Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: final report on a hallmark clinical investigation

2004 ◽  
Vol 2 (4) ◽  
pp. 574-583 ◽  
Author(s):  
J. Lusher ◽  
C. Abildgaard ◽  
S. Arkin ◽  
P. M. Mannucci ◽  
R. Zimmermann ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Recombinant Dna ◽  
Clinical Investigation ◽  
Final Report ◽  
Antihemophilic Factor

Human Recombinant DNA–Derived Antihemophilic Factor (Factor VIII) in the Treatment of Hemophilia A

1990 ◽  
Vol 323 (26) ◽  
pp. 1800-1805 ◽  
Author(s):  
Richard S. Schwartz ◽  
Charles F. Abildgaard ◽  
Louis M. Aledort ◽  
Steven Arkin ◽  
Arthur L. Bloom ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Recombinant Dna ◽  
Antihemophilic Factor

A Multicenter Study of Recombinant Factor VIII (RecombinateTM) in Previously Treated Patients with Hemophilia A

1997 ◽  
Vol 77 (04) ◽  
pp. 660-667 ◽  
Author(s):  
G C White ◽  
S Courter ◽  
G L Bray ◽  
M Lee ◽  
E D Gomperts ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Recombinant Dna ◽  
Home Treatment ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Open Label ◽  
Treat Ment ◽  
Previously Treated Patients ◽  
Bleeding Episodes

SummaryA prospective, open-label multicenter investigation has been conducted to compare pharmacokinetic parameters of recombinant DNA-derived FVIII (rFVIII) and plasma-derived FVIII concentrate (pdFVIII) and to assess safety and efficacy of long-term home-treat- ment with rFVIII for subjects with hemophilia A. Following comparative in vivo pharmacokinetic studies, 69 patients with severe (n = 67) or moderate (n = 2) hemophilia A commenced a program of home treatment using rFVIII exclusively for prophylaxis and treatment of all bleeding episodes for a period of 1.0 to 5.7 years (median 3.7 years). The mean in vivo half-lives of rFVIII and pdFVIII were both 14.7 h. In vivo incremental recoveries at baseline were 2.40%/IU/kg and 2.47%/IU/kg, respectively (p = 0.59). The response to home treatment with rFVIII was categorized as good or excellent in 3,195 (91.2%) of 3,481 evaluated bleeding episodes. Thirteen patients received rFVIII for prophylaxis for twenty-four surgical procedures. In all cases, hemostasis was excellent. Adverse reactions were observed in only 13 of 13,591 (0.096%) infusions of rFVIII; none was serious. No patient developed an inhibitor to r FVIII.

scholarly journals Pharmacokinetic Parameter Driven Outcomes Model Predicts a Reduction in Bleeding Events Associated with BAY 81-8973 Versus Antihemophilic Factor (Recombinant) Plasma/Albumin- Free Method in a Chinese Healthcare Setting

2022 ◽  
Author(s):  
Rong Chen ◽  
Dmitry Gultyaev ◽  
Johanna Lister ◽  
Rong Han ◽  
Nan Hu ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Cost Savings ◽  
Standard Of Care ◽  
Healthcare Setting ◽  
Bleeding Events ◽  
Plasma Albumin ◽  
Lifetime Horizon ◽  
Life Years ◽  
Antihemophilic Factor

Abstract Background: Long-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population. Methods: Head-to-head PK profile data of BAY 81-8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year. Results: Cumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3%, 9.3% and 19.3%, respectively for BAY 81-8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. BAY 81-8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM. Conclusion: Based on modeled head-to-head comparisons, differences in PK-properties between BAY 81-8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81-8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A.

scholarly journals How we choose factor VIII to treat hemophilia

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4108-4114 ◽  
Author(s):  
Pier Mannuccio Mannucci ◽  
Maria Elisa Mancuso ◽  
Elena Santagostino
Keyword(s):  
Factor Viii ◽  
Replacement Therapy ◽  
Hemophilia A ◽  
Recombinant Dna ◽  
Tolerance Induction ◽  
Coagulation Factors ◽  
Pathogen Transmission ◽  
Recombinant Dna Technology ◽  
Mammalian Cell Cultures ◽  
Main Determinants

AbstractIn high-income countries, the large availability of coagulation factors for replacement therapy of patients with hemophilia A has raised the life expectancy of these lifelong bleeders to that of males from the general population. The practicing clinician is offered a multitude of choices among several commercial brands of factor VIII extracted from human plasma or engineered from mammalian cell cultures by means of recombinant DNA technology. This article has the goal to offer our opinions on how to choose among the different products, that we consider interchangeable relevant to their clinical efficacy in the control of bleeding and safety from pathogen transmission. Hence, the main determinants of our choices are price and the risk of occurrence of factor VIII inhibitory alloantibodies. With this as background, we present the rationale underlying the choices for different categories of patients with severe hemophilia A: previously untreated patients, multiply treated patients, and patients undergoing immune tolerance induction with large doses of factor VIII to eradicate inhibitors. Mention is also made to the possible strategies that should be implemented to make available coagulation factors for replacement therapy in developing countries.

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.

scholarly journals Immunologic Studies of Antihemophilic Factor (AHF, Factor VIII) II. Properties of Cross-reacting Material

Blood ◽  
1970 ◽  
Vol 35 (6) ◽  
pp. 809-820 ◽  
Author(s):  
LEON W. HOYER ◽  
ROBERT T. BRECKENRIDGE
Keyword(s):  
Calcium Phosphate ◽  
Physical Properties ◽  
Factor Viii ◽  
Barium Sulfate ◽  
Genetic Variant ◽  
Hemophilia A ◽  
Procoagulant Activity ◽  
Normal Plasma ◽  
Fraction I ◽  
Antihemophilic Factor

Abstract Patients with a genetic variant of hemophilia A have in their plasmas material which has antigenic characteristics similar to those of antihemophilic factor (AHF). The physical properties of the biologically inactive cross-reacting material (CRM) are like those of AHF from normal plasma. The CRM is concentrated in Cohn fraction I and in cryoprecipitates and is not adsorbed from plasma by calcium phosphate or barium sulfate. It is inactivated by heating to 56° for 30 minutes. The CRM is less sensitive to thrombin inactivation than AHF and is recovered in serum. The similar properties of AHF and CRM support the hypothesis that patients with this genetic variant of hemophilia A synthesize a material similar to AHF but lacking procoagulant activity.

Pharmacokinetic Properties of Recombinant Factor VIII Compared with a Monoclonally Purified Concentrate (Hemofil® M)

1992 ◽  
Vol 68 (04) ◽  
pp. 433-435 ◽  
Author(s):  
M Morfini ◽  
G Longo ◽  
A Messori ◽  
M Lee ◽  
G White ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Recombinant Dna ◽  
Volume Of Distribution ◽  
Pharmacokinetic Properties ◽  
Recombinant Fviii ◽  
Reported Data ◽  
In Vivo Recovery

SummaryA recombinant FVIII preparation, Recombinate™, was compared with a high-purity plasma-derived concentrate, Hemofil® M, in 47 hemophilia A patients in a cross-over evaluation of pharmacokinetic properties. The recombinant material showed a significantly lower clearance, volume of distribution, and higher in vivo recovery, but a similar half-life to the plasma-based product.In a comparison with reported data from other standard concentrates, the recombinant preparation exhibited potentially better pharmacokinetic properties in that its clearance was slower and its half-life was longer.We conclude that the recombinant DNA method of preparation does not adversely affect the biological and pharmacological characteristics of the factor VIII molecule.

scholarly journals Expression of the blood-clotting factor-VIII cDNA is repressed by a transcriptional silencer located in its coding region

Blood ◽  
1995 ◽  
Vol 85 (9) ◽  
pp. 2447-2454 ◽  
Author(s):  
RC Hoeben ◽  
FJ Fallaux ◽  
SJ Cramer ◽  
DJ van den Wollenberg ◽  
H van Ormondt ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Factor Viii ◽  
Hemophilia A ◽  
Recombinant Dna ◽  
Transcription Unit ◽  
Current Treatment ◽  
Clotting Factor ◽  
Large Animal ◽  
Coding Region ◽  
Large Animal Models

Hemophilia A is caused by a deficiency of factor-VIII procoagulant (fVIII) activity. The current treatment by frequent infusions of plasma-derived fVIII concentrates is very effective but has the risk of transmittance of blood-borne viruses (human immunodeficiency virus [HIV], hepatitis viruses). Use of recombinant DNA-derived fVIII as well as gene therapy could make hemophilia treatment independent of blood-derived products. So far, the problematic production of the fVIII protein and the low titers of the fVIII retrovirus stocks have prevented preclinical trials of gene therapy for hemophilia A in large-animal models. We have initiated a study of the mechanisms that oppose efficient fVIII synthesis. We have established that fVIII cDNA contains sequences that dominantly inhibit its own expression from retroviral as well as from plasmid vectors. The inhibition is not caused by instability of the fVIII mRNA (t1/2, > or = 6 hours) but rather to repression at the level of transcription. A 305-bp fragment is identified that is involved in but not sufficient for repression. This fragment does not overlap the region recently identified by Lynch et al (Hum Gene Ther 4:259, 1993) as a dominant inhibitor of RNA accumulation. The repression is mediated by a cellular factor (or factors) and is independent of the orientation of the element in the transcription unit, giving the repressor element the hallmarks of a transcriptional silencer.

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