Extending health equity to people with moderate and mild hemophilia A: revisiting the HAVEN 6 trial.

Congenital hemophilia A (HA) disease severity has traditionally been categorized according to intrinsic factor (F)VIII levels, with <1% of normal indicating severe HA, 1% to 5% moderate HA, and 6% to 40% mild HA. However, mounting evidence illustrates considerable variability in bleeding phenotype regardless of FVIII level. Despite treatment advances, people with moderate or mild HA may be neglected, as treatment guidelines and established norms focus on FVIII levels, and many clinical trials do not include people with FVIII > 1%.

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.

Outcomes and management of invasive procedures in participants with hemophilia A post gene therapy: a post hoc analysis of the GENEr8-1 phase III trial.

Background: Hemophilia A is caused by coagulation factor VIII (FVIII) deficiency and increases bleeding risk during invasive procedures.

Objectives: To investigate FVIII concentrate use and bleeding outcomes for invasive procedures after valoctocogene roxaparvovec gene transfer.

Design: This manuscript presents post hoc analysis of the phase III GENEr8-1 trial.

Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial.

Background: Valoctocogene roxaparvovec, an adeno-associated virus-mediated gene therapy for severe hemophilia A, enables endogenous factor (F)VIII expression and provides bleed protection.

Objectives: Determine valoctocogene roxaparvovec durability, efficacy, and safety 4 years after treatment.

Methods: In the phase 3 GENEr8-1 trial, 134 adult male persons with severe hemophilia A without inhibitors and previously using FVIII prophylaxis received a 6 × 10 vg/kg infusion of valoctocogene roxaparvovec.

Long-term safety and efficacy of fitusiran prophylaxis, and perioperative management in people with hemophilia A or B.

Fitusiran is an investigational small interfering RNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia. Here we present the results of the completed Phase 2 open-label extension study, which evaluated the long-term safety and efficacy of fitusiran in participants with moderate or severe hemophilia A or B, with or without inhibitors. Male participants who had completed the Phase 1 study (NCT02035605) were enrolled.

A novel gene editing lexicon strategy for the haemophilia community: Research plan for development and preliminary results.

Introduction: Despite the progress in gene editing platforms like CRISPR/Cas9 with the potential to transform the standard of care for haemophilia, the language used to explain and discuss gene editing is not aligned across the haemophilia community. Here, we present the objective and rationale for developing a clear, consistent, and globally aligned gene editing lexicon to address these communication gaps.

Methods: Effectively communicating complex gene editing concepts requires a clear and consistent vocabulary.

Evaluation of an automated von Willebrand factor glycoprotein IbM activity assay compared with 3 alternative von Willebrand factor activity assays.

Background: To overcome deficiencies of the traditional von Willebrand factor (VWF) ristocetin cofactor activity assay (VWF:RCo), several automated assays for VWF platelet-binding activity have been developed. Information on the performance of these assays and their diagnostic utility remains limited.

Objectives: To validate the VWF:glycoprotein IbM assay INNOVANCE VWF Ac and compare it with an automated VWF:RCo assay as well as with an automated assay and a manual VWF:Ab assay and to generate reference ranges and analyze reproducibility of the VWF:glycoprotein IbM assay.

Transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: A simulation study for individuals with severe haemophilia A.

Introduction: Valoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8-1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8-1 enrolment since emicizumab was an investigational therapy at the time of trial initiation.

Aim: Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec.

Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A.

Background: Valoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection.

Objectives: To present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial.

Methods: GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis.

Long-term outcomes with emicizumab in hemophilia A without inhibitors: results from the HAVEN 3 and 4 studies.

Background: Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX and FX, mimicking the function of missing or deficient activated FVIII in people with hemophilia A (HA).

Objectives: To evaluate the long-term efficacy and safety of emicizumab prophylaxis in people with HA without FVIII inhibitors in the HAVEN 3 and 4 studies.

Methods: HAVEN 3 and 4 were phase 3 open-label studies.

Effect of etranacogene dezaparvovec on quality of life for severe and moderately severe haemophilia B participants: Results from the phase III HOPE-B trial 2 years after gene therapy.

Introduction: For people with haemophilia B (PwHB), bleeding may occur despite prophylaxis, negatively affecting health-related quality of life (HRQoL). The pivotal phase 3 HOPE-B trial investigating the adeno-associated virus gene transfer product, etranacogene dezaparvovec (EDZ), demonstrated sustained factor IX (FIX) activity and bleed protection in PwHB with baseline FIX levels ≤2%.

Aim: Assess how EDZ affects HRQoL in HOPE-B trial participants.

Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial.

Background: Etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment, was shown to be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after gene therapy in a phase 3 trial. We report post-hoc 24-month efficacy and safety data from this trial to evaluate the longer-term effects of etranacogene dezaparvovec in individuals with haemophilia B.

Methods: The phase 3 HOPE-B trial enrolled males aged 18 years or older with inherited haemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%), with a severe bleeding phenotype and who were on stable continuous factor IX prophylaxis.

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.

A global comparative field study to evaluate the factor VIII activity of efanesoctocog alfa by one-stage clotting and chromogenic substrate assays at clinical haemostasis laboratories.

Introduction: Structural and chemical modifications of factor VIII (FVIII) products may influence their behaviour in FVIII activity assays. Hence, it is important to assess the performance of FVIII products in these assays. Efanesoctocog alfa is a new class of FVIII replacement therapy designed to provide both high sustained factor activity levels and prolonged plasma half-life.

Etranacogene dezaparvovec for the treatment of adult patients with severe and moderately severe hemophilia B.

Introduction: Etranacogene dezaparvovec is the first gene therapy approved for treatment of adults with severe and moderately severe hemophilia B.

Areas Covered: This review describes the results of the clinical trial program of AMT-060 and etranacogene dezaparvovec, outlining the pharmacokinetic, clinical efficacy and safety data. With the entry of etranacogene dezaparvovec into the market, this review summarizes the treatment landscape in hemophilia B and discusses the current unknowns in the field.

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.

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

Background: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL).

Objectives: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1.

Methods: Participant-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).

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.

Corrigendum to 'Efficacy of emicizumab is maintained throughout dosing intervals for bleed prophylaxis' [Research and Practice in Thrombosis and Haemostasis, Volume 7, Issue 2, February 2023, 100077].

[This corrects the article DOI: 10.1016/j.rpth.