Pharmacokinetics of plasma-derived and recombinant factor IX - implications for prophylaxis and on-demand therapy

Haemophilia ◽  
2013 ◽  
Vol 19 (6) ◽  
pp. 808-813 ◽  
Author(s):  
S. Björkman
Keyword(s):  
Factor Ix ◽  
On Demand ◽  
Recombinant Factor Ix

Evaluation of the Safety, Efficacy of Recombinant Factor IX (nonacog alfa) in Japanese Patients with Hemophilia B- Interim Result of Post Marketing Surveillance Study -

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3378-3378
Author(s):  
Takashi Suzuki ◽  
Katsuyuki Fukutake ◽  
Kagehiro Amano ◽  
Hideji Hanabusa ◽  
Masashi Taki ◽  
...  
Keyword(s):  
Research Funding ◽  
Factor Ix ◽  
Hemophilia B ◽  
Surveillance Study ◽  
Interim Result ◽  
Average Dose ◽  
Registration System ◽  
On Demand ◽  
Post Marketing Surveillance ◽  
Recombinant Factor Ix

Abstract Abstract 3378 Objective: Nonacog alfa (Benefix®) has been available in Japan since January 2010 and is being used widely for prophylaxis in patients with hemophilia B as the first recombinant factor IX. We have been conducting a surveillance study in order to investigate adverse events, safety and efficacy with routine use conditions in all patients receiving Benefix. The recovery of recombinant factor IX was measured to assess factors affecting appropriate dosing of nonacog alfa. Method: All patients who were administered Benefix were enrolled in this study by central registration system until 300 patients were registered. The initial dose was around 50 IU/kg, but subsequent doses may have been modified according to condition of the patient and recovery. Observation period was 12 and 24 months for previously treated patient (PTP) and previously untreated patients (PUP), respectively. Follow up data (e.g. bleeding episode, adverse event, status of administration, etc) was recorded for every 6 month period. Result: 319 patients including 32 PUPs were registered from 173 institutions during 2 years. 177 patients including 14 PUPs were included in this interim analysis as the data cutoff was Jan 2012. Duration of the observation was 6 to 12 months (PUPs: 6 to 18 months). Disease severity was 52.0% (severe), 28.8% (moderate), 15.8% (mild) and 3.4% (unknown). Total frequency of the administration was 1 to 240 infusions (median: 41 infusions). Some patients received more than one Benefix regimen (e.g. prophylaxis + on demand) and assessment was conducted by each regimen (prophylaxis: 98, on demand: 55, hemostasis during surgery: 13, others: 38). Total 512 bleeding episodes (spontaneous: 440, traumatic: 66, unknown: 6) were reported from 55 patients who received on demand therapy. An average of 2.2 times infusions was needed for hemostasis. The average dose was 41IU/kg. Regarding 98 patients who received prophylactic regimen, the most common regimen was twice-weekly administration (62.4%) and its average dose was 40 IU/kg. Analyzed by age, the average dose was 44 IU/kg and 35 IU/kg for <15 years old and ≥ 15 years old, respectively. No bleeding was observed in 68.3% (by age: 75.0% of <15 years old, 62.8% of ≥ 15 years old). Average frequency of bleeding was 3.8 times (median: 2, max: 45) in 6 months period. Factor IX levels were measured in 82 patients after first dose (median dose: 44IU/kg, range: 17 to 120 IU/kg). Median reciprocal of observed recovery was 1.28 (min-max). Weak negative correlation (r2 = 0.463, p=0.036) was observed between weight and recovery. A correlation was not seen between the recovery and age. Adverse drug reaction was observed 2.3% of patients (2 headaches, 1 vertigo, 1 dyspnea, 1 nausea, 1 urticaria and 1 itching of injection site). No patients developed inhibitor related to nonacog alfa. Conclusion: Nonacog alfa was safe and effective on both prophylactic and on demand regimen in clinical practice. 68.3 % of no bleeding rate was comparable to plasma-derived factor IX. The variability in recovery was consistent with what has been reported by others. This surveillance study is still ongoing and final result will be obtained in year 2014. Disclosures: Suzuki: Pfizer Japan Inc.: Research Funding. Fukutake:Pfizer Japan Inc.: Research Funding. Amano:Pfizer Japan Inc.: Research Funding. Hanabusa:Pfizer Japan Inc.: Research Funding. Taki:Pfizer Japan Inc.: Research Funding. Matsushita:Pfizer Japan Inc.: Research Funding. Shima:Pfizer Japan Inc.: Research Funding. Sakai:Pfizer Japan Inc.: Research Funding. Iizuka:Pfizer Japan Inc: Employment. Shibasaki:Pfizer Japan Inc.: Employment.

The Effect of Prophylactic Recombinant Factor IX and Glycopegylated Factor IX to Normalize Articular Wound Healing Following Hemarthrosis Examined in Hemophilia B Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 549-549
Author(s):  
Junjiang Sun ◽  
Eric Livingston ◽  
Tom Knudsen ◽  
Dougald M. Monroe ◽  
Mirella Ezban ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Wound Healing ◽  
Bone Mineral ◽  
Research Funding ◽  
Factor Ix ◽  
Hemophilia B ◽  
Mineral Density ◽  
On Demand ◽  
Recombinant Factor Ix ◽  
B Mice

Abstract Background Recurrent bleeding into joints results in a crippling arthritis, the consequence of intra-articular (IA) pathologic lysed red blood cell iron and inflammatory signals from macrophages/monocytes. Hemophilic mice that experience joint bleeding develop synovial and osteochondral changes that mimic the changes seen in human hemophilia. We previously examined in hemophilia B mice the efficacy of conventional recombinant factor IX (rFIX) compared to a half-life extended polyethyleneglycol-conjugated factor IX (N9-GP) to support wound healing when administered "on demand" after the initiation of induced joint hemorrhage. In the "on-demand" scenario, N9-GP improved wound healing when compared to rFIX, although neither treatment group demonstrated completely normal joint healing (as observed in hemostatically normal mice that experienced the same injury). We test the hypothesis that the prophylactic use of N9-GP may support wound healing in synovium, cartilage, and bone and may do so more effectively than rFIX. Method: FIX deficient mice were treated prophylactically with either rFIX or N9-GP at the dose of 250 IUnits human factor IX/kg 30 minutes, 24hr or 72hr prior to the induction of unilateral hemarthosis. Injured hemostatically normal (iWT) mice were treated with I.V. normal saline as the controls. Joint diameter was measured daily to quantify joint swelling. Plasma and tissues were harvested from cohorts of mice (n = 8-10/group) at two weeks after hemarthrosis. Pathologic synovial hyperplasia, neovascularization, iron deposition and macrophage infiltration of the synovium were quantified by histologic examination. Integrity of trabecular bone neighboring the hemarthrosis was quantified by microComputed Tomography (mCT). Result: WT mice developed no detectable joint swelling at days 1-14 after the joint bleeding challenge, whereas mice treated prophylactically with rFIX were protected from joint swelling only in the cohort treated 24 hours prior to hemarthrosis. Joint swelling did not develop in groups that received prophylactic N9-GP using any of the 3 schedules. No mouse treated with rFIX (n = 28 total) or N9-GP (n=27 total) developed FIX inhibitors or FIX-binding IgG. Synovitis was graded 0 to 10 by Valentino mouse hemophilic synovitis score, with a mean score in the iWT mice of 1.0±0.5 and in the injured untreated FIX-/- mice of 4.9±1.4. Synovitis was greatly diminished although not eliminated by prophylactic N9-GP given 30 minutes prior to injury (1.7±1.2), and this result contrasted with the relatively less good healing provided by rFIX given 30 minutes prior to injury (3.9±1.1). Synovitis, iron staining, and persistence of macrophages within the joint were each diminished by N9-GP and rFIX prophylaxis. The degree of protection diminished as the interval between dosing and injury increased. Better protection was seen using N9-GP when compared to rFIX at each timepoint. Strikingly, rFIX at this dose provided minimal or no prophylactic protection from synovial neoangiogenesis (vessels/hpf) at two weeks after hemarthrosis even when given at the shortest interval preceding the injury. Injured, untreated FIX-/- mice developed 17.6±5.1 vessels/hpf compared to rFIX given 30 minutes prior to injury (16.1±4.8), 24 hours prior (17.8±5.4) or 72 hours prior (17.1±6.3). In contrast, iWT mice displayed 7.1±3.1 at two weeks after injury, which was comparable to N9-GP given 30 minutes prior to injury (9.4±2.4) and better than N9-GP given 24 hours prior (12.6±3.3) or 72 hours prior (13.1±5.6). Consistent with previous reports, hemophilic mice when compared to iWT mice demonstrated acute losses of bone mineral density in the bone adjacent to the joint experiencing bleeding, as well as structural defects in the number, thickness, and spacing of the bone trabeculae. Prophylactic rFIX or N9-GP given at 30 minutes or 24 hours prior to injury resulted in protection that did not differ statistically from findings in iWT mice. When prophylaxis was given at 72 hours prior to injury, significant volumetric bone mineral density loss of at least 20% was evident in the rFIX group (vBMD 98 mgHA) compared to iWT (131 mgHA) and N9-GP given 72 hours prior (125 mgHA). Conclusion: The support of normal wound healing in joint and bone following hemarthrosis was significantly improved by N9-GP prophylaxis when compared to rFIX in hemophilia B mice, with neoangiogenesis particularly improved. Disclosures Knudsen: Novo Nordisk: Employment. Monroe:Novo Nordisk: Honoraria, Research Funding. Ezban:Novo Nordisk: Employment. Bateman:Novo Nordisk: Honoraria, Research Funding; Baxter: Honoraria, Research Funding. Monahan:CSL Behring: Consultancy, Honoraria; Pfizer: Honoraria; Chatham LLC: Consultancy; Baxter/Baxalta: Consultancy, Honoraria, Research Funding; Prolor: Research Funding; Bayer: Consultancy; Novo Nordisk: Consultancy, Honoraria, Research Funding; Asklepios BioPharmaceutical: Consultancy, Patents & Royalties: Author I.P. licensed by UNC to AskBio, Research Funding.

Recombinant Factor IX

1997 ◽  
Vol 78 (01) ◽  
pp. 261-265 ◽  
Author(s):  
Gilbert C White ◽  
Aime Beebe ◽  
Brenda Nielsen
Keyword(s):  
Factor Ix ◽  
Recombinant Factor Ix

Nonacog Alpha - an Efficient Therapeutic Option in Hemostase Management for Hemophilia Type B in Patients with Elective Arthropalsties

2018 ◽  
Vol 69 (7) ◽  
pp. 1911-1914
Author(s):  
Oana Viola Badulescu ◽  
Razvan Tudor ◽  
Wilhelm Friedl ◽  
Manuela Ciocoiu ◽  
Paul Dan Sirbu
Keyword(s):  
Therapeutic Option ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Joint Disease ◽  
Type B ◽  
Total Endoprosthesis ◽  
Recombinant Factor Ix ◽  
Bleeding Episodes ◽  
Low Incidence ◽  
Articular Pathology

Hemophilia is a hereditary coagulopathy that is largely in the attention of developing countries, not because of its low incidence, but because of the high costs involved in the treatment of the disease and its disabling consequences of the disease, if treated inappropriately. The concentrates of coagulation factors currently available for the substitution treatment of hemophilic patients have undergone additional viral purification and inactivation techniques, in order to achieve a higher infectious safety, an aspect that also implies an increase in treatment costs for these patients. Currently, the major morbidity of patients with hemophilia is represented by the disabling articular pathology, secondary to repetitive bleeding episodes developed in the articular space. Although it has been proved that the prophylactic administration of coagulation factors helps to prevent joint disease in the case of patients that were not subject to prophylaxis, the repeated bleeding in the joints induces synovitis, which is irreversible and may progress despite subsequent prophylaxis. Under these conditions, total joint arthroplasty remains the only solution to reduce both, pain and subsequent bleeding episodes of hemophilic arthropathy. Effective hemostasis is a basic condition for successful interventions in hemophilic patients. In this regard, this paper aims to highlight the effectiveness of Nonacog Alpha, a product that contains recombinant factor IX, in the management of hemostasis, in the case of a patient with type B hemophilia, with indication of total endoprosthesis of the left hip.

scholarly journals Treatment of hemophilia B: focus on recombinant factor IX

2013 ◽  
pp. 33 ◽  
Author(s):  
Massimo Franchini ◽  
Frattini ◽  
Crestani ◽  
Sissa ◽  
Bonfanti
Keyword(s):  
Factor Ix ◽  
Hemophilia B ◽  
Recombinant Factor Ix

scholarly journals Long-term safety and efficacy of extended-interval prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) in subjects with haemophilia B

2017 ◽  
Vol 117 (03) ◽  
pp. 508-518 ◽  
Author(s):  
K.John Pasi ◽  
Kathelijn Fischer ◽  
Margaret Ragni ◽  
Beatrice Nolan ◽  
David J. Perry ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Ix ◽  
Safety And Efficacy ◽  
Haemophilia B ◽  
Treatment Groups ◽  
Fc Fusion Protein ◽  
Recombinant Factor Ix ◽  
Bleeding Episodes ◽  
Supplementary Material

SummaryThe safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents ≥12 years) and Kids B-LONG (children <12 years) studies of subjects with haemophilia B (≤2 IU/dl). Here, we report interim, long-term safety and efficacy data from B-YOND, the rFIXFc extension study. Eligible subjects who completed B-LONG or Kids B-LONG could enrol in B-YOND. There were four treatment groups: weekly prophylaxis (20–100 IU/kg every 7 days), individualised prophylaxis (100 IU/kg every 8–16 days), modified prophylaxis (further dosing personalisation to optimise prophylaxis), and episodic (ondemand) treatment. Subjects could change treatment groups at any point. Primary endpoint was inhibitor development. One hundred sixteen subjects enrolled in B-YOND. From the start of the parent studies to the B-YOND interim data cut, median duration of rFIXFc treatment was 39.5 months and 21.9 months among adults/adolescents and children, respectively; 68/93 (73.1 %) adults/adolescents and 9/23 (39.1 %) children had ≥100 cumulative rFIXFc exposure days. No inhibitors were observed. Median annualised bleeding rates (ABRs) were low in all prophylaxis regimens: weekly (≥12 years: 2.3; <6 years: 0.0; 6 to <12 years: 2.7), individualised (≥12 years: 2.3; 6 to <12 years: 2.4), and modified (≥12 years: 2.4). One or two infusions were sufficient to control 97 % (adults/adolescents) and 95 % (children) of bleeding episodes. Interim data from B-YOND are consistent with data from B-LONG and Kids B-LONG, and confirm the longterm safety of rFIXFc, absence of inhibitors, and maintenance of low ABRs with prophylactic dosing every 1 to 2 weeks.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Switching to recombinant factor IX Fc fusion protein prophylaxis results in fewer infusions, decreased factor IX consumption and lower bleeding rates

2014 ◽  
Vol 168 (1) ◽  
pp. 113-123 ◽  
Author(s):  
Jerry Powell ◽  
Amy Shapiro ◽  
Margaret Ragni ◽  
Claude Negrier ◽  
Jerzy Windyga ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Ix ◽  
Fc Fusion Protein ◽  
Recombinant Factor Ix
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