scholarly journals Critical Review of the Pivotal Studies of Four rFVIII Products for the Treatment of Hemophilia A Patients: The Role of Octocog Alfa

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Matteo Nicola Dario Di Minno ◽  
Lucia D'Angiolella ◽  
Paolo Angelo Cortesi ◽  
Angelo Claudio Molinari ◽  
Lorenzo Giovanni Mantovani
Keyword(s):  
Hemophilia A ◽  
Similar Efficacy ◽  
Severe Form ◽  
The Other ◽  
Clotting Factor ◽  
Management Options ◽  
Structural Modifications ◽  
Bayer Healthcare ◽  
Recombinant Fviii

INTRODUCTION: Hemophilia A is a rare congenital bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). The severe form of the disease is characterized by spontaneous bleeds, especially into the joints. Prophylaxis, based on regularly intravenous administration of the missing factor to avoid hemorrhages, represents the gold standard of treatment. In recent years, new products that significantly improve the treatment management options for patients with hemophilia have become available in the market.OBJECTIVE: To critically evaluate the pivotal studies of recombinant FVIII (rFVIII) products, approved in Europe within the first half of 2018 having obtained the indication for a prophylaxis dosing regimen based also on a twice weekly infusion frequency or even less, highlighting their limitations or strengths.METHODS: A systematic literature search was conducted, and several databases (PubMed and Embase) were consulted.RESULTS: Nine clinical trials involving patients with severe hemophilia A without inhibitor were included in this analysis. Four rFVIII products (Elocta®, Biogen, Cambridge, MA, USA; Kovaltry®, Bayer HealthCare Pharmaceuticals, Germany; Afstyla®, CSL Behring GmbH, Germany; Adynovi®, Baxalta Innovation GmbH, Austria) with different pharmacokinetic profiles were evaluated. The trials included in this analysis had different designs and heterogeneous methods were utilized to assess the study outcomes. The baseline characteristics of the patients enrolled in the studies were also often different and sometimes not adequately described. LEOPOLD II, a trial to compare prophylaxis to on-demand therapy with an unmodified rFVIII product (Kovaltry®, octocog alfa), was the only completely randomized trial that enrolled a more critical patient population in terms of compromised joint condition than the other studies. Based on these side-by-side comparison, Octocog alfa reported similar efficacy, in terms of annualized bleeding rate, to the other rFVIII products, including extended half-life.CONCLUSIONS: Even without structural modifications, octocog alfa may be considered a useful treatment option for two times a week prophylaxis in a selected population of haemophilia patients.

BAY 94–9027, a PEGylated Recombinant Human FVIII, Shows Less Immunogenicity Compared to Un-PEGylated Recombinant FVIII

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2214-2214 ◽  
Author(s):  
Inge A Ivens ◽  
Ruprecht Zierz ◽  
Jesper Haaning ◽  
Thomas McDonald
Keyword(s):  
Neutralizing Antibodies ◽  
Hemophilia A ◽  
Control Release ◽  
Human Protein ◽  
Coagulation System ◽  
Dependent Manner ◽  
Employment Equity ◽  
Bayer Healthcare ◽  
Equity Ownership ◽  
Recombinant Fviii

Abstract Abstract 2214 Background: BAY 94–9027, a recombinant FVIII candidate containing a single, large, branched polyethylene glycol (PEG) molecule conjugated to a specific amino acid, is intended for replacement therapy in hemophilia A. It has been demonstrated to have extended efficacy due to prolonged half life compared to un-PEGylated FVIII in preclinical models(Mei et al. Blood, 2010 118(2) 270–279). This may allow less frequent treatment than with current FVIII products. Methods: Binding (bAB) and activity neutralizing antibodies (nAB) were measured in 3 animal models: hemophilia A mice (FVIII deficient), normal rats and normal rabbits, both with a normal coagulation system. Male hemophilia A mice received once weekly intravenous (IV) injections of BAY 94–9027 for 5 weeks. An un-PEGylated rFVIII molecule (rFVIII) was injected as comparator at the same frequency to give comparable exposure by AUC or dose. Normal rats and rabbits were dosed IV every other day for 2 weeks and blood samples were analyzed for antibodies during treatment and after the end of treatment. Analysis of bABs was based on an ELISA assay. The analysis of nABs was based on a modified FVIII Chromogenic assay (Coatest SP FVIII, Dia Pharma) assay. nAB titers were defined as 50% inhibition of 1 IU/mL rFVIII (in accordance to the definition of FVIII Bethesda units). Results: Previous nonclinical experiments show that animals are likely to have a much higher frequency of anti-FVIII antibody formation than is seen in humans due to the foreignness of this human protein in animals. As expected, antibodies to BAY 94–9027 or rFVIII developed in hemophilia A mice, rats and rabbits since the human protein acts as antigen. In the day 21 and day 36 mouse samples, bABs and nABs against BAY 94–9027 and rFVIII were detected in a time- and dose-dependent manner. By day 21 (after 3 administrations), mice treated with rFVIII showed statistically higher mean titers and more mice had measurable antibodies compared to animals treated with BAY 94–9027 at the same dose. By day 36 (after 5 administrations), animals treated with rFVIII showed statistically higher mean titers than those treated with BAY 94–9027 when comparing both, doses or overall exposure (AUC). At the end of the study, 17/36 mice (47%) treated with BAY 94–9027 had bAB titers, of which 8 (47% of animals with binding antibodies or 22% of all mice treated with BAY 94–9027) showed neutralizing (inhibitory) potential. Whereas, 20/24 (83%) mice treated with rFVIII (un-PEGylated comparator) had detectable bAB titer, of which 18 (90% of animals with binding antibodies or 75% of all animals treated with rFVIII) showed neutralizing potential. In normal rats and rabbits anti-drug bAB and nABs were assessed on days 7, 9 and 15 during treatment and twice after the end of the 2 week treatment. Results confirmed the findings in Hemophilia A mice that, generally more animals responded with bAB and nABs to rFVIII than with BAY 94–9027, the PEGylated protein. Conclusions: The results indicate that BAY 94–9027, which has the same acute efficacy and prolonged duration of protection from bleeding, as seen in hemophilia A mouse efficacy studies (Mei et al. Blood, 2010 118(2) 270–279), was significantly less immunogenic in hemophilia A mice, normal rats and normal rabbits when compared to un-PEGylated rFVIII. This confirms findings with other PEGylated proteins, which indicate that specially branched PEGs may shield antigenic epitopes on the protein surface and can make it less immunogenic (BN Novicov et al. J Control Release, 2010. doi:10.1016/j.jconrel.2010. 06.003). Clinical studies need to assess if these findings can be confirmed in humans. Disclosures: Ivens: Bayer HealthCare Pharmaceuticals: Employment, Equity Ownership. Zierz: Bayer Schering Pharma: Employment, Equity Ownership. Haaning: Bayer HealthCare Pharmaceuticals: Employment, Equity Ownership. McDonald: Bayer HealthCare Pharmaceuticals: Employment, Equity Ownership.

Age at first treatment and immune tolerance to factor VIII in severe hemophilia

2003 ◽  
Vol 89 (03) ◽  
pp. 475-479 ◽  
Author(s):  
Eveline Mauser-Bunschoten ◽  
Kathelijn Fischer ◽  
Marijke van den Berg ◽  
Johanna van der Bom
Keyword(s):  
Cohort Study ◽  
Factor Viii ◽  
Hemophilia A ◽  
Treatment Center ◽  
Clotting Factor ◽  
Confounding Factors ◽  
Severe Hemophilia ◽  
Inhibitory Antibodies

SummaryFindings from a recent study suggest that earlier start of treatment with factor VIII in patients with severe hemophilia is associated with a higher risk to develop inhibitors.We set out to assess the association between age of first administration of clotting factor VIII and the risk to develop inhibitors in infants with severe hemophilia A.This work was a cohort study, carried out in the national hemophilia treatment center. The study included eighty-one consecutive patients with severe hemophilia A who received their first dose of factor VIII between 1975 and 1998. Patients were followed until their last visit in 2001 or 2002.The average follow-up was 16 years (range 3-26). Persistent inhibitory antibodies developed in 12 of 81 patients (15%).Cumulative incidence at 100 exposure days was 34% (95% confidence interval 7-61%) in patients starting therapy before the age of 6 months, 20% (4-36%) in patients starting therapy between 6 months and 1 year, 13% (0-27%) in those starting therapy between 1 and 1.5 years, and 0% in those who started therapy beyond 1.5 years of age (p for trend 0.03).Our findings confirm that age of first factor VIII administration in children with severe hemophilia A is inversely associated with the risk to develop antibodies against factor VIII. The role of confounding factors such as the type of factor VIII mutation and environmental factors needs to be evaluated.

Plasma Levels of Protein S, Protein C, and Factor X: Effects of Sex, Hormonal State and Age

1995 ◽  
Vol 74 (05) ◽  
pp. 1271-1275 ◽  
Author(s):  
C M A Henkens ◽  
V J J Bom ◽  
W van der Schaaf ◽  
P M Pelsma ◽  
C Th Smit Sibinga ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Postmenopausal Women ◽  
Protein C ◽  
Blood Donors ◽  
Premenopausal Women ◽  
Protein S ◽  
The Other ◽  
Factor X ◽  
Normal Ranges

SummaryWe measured total and free protein S (PS), protein C (PC) and factor X (FX) in 393 healthy blood donors to assess differences in relation to sex, hormonal state and age. All measured proteins were lower in women as compared to men, as were levels in premenopausal women as compared to postmenopausal women. Multiple regression analysis showed that both age and subgroup (men, pre- and postmenopausal women) were of significance for the levels of total and free PS and PC, the subgroup effect being caused by the differences between the premenopausal women and the other groups. This indicates a role of sex-hormones, most likely estrogens, in the regulation of levels of pro- and anticoagulant factors under physiologic conditions. These differences should be taken into account in daily clinical practice and may necessitate different normal ranges for men, pre- and postmenopausal women.

Prevalence of Inhibitors in a Population of 3435 Hemophilia Patients in France

1992 ◽  
Vol 67 (06) ◽  
pp. 600-602 ◽  
Author(s):  
Y Sultan ◽  
Keyword(s):  
Hemophilia A ◽  
Hemophilia B ◽  
Study Group ◽  
Cooperative Study ◽  
Population Prevalence ◽  
French Study ◽  
Number Of Patients ◽  
High Incidence ◽  
Recombinant Fviii ◽  
High Responders

SummaryA cooperative study between the 37 centers of the French Hemophilia Study Group was undertaken to establish the prevalence of inhibitor patients in the French hemophilia population. The prevalence reported in the literature varies widely from 3.6% to 17.5%. Some of the studies are dealing with a small number of patients and inhibitor patients are reported either to the total number of hemophiliacs or to the severely affected ones. The French study provided information concerning 3,435 hemophiliacs and showed a prevalence of 6.2% for the overall population. Prevalence of inhibitors was found to be 7% in the population of hemophilia A patients and 12.8% in the population of severely affected ones. The prevalence of inhibitors in the population of hemophilia B patients was 2% and 4% in the population of severely affected hemophilia B patients. The cooperative study also showed that 47.5% of inhibitors are detected before 10 years of age and that 82% of inhibitor patients are high responders. Analysis of inhibitor detection in patients under the age often showed that there was a peak in the population of 2 years old children. Although not comparable to the present study the high incidence of inhibitors with ultrapurified and recombinant FVIII reported in previously untransfused patient may be borne in mind.

The Immunological Properties of Factor VIII

1966 ◽  
Vol 16 (03/04) ◽  
pp. 559-573 ◽  
Author(s):  
L Uszyński
Keyword(s):  
Factor Viii ◽  
Inhibitory Activity ◽  
Hemophilia A ◽  
Severe Form ◽  
Molecular Defect ◽  
Bovine Plasma ◽  
Human Factor Viii ◽  
Antigenic Properties ◽  
Coagulation Tests ◽  
Normal Human

SummaryRabbits immunized against human AHG fibrinogen-free preparations, were shown to produce anti-AHG antibodies. The inhibitory activity of these antibodies was tested by thromboplastin generation test, thrombelastography, and the specific anti-AHG antibodies neutralization test. The latter test permitted quantitative determination of antigenic form of factor VIII. The inhibitory activity of anti-FI-O-Ta serum resulted exclusively from the anti-AHG antibodies which in coagulation tests behaved like circulating anticoagulants directed against factor VIII.The anti-AHG antibodies were neutralizable by normal human serum or plasma even contained only trace of AHG activity after storage. There was no antigenic form of factor VIII in the severely affected patients with hemophilia A, von Willebrand’s disease nor in the normal plasma adsorbed on bentonite. The presented results suggest a molecular defect of factor VIII in patients with hemophilia A. The severe form of this disease depends, probably, on a major impairment of AHG biosynthesis, leading to changes in the antigenic properties of the molecule. The AHG from rabbit, porcine and bovine plasma respectively did not neutralize the anti-AHG antibodies formed in rabbits immunized against human factor VIII preparations.

Studies on the Pathogenesis of the Generalized Shwartzman Reaction

1964 ◽  
Vol 12 (02) ◽  
pp. 471-483 ◽  
Author(s):  
F Rodríguez-Erdmann
Keyword(s):  
Clotting Factor ◽  
Factor V ◽  
Clotting System ◽  
Platelet Factor ◽  
Trigger Mechanism ◽  
Haemorrhagic Diathesis ◽  
Shwartzman Reaction ◽  
Ca Ions

SummaryThe rôle of the clotting system in the pathogenesis of the generalized Shwartzman reaction (gSr) has been stressed in recent years. The clotting system is activated ubiquitously and as a result of it, fibrin is deposited intravascularly and a haemorrhagic diathesis develops. Evidence is presented herein, that endotoxin does not activate purified prothrombin, nor does endotoxin influence the convertion of prothrombin when it is activated in the presence of purified platelet-factor 3 (or caephalin) purified Ac-G (factor V) and Ca-ions.The trigger mechanism of the gSr also seems to be in the so-called prephase of clotting mechanism. Data are presented, which show that endotoxin activates the Hageman factor in vitro. The importance of this clotting factor and of platelet-factor 3 is discussed. Also the rôle played by the RES and cardiodynamic and vascular components are taken in consideration in the discussion.

A Multicenter Pharmacosurveillance Study for the Evaluation of the Efficacy and Safety of Recombinant Factor VIII in the Treatment of Patients with Hemophilia A

1997 ◽  
Vol 78 (05) ◽  
pp. 1352-1356 ◽  
Author(s):  
Emel Aygören-Pürsün ◽  
Inge Scharrer ◽  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Parvovirus B19 ◽  
Subjective Evaluation ◽  
Recombinant Factor Viii ◽  
Fviii Inhibitor ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Bleeding Episodes ◽  
Recombinant Fviii

SummaryIn this open multicenter study the safety and efficacy of recombinant factor VIII (rFVIII) was assessed in 39 previously treated patients with hemophilia A (factor VIII basal activity ≤15%).Recombinant FVIII was administered for prophylaxis and treatment of bleeding episodes and for surgical procedures. A total of 3679 infusions of rFVIII were given. Efficacy of rFVIII as assessed by subjective evaluation of response to infusion and mean annual consumption of rFVIII was comparable to that of plasma derived FVIII concentrates. The incremental recovery of FVIII (2.4 ± 0,83%/IU/kg, 2.12 ± 0.61%/IU/kg, resp.) was within the expected range. No clinical significant FVIII inhibitor was detected in this trial. Five of 16 susceptible patients showed a seroconversion for parvovirus B19. However, the results are ambiguous in two cases and might be explained otherwise in one further case. Thus, in two patients a reliable seroconversion for parvovirus B19 was observed.

On the role of the dispute between "non-possessors" and "Josephites" in the culture of Moscow's prediction

1998 ◽  
pp. 61-62
Author(s):  
N. S. Jurtueva
Keyword(s):  
The Other ◽  
Moral Transformation ◽  
15Th Century ◽  
The Future ◽  
Secular Power

In the XIV century. centripetal tendencies began to appear in the Moscow principality. Inside the Russian church, several areas were distinguished. Part of the clergy supported the specificobar form. The other understood the need for transformations in society. As a result, this led to a split in the Russian church in the 15th century for "non-possessors" and "Josephites". The former linked the fate of the future with the ideology of hesychasm and its moral transformation, while the latter sought support in alliance with a strong secular power.

From Container to Claustrum: Projective Identification in Couples

2014 ◽  
Vol 4 (2) ◽  
Author(s):  
Tamara Feldman
Keyword(s):  
Psychological Health ◽  
Projective Identification ◽  
The Self ◽  
The Other ◽  
Intimate Partners ◽  
And Control ◽  
The Relationship ◽  
As If

This paper is a contribution to the growing literature on the role of projective identification in understanding couples' dynamics. Projective identification as a defence is well suited to couples, as intimate partners provide an ideal location to deposit unwanted parts of the self. This paper illustrates how projective identification functions differently depending on the psychological health of the couple. It elucidates how healthier couples use projective identification more as a form of communication, whereas disturbed couples are inclined to employ it to invade and control the other, as captured by Meltzer's concept of "intrusive identification". These different uses of projective identification affect couples' capacities to provide what Bion called "containment". In disturbed couples, partners serve as what Meltzer termed "claustrums" whereby projections are not contained, but imprisoned or entombed in the other. Applying the concept of claustrum helps illuminate common feelings these couples express, such as feeling suffocated, stifled, trapped, held hostage, or feeling as if the relationship is killing them. Finally, this paper presents treatment challenges in working with more disturbed couples.

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