Pharmacokinetics of a new human plasma‐derived double virus inactivated and nanofiltered factor IX concentrate in previously treated severe or moderately severe haemophilia B patients

Haemophilia ◽  
2019 ◽  
Vol 25 (6) ◽  
Author(s):  
Giancarlo Castaman ◽  
Alessandra Borchiellini ◽  
Elena Santagostino ◽  
Giuseppe Tagariello ◽  
Margit Serban ◽  
...  
Keyword(s):  
Human Plasma ◽  
Factor Ix ◽  
Severe Haemophilia ◽  
Haemophilia B ◽  
Previously Treated

Performances of an Artificial Reagent for the One-stage Factor IX Assay

1975 ◽  
Vol 33 (03) ◽  
pp. 547-552 ◽  
Author(s):  
L Meunier ◽  
J. P Allain ◽  
D Frommel
Keyword(s):  
Human Plasma ◽  
Factor Ix ◽  
Severe Haemophilia ◽  
Normal Human Plasma ◽  
Haemophilia B ◽  
One Stage ◽  
Normal Human ◽  
The One

SummaryA mixture of adsorbed normal human plasma and chicken plasma was prepared as reagent for factor IX measurement using a one-stage method. The substrate was found to be specific for factor IX. Its performances tested on samples displaying factor IX activity ranging from <l%–2,500% compared favorably with those obtained when using the plasma of severe haemophilia B patients as substrate.

Management of Haemophilia in Sweden

1976 ◽  
Vol 35 (03) ◽  
pp. 510-521 ◽  
Author(s):  
Inga Marie Nilsson
Keyword(s):  
Factor Viii ◽  
Total Population ◽  
Age Groups ◽  
Factor Ix ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Haemophilia B ◽  
Human Fraction ◽  
Mild Haemophilia

SummaryThe incidence of living haemophiliacs in Sweden (total population 8.1 millions) is about 1:15,000 males and about 1:30,000 of the entire population. The number of haemophiliacs born in Sweden in 5-year periods between 1931-1975 (June) has remained almost unchanged. The total number of haemophilia families in Sweden is 284 (77% haemophilia A, 23% haemophilia B) with altogether 557 (436 with A and 121 with B) living haemophiliacs. Of the haemophilia A patients 40 % have severe, 18 % moderate, and 42 % mild, haemophilia. The distribution of the haemophilia B patients is about the same. Inhibitors have been demonstrated in 8% of the patients with severe haemophilia A and in 10% of those with severe haemophilia B.There are 2 main Haemophilia Centres (Stockholm, Malmo) to which haemophiliacs from the whole of Sweden are admitted for diagnosis, follow-up and treatment for severe bleedings, joint defects and surgery. Minor bleedings are treated at local hospitals in cooperation with the Haemophilia Centres. The concentrates available for treatment in haemophilia A are human fraction 1-0 (AHF-Kabi), cryoprecipitate, Antihaemophilic Factor (Hyland 4) and Kryobulin (Immuno, Wien). AHF-Kabi is the most commonly used preparation. The concentrates available for treatment in haemophilia B are Preconativ (Kabi) and Prothromplex (Immuno). Sufficient amounts of concentrates are available. In Sweden 3.2 million units of factor VIII and 1.0 million units of factor IX are given per year. Treatment is free of charge.Only 5 patients receive domiciliary treatment, but since 1958 we in Sweden have practised prophylactic treatment of boys (4–18 years old) with severe haemophilia A. At about 5-10 days interval they receive AHF in amounts sufficient to raise the AHF level to 40–50%. This regimen has reduced severe haemophilia to moderate. The joint score is identical with that found in moderate haemophilia in the same age groups. For treatment of patients with haemophilia A and haemophilia B complicated by inhibitors we have used a large dose of antigen (factor VIII or factor IX) combined with cyclophosphamide. In most cases this treatment produced satisfactory haemostasis for 5 to 30 days and prevented the secondary antibody rise.

An open clinical study assessing the efficacy and safety of Factor IX Grifols®, a high-purity Factor IX concentrate, in patients with severe haemophilia B

Haemophilia ◽  
2009 ◽  
Vol 16 (2) ◽  
pp. 240-246 ◽  
Author(s):  
T. LISSITCHKOV ◽  
M. MATYSIAK ◽  
K. ZAWILSKA ◽  
L. GERCHEVA ◽  
A. ANTONOV ◽  
...  
Keyword(s):  
Clinical Study ◽  
High Purity ◽  
Factor Ix ◽  
Severe Haemophilia ◽  
Efficacy And Safety ◽  
Haemophilia B

scholarly journals Phase 1-2 Clinical Trial of a Recombinant AAV5 Vector Containing the Human FIX Gene in Patients with Severe or Moderately Severe Haemophilia B

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5948-5948 ◽  
Author(s):  
Wolfgang A. Miesbach ◽  
Christian Meyer ◽  
Bart Nijmeijer ◽  
Florence Salmon ◽  
Nadina Grosios ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Replacement Therapy ◽  
Research Funding ◽  
Factor Ix ◽  
Activity Level ◽  
Severe Haemophilia ◽  
Haemophilia B ◽  
Commercial Scale ◽  
Number Of Patients ◽  
History Of

Abstract Gene therapy has been successfully used in a research setting in a limited number of patients with severe haemophilia B, primarily using vectors based on adeno-associated virus (AAV) serotype 2 and 8. Several research groups and companies are exploring new developments to improve current treatment strategies to eventually make gene therapy available for a larger number of patients. Pre-existing immunity to AAV capsid proteins may limit the availability of such therapies to small sub-groups of patients. A low prevalence of natural neutralizing antibodies against AAV5 compared with other serotypes has been demonstrated (Calcedo et al., Clin Vaccine Immunol 2009, 18:1586-1588). We use a recombinant AAV5 containing the codon optimized human factor IX gene (AAV5-hFIX), using a baculovirus production process that allows commercial scale manufacturing of the AAV5-hFIX drug product. Human FIX expression levels in macaques treated i.v. with AAV5-hFIX at a dose of 5 × 10^12 gc/kg were high enough to expect therapeutic effect on the haemophiliac phenotype in haemophilia B patients. Such levels were achieved in humans during AAV8-hFIXco clinical study (Nathwani et al., NEJM 2011, 365:2357-2365). hFIX levels in dose-escalating GLP toxicity studies in cynomolgus monkeys and mice showed linear dose responses using doses up to 1 × 10˄14 and 2.3 × 10^14 cg/kg, respectively, and no specific safety concerns. In human studies with AAV5 containing the human porbilinogen deaminase (PBGD) gene, administered in doses up to 2 x 10^13 gc/kg to patients with acute intermittent porphyria, no safety concerns were raised (D’Avola et al., ASGCT, Washington DC, 2014). Importantly, in this study no liver enzyme perturbations were observed following administration of AAV5. The primary objective of the proposed study is to investigate the safety of systemic administration of AAV5-hFIX to adult patients with severe or moderately severe haemophilia B. The multicentre trial has an open-label, uncontrolled, single-dose, dose-ascending design and consists of two cohorts. The study population consists of male patients, aged ≥18 years, with severe or moderately severe haemophilia B and a severe bleeding phenotype [i.e. known FIX deficiency with plasma FIX activity level <1% (severe), or plasma FIX activity level ≥1% and ≤2% (moderately severe) and currently on prophylactic FIX replacement therapy for a history of bleeding, or currently on on-demand therapy with a current or past history of frequent bleeding defined as four or more bleeding episodes in the last 12 months, or chronic haemophilic arthropathy. Patients should have had more than 150 previous exposure days of treatment with FIX protein. Subjects are allocated to one of two cohorts with the following planned dose levels: Cohort 1 (5 subjects) with AAV5-hFIX 5.0 × 10^12 gc/kg and Cohort 2 (5 subjects) with AAV5-hFIX 2.0 × 10^13 gc/kg. Key efficacy assessments include factor IX plasma levels, the need for FIX replacement therapy, incidence of spontaneous bleedings and health-related quality of life measurements. In conclusion, AAV5-hFIX produced in commercial scale represents a novel approach to gene therapy of haemophilia B. Disclosures Miesbach: uniQure: Consultancy; Bayer: Research Funding; Baxter: Research Funding; CSL Behring: Research Funding; Biotest: Research Funding; Octapharma: Research Funding. Meyer:uniQure B. V.: Employment. Nijmeijer:uniQure B. V.: Employment. Salmon:uniQure B. V.: Employment. Grosios:uniQure B. V.: Employment. Petry:uniQure B. V,: Employment. Leebeek:uniQure B. V.: Consultancy; CSL Behring: Research Funding; Baxter: Research Funding.

A Pharmacokinetic Study of the Plasma-Derived Factor IX AlphaNine® and Its Comparison with the Recombinant Factor IX BeneFIX®, in Previously Treated Patients with Severe Hereditary Hemophilia B.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3955-3955
Author(s):  
Vicente R. Cortina ◽  
T. Lissichkov ◽  
K. Zavilska ◽  
M. Matysiak ◽  
L. Gercheva ◽  
...  
Keyword(s):  
Half Life ◽  
Factor Ix ◽  
Hemophilia B ◽  
Severe Haemophilia ◽  
Open Label ◽  
Recombinant Factor Ix ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
In Vivo Recovery

Abstract Objectives The objective of the present study was two fold: first, to determine the pharmacokinetic (PK) profile of the plasma-derived FIX concentrate AlphaNine® in patients with congenital severe haemophilia B (FIX:C 2%). To do this, two PK studies were carried out one six months after the first. The second objective was a comparison of the Alphanine® PK profile with the recombinant Factor IX, BeneFIX®. Patients and methods The first study was a prospective, five-center, open-label, comparative, PK study carried out in 25 severe hemophilia B patients who received 2 single doses of 65–75 IU/kg of AlphaNine® within 6 months (t=0 and t=6). The following parameters were assessed: in vivo recovery, half-life, AUC, mean residence time and clearance. As an extension of the study, a single dose of 65–75 IU/kg of BeneFIX® was administered in 9 out of 25 patients, after a wash-out period of 7–15 days. Results Table 1 summarizes the results obtained when comparing AlphaNine® within a period of time of 6 months (PK1 vs PK2) in 25 patients. Table 2 shows the results obtained when comparing the in vivo recovery of AlphaNine ® vs BeneFIX ® in the 9 patients studied. Conclusions These results confirm that AlphaNine® PK has similar profile as other plasma derived FIX products presently available to treat Hemophilia B patients. In addition, our results show that the recombinant FIX studied, BeneFIX® has a reduced in vivo recovery when is compared to AlphaNine®. Table 1 Parameter AlphaNine® (PK1) t=0 m AlphaNine® (PK2) t=6 m Results are expressed as Mean (SD) In vivo recovery (IU/dl:IU/kg) 1.0 (0.2) 1.2 (0.4) Half-life (h) 34.5 (6.2) 33.7 (5.4) Clearance (ml/min) 0.07 (0.01) 0.07 (0.01) AUC0-inf (IUxh/dl) 1602 (312) 1644 (360) MRT0-inf (h) 35.8 (5.4) 34.6 (5.2) Table 2 Parameter AlphaNine® (PK2) BeneFIX® Results are expressed as Mean (SD); * p<0.05 for the comparison of the in vivo recovery for the BeneFIX® group with the AlphaNine® PK2 In vivo recovery (IU/dl:IU/kg) 1.3 (0.5) 0.8 (0.2)*

Review of Data for Monoclonal Antibody-purified Plasma-derived Factor IX

2011 ◽  
Vol 07 (04) ◽  
pp. 257
Author(s):  
Massimo Morfini ◽  
Wolfhart Kreuz ◽  
◽  
Keyword(s):  
Monoclonal Antibody ◽  
Treatment Strategies ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Recurrent Bleeding ◽  
Haemophilia B ◽  
On Demand ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Major Treatment

Haemophilia B is attributed to a mutation in the gene that produces coagulation factor IX (FIX), resulting in FIX deficiency. Treatment of haemophilia B currently consists of replacing the deficient FIX by intravenous administration of exogenous FIX. There are two major treatment strategies: prophylactic FIX administration (to prevent recurrent bleeding episodes in patients), and on-demand FIX administration (to control existing bleeding in patients when it occurs). Prothrombin complex concentrates (PCCs), which were initially used to treat haemophilia B patients, have been available for approximately 40 years. However, PCCs have been largely replaced by highly purified plasma-derived FIX and recombinant FIX, which have benefited from improvements in purification and viral inactivation, reduction or elimination methods. Monoclonal antibody-purified plasma-derived FIX (MAb pd-FIX) has been extensively evaluated in clinical trials and has proved to be safe and efficacious for surgical prophylaxis and for on-demand and prophylactic treatment in previously untreated and previously treated patients. While intermittent dosing is the conventional method of administration, MAb pd-FIX is also suitable for continuous intravenous infusion; this dosing method has been shown to result in normal haemostasis in patients with haemophilia B. This article reviews the data available for MAb pd-FIX.

scholarly journals Pharmacokinetics, safety and efficacy of a recombinant factor IX product, trenonacog alfa in previously treated haemophilia B patients

Haemophilia ◽  
2017 ◽  
Vol 24 (1) ◽  
pp. 104-112 ◽  
Author(s):  
P. W. Collins ◽  
D. V. K. Quon ◽  
M. Makris ◽  
P. Chowdary ◽  
C. L. Kempton ◽  
...  
Keyword(s):  
Factor Ix ◽  
Safety And Efficacy ◽  
Haemophilia B ◽  
Recombinant Factor Ix ◽  
Previously Treated
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