scholarly journals A Novel Approach to Immune Tolerance Induction in Hemophilia Α with Factor VIII Inhibitor

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5042-5042 ◽  
Author(s):  
Courtney D. Thornburg ◽  
Jonathan M. Ducore
Keyword(s):  
Factor Viii ◽  
Research Funding ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Fviii Inhibitor ◽  
Fviii Activity ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Factor VIII (FVIII) inhibitors are currently the most significant complication of hemophilia A therapy. Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication. However, the optimal ITI regimen has not been identified. We describe an ITI approach for an adolescent male with severe hemophilia A and recurrent and refractory high-titer FVIII inhibitor. This strategy is now being tested in a randomized, controlled trial (NCT03204539). A 1-year-old white, Hispanic male with severe hemophilia A, intron 22 inversion, developed a FVIII inhibitor while receiving on-demand treatment with recombinant FVIII (rFVIII). Due to life-threatening bleeding despite bypassing agents, he was immediately started on ITI with daily rFVIII along with intravenous immunoglobulin (IVIg), solumedrol, and rituximab. He achieved tolerance after 15 months and was switched to every-other-day dosing for prophylaxis. Unfortunately, on prophylaxis he had breakthrough bleeding and inhibitor recurrence, and has required additional ITI regimens over the past 14 years (Table 1). Most recently, the family agreed to switch to Wilate® [von Willebrand Factor/Coagulation Factor VIII Complex (Human); Octapharma USA, Inc.; Hoboken, NJ; U.S. License No. 1646] as an alternative von Willebrand factor (VWF)/FVIII concentrate since he was unable to achieve tolerance on prior plasma-derived (pd) VWF/FVIII concentrate at 100 international units (IU)/kg daily for ~4 years. Wilate® was started when inhibitor titer was 1.5 Bethesda Units (BU). Initial FVIII recovery was 30% and 24-hour trough level was 1%. After several months, blood samples were sent to a diagnostic laboratory at Haemophilie-Zentrum Rhein Main GmbH for lot selection. Lot selection entails measuring residual FVIII activity when patient plasma is mixed with different lots of VWF/FVIII in vitro. This involves using the modified New Oxford method to measure residual FVIII activity after incubation of a FVIII source (lot) with the inhibitor patient plasma. The inhibitor titer is the reciprocal of the dilution of patient plasma that results in 50% of residual FVIII, similar to the Bethesda Unit. Ideally, the lot providing the highest residual FVIII activity will more effectively challenge the immune system, provide better prevention and control of bleeding, and have shorter time to tolerance. Investigators have demonstrated the utility of lot section in in vitro studies. The patient's plasma was tested against 6 lots of Wilate® and the lot with the lowest inhibitor activity was selected for prescription. This lot was allocated to this patient, and the prescribing physician included the lot number on the factor prescription for distribution to the patient via the patient's specialty pharmacy. The patient received Wilate® from the same lot for ~11 months. During that time, his inhibitor decreased from 2.6 BU to 0 after 5 months. A new plasma sample was tested against an additional 5 lots of Wilate®. Inhibitor was negative at that time and all lots of Wilate® revealed a negative inhibitory activity. One lot was selected for ongoing treatment. After 18 months his 48-hour trough FVIII level was detectable. He had blood drawn for pharmacokinetic analysis, which showed FVIII recovery of 55% and an estimated half-life of 6.75 hours. He was switched to every-other-day dosing and has had only one trauma-induced soft-tissue bleed despite increased physical activity, with negative inhibitor and a 48-hour trough of 2%. Disclosures Thornburg: Shire: Research Funding; CSL Behring: Research Funding; ATHN: Research Funding; Bayer Pharmaceuticals: Research Funding; Octapharma: Research Funding; Bioverativ: Consultancy; Genentech: Speakers Bureau; Biomarin: Consultancy; Bluebird Bio: Consultancy; NovoNordisk: Research Funding; Johns Hopkins All Children's Hospital: Research Funding. Ducore:OPKO: Other: investigator; HemaBiologics: Consultancy, Other: investigator, travel support; Shire: Consultancy, Other: travel support, investigator; Biomarin: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Bayer Healthcare: Consultancy, Other: travel support, investigator; Pfizer: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator; CSL Behring: Other: investigator.

scholarly journals Factor VIII Inhibitors: Von Willebrand Factor Makes A Difference In Vitro and In Vivo

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 709-709
Author(s):  
Qizhen Shi ◽  
Erin L. Kuether ◽  
Jocelyn A. Schroeder ◽  
Crystal L. Perry ◽  
Scot A. Fahs ◽  
...  
Keyword(s):  
Protective Effect ◽  
Hemophilia A ◽  
Inhibitory Antibody ◽  
Chromogenic Assay ◽  
Fviii Activity ◽  
Inhibitory Antibodies ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 709 The important association between von Willebrand factor (VWF) and factor VIII (FVIII) has been investigated for decades, but the effect of VWF on FVIII inhibitors is still controversial. Studies have demonstrated that some anti-FVIII inhibitory antibodies inhibit VWF-FVIII interaction, while others rely on the presence of VWF to inhibit FVIII activities. The influence of VWF on the Bethesda assay, which is routinely used in the clinic to determine the titer of FVIII-neutralizing inhibitors, is still uncertain because the plasma from hemophilia A patients with inhibitors contains normal levels of VWF. To explore the effect of VWF on the reactivity of FVIII inhibitors, we immunized VWF and FVIII double knockout (VWFnullFVIIInull) mice with recombinant human B-domain deleted FVIII (rhFVIII) to induce anti-FVIII inhibitory antibody development. Inhibitory plasma was collected and the titer of inhibitors was determined by Bethesda assay. Murine plasma-derived VWF (from FVIIInull mice) or recombinant human VWF (rhVWF) was used to study the influence of VWF on inhibitor inactivation of FVIII activity (FVIII:C). The remaining FVIII:C after inactivation was determined by chromogenic assay. When inhibitory plasma was incubated with rhFVIII in the presence of 1 U/ml VWF, the residual FVIII activity recovered was higher than in the absence of VWF, resulting in 6.82 ± 1.12 (n = 27) fold lower apparent inhibitor titers. This protective effect is VWF dose dependent. The source of VWF (plasma-derived murine VWF vs. rhVWF) did not affect its protection of FVIII from inhibitor inactivation and VWF does not affect FVIII:C measured in the chromogenic assay in the absence of inhibitors. Interestingly, we found that inhibitor inactivation of FVIII:C in the absence of VWF occurred much faster than in its presence. When the usual 2 hr. incubation at 37°C was omitted from the Bethesda assay, adding rhVWF to rFVIII before mixing with inhibitory plasma resulted in 67.29 ± 20.18 (n = 5) fold lower apparent inhibitor titers than without added VWF. In contrast, if VWF was added to inhibitory plasma first and then mixed with rhFVIII, the inhibitor titers were only 11.04 ± 3.56 (n = 5) fold lower than without added VWF. These results indicate that rhFVIII present in a preformed VWF-FVIII complex is protected from inhibitory antibody inactivation. Conversely, when VWF and inhibitory plasma are added to rhFVIII at the same time, the VWF and inhibitors appear to compete to bind to rhFVIII. Inhibitor titers were lower than in the absence of VWF, but the protective effect is not as efficient as when VWF and rhFVIII were already associated with one another before encountering inhibitors. To confirm the protective effect of VWF on FVIII from inhibitor inactivation, we infused FVIIInull or VWFnullFVIIInull mice with inhibitory plasma and rhFVIII followed by a tail clip survival test. When rhFVIII was infused into FVIIInull mice to 2% followed by inhibitory plasma infusion, all mice with inhibitor titer of 2.5 BU/ml (n = 4) survived tail clipping, and 2 of 4 survived with either 25 BU/ml or 250 BU/ml. If inhibitory plasma was infused first followed by rhFVIII infusion, then only 2 of 6 mice with inhibitor titers of 2.5 BU/ml survived tail clip challenge and none survived with 25 BU/ml and 250 BU/ml. In the first set of mice the infused FVIII was able to form a protective complex with endogenous VWF before encountering inhibitors, while in the second set FVIII is exposed to VWF and pre-infused inhibitory antibodies at the same time, a competitive binding that appears to reduce VWF's protective effect. In contrast, when rhFVIII was infused into VWFnullFVIIInull mice followed by inhibitory plasma infusion, no animals (n = 4 for each group) survived tail clipping with inhibitor titers of 2.5 BU/ml or higher. In summary, our studies demonstrate that VWF exerts a protective effect, reducing inhibitor inactivation of FVIII, both in vitro and in vivo. While the role of VWF in stabilizing plasma FVIII in a milieu rich in proteases has been appreciated for decades, our results indicate that treatment utilizing products containing a complex of FVIII with VWF may be especially beneficial in hemophilia A patients with inhibitors. Disclosures: No relevant conflicts of interest to declare.

A Case Series Evaluating the Use of a Von Willebrand Factor/Factor VIII Concentrate (Wilate®) for Immune Tolerance Induction (ITI) in Children with Severe Factor VIII Deficiency

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5050-5050
Author(s):  
Mark J. Belletrutti ◽  
Roxanne Seiferman-Nelson ◽  
Bonny Granfield
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Bleeding Episodes ◽  
Recombinant Fviii ◽  
Von Willebrand

Abstract Introduction: Development of circulating anti-factor VIII antibodies (inhbitors) is the most serious and challenging complication in the treatment of hemophilia A. Up to 38% of hemophilia patients develop inhibitors with recombinant FVIII (rFVIII) products (Gouw et al. N Engl J Med. 2013; 368:231-239). The presence of inhibitors leads to an increased risk of bleeding, poor physical functioning and quality of life (Benson et al., Eur. J. Haematol. 2012; 88:371-379). Immune tolerance induction (ITI) is the most common method for eliminating inhibitors, historically performed with high dose, and prolonged treatment with plasma-derived (pd), or recombinant FVIII (rFVIII) concentrates. Although ITI for the eradication of inhibitors has become standard of care for hemophilia patients the therapeutic superiority of a particular product type (rFVIII vs. pd-FVIII) has not yet been conclusively demonstrated. In accordance with its role in stabilizing FVIII, the presence of von Willebrand factor (VWF) in pd-FVIII concentrates has been shown to improve the outcome of ITI. Wilate® (Octapharma) is a high-purity human plasma derived complex containing two proteins (VWF and FVIII) in a 1:1 ratio. The aim of this study was to determine the effectiveness of Wilate for primary ITI therapy for six patients with severe hemophilia A. Patients and Methods: The case history for six pediatric hemophilia A patients prior to and during primary Wilate ITI was reviewed. For 5/6 patients, inhibitors developed during rFVIII factor replacement therapy. For the sixth patient, inhibitors were detected at the time of hemophilia diagnosis. ITI began once patients achieved an inhibitor titer of less than 10 BU/mL. The ITI dosing regimen ranged from 50-60 IU/Kg of Wilate three times per week to 200 IU/Kg once daily. Inhibitor titers were measured regularly, prior to and during ITI using the Nijmegen-Bethesda assay. The number of port-a-cath infections and bleeding episodes were also monitored. ITI success was defined as: an undetectable inhibitor level (<0.6 BU/mL), FVIII plasma recovery ≥ 66% of predicted, and FVIII half-life ≥6 hours. Results: Wilate ITI was well tolerated in all patients, with no product-related adverse events. All patients had a port-a-cath device inserted for Wilate injections. Two port-a-cath infections occurred during ITI. Five of six patients had poor prognostic factors for ITI outcome. These poor prognostic factors included a high-risk FVIII gene mutation, historical peak inhibitor titer greater than 50 BU/mL, age of ITI onset greater than 6 years, and ITI onset more than 12 months from inhibitor development. The frequency of these poor prognostic factors varied amongst the patients: 1 patient had 4, 1 patient had 2, and 3 patients presented with 1 poor prognostic factor. Despite the presence of these high-risk factors, Wilate was successful at reducing the inhibitor titers to undetectable levels in all patients. Furthermore, inhibitor titers have remained low or undetectable without significant spikes for the duration of treatment. Patient plasma recovery and FVIII half-life results have also indicated that patients are progressing towards successful ITI. Importantly, for 6/6 patients (including 3 patients who had previously been treated with Anti-Inhibitor Coagulant Complex (FEIBA) prophylaxis therapy) - Wilate therapy was successful at reducing the number of bleeding episodes allowing for the cessation of FEIBA prophylaxis. Since commencing Wilate ITI, 6/6 patients have not reported any major bleeding episodes. The improved clinical outcome was perceived by the patients as an improved well-being, and quality of life. Conclusion: Wilate ITI was found to be well tolerated, safe, and successful at reducing inhibitor levels to below the detectable range for six severe hemophilia A patients. Patients experienced no treatment related adverse events, had a low rate of port-a-cath infections, and did not present with any major bleeding episodes while on Wilate ITI. In light of the 3-5 fold increase in overall treatment costs of immune tolerance induction, careful consideration should be given to choice of product (rFVIII versus pd-FVIII) – especially for patients at high-risk of failure. (Dimichele et al. Haemophilia 2004: 10 Suppl 4;140-145). The present data suggest that Wilate, a pd-FVIII product, is effective in managing patients with inhibitors. Disclosures Belletrutti: Baxter Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring Canada: Honoraria.

Neutralisation of factor VIII inhibitors by anti-idiotypes isolated from phage-displayed libraries

2016 ◽  
Vol 116 (07) ◽  
pp. 32-41 ◽  
Author(s):  
Anja Schmidt ◽  
Kerstin Brettschneider ◽  
Jörg Kahle ◽  
Aleksander Orlowski ◽  
Karin Becker-Peters ◽  
...  
Keyword(s):  
Factor Viii ◽  
Tolerance Induction ◽  
Coagulation Factor ◽  
Cross Reactivity ◽  
Hybridoma Cells ◽  
Haemophilia A ◽  
Immune Tolerance Induction ◽  
Fviii Inhibitor ◽  
Antiidiotypic Antibody

SummaryFollowing replacement therapy with coagulation factor VIII (FVIII), up to 30 % of haemophilia A patients develop FVIII-specific inhibitory antibodies (FVIII inhibitors). Immune tolerance induction (ITI) is not always successful, resulting in a need for alternative treatments for FVIII inhibitor-positive patients. As tolerance induction in the course of ITI appears to involve the formation of anti-idiotypes specific for anti-FVIII antibodies, such anti-idiotypes might be used to restore haemostasis in haemophilia A patients with FVIII inhibitors. We isolated antiidiotypic antibody fragments (scFvs) binding to murine FVIII inhibitors 2-76 and 2-77 from phage-displayed libraries. FVIII inhibitor/anti-idiotype interactions were very specific as no cross-reactivity with other FVIII inhibitors or isotype controls was observed. ScFvs blocked binding of FVIII inhibitors to FVIII and neutralised their cognate inhibitors in vitro and a monoclonal mouse model. In addition, scFv JkH5 specific for FVIII inhibitor 2-76 stained 2-76-producing hybridoma cells. JkH5 residues R52 and Y226, located in complementary determining regions, were identified as crucial for the JkH5/2-76 interaction using JkH5 alanine mutants. SPR spectroscopy revealed that JkH5 interacts with FVIII inhibitor 2-76 with nanomolar affinity. Thus, FVIII inhibitorspecific, high-affinity anti-idiotypes can be isolated from phagedisplayed libraries and neutralise their respective inhibitors. Furthermore, we show that anti-idiotypic scFvs might be utilised to specifically target inhibitor-specific B cells. Hence, a pool of anti-idiotypes could enable the reestablishment of haemostasis in the presence of FVIII inhibitors in patients or even allow the depletion of inhibitors by targeting inhibitor-specific B cell populations.

Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 407-412 ◽  
Author(s):  
Rebecca Kruse-Jarres
Keyword(s):  
Factor Viii ◽  
Randomized Clinical Trials ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Primary Prophylaxis ◽  
Bleeding Complications ◽  
Fviii Inhibitor ◽  
Optimal Dosing ◽  
Fviii Activity ◽  
Replacement Product

Abstract Hemophilia A is a rare bleeding disorder treated with numerous factor VIII (FVIII)–containing replacement concentrates. This treatment approach has led to the formation of alloantibodies that neutralize the FVIII activity (inhibitors) conveyed by these commercially available concentrates in ∼ 25% of patients with severe hemophilia A (FVIII activity < 1% of normal). This phenomenon significantly complicates the treatment of these patients and compromises the effectiveness and efficiency of these products to reverse or prevent bleeding complications. Studying the population with alloantibody inhibitors is imperative but difficult due to the overall small number of individuals affected and the heterogeneity within this limited group. Furthermore, few randomized clinical trials have been conducted to answer pertinent questions so many controversies persist. This article focuses on the conflicting data on the variables associated with alloantibody FVIII inhibitor development with a particular emphasis on age and intensity of first treatment, the role of primary prophylaxis regimens in modulating this phenomenon, and the degree of purity of FVIII product as a potential contributing risk factor. The optimal dosing regimen and type of FVIII replacement product that should be used to achieve the highest success rate in immune tolerance induction (ITI) protocols are also discussed, as well as whether the addition of immunomodulatory agents, especially rituximab, to ITI regimens enhances the durability of ITI and the eradication of alloantibody FVIII inhibitors.

scholarly journals Targeting FVIII expression to endothelial cells regenerates a releasable pool of FVIII and restores hemostasis in a mouse model of hemophilia A

Blood ◽  
2010 ◽  
Vol 116 (16) ◽  
pp. 3049-3057 ◽  
Author(s):  
Qizhen Shi ◽  
Scot A. Fahs ◽  
Erin L. Kuether ◽  
Brian C. Cooley ◽  
Hartmut Weiler ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hemophilia A ◽  
Subcutaneous Administration ◽  
Inhibitory Effect ◽  
Specific Expression ◽  
Releasable Pool ◽  
Fviii Activity ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The natural cell type(s) that synthesize and release factor VIII (FVIII) into the circulation are still not known with certainty. In vitro studies indicate that artificial expression of FVIII in endothelial cells produces an intracellular pool of FVIII that can be mobilized together with its carrier protein, von Willebrand factor (VWF), by agonists. Here, we show that expression of human B-domain deleted FVIII (hFVIII) in the vascular endothelium of otherwise FVIII-deficient mice results in costorage of FVIII and VWF in endothelial Weibel-Palade bodies and restores normal levels and activity of FVIII in plasma. Stored FVIII was mobilized into the circulation by subcutaneous administration of epinephrine. Human FVIII activity in plasma was strictly dependent on the presence of VWF. Endothelial-specific expression of hFVIII rescued the bleeding diathesis of hemophilic mice lacking endogenous FVIII. This hemostatic function of endothelial cell–derived hFVIII was suppressed in the presence of anti-FVIII inhibitory antibodies. These results suggest that targeting FVIII expression to endothelial cells may establish a releasable pool of FVIII and normalize plasma FVIII level and activity in hemophilia A, but does not prevent the inhibitory effect of anti-FVIII antibodies on the hemostatic function of transgene-derived hFVIII as is seen with platelet-derived FVIII expression.

scholarly journals Recombinant VWF Fragments Improve Bioavailability of Subcutaneous Factor VIII in Hemophilia A Mice

Blood ◽  
2020 ◽  
Author(s):  
Nadine Vollack-Hesse ◽  
Olga Oleshko ◽  
Sonja Werwitzke ◽  
Barbara Solecka-Witulska ◽  
Christoph Kannicht ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Dependent Manner ◽  
High Concentrations ◽  
Von Willebrand ◽  
Willebrand Factor

Conventional treatment of hemophilia A (HA) requires repetitive intravenous (IV) injection of coagulation factor VIII (FVIII). Subcutaneous (SC) administration of FVIII is inefficient because of binding to the extravascular matrix, in particular to phospholipids (PL), and subsequent proteolysis. To overcome this, recombinant dimeric fragments of von Willebrand factor (VWF) containing the FVIII stabilizing D3 domain were engineered. Two fragments, called VWF-12 and VWF-13, demonstrated high binding affinity to recombinant human FVIII (rhFVIII) and suppressed PL-binding in a dose-dependent manner. High concentrations of VWF fragments did not interfere with the functional properties of full-length VWF in vitro. The HA mouse model was used to study the effects of VWF-12 or VWF-13 on the in vivo pharmacokinetics of rhFVIII, demonstrating (i) no significant impact on rhFVIII recovery or half-life after a single IV administration; (ii) enhanced bioavailability (up to 18.5 %) of rhFVIII after SC administration; (iii) slow absorption (cmax 6h) and prolonged half-life (up to 2.5-fold) of rhFVIII after SC administration. Formation of anti-FVIII antibodies was not increased after administration of rhFVIII/VWF-12 SC compared to rhFVIII IV. A single SC dose of rhFVIII/VWF-12 provided protection in the HA tail bleeding model for up to 24h. In conclusion, recombinant VWF fragments support FVIII delivery through the SC space into vascular circulation without interfering with VWF or FVIII function. Slow resorption and excretion of FVIII after SC administration highlight the potential application of VWF fragments for SC FVIII prophylaxis in HA.

Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A

2010 ◽  
Vol 104 (11) ◽  
pp. 931-940 ◽  
Author(s):  
Giuseppe Lippi ◽  
Massimo Franchini
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Immune Tolerance ◽  
High Titer ◽  
Tolerance Induction ◽  
Haemophilia A ◽  
Immune Tolerance Induction ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients.

scholarly journals Treatment of Haemophilia a (HA) Patients with Inhibitors: Immune Tolerance Induction with a Single Factor VIII/Von Willebrand Factor Concentrate in an Observational Immune Tolerance Induction Study (ObsITI)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2482-2482
Author(s):  
C. Escuriola Ettingshausen ◽  
Erik Berntorp ◽  
Yesim Dargaud ◽  
Zeynep Gutowski ◽  
Claude Negrier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Von Willebrand Factor ◽  
Immune Tolerance ◽  
Research Funding ◽  
Tolerance Induction ◽  
Advisory Committees ◽  
Immune Tolerance Induction ◽  
Inhibitor Titre ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Introduction and objectives: Development of neutralising inhibitors against factor VIII (FVIII) is one of the most serious and costly complications in the treatment of HA. An ongoing international, open-label, uncontrolled, multicentre observational study, ObsITI (ClinicalTrials.gov. NCT 02207894) started in 2005 to assess immune tolerance induction (ITI), the standard of care in patients with inhibitors. The study evaluates patient- and therapy-related variables on ITI course, outcome and morbidity in HA patients with inhibitors. ObsITI satellite studies additionally look at other factors related to tolerisation. Methods and Materials: As of February 2018, 193 patients from 20 countries undergoing ITI have been recruited in ObsITI. 152 patients completed the study and 41 are ongoing. A subgroup of more than 80 prospective patients were treated exclusively during the complete ITI course with a single plasma-derived (pd) FVIII concentrate that contains von Willebrand factor (VWF) in a VWF/FVIII ratio of 0.4 (Octapharma AG). According to the recommended Bonn protocol, low responders at ITI start received 50-100 IU FVIII kg-1 daily, or every other day; high responders received 100 IU FVIII kg-1 every 12 hours. Results: In this ongoing study, the majority of patients treated with the pdFVIII/VWF product achieved a negative inhibitor titre. ITI outcome was significantly correlated with the bleeding rate during ITI, the peak titre during ITI, the inhibitor titre at start of ITI >10 BU, and the number of poor prognosis factors. Conclusion: Treatment with this particular pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in HA patients with inhibitors and corroborates previously published success rates (77.1% complete/partial success in 48 inhibitor patients undergoing ITI with the same product). Disclosures Escuriola Ettingshausen: SOBI: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria; Roche: Honoraria; Grifols: Honoraria; Pfizer: Honoraria; LFB: Honoraria. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Research Funding. Pavlova:Novo Nordisk: Honoraria; Octapharma: Honoraria. Oldenburg:Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Economic Impact of Immune Tolerance Induction (ITI) with Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) Compared to Conventional Recombinant Factor VIII (rFVIII)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3520-3520
Author(s):  
Nanxin Li ◽  
Koo Wilson ◽  
Marc Botteman ◽  
Daniel Nicoloso ◽  
Sangeeta Krishnan ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Research Funding ◽  
Impact Analysis ◽  
Budget Impact ◽  
Hemophilia A ◽  
Case Reports ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Clinical Profiles

Abstract Introduction: Hemophilia A results from a clotting protein factor VIII (FVIII) deficiency, which leads to the need for the use of exogenous FVIII. Such therapy is effective unless alloantibodies (inhibitors) develop and render FVIII replacement ineffective. Patients with high-titer inhibitors may try to eradicate the presence of these inhibitors by undergoing ITI, an often costly process that requires the prolonged use of frequent doses of FVIII to induce FVIII antigen-specific tolerance. There is no consensus on the best approach to achieve tolerance and no product has been approved by any regulatory agency for ITI treatment in hemophilia A patients with inhibitors. The Fc portion of rFVIIIFc has shown immunomodulatory properties in mice, and chart reviews and case reports suggest that tolerization with rFVIIIFc in first-attempt ITI patients can potentially be achieved rapidly (i.e., ≤18 months) and therefore may possibly offer cost savings compared to conventional rFVIII. This analysis assessed the economic consequences and budget impact of using rFVIIIFc vs. conventional rFVIII for first-attempt immune tolerance induction (ITI) in hemophilia A patients with inhibitors. Methods: A literature-based model was developed to estimate the effect of rFVIIIFc vs conventional rFVIII on drug cost of first-attempt ITI, based on modelled ITI duration and outcome (rates and time to ITI success or failure) for US patients with varying clinical profiles (e.g., historical peak titer, FVIII dose) over a 3-year period. In the model, at any given time after ITI initiation (on either rFVIIIFc or rFVIII), a patient was categorized as ongoing ITI, post-ITI as success, or post-ITI as failure. The duration and outcomes for patients treated with rFVIIIFc ITI were based on observed data for first-attempt ITI patients with varied clinical profiles and ITI regimens from in chart reviews and case reports (n = 9). In the absence of direct head-to-head observations, the duration and outcome of ITI for the exact same patients in a scenario in which they received rFVIII (instead of rFVIIIFc) at the same doses were estimated indirectly using a previously published regression model (Bojke et al. 2009, Value in Health, 12(7), A378-A379) based on data for 113 patients from international and national registries that adjusts for historical and pre-ITI titer levels, time from inhibitor diagnosis to ITI start, and ITI factor dose. To place the cost comparison results in the perspective of a third-party US payer, a budget impact analysis was undertaken on a population of typical hemophilia A patients (after adjusting for patient characteristics) who are embarking on first-attempt ITI in a plan of 10 million insured members. In this analysis, the number of patients starting ITI each year was assumed constant, and patients who successfully eradicated inhibitors with ITI would transition back to FVIII prophylaxis. Results: The model predicted that, compared to rFVIII, rFVIIIFc would result in a reduction in estimated time to ITI success (rFVIIIFc: 9.43 months, rFVIII: 16.80 months), increased success probability at 20 months (rFVIIIFc: 67%, rFVIII: 25%), and lower 3-year per-patient costs (rFVIIIFc: $1,709,000, rFVIII: $3,630,000), respectively. In the budget impact analysis for a US health plan of 10 million insured members, 11.2 patients were expected to be newly diagnosed hemophilia A patients, among whom 1.17 patients were expected to develop inhibitors to FVIII and initiate ITI each year. By year 3, the predicted number of successful ITI patients increased by 23% and the budget savings for the plan were $103,738 per patient per year (for the ~1 patient who started ITI each year) after the inclusion of rFVIIIFc for ITI and subsequent prophylaxis when patients successfully eradicated inhibitors. Conclusions: Based on this mathematical economic model of first-attempt ITI patients, the modeled faster time to tolerization with rFVIIIFc vs. rFVIII, resulted in estimated per-patient and overall budget savings in ITI from a US payer perspective. Current prospective studies (e.g. verITI-8) will provide additional evidence on the efficacy of rFVIIIFc for ITI in Hemophilia A patients with inhibitors. Disclosures Li: Bioverativ: Employment. Wilson:SOBI: Employment. Botteman:Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding; Pharmerit International: Employment, Equity Ownership, Research Funding; Celgene: Research Funding; Bioverativ: Consultancy, Other: Provided consulting to Bioverativ, Research Funding. Nicoloso:Bioverativ: Other: an employee of Pharmerit, which provided consulting to Bioverativ. Krishnan:Bioverativ: Employment. Su:Bioverativ: Employment.

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