Safety and efficacy of a fitusiran antithrombin-based dose regimen in people with hemophilia A or B: the ATLAS-OLE study.

Fitusiran, a subcutaneous investigational siRNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia. This phase 3 open-label extension study (ATLAS‑OLE, NCT03754790) evaluated safety and efficacy of antithrombin-based dose regimen (AT-DR) in males ≥ 12 years with severe hemophilia A/B, with/without inhibitors. The original 80 mg monthly (QM) dose regimen (ODR) was optimized to AT-DR targeting AT activity levels 15-35% to mitigate thrombotic risk (starting dose 50 mg once every 2 months [Q2M], individually adjusted to 20 mg Q2M or 20/50/80 mg QM as needed).

Accurate evaluation of factor VIII activity of efanesoctocog alfa in the presence of emicizumab.

Background: Efanesoctocog is a B-domain-deleted, Fc-fusion factor (F)VIII linked to the D'D3 domain of von Willebrand factor and 2 XTEN polypeptides, designed for an ultra-extended half-life for prophylaxis in hemophilia A, but also aiding in managing acute bleeding or surgery in patients on long-term emicizumab. However, no current laboratory method accurately measures FVIII levels in the presence of emicizumab.

Objectives: To test whether the bovine chromogenic FVIII assay, specifically calibrated for efanesoctocog, could provide an accurate assessment of efanesoctocog activity.

Bleed treatment with eptacog beta (rFVIIa) results in a low incidence of rebleeding in adult and adolescent patients with haemophilia A or B with inhibitors.

Introduction: Eptacog beta is a novel human recombinant FVIIa approved for use in the United States, European Union, United Kingdom and Mexico for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors (≥12 years). It is also indicated for perioperative care in the same patient population in Europe and the United Kingdom.

Aim: To assess the incidence of rebleeding and review treatment outcomes in subjects with haemophilia with inhibitors enrolled in the phase 3 PERSEPT 1 clinical trial.

JTH in Clinic: deconstructing the ISTH hemophilia guidelines for the clinician.

Recently, the International Society on Thrombosis and Haemostasis (ISTH) Hemophilia Guidelines were published in this journal. The authors of these guidelines should be commended for a herculean task that took years to complete, and while this is no doubt a welcome addition to the literature, it does leave many questions for the clinician. This is primarily because 11 of the 13 recommendations are conditional, essentially meaning "that clinicians and patients need to consider individual preferences as well as the specific circumstances in which the decision is being made for implementation of the recommendation.

Concizumab prophylaxis in people with haemophilia A or haemophilia B without inhibitors (explorer8): a prospective, multicentre, open-label, randomised, phase 3a trial.

Background: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in development as a once-daily, subcutaneous prophylaxis for patients with haemophilia A or haemophilia B with or without inhibitors. We aimed to assess the efficacy and safety of concizumab in patients with haemophilia A or B without inhibitors. Here we report the results from the confirmatory analysis cutoff.

Induction of factor VIII tolerance by hemophilia gene transfer to eradicate factor VIII inhibitors.

Patients with hemophilia A can develop antifactor antibodies to factor VIII. The incidence is ∼30%, and such patients suffer worse morbidity and mortality. The only proven method to eradicate these inhibitors is via immune tolerance induction therapy, which consists of infusing factor VIII concentrates at regular intervals.

CHIEF: A retrospective self-control study of children with severe hemophilia A without inhibitors comparing emicizumab to FVIII prophylaxis.

Background: Hemophilia A (HA) is an X-linked bleeding disorder diagnosed by a deficiency in factor VIII (FVIII). For severe HA (SHA), prophylaxis clotting factor concentrates (CFC) has become the standard of care; however, it imparts a high treatment burden and typically results in an annualized bleeding rate (ABR) of 2-6. Emicizumab, a subcutaneously administered FVIII substitute, has become the de facto standard-of-care prophylaxis for children with SHA in many countries.

Real-world effectiveness of eptacog beta in patients with haemophilia and inhibitors: A multi-institutional case series.

Introduction: The management of bleeding events (BEs) in haemophilia A (HA) and B (HB) patients with inhibitors necessitates the use of bypassing agents. The recombinant factor VIIa bypassing agent eptacog beta has demonstrated efficacy at treating BEs and managing perioperative bleeding in adults in phase three clinical studies.

Aim: To provide real-world descriptions of eptacog beta use for BE treatment in patients on emicizumab or eptacog beta prophylaxis.

Simoctocog alfa (Nuwiq) in children: early steps in life's journey for people with severe hemophilia A.

People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent recurrent and potentially life-threatening bleeds that significantly impact day-to-day life. Factor VIII (FVIII) prophylaxis is well-established in children and has been shown to reduce the development of hemophilic arthropathy.

Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial.

Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods).

Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks.

Background: Emicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4).

Objectives: Here, we describe pharmacokinetics (PKs), pharmacodynamics (PDs), and exploratory safety biomarkers in HAVEN 1 to 4.

Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b open-label trial.

Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up.

Current practices in pediatric hospital-acquired thromboembolism: Survey of the Children's Hospital Acquired Thrombosis (CHAT) Consortium.

Background: A rise in hospital-acquired venous thromboembolism (HA-VTE) in children has led to increased awareness regarding VTE prophylaxis and risk assessment. Despite no consensus exists regarding these practices in pediatrics.

Objective: To describe common practices in VTE prophylaxis, VTE risk assessment models, and anticoagulation dosing strategies in pediatric hospitals that are members of the Children's Hospital Acquired Thrombosis (CHAT) Consortium.

Prophylaxis with a recombinant factor VIII Fc in hemophilia A: long-term follow-up on joint health, efficacy, and safety from phase 3 studies in children and adults.

Background: Recurrent joint bleeds are a major cause of morbidity in severe hemophilia. Prophylaxis with efmoroctocog alfa (a recombinant factor VIII Fc fusion protein, [rFVIIIFc]) has demonstrated benefits beyond bleed control, including joint health maintenance.

Objectives: To assess long-term efficacy and safety of rFVIIIFc prophylaxis in severe hemophilia A in phase 3 pivotal (A-LONG/Kids A-LONG) and extension (ASPIRE) studies.

Delivery of gene therapy in haemophilia treatment centres in the United States: Practical aspects of preparedness and implementation.

Introduction: Haemophilia treatment centres (HTCs) and healthcare providers (HCPs) will need to adapt to a new treatment paradigm with the emergence of adeno-associated virus (AAV)-based gene therapy for the treatment of haemophilia in adults.

Aim: This review examines the upcoming patient and institutional journeys, along with practical aspects of preparedness for clinical delivery of gene therapy by HTCs.

Methods: Based on our clinical experience and examination of published literature, we explored the parallel journeys for patients and treatment centres to navigate before, during, and after administration of gene therapy.

Neutralizing antidrug antibody to emicizumab in patients with severe hemophilia A: Case report of a first noninhibitor patient and review of the literature.

Background: Hemophilia A (HA) is a genetic bleeding disorder characterized by the deficiency of the coagulation protein factor (F) VIII (FVIII). The development of neutralizing antidrug antibodies (ADAs) to factor concentrates (inhibitors) created an unmet need for novel therapies. The first agent to address this need is emicizumab.

Efficacy and safety evaluation of eptacog beta (coagulation factor VIIa [recombinant]-jncw) for the treatment of hemophilia A and B with inhibitors.

Introduction: Bypassing agents (BPAs) are used to treat acute bleeding episodes, manage bleeding during perioperative care, and prophylactically minimize bleed occurrence in persons with hemophilia A or B with inhibitors (PwHABI). However, the effectiveness of BPAs that have been prescribed for the last several decades can be variable, motivating the development of a new recombinant activated factor VII, eptacog beta.

Areas Covered: This review covers key eptacog beta findings from phase 1b and phase 3 (PERSEPT) clinical trials, which formed the basis for its regulatory approval to treat PwHABI ages 12 and older.

The immunogenicity, safety, and efficacy of N8-GP in previously untreated patients with severe hemophilia A: pathfinder6 end-of-trial results.

Background: The pathfinder6 (NCT02137850) international phase 3 trial examined immunogenicity, safety, and efficacy of the extended half-life factor VIII (FVIII) replacement product N8-GP (turoctocog alfa pegol; Esperoct) in previously untreated patients (PUPs) with hemophilia A.

Objectives: We present end-of trial results for extended PUP N8-GP treatment for up to a median (range) 2.5 (0.

Effects of PK-guided prophylaxis on clinical outcomes and FVIII consumption for patients with moderate to severe Haemophilia A.

Introduction: In recent years, there has been increased focus on individualizing treatment for persons with hemophilia including pharmacokinetic-guided (PK) dosing.

Aims: In this retrospective study clinical outcomes before and after PK-guided prophylaxis were examined.

Materials And Methods: Eight Haemophilia Treatment Centres from the United States participated in the study and included 132 patients classified into two cohorts: those undergoing a PK-assessment for product switch (switchers) or to optimize treatment (non-switchers).

How I treat pediatric venous thromboembolism in the DOAC era.

The direct oral anticoagulants (DOACs) rivaroxaban and dabigatran are newly licensed for the treatment and prevention of venous thromboembolism (VTE) in children and mark a renaissance in pediatric anticoagulation management. They provide a convenient option over standard-of-care anticoagulants (heparins, fondaparinux, and vitamin K antagonists) because of their oral route of administration, child-friendly formulations, and significant reduction in monitoring. However, limitations related to therapeutic monitoring when needed and the lack of approved reversal agents for DOACs in children raise some safety concerns.

Antithrombin lowering in hemophilia: a closer look at fitusiran.

Thrombin is a key enzyme in the maintenance of normal hemostatic function and is the central product of an interconnected set of simultaneously occurring cellular and proteolytic events. Antithrombin (AT) is a natural anticoagulant that downregulates different components of the clotting process, particularly thrombin generation. In good health, well-regulated hemostasis is the result of a balance between procoagulant and anticoagulant elements.