◽  
De Novo ◽  
Observation Time ◽  
Full Length ◽  
Recombinant Factor Viii ◽  
Phase Iii ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Safety And Efficacy

SummaryThe safety of full-length sucrose-formulated recombinant factor VIII (rFVIII-FS; KOGENATE® FS) for up to 24 months of use was evaluated in a postmarketing observational study in Europe. Long-term safety and efficacy data were available for 212 patients with severe haemophilia A, including 13 previously untreated patients (PUPs) and 12 patients with 1–19 exposure days (EDs). Patients accumulated a mean (± SD) of 187 (121) EDs to rFVIII-FS and received a total of 39,627 infusions, mainly for prophylaxis and for the treatment of 4,283 spontaneous or trauma-related bleeds during an average observation time of 710 (136) days. Of these bleeding episodes, 85.4% were successfully treated with one or two infusions of rFVIII-FS. Haemostasis was also evaluated during 46 minor to major surgical pro- cedures, and the response to infusion was “excellent” or “good” in all cases. FVIII inhibitor formation was observed in six patients (two de novo; four persistent or recurrent). The de novo cases represent 8.0% (2 of 25) of patients who reported 0–19 previous EDs at study entry. Four of the five patients who reported possible drug-related adverse effects developed inhibitors. The results of this observational study demonstrate the efficacy and safety of rFVIII-FS during normal clinical use in the treatment of patients with severe haemophilia A. Furthermore, these findings are consistent with those of previous phase III clinical studies with rFVIII-FS, particularly with regard to its efficacy and low incidence of inhibitor formation.

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.

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.

Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6367-6370 ◽  
Author(s):  
Charles R.M. Hay ◽  
Ben Palmer ◽  
Elizabeth Chalmers ◽  
Ri Liesner ◽  
Rhona Maclean ◽  
...  
Keyword(s):  
United Kingdom ◽  
Factor Viii ◽  
Hemophilia A ◽  
Interquartile Range ◽  
Severe Hemophilia ◽  
The United Kingdom ◽  
Potential Risk Factors ◽  
History Of ◽  
Previously Treated Patients ◽  
Adjusted Incidence

Abstract The age-adjusted incidence of new factor VIII inhibitors was analyzed in all United Kingdom patients with severe hemophilia A between 1990 and 2009. Three hundred fifteen new inhibitors were reported to the National Hemophilia Database in 2528 patients with severe hemophilia who were followed up for a median (interquartile range) of 12 (4-19) years. One hundred sixty (51%) of these arose in patients ≥ 5 years of age after a median (interquartile range) of 6 (4-11) years' follow-up. The incidence of new inhibitors was 64.29 per 1000 treatment-years in patients < 5 years of age and 5.31 per 1000 treatment-years at age 10-49 years, rising significantly (P = .01) to 10.49 per 1000 treatment-years in patients more than 60 years of age. Factor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being greatest in early childhood and in old age. HIV was associated with significantly fewer new inhibitors. The inhibitor incidence rate ratio in HIV-seropositive patients was 0.32 times that observed in HIV-seronegative patients (P < .001). Further study is required to explore the natural history of later-onset factor VIII inhibitors and to investigate other potential risk factors for inhibitor development in previously treated patients.

scholarly journals Bioengineering hemophilia A–specific microvascular grafts for delivery of full-length factor VIII into the bloodstream

2019 ◽  
Vol 3 (24) ◽  
pp. 4166-4176 ◽  
Author(s):  
Joseph Neumeyer ◽  
Ruei-Zeng Lin ◽  
Kai Wang ◽  
Xuechong Hong ◽  
Tien Hua ◽  
...  
Keyword(s):  
Genetic Engineering ◽  
Factor Viii ◽  
Hemophilia A ◽  
Scid Mice ◽  
Full Length ◽  
Piggybac Transposon ◽  
Key Points

Key Points HA-specific iPSC-derived ECs overexpress full-length F8 after genetic engineering via a piggyBac transposon system. Bioengineered microvascular grafts deliver full-length FVIII into the bloodstream and restore hemostasis in hemophilic SCID mice.

Non-Inversion Factor VIII Mutations in 80 Hemophilia A Families Including 24 with Alloimmune Responses

2002 ◽  
Vol 87 (02) ◽  
pp. 273-276 ◽  
Author(s):  
Miao-Liang Liu ◽  
Shelley Nakaya ◽  
Arthur Thompson
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
De Novo ◽  
High Titer ◽  
Direct Sequencing ◽  
Normal Variant ◽  
Missense Mutations ◽  
Gene Deletions ◽  
Intron Splice ◽  
Splice Junctions

SummaryHeteroduplex screening identified 74 small mutations in the factor VIII genes of 72 families with hemophilia A. In addition, patients from 3 families with high titer inhibitors had partial gene deletions and 5 unrelated families that were negative for heteroduplex formation had a mutation on direct sequencing. The latter had mild hemophilia A with an inhibitor, and sequencing their exon 23 fragments found a transition predicting a recurrent Arg2150 to His. Of 69 distinct mutations (including the 3 partial gene deletions), 47 are novel. Of small mutations, 51 were missense (one possibly a normal variant and two that could also alter splicing) at 39 sites, 13 were small deletions or insertions (3 inframe and one a normal variant in an intron), 13 were nonsense at 12 sites and 2 altered intron splice junctions. In 24 families, at least one affected member had evidence for an alloimmune response to factor VIII; of these, 11 were associated with missense mutations. In 14 families, de novo origin was demonstrated.

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.

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