Faculty Opinions recommendation of Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A.

SummaryInhibitor development represents the most serious side effect of haemophilia treatment. Any difference in risk of inhibitor formation depending on the product used might be of clinical relevance. It was this study’s objective to assess inhibitor development according to clotting factor concentrate in severe haemophilia A and B. The European Haemophilia Safety Surveillance (EUHASS) was set up as a study monitoring adverse events overall and according to concentrate. Since October 2008, inhibitors were reported at least quarterly. Number of treated patients was reported annually, specifying the number of patients completing 50 exposure days (Previously Untreated Patients, PUPs) without inhibitor development. Cumulative incidence, incidence rates and 95 % confidence intervals (CI) were calculated. Data from October 1, 2008 to December 31, 2012 were analysed for 68 centres that validated their data. Inhibitors developed in 108/417 (26 %; CI 22–30 %) PUPs with severe haemophilia A and 5/72 (7 %; CI 2–16%) PUPs with severe haemophilia B. For Previously Treated Patients (PTPs), 26 inhibitors developed in 17,667 treatment years [0.15/100 treatment years; CI 0.10–0.22) for severe haemophilia A and 1/2836 (0.04/100; (CI 0.00–0.20) for severe haemophilia B. Differences between plasma-derived and recombinant concentrates, or among the different recombinant FVIII concentrates were investigated. In conclusion, while confirming the expected rates of inhibitors in PUPs and PTPs, no class or brand related differences were observed.

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Efficacy and safety of the drug Octofactor in prophylactic treatment in patients with severe haemophilia A

Russian Journal of Pediatric Hematology and Oncology ◽

10.17650/2311-1267-2018-5-3-60-73 ◽

2018 ◽

Vol 5 (3) ◽

pp. 60-73 ◽

Cited By ~ 1

Author(s):

T. A. Andreeva ◽

V. Yu. Zorenko ◽

I. L. Davydkin ◽

V. N. Konstantinova ◽

O. E. Zalepukhina ◽

...

Keyword(s):

Hemophilia A ◽

Bleeding Episode ◽

Coagulation Factor ◽

Preventive Treatment ◽

Haemophilia A ◽

Severe Haemophilia ◽

Efficacy And Safety ◽

Spontaneous Bleeding ◽

Bleeding Episodes ◽

Blood Coagulation Factor Viii

Relevance.The development of a new recombinant blood coagulation factor VIII preparation is a promising step towards optimizing the treatment of hemophilia A. An introduction of a new medication into clinical practice precedes a clinical trials to evaluate the efficacy and safety.Materials and methods.The efficacy and safety of the domestic recombinant B-domain deleted blood coagulation factor VIII (FVIII) (moroctocog alfa, Octofactor®, JSC “GENERIUM”) were studied in the preventive treatment of 31 patients aged 21 to 52 years with severe haemophilia A. The Octofactor was administered in doses of 40 ± 5 IU/kg 3 times per week at intervals of at least 48 hours for 21 ± 1 weeks.Results.The efficacy of therapy was evaluated in 30 patients, since 1 patient refused to participate in the trial after the first injection of the study medication. There were registered 43 episodes of bleeding among 11 patients in the course of the preventive treatment with Octofactor. The average number of bleeding episodes was 1.4 ± 2.58. There were 43 bleeding episodes, 9 (20.9 %) of them were posttraumatic, 34 (79.1 %) of them were spontaneous. The average number of the spontaneous bleeding episodes (a major criterion of the efficacy) was 1.13 ± 2.19, which showed a low incidence of exacerbations of the hemorrhagic syndrome in the course of preventive treatment with Octofactor. Among all registered bleeding episodes there were 6 (14 %) mild episodes, 37 (86 %) moderate episodes. Among all spontaneous bleedings there were 6 mild episodes (17.6 %), 28 (82.4 %) moderate episodes. All posttraumatic bleedings were moderate. The vast majority (36, or 83.7 %) of bleeding episodes were stopped with administration of the Octofactor. The average number of administrations of the Octofactor for arresting 1 bleeding episode was 1.2 ± 0.56, for 1 spontaneous bleeding episode – 1.2 ± 0.59. On average, it was required to administer 3534.9 ± 2329.02 IU of the Octofactor to stop 1 episode of bleeding. In the vast majority of patients with severe hemophilia A (83.3–86.7 %), the remaining activity FVIII was 1 % or more after the administration of the Octofactor in 48 hours. The total amount of the Octofactor, introduced for the prevention of bleeding, was 6,107,000 IU, to stop bleeding – 152,000 IU. The safety of therapy was evaluated in 31 patients. There were recorded 25 adverse events (AE) in 17 patients. Among them the laboratory ones prevailed in 23 (92 %) cases, which is not associated with the use of the trial medication. There were noted nausea and an unpleasant aftertaste in the mouth in 1 patient during the first administration of the Octofactor, and therefore he refused to continue to participate in the trial. Causality 2 AE with the study drug was regarded as definite. Such AE are expected and described in the instructions to the preparation. All AE were not serious and mild and resolved without outcomes. There were no presented thromboembolic events and immunogenic reactions.Conclusions.The obtained data testify to the efficacy and safety of the Octofactor both for preventive measures and for stopping bleeding in adult patients with severe hemophilia A.

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Pharmacokinetics, Coagulation Factor Consumption, and Product Efficacy in Patients Crossing Over from Full-Length FVIII to B-Domain Deleted R-FVIII and Back to Full-Length FVIII.

Blood ◽

10.1182/blood.v112.11.2269.2269 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2269-2269

Author(s):

Catherine J Rea ◽

Alex Dunkerley ◽

Benny Sorensen ◽

Savita Rangarajan

Keyword(s):

Clinical Efficacy ◽

Half Life ◽

Coagulation Factor ◽

Outcome Data ◽

Full Length ◽

Haemophilia A ◽

Severe Haemophilia ◽

Efficacy And Safety ◽

Significant Difference ◽

Recovery Times

Abstract Introduction: Treatment with B-domain deleted recombinant factor VIII (BDD-rFVIII) has proven to be effective and safe both in clinical trials and post marketing surveillance studies. However, intermittent concerns have been raised regarding the pharmacokinetic performance, efficacy and incidence of inhibitor formation with the BDD-rFVIII product. Aims: The objective of the present study was to perform a retrospective survey of half-life measurements, clinical efficacy and safety in patients with severe Haemophilia A, when switching treatment from full-length FVIII (FL-FVIII) to BDD- rFVIII and then back to full-length FVIII. We hypothesized that the biological half-life of FVIII would be equal regardless of the product used. Furthermore, we hypothesized that the total factor consumption and bleeding frequency would be indistinguishable irrespective of product used. Finally, we report on safety as evaluated by development of inhibitors and clinical outcome following surgery. Methods: Patients treated with BDD-rFVIII (between 1998 and 2008) were identified from an in-house database. Data collected included annual half-life (T/2) and recovery times (K values), total coagulation factor consumption, and number of bleeds per year as measures of clinical efficacy. Safety data consisted of surgical outcome data and incidence of inhibitor formation. The information was extracted from electronic databases and verified by a review of patients’ clinical notes. The outcome data was non-parametric, hence, paired analysis was performed using Wilcoxon signed rank test and Friedman ANOVA. Data is given as a median value and range. P-value < 0.05 was set as level of statistical significance. Results: In total, 70 patients received BDD-rFVIII on at least one occasion. Following a specified list of criteria, evaluable data was obtainable for 15 males, all with verified severe Haemophilia A (FVIII:C <1%). The average age was 10.2 years (median 10, range 4–17). The median duration on BDD-rFVIII was 30 months (range 20–54). Using the one-way non-parametric ANOVA, no statistically significant difference was detected between the half-life and recovery times recorded during the switch from FL-FVIII (T/2 median 9.15 hours, range 6.4–22; K median 2.7, range 2.0–3.4) to BDD-rFVIII (T/2 median 9.7, range 4.7–16.8; K median 1.8, range 1.0–3.5) and back to FL-FVIII (T/2 median 9.0, range 5.0–19.5; K median 2.0, range 1.6–2.8). Furthermore, there was no significant difference in coagulation factor usage (BDD-rFVIII median 4803 iu/kg/year, range 659–11304; FL-FVIII median 5349, range 1691–10146), nor number of reported bleeds (BDDrFVIII median 6, range 0–24; FL-FVIII median 5.0, range 0–17). None of the 15 patients developed an inhibitor on BDD-rFVIII. Of the total 70 patients, 11 received BDD-rFVIII to cover surgical procedures (8 minor, 3 major interventions). There were no reports of excess bleeding. Conclusions: In this retrospective survey, BDD-rFVIII was found to be equivalent to other FVIII products in terms of half-life measurements, clinical efficacy and safety.

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Absence of Inhibitors in Previously Untreated Patients with Severe Haemophilia A after Exposure to a Single Intermediate Purity Factor VIII Product

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657681 ◽

1997 ◽

Vol 78 (03) ◽

pp. 1027-1029 ◽

Cited By ~ 48

Author(s):

T T Yee ◽

M D Williams ◽

F G H Hill ◽

C A Lee ◽

K J Pasi

Keyword(s):

Factor Viii ◽

High Purity ◽

Specific Activity ◽

Haemophilia A ◽

Severe Haemophilia ◽

True Incidence ◽

Conventional Fractionation ◽

Heat Treated ◽

Recombinant Fviii ◽

Von Willebrand

SummaryUse of high purity and recombinant factor VIII (FVIII) concentrates has been thought to be associated with an increased incidence of FVIII inhibitors in patients with severe haemophilia A. Comparison with comparable historical control groups has suggested that the true incidence of inhibitors in patients with severe haemophilia A was ~20-25%, similar to the incidence seen with new high purity and recombinant FVIII products.We have conducted a study of inhibitor development in a cohort of 37 boys with severe haemophilia A (VIII: C <2 u/dl) exposed only to a single FVIII concentrate (BPL 8Y) with no previous blood or blood product exposure. This factor VIII concentrate is an intermediate purity product with a specific activity of ~2 IU/mg protein and contains well preserved von Willebrand factor multimers. It is manufactured by conventional fractionation technologies and terminally dry heat treated at 80° C for 72 h.

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NuProtect: Immunogenicity, efficacy and safety of treatment with Human-cl rhFVIII in previously untreated patients with severe haemophilia A

http://isrctn.org/> ◽

10.1186/isrctn50040185 ◽

2013 ◽

Author(s):

Raina Liesner

Keyword(s):

Haemophilia A ◽

Severe Haemophilia ◽

Efficacy And Safety

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Case Report on a Female Patient with Congenital Haemophilia a and An Acquired Type-2 Inhibitor to FVIII

Blood ◽

10.1182/blood.v112.11.4525.4525 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4525-4525

Author(s):

Karin Kurnik ◽

Christoph Bidlingmaier

Keyword(s):

Half Life ◽

Female Child ◽

Haemophilia A ◽

Severe Haemophilia ◽

Hormonal Change ◽

Fviii Inhibitor ◽

Intron 22 Inversion ◽

Depth Analysis ◽

Recombinant Fviii

Abstract Only rare cases of female haemophilia have been reported. Moreover, no case of congenital haemophilia A associated with an acquired type-2 inhibitor to FVIII in a female child has been described in literature yet. We report the case of a 15-year old girl, diagnosed with severe haemophilia A (FVIII:C <1%) at the age of 13 months. Her father suffered from severe haemophilia A (FVIII:C <1%) due to an intron 22 inversion. In the girl both an intron 22 inversion and a non-random X-inactivation were found. At 3 years the girl received prophylactic treatment, and recombinant FVIII (3 × 40 IU/kg/week) from 6 years of age. Bleeding episodes were rare. Aged 13 she developed two large spontaneous haematomas. In-depth analysis confirmed decreased FVIII-recovery, –half-life and an inhibitor titre of 7.6 BU following type-2 kinetics (haemophilic autoantibodies). All of the few reported children with an aquired FVIII inhibitor presented with other autoimmune diseases or had used penicillin. Our patient showed none of this, but interestingly experienced menarche 4 weeks after inhibitor detection. This lets us speculate that the ethiology of the inhibitor formation in our patient at the time of hormonal change might be similar to that in pregnant or postpartum women. Taking into account the recommendations of Ma et al. (2006) regarding inhibitor development during pregnancy in healthy women, we initiated a modified ITI with 75 IU/kg rFVIII concentrate (4,000 IU per infusion) every other day without additional immunosuppressive therapy. After 6 weeks of ITI, inhibitor titres declined and became negative after 8 months, resulting in a normal FVIII half-life till now.

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