- International comparative field study evaluating the assay performance of AFSTYLA in plasma samples at clinical hemostasis laboratories. [Journal Article]
- JTJ Thromb Haemost 2017 Dec 23
- CONCLUSIONS: Introduction AFSTYLA (antihemophilic factor [recombinant] single chain) is a novel B-domain truncated recombinant factor VIII (rFVIII). For AFSTYLA, an approximate 50% discrepancy was observed between results of the one-stage (OS) and chromogenic substrate (ChS) FVIII activity assays. An investigation was undertaken to test whether there is a linear relationship between ChS and OS assay results that would allow reliable clinical interpretation of results independent of the assay method used. Aims To provide confidence in future clinical monitoring, this field study investigated the performance of AFSTYLA and a full-length rFVIII (Advate®) in FVIII activity assays routinely performed in clinical laboratories. Methods The comparison of AFSTYLA and Advate was performed in an international, multicenter and blinded field study of simulated post-infusion samples. The study documented the extent of variability between methods and laboratories and characterized the relationship between the ChS and OS assays. Results Results from 23 laboratories demonstrate that intra and interlaboratory variability in OS assays were similar for both products. When comparing within the OS assay format, there was a similar and reagent-correlated variability in response to different activators for both AFSTYLA and Advate. The OS underestimation was highly predictable and consistent across the complete range of FVIII plasma concentrations. Conclusion Post-infusion plasma AFSTYLA levels can be monitored in patients by the OS and ChS assays. The consistent and predictable difference between the two assay formats provides clinicians with adequate guidance on how to interpret the results of the OS assay using a single conversion factor.
- Identification of aggregates in therapeutic formulations of recombinant full-length factor VIII products by sedimentation velocity analytical ultracentrifugation. [Journal Article]
- JTJ Thromb Haemost 2018; 16(2):303-315
- CONCLUSIONS: Background The development of inhibitory anti-factor VIII antibodies is the most serious complication in the management of patients with hemophilia A. Studies have suggested that recombinant full-length FVIII is more immunogenic than plasma-derived FVIII, and that, among recombinant FVIII products, Kogenate is more immunogenic than Advate. Aggregates in biopharmaceutical products are considered a risk factor for the development of anti-drug antibodies. Objective To evaluate recombinant full-length FVIII products for the presence of aggregates. Methods Advate, Helixate and Kogenate were reconstituted to their therapeutic formulations, and subjected to sedimentation velocity (SV) analytical ultracentrifugation (AUC). Additionally, Advate and Kogenate were concentrated and subjected to buffer exchange by ultrafiltration to remove viscous cosolvents for the purpose of measuring s20,wvalues and molecular weights. Results The major component of all three products was a population of ~7.5 S heterodimers with a weight-average molecular weight of ~230 kDa. Helixate and Kogenate contained aggregates ranging from 12 S to at least 100 S, representing ≈ 20% of the protein mass. Aggregates greater than 12 S represented < 3% of the protein mass in Advate. An approximately 10.5 S aggregate, possibly representing a dimer of heterodimers, was identified in buffer-exchanged Advate and Kogenate. SV AUC analysis of a plasma-derived FVIII product was confounded by the presence of von Willebrand factor in molar excess over FVIII. Conclusions Aggregate formation has been identified in recombinant full-length FVIII products, and is more extensive in Helixate and Kogenate than in Advate. SV AUC is an important method for characterizing FVIII products.
- Pattern of bleeding in a large prospective cohort of haemophilia A patients: A three-year follow-up of the AHEAD (Advate in HaEmophilia A outcome Database) study. [Journal Article]
- HHaemophilia 2018; 24(1):85-96
- CONCLUSIONS: These data confirm that the goal of zero bleeds is achievable, although not yet achieved in all patients. Understanding reasons behind the lower response to standard prophylaxis regimens in some patients and personalizing prophylactic treatment may further improve outcome in patients with haemophilia A.
- Analyses of the FranceCoag cohort support differences in immunogenicity among one plasma-derived and two recombinant factor VIII brands in boys with severe hemophilia A. [Journal Article]
- HHaematologica 2018; 103(1):179-189
- Around one third of boys with severe hemophilia A develop inhibitors (neutralizing antibodies) against their therapeutic factor VIII product. This adverse effect may result in more life-threatening b...
Around one third of boys with severe hemophilia A develop inhibitors (neutralizing antibodies) against their therapeutic factor VIII product. This adverse effect may result in more life-threatening bleeding, disability, impaired quality of life, and costly care. We compared the incidence of inhibitors in boys treated with the three factor VIII products most used in France: one plasma-derived (Factane) and two recombinant products (Advate and Kogenate Bayer). A previously untreated cohort of patients was created in 1994 to investigate risk factors for inhibitor development. We selected boys with severe hemophilia A (factor VIII <1 IU/dL) first treated with one of the three factor VIII products studied. Details of product infusions, inhibitor assays and main fixed and time-varying inhibitor risk factors were recorded for the first 75 exposure days. Three outcomes (all inhibitors, high-titer inhibitors and subsequently treated inhibitors) were analyzed by univariate and multivariate Cox models. We studied 395 boys first treated between 2001 and 2016 (131, 137, and 127 with Factane, Advate, and Kogenate Bayer, respectively). Clinically significant inhibitors were diagnosed in 121 patients (70 high-titer). The incidence of high-titer inhibitors was significantly associated with the factor VIII product received (P=0.005): the cumulative incidence at 75 exposure days was 12.7% (95% CI: 7.7-20.6) with Factane, 20.4% (95% CI: 14.0-29.1) with Advate, and 31.6% (95% CI: 23.5-41.7) with Kogenate Bayer. The low inhibitor incidence observed with Factane is concordant with recent findings from the SIPPET randomized trial. These consistent results from observational and experimental studies should lead to improved care for previously untreated patients and cost savings for healthcare systems worldwide.
- Efficacy of Octocog Alfa (Advate) in a Child with Type 3 von Willebrand Disease and Alloantibodies. [Case Reports]
- JCJ Clin Med 2017 Sep 18; 6(9)
- Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder and is caused by either a quantitative and/or qualitative defect of the multimeric glycoprotein vonWillebrand factor (VWF...
Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder and is caused by either a quantitative and/or qualitative defect of the multimeric glycoprotein vonWillebrand factor (VWF).[...].
- Meta-analysis on incidence of inhibitors in patients with haemophilia A treated with recombinant factor VIII products. [Journal Article]
- BCBlood Coagul Fibrinolysis 2017; 28(8):627-637
- : Recent cohort studies showed differences in inhibitor incidence in previously untreated patients (PUPs) with haemophilia A treated with recombinant factor VIII (rFVIII) concentrates. We carried out...
: Recent cohort studies showed differences in inhibitor incidence in previously untreated patients (PUPs) with haemophilia A treated with recombinant factor VIII (rFVIII) concentrates. We carried out a systematic literature search and meta-analysis for all randomized clinical trials and observational studies published from 1 January 1988 to 31 August 2015, to assess the incidence of inhibitor development and the relationship with rFVIII product used in PUPs and minimally treated patients (MTPs, ≤5 previous exposure days), with severe haemophilia. The primary outcome measure was development of all inhibitors and high-titre inhibitors. We computed pooled meta-analytic estimates according to the rFVIII product used with the inverse-variance method, assuming a fixed, or a random-effects model if significant between-studies heterogeneity was present. Out of 781 articles, 16 published between 1998 and 2015 were included in the meta-analysis, involving a total of 2094 haemophilia A PUPs or MTPs. The pooled estimate of all inhibitors was 0.27 (95% confidence interval 0.23-0.31). No significant difference in pooled inhibitor incidence across products was found (P = 0.72). Meta-analysis of studies reporting inhibitor hazard ratios with different rFVIII products, adjusted to different risk factors, showed that PUPs/MTPs treated with Advate had a pooled inhibitor hazard ratio estimate of 0.63 (95% confidence interval 0.48-0.83) as compared with Kogenate FS. The overall inhibitor incidence in PUPs/MTPs was 27%. Differences between products were found considering hazard ratios in which potential confounders were taken into account.
- Evaluation of recombinant factor VIII Fc (Eloctate) activity by thromboelastometry in a multicenter phase 3 clinical trial and correlation with bleeding phenotype. [Journal Article]
- BCBlood Coagul Fibrinolysis 2017; 28(7):540-550
- : The aim of this study was to compare the hemostatic efficacy of recombinant factor VIII Fc (rFVIIIFc) (Eloctate) and Advate by ex-vivo rotation thromboelastometry (ROTEM) of whole blood and to expl...
: The aim of this study was to compare the hemostatic efficacy of recombinant factor VIII Fc (rFVIIIFc) (Eloctate) and Advate by ex-vivo rotation thromboelastometry (ROTEM) of whole blood and to explore potential ROTEM parameters that may be more predictive of a patient's bleeding tendency than plasma FVIII activity. Thirteen clinical sites were selected to perform ROTEM on freshly collected blood samples from 44 patients in the phase 3 study for rFVIIIFc, including 16 patients undergoing sequential pharmacokinetic assessment of Advate and rFVIIIFc. Equivalent hemostatic activity was observed for rFVIIIFc and Advate in postinfusion samples, followed by improvements for rFVIIIFc in clotting time, clot formation time and alpha angle (α) for a longer duration than Advate, consistent with the pharmacokinetic improvements reported previously for rFVIIIFc. Our study did not demonstrate a statistical correlation between a patient's ROTEM activity at baseline or at trough and the occurrence of spontaneous bleeds while on prophylactic therapy. However, an association was observed between postinfusion clotting time and the occurrence of one or more spontaneous bleeds vs. no bleeds over a follow-up period of 1 year (P = 0.003). How well a patient's whole blood clotting deficiency is corrected after a dose of FVIII may be an indicator of subsequent bleeding tendency in patients with otherwise equivalent FVIII peak and trough levels. The technical challenges of standardizing the ROTEM, largely overcome in the current study, may however preclude the use of this method for widespread assessment of global hemostasis unless additional assay controls or normalization procedures prove to be effective.
- Large scale studies assessing anti-factor VIII antibody development in previously untreated haemophilia A: what has been learned, what to believe and how to learn more. [Review]
- BJBr J Haematol 2017; 178(1):20-31
- Minimizing the risk of inhibitor development by acting on modifiable risk factors remains a sensible goal for treatment optimization in haemophilia A. By critically appraising published studies asses...
Minimizing the risk of inhibitor development by acting on modifiable risk factors remains a sensible goal for treatment optimization in haemophilia A. By critically appraising published studies assessing inhibitor development, this review addresses the role of studies in previously untreated patients (PUPs) for establishing the immunogenicity of new concentrates, suggest novel research design to be adopted in future studies and discuss clinical practice implications of the reported differential immunogenicity of Kogenate Bayer and Advate factor VIII concentrates. Three considerations are relevant here: (i) all of the existing concentrates, when tested following the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee recommendation, were shown to be safe; as a consequence, (ii) when considering using any newly introduced product, one should be aware that it could, in future, turn out to be as immunogenic as Kogenate Bayer, and (iii) at the population level, it might be wiser not to use Kogenate Bayer in PUPs, if the choice is against Advate. When presenting the risk of developing inhibitors to the individual patient (or their family), the message remains that the risk can be as high as 40%, without any efficient instrument to predict individual inhibitor risk. Patients should be invited to enrol into a randomized registry trial, including random assignment to trials with new investigational products.
- Turoctocog Alfa -- Benefit Assessment According to §35a Social Code Book V [BOOK]
- BOOKInstitute for Quality and Efficiency in Health Care (IQWiG): Cologne, Germany
- The aim of the present report is to assess the added benefit of turoctocog alfa compared with the appropriate comparator therapy (ACT) in the treatment and prophylaxis of bleeding in patients with ha...
The aim of the present report is to assess the added benefit of turoctocog alfa compared with the appropriate comparator therapy (ACT) in the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). The Federal Joint Committee (G-BA) specified the ACT for the therapeutic indication as follows:recombinant or human plasma-derived coagulation factor VIII products. The company chose the recombinant coagulation factor octocog alfa as one of the options specified as ACT by the G-BA, but limited its selection to a third-generation octocog alfa (Advate). This approach was not accepted. According to the G-BA’s specification, all products containing the drug octocog alfa would have to be considered. The ACT specified by the G-BA is therefore used for the assessment. The assessment was conducted based on patient-relevant outcomes.
New Search Next
- Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. [Multicenter Study]
- HHaemophilia 2017; 23(2):238-246
- CONCLUSIONS: Twice-weekly prophylaxis with BAX 855 was safe and efficacious in paediatric PTPs with severe haemophilia A.