Hemophilia Therapy Research Articles

PB0150 Fibrin Clot Formation is a Reliable Biological Marker to Evaluate FVIII Replacement Therapy in Hemophilia A Patients

PB0150 Fibrin Clot Formation is a Reliable Biological Marker to Evaluate FVIII Replacement Therapy in Hemophilia A Patients

OC 44.2 Developing Humanized Mouse Models as a Testing Platform for Immune Tolerance Induction Therapy for Antibody-Positive Hemophilia a Patients

OC 44.2 Developing Humanized Mouse Models as a Testing Platform for Immune Tolerance Induction Therapy for Antibody-Positive Hemophilia a Patients

PB0640 Safety and Efficacy of Combined Dual Antiplatelet Therapy and FVIII Prophylaxis in Hemophilia A Patients after the Acute Coronary Syndrome

PB0640 Safety and Efficacy of Combined Dual Antiplatelet Therapy and FVIII Prophylaxis in Hemophilia A Patients after the Acute Coronary Syndrome

PB1259 Emicizumab Prophylaxis: A Novel Alternative Therapy for Severe Hemophilia A Patients with and without Inhibitors

PB1259 Emicizumab Prophylaxis: A Novel Alternative Therapy for Severe Hemophilia A Patients with and without Inhibitors

OC 30.2 Stable Factor VIII Expression and Improvement in Bleeding Phenotype Following Early Childhood Treatment with Adeno-associated Viral Gene Therapy in the Severe Hemophilia A Dog Model

OC 30.2 Stable Factor VIII Expression and Improvement in Bleeding Phenotype Following Early Childhood Treatment with Adeno-associated Viral Gene Therapy in the Severe Hemophilia A Dog Model

Characteristics of FXa-storing platelets in hemophilia B mice and the influence of alcohol on the platelets

Platelet-stored activated blood coagulation factor X (FXa) has great potential in the gene therapy of hemophilia B (HB). However, we still need to understand more about the properties of FXa-storing platelets and how dietary factors affect them. We created transgenic mice called 2bFXa-HB, which had stable expression and storage of FXa in their platelets, resulting in the alleviation of the bleeding disorder in these mice. Even after inducing anti-factor IX (FIX) inhibitors in 2bFXa-HB mice, the hemorrhage phenotype could still be rescued by the expression of FXa. The activation capacity of 2bFXa-HB platelets remained unchanged, and there were no signs of elevated thrombotic risk in these mice. In an acute alcohol exposure mouse model, a single administration of alcohol reduced both the number of platelets and their activation capacity, as well as impaired coagulation function. However, it did not increase the markers of thrombotic risk in either 2bFXa-HB or HB mice. These results suggest that FXa storage in platelets is safe and effective for treatment of HB, but alcohol could impair the therapeutic effect of FXa-containing platelets.

OC 52.4 The Impact of Steroids Following Gene Therapy for Haemophilia: Results from the Exigency Study

OC 52.4 The Impact of Steroids Following Gene Therapy for Haemophilia: Results from the Exigency Study

PB0190 Structural, Functional and Carcinogenicity as Essential Liver Biomarkers for Gene Therapy of Hemophilia A

PB0190 Structural, Functional and Carcinogenicity as Essential Liver Biomarkers for Gene Therapy of Hemophilia A

Ethical aspects of hemophilia gene therapy: a qualitative interview study with stakeholders

BackgroundThere are great expectations for the potential role of gene therapy in the treatment of hemophilia. At the same time, developments in the field of hemophilia gene therapy have always raised ethical issues. It remains unknown how these ethical issues are perceived by stakeholders, particularly regarding the most recent developments in the field. ObjectivesTo obtain insight into stakeholders’ morally reasoned opinions on gene therapy for hemophilia. MethodsWe conducted qualitative research with Dutch people with hemophilia (n = 13), parents of children with hemophilia (n = 5), physicians (n = 4), nurses (n = 3), a regulator (n = 1), and a representative from a pharmaceutical company (n = 1). We conducted semistructured interviews based on a topic list and reported the results according to the Consolidated Criteria for Reporting Qualitative Research guidelines. ResultsWe identified 3 main themes. The theme freedom and independence describes the hope people with hemophilia have of increasing their freedom through gene therapy, as well as concerns that gene therapy increases their dependence on their treatment center. The theme trust and altruism describes how people with hemophilia have a high level of trust in their physician and treatment center as well as in scientific research. As a result of this trust, they are willing to participate in research to help other people with hemophilia. The theme incremental benefits describes doubts respondents have about the added value of gene therapy compared to standard treatment. ConclusionStakeholders embrace the theoretical potential of gene therapy, while several people with hemophilia question the added value of the current gene transfer products for themselves.

Coagulation factor VIII regulates von Willebrand factor homeostasis invivo

BackgroundCoagulation factor VIII (FVIII) and von Willebrand factor (VWF) circulate as a noncovalent complex, but each has its distinct functions. Binding of FVIII to VWF results in a prolongation of FVIII’s half-life in circulation and modulates FVIII’s immunogenicity during hemophilia therapy. However, the biological effect of FVIII and VWF interaction on VWF homeostasis is not fully understood. ObjectivesTo determine the effect of FVIII in VWF proteolysis and homeostasis in vivo. MethodsMouse models, recombinant FVIII infusion, and patients with hemophilia A on a high dose FVIII for immune tolerance induction therapy or emicizumab for bleeding symptoms were included to address this question. ResultsAn intravenous infusion of a recombinant B-domain less FVIII (BDD-FVIII) (40 and 160 μg/kg) into wild-type mice significantly reduced plasma VWF multimer sizes and its antigen levels; an infusion of a high but not low dose of BDD-FVIII into Adamts13+/- and Adamts13-/- mice also significantly reduced the size of VWF multimers. However, plasma levels of VWF antigen remained unchanged following administration of any dose BDD-FVIII into Adamts13-/- mice, suggesting partial ADAMTS-13 dependency in FVIII-augmented VWF degradation. Moreover, persistent expression of BDD-FVIII at ∼50 to 250 U/dL via AAV8 vector in hemophilia A mice also resulted in a significant reduction of plasma VWF multimer sizes and antigen levels. Finally, the sizes of plasma VWF multimers were significantly reduced in patients with hemophilia A who received a dose of recombinant or plasma-derived FVIII for immune tolerance induction therapy. ConclusionOur results demonstrate the pivotal role of FVIII as a cofactor regulating VWF proteolysis and homeostasis under various (patho)physiological conditions.

Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1

BackgroundSevere hemophilia A (HA) negatively impacts health-related quality of life (HRQOL). ObjectivesWe aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1. MethodsParticipant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS). Participants completed the questionnaires at baseline and through 104 weeks postinfusion with 6 × 1013 vg/kg of valoctocogene roxaparvovec. Scores were analyzed per participant characteristics and outcomes. ResultsFor 132 HIV-negative participants, mean change from baseline in Haemo-QOL-A Total Score met the anchor-based clinically important difference (CID: 5.5) by week 12; the mean (SD) increase was 7.0 (12.6) at week 104. At week 104, improvement in Consequences of Bleeding, Treatment Concern, Worry, and Role Functioning domain scores exceeded the CID (6). EQ-5D-5L Utility Index scores improved above the CID at week 52, but not at week 104. EQ-5D-5L visual analog scale and HAL scores increased from baseline to week 104. Participants reported less activity and work impairment at week 104 than baseline. Participants with problem joints had lower mean baseline Haemo-QOL-A Total and domain scores than those without them, but improved over 104 weeks, except for 11 participants with ≥3 problem joints. Participants with 0 bleeds during the baseline prophylaxis period reported Haemo-QOL-A score improvements above the CID, including in the Consequences of Bleeding domain. ConclusionValoctocogene roxaparvovec provided clinically meaningful HRQOL improvement for men with severe HA.

Molecular Evaluation and Vector Integration Analysis of HCC Complicating AAV Gene Therapy for Hemophilia B.

Molecular Evaluation and Vector Integration Analysis of HCC Complicating AAV Gene Therapy for Hemophilia B.

Toward non-factor therapy in hemophilia: an antithrombin insensitive Gla-domainless factor Xa as tissue factor pathway inhibitor bait

BackgroundGla-domainless factor (F) Xa (GD-FXa) was proposed as a trap to endogenous anticoagulant tissue factor pathway inhibitor (TFPI) to restore thrombin generation in hemophilia. Using computational chemistry and experimental approaches, we previously showed that S195A GD-FXa also binds TFPI and restores ex vivo coagulation in plasma obtained from person(s) with hemophilia. MethodsTo design a GD-FXa variant with improved anti-TFPI affinity, we performed molecular dynamics simulations and identified suitable sites for mutagenesis. The calculations identified residues R150FXa and K96Fxa as cold-spots of interaction between GD-FXa and the K2 domain of TFPI. In the three-dimensional model, both residues face toward TFPI hydrophobic residues and are thus potential candidates for mutagenesis into hydrophobic residues to favor an improved protein–protein interaction. ResultsCatalytically inactive GD-FXa variants containing the S195A mutation and the additional mutations K96Y, R150I, R150G, R150F, and K96YR150F, were produced to experimentally confirm these computational hypotheses. Among these mutants, the R150FFXa and the K96YR150FFXa were slightly more effective than S195A GD-FXa in restoring coagulation in FVIII deficient plasmas. However, in surface plasmon resonance experiments, they showed TFPI binding affinities in the same range and acted similarly as S195A GD-FXa in FXa/TFPI competition assays. In contrast, the R150 mutants completely lost their interactions with antithrombin as observed in the surface plasmon resonance experiments. ConclusionsWe therefore conclude that their antithrombin resistance is responsible for their improved thrombin generation, through an extension of their half-lives.

HTRS2023.P2.13 Off-target toxicity of CART cell therapy in murine hemophilia A with inhibitors

HTRS2023.P2.13 Off-target toxicity of CART cell therapy in murine hemophilia A with inhibitors

Evaluating Gene Therapy as a Potential Paradigm Shift in Treating Severe Hemophilia.

Hemophilia is characterized by a deficiency in coagulation factors VIII or IX. The general standard of care for severe hemophilia is frequent intravenous recombinant or plasma-derived factor replacement to prevent bleeding. While this treatment is effective in preventing bleeding, frequent infusions are burdensome for patients. Nonadherence to the therapeutic regimen leaves people with hemophilia at risk for spontaneous and traumatic bleeds into joints as well as life-threatening bleeds such as intracranial hemorrhage. The chronicity of the disorder often leads to the formation of target joints, causing long-term pain and impairing mobility. As a monogenic disorder with well-understood genetics, hemophilia is an ideal disorder for implementing innovations in gene therapies. Indeed, recent approvals of two gene therapy products have the potential to shift the hemophilia treatment paradigm. Valoctocogene roxaparvovec and etranacogene dezaparvovec-drlb are gene therapies for hemophilia A and B, respectively. These therapies, given as a single intravenous infusion, may improve patients' quality of life, decreasing treatment burden and resulting in factor expression that virtually eliminates the need for factor replacement. Since both treatments involve viral vectors targeted to the liver, short- and long-term safety and efficacy monitoring involves monitoring liver enzymes to track liver health. Long-term monitoring of efficacy, durability of gene expression, and safety are ongoing. Gene therapy presents a promising new therapeutic option for patients with hemophilia and warrants continued innovation and investigation.

Hemophilia in Jordan: An Economic Burden Dilemma of Rare Disease

Jordan is an upper-middle-income country with high expenditures on pharmaceuticals. The development of new rare disease (e.g. hemophilia) therapies has encountered significant obstacles with respect to economic the cost of the disease and treatment. The aim of this overview was to estimate current annual spending on hemophilia treatment in Jordan and estimate the financial impact of adapting a new medication (Emicizumab) recently used for treating hemophilia patients in Jordan. Methods: based on the literature review, direct medical costs were quantified, required items’ costs from the actual practice in Jordan were elicited from an expert panel, and a focus group meeting with the same was conducted one month later to determine the current estimated number of hemophilia Patients in Jordan, identify current treatment on demand quantities and their prices. All related medical costs were also identified (e.g. bleeding, the estimated number of hospital days, and/or Intensive Care Unit per bleeding episodes). Estimation of the annual consumption of current on-demand treatment quantities and cost were calculated and compared with scenarios of adding the new therapy (Emicizumab). Results: showed that the financial impact of using Emicizumab S.C. instead of Recombinant Factor VIIa I.V. on the budget of the Jordanian government will be 425,747 JOD ($601,338) annually. Conclusions: the economic advantages of a new hemophilia treatment might be very substantial for patients.

Focal Anticoagulation by Somatic Gene Transfer: Towards Preventing Cardioembolic Stroke.

Cardioembolic stroke (CS) has emerged as a leading cause of ischaemic stroke (IS); distinguished by thrombi embolising to the brain from cardiac origins; most often from the left atrial appendage (LAA). Contemporary therapeutic options are largely dependent on systemic anticoagulation as a blanket preventative strategy, yet this does not represent a nuanced or personalised solution. Contraindications to systemic anticoagulation create significant unmedicated and high-risk cohorts, leaving these patients at risk of significant morbidity and mortality. Atrial appendage occlusion devices are increasingly used to mitigate stroke risk from thrombi emerging from the LAA in patients ineligible for oral anticoagulants (OACs). Their use, however, is not without risk or significant cost, and does not address the underlying aetiology of thrombosis and CS. Viral vector-based gene therapy has emerged as a novel strategy to target a spectrum of haemostatic disorders, achieving success through the adeno-associated virus (AAV) based therapy of haemophilia. Yet, thrombotic disorders, such as CS, have had limited exploration within the realm of AAV gene therapy approaches-presenting a gap in the literature and an opportunity for further research. Gene therapy has the potential to directly address the cause of CS by localised targeting of the molecular remodelling that serves to promote thrombosis.

Gene therapy for hemophilia: Current status and future perspectives

Hemophilia is an inherited bleeding disorder caused by the lack of a protein necessary for blood clotting. Gene therapy for hemophilia involves the introduction of a healthy gene into the patient's cells to produce the missing protein. There are two main types of gene therapy for hemophilia: ex vivo gene therapy, which involves the extraction of cells from the patient, introduction of the healthy gene into these cells in the laboratory, and reintroduction of the modified cells into the patient; and in vivo gene therapy, which involves the direct delivery of the healthy gene into the patient's body using viral vectors. However, there are still challenges in the large-scale implementation of gene therapy, including safety and long-term efficacy, and the costs associated with the technology.

EE555 Cost-Effectiveness of Etranacogene Dezaparvovec for the Treatment of Hemophilia B

Etranacogene dezaparvovec (Etranadez) is a new gene therapy for hemophilia B. This study assessed the cost-effectiveness of Etranadez compared with Factor IX (FIX), in hemophilia B patients without inhibitors eligible for prophylaxis. A special consideration in this assessment was employing a cost savings cap for the new therapy as the existing treatments come at exceptionally high costs.

Towards achieving a haemophilia-free mind.

Towards achieving a haemophilia-free mind.