scholarly journals Comparative field study: impact of laboratory assay variability on the assessment of recombinant factor IX Fc fusion protein (rFIXFc) activity

2014 ◽  
Vol 112 (11) ◽  
pp. 932-940 ◽  
Author(s):  
Yang Buyue ◽  
Sara Bardan ◽  
Robert Peters ◽  
Haiyan Jiang ◽  
George Kamphaus ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Field Study ◽  
Factor Ix ◽  
One Stage ◽  
Chromogenic Assay ◽  
Fc Fusion Protein ◽  
Recombinant Factor Ix ◽  
Assay Methods ◽  
The Mean ◽  
The One

SummaryDue to variability in the one-stage clotting assay, the performance of new factor IX (FIX) products should be assessed in this assay. The objective of this field study was to evaluate the accuracy of measuring recombinant FIX Fc fusion protein (rFIXFc) activity in clinical haemostasis laboratories using the one-stage clotting assay. Human haemophilic donor plasma was spiked with rFIXFc or BeneFIX® at 0.80, 0.20, or 0.05 IU/ml based on label potency. Laboratories tested blinded samples using their routine one-stage assay and in-house FIX plasma standard. The mean spike recoveries for BeneFIX (n=30 laboratories) were 121 %, 144 %, and 168 % of expected at nominal 0.80, 0.20, and 0.05 IU/ml concentrations, respectively. Corresponding rFIXFc spike recoveries were 88 %, 107 %, and 132 % of expected, respectively. All BeneFIX concentrations were consistently overestimated by most laboratories. rFIXFc activity was reagent-dependent; ellagic acid and silica gave higher values than kaolin, which underestimated rFIXFc. BeneFIX demonstrated significantly reduced chromogenic assay activity relative to one-stage assay results and nominal activity, while rFIXFc activity was close to nominal activity at three concentrations with better dilution linearity than the typical one-stage assay. In conclusion, laboratory- and reagent-specific assay variabilities were revealed, with progressively higher variability at lower FIX concentrations. Non-parallelism against the FIX plasma standard was observed in all one-stage assays with rFIXFc and BeneFIX, leading to significant overestimation of FIX activity at lower levels and generally high inter-laboratory variability. Compared to the accuracy currently achieved in clinical laboratories when measuring other rFIX products, most laboratories measured rFIXFc activity with acceptable accuracy and reliability using routine one-stage assay methods and commercially available plasma standards.

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

scholarly journals Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-Fc fusion protein: A randomized trial

2019 ◽  
Vol 3 (2) ◽  
pp. 268-276 ◽  
Author(s):  
Carmen Escuriola Ettingshausen ◽  
Inga Hegemann ◽  
Mindy L. Simpson ◽  
Adam Cuker ◽  
Roshni Kulkarni ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Randomized Trial ◽  
Protein A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Fc Fusion Protein ◽  
Recombinant Factor Ix

scholarly journals Validation of the manufacturing process used to produce long‐acting recombinant factor IX Fc fusion protein

Haemophilia ◽  
2014 ◽  
Vol 20 (4) ◽  
Author(s):  
J. McCue ◽  
D. Osborne ◽  
J. Dumont ◽  
R. Peters ◽  
B. Mei ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Manufacturing Process ◽  
Factor Ix ◽  
Fc Fusion Protein ◽  
Recombinant Factor Ix ◽  
Long Acting

Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B-LONG): results from a multicentre, non-randomised phase 3 study

2017 ◽  
Vol 4 (2) ◽  
pp. e75-e82 ◽  
Author(s):  
Kathelijn Fischer ◽  
Roshni Kulkarni ◽  
Beatrice Nolan ◽  
Johnny Mahlangu ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Ix ◽  
Phase 3 ◽  
Haemophilia B ◽  
Fc Fusion Protein ◽  
Recombinant Factor Ix

Pharmacokinetic In Vivo Comparison Using 1-Stage and Chromogenic Substrate Assays with Two Formulations of Hemofil-M

1996 ◽  
Vol 76 (06) ◽  
pp. 0950-0956 ◽  
Author(s):  
Christine Lee ◽  
Trevor Barrowcliffe ◽  
Gordon Bray ◽  
Ed Gomperts ◽  
Anthony Hubbard ◽  
...  
Keyword(s):  
Factor Viii ◽  
Pharmacokinetic Studies ◽  
Chromogenic Substrate ◽  
Single Centre ◽  
One Stage ◽  
Chromogenic Assay ◽  
The Usa ◽  
The Mean ◽  
The One

SummaryIn a study to demonstrate the safety and pharmacokinetics (half-life and recovery) of two different method M purified AHF (Hemofil-M) concentrates processed in the USA and Spain, two different methods of factor VIII assay (one-stage clotting and chromogenic) have been compared in vivo. The study was a single centre blinded, randomised, crossover study. Twelve patients with severe haemophilia A (VIII: C <2 u/dl) were divided into two subgroups of six. None had received factor VIII concentrate within 48 h preceding the study. Twenty-four pharmacokinetic studies were performed in the 12 patients. Each subgroup received two different lots of study material (US and Spanish) at a dose of 50 u/kg seven days apart. A second randomisation was nominal potency, high: 1000 u or mid: 500 u per vial. The potency label was a one-stage clotting assay using the mega I standard. A standard pharmacokinetic study was performed over 24 h and each blinded sample was analysed in duplicate by a one-stage clotting (aPTT) and a chromogenic (Chromogenix AB; CS) assay at the Royal Free and NIBSC. Pharmacokinetic modelling was performed. The mean label for Hemofil-M using the chromogenic substrate assay was 79% that using the one stage assay (Mega I standard). The recovery was 17-28% higher measured by chromogenic compared to the clotting assay. Since most clinicians use the clotting assay, potency labelling using the chromogenic assay, will overestimate predicted Hemofil-M recovery by as much as 25%.

scholarly journals Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B

2013 ◽  
Vol 369 (24) ◽  
pp. 2313-2323 ◽  
Author(s):  
Jerry S. Powell ◽  
K. John Pasi ◽  
Margaret V. Ragni ◽  
Margareth C. Ozelo ◽  
Leonard A. Valentino ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Ix ◽  
Hemophilia B ◽  
Phase 3 ◽  
Fc Fusion Protein ◽  
Recombinant Factor Ix
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