Denecimig (Mim8) is a next-generation, activated factor VIII mimetic, fully human bispecific IgG4 antibody in development for subcutaneous prophylaxis in bleeding episodes for patients with hemophilia A (HA) with/without inhibitors. FRONTIER4 (NCT05685238) is an open-label extension study to assess safety and efficacy of denecimig. Here we present an interim analysis of patients receiving denecimig once-every-2-weeks (Q2W) in FRONTIER4. Patients with HA aged ≥12 years who had participated in the denecimig phase 2 study and ≥12 weeks of its extension and entered Arm 1 of the FRONTIER4 phase 3 study received denecimig Q2W for 26 weeks using a tiered dosing approach according to body weight range. The primary endpoint was number of treatment-emergent adverse events (TEAEs); secondary endpoints included injection-site reactions, occurrence of anti-denecimig antibodies, denecimig plasma concentrations, and number of treated bleeds. Thirty-seven patients were enrolled who received denecimig for a mean of 1.73 years in the phase 2 study. Sixty TEAEs were reported in 20 patients. Most TEAEs were mild/moderate in severity (98.3%), unlikely to be related to denecimig (75.0%), and resolved during the time frame of this analysis (90.0%). No TEAEs led to permanent discontinuation of denecimig, and none were fatal. Two patients reported 14 injection site reactions. Denecimig plasma concentrations were stable through week 26. The estimated mean annualized bleeding rate was 0.38 bleeds/patient year. Most patients experienced zero treated bleeds (83.8%). In summary, denecimig administered Q2W was well tolerated, with few patients experiencing treated bleeds and no safety concerns. NCT05685238

Background Haemophilia B is a rare, X-linked disorder leading to deficient or dysfunctional clotting factor IX (FIX) and bleeding complications. Objectives The objective of this systematic review and meta-analysis was to summarise bleeding events in people with haemophilia B of any severity without inhibitors receiving prophylactic FIX replacement therapies to better understand disease burden and unmet needs. Methods A systematic search was conducted to identify clinical trials and observational studies reporting ABR, annualised joint bleeding rate, spontaneous bleeding events, traumatic bleeding events, and percentage of patients with zero bleeding events. Bleeding outcomes were specified as total, treated, or unspecified and analysed using the random-effects model. Subgroup meta-analyses assessed differences by age, treatment type, follow-up duration, and publication date, when feasible. Results The search yielded 5,684 citations; 24 clinical trials and 53 observational studies were included in the meta-analysis. Treated ABR was 2.23 (95% confidence interval [CI] 1.52, 3.27) in 13 trials; treated or unspecified ABR was 2.25 (95% CI 1.67, 3.03) in 22 trials. In 48 observational studies, treated or unspecified ABR was 2.08 (95% CI 1.62, 2.66). ABR was generally lower for patients <12 years of age (versus ≥12 years of age) and patients treated with EHL (versus SHL). Conclusions Results from this meta-analysis reflect advances in haemophilia B treatment, but also highlight unmet needs, with many patients experiencing 2 or more bleeding events per year. Inconsistent ABR definitions and variability in follow-up times may introduce heterogeneity in the combined estimates.

The therapeutic landscape for haemophilia is rapidly evolving beyond traditional factor replacement to include nonfactor therapies and adeno-associated virus (AAV) gene therapy. These innovations promise effective, long-term prophylaxis with reduced treatment burden but introduce new complexities in clinical management. This review provides a comprehensive analysis of these emerging treatments, focusing on key practical challenges. For nonfactor therapies-including emicizumab, concizumab, marstacimab and fitusiran-critical considerations for bleed management, surgical procedures, and transitioning between products, emphasizing that these agents are for prophylaxis only and require specific, often product-specific, concomitant factor or bypassing agent protocols for acute haemostasis. We further examine the safety profiles of these agents, with a focus on thrombotic risk, which can arise from drug-drug interactions, an excessive procoagulant effect, or the unmasking of baseline risk factors. Immunogenicity, while less frequent than with traditional factors, remains a consideration requiring ongoing pharmacovigilance. Finally, we address the central immunogenicity challenge in AAV gene therapy: managing cytotoxic T-cell-mediated hepatotoxicity that can threaten transgene expression. The role of corticosteroid immunomodulation-both prophylactic and reactive-is explored across clinical trials for haemophilia A and B, highlighting variable responses and the need for tailored strategies. This review synthesizes current evidence to help clinicians navigate this new therapeutic era, optimizing outcomes while mitigating the risks associated with these transformative treatments.

The landscape of hemophilia treatment has recently undergone a drastic transformation with the advent of novel therapies, including extended half-life factor concentrates, nonfactor therapies, rebalancing agents, and gene therapies. While these advancements have improved patient outcomes, they have introduced challenges in laboratory monitoring. Traditional assays such as prothrombin time, activated partial thromboplastin time, and 1-stage clotting assays may not accurately reflect the hemostatic status in patients receiving these new treatments. This article reviews the evolution of hemophilia therapies and the corresponding challenges in laboratory testing, emphasizing the need for updated monitoring strategies to ensure optimal patient management.

Introduction The therapeutic landscape for patients with haemophilia A (PwHA) is rapidly evolving with the introduction of extended half-life FVIII (EHL-FVIII) and non-FVIII therapies that mimic FVIII, such as emicizumab (EMI). Monitoring non-factor therapies in the laboratory poses challenges; however, the thrombin generation assay (TGA) can be utilized to evaluate hemostatic capacity.Aim To compare the endogenous thrombin potential (ETP) and peak thrombin (PT) in pediatric patients with moderate to severe haemophilia A (SHA) undergoing EHL-FVIII therapies and EMI.Methods Platelet-poor plasma (PPP) from PwHA on EHL-FVIII or EMI prophylaxis was tested on the calibrated automated thrombogram (CAT) using PPP low reagent.Results ETP and PT were significantly higher in the EHL-FVIII group compared to the EMI group.Conclusion Pediatric patients on EHL-FVIII prophylaxis demonstrated higher ETP in vitro using PPP compared to those on EMI prophylaxis. These findings highlight the need for further systematic investigations to explore the implications of these differences in bleed control.

BACKGROUND:Pediatric venous thromboembolism (VTE) lacks robust, age-specific evidence to guide parenteral anticoagulation. Prior FondaKIDS studies suggested feasibility of fondaparinux but were limited by small samples, heterogeneous endpoints, and non-standardized assessments. OBJECTIVE:To assess long-term, real-world evidence on the safety, efficacy, and pharmacokinetics of fondaparinux in pediatric VTE using standardized dosing and harmonized outcome definitions. METHODS:This retrospective cohort study at Children's Hospital Los Angeles included patients <18 years receiving at least one dose of fondaparinux (n = 366). A weight-based dosing algorithm targeting anti-Xa 0.5-1.0 mg/L was applied. Endpoints were aligned with International Society on Thrombosis and Hemostasis (ISTH) pediatric standards, with imaging at Month 1 and Month 3 (±15 days) and "any time" analyses. Efficacy outcomes included clot resolution and recurrence. Safety outcomes included major bleeding, post-thrombotic syndrome (PTS), mortality, and adverse events of special interest. RESULTS:Therapeutic anti-Xa levels were achieved in 92.6% within a median of 3 days, with ~55% requiring no dose adjustment. At 3 months, complete resolution occurred in 44.9% (primary VTE) and 44.0% (all VTEs); 66.2% achieved complete or partial resolution. Overall, 75.1% achieved resolution at any time, consistent across subgroups. One-year VTE recurrence was ~8%. Major bleeding occurred in 1.9% (no fatalities); PTS in 1.6%. Mortality of 8.7% was driven by comorbidities. CONCLUSIONS:This largest pediatric fondaparinux cohort demonstrates rapid therapeutic anticoagulation, clinically meaningful clot resolution, and low bleeding risk using standardized dosing and ISTH-harmonized endpoints, supporting its role as a once-daily parenteral option when DOACs are unsuitable and informing pediatric labeling.

ABSTRACT:Concizumab is a novel nonfactor replacement therapy for once-daily subcutaneous prophylactic treatment of hemophilia A/B (HA/HB) with and without inhibitors. Concizumab was superior to on-demand treatment in patients with HA/HB without inhibitors in the prospective, multicenter, open-label phase 3 explorer8 study. Here, longer-term efficacy and safety results from the start of the study up to the 56-week cutoff are presented. Males aged ≥12 years with HA/HB were randomized 1:2 to no prophylaxis (group 1) or concizumab (group 2) or allocated to concizumab (groups 3 and 4). Assessments at the 56-week cutoff included efficacy, pharmacokinetics/pharmacodynamics, and safety. The 56-week cutoff was defined as when all patients in groups 2 to 4 had completed the visit at 56 weeks or permanently discontinued treatment. Of 148 patients in the full analysis set, 21 were randomized to no prophylaxis (group 1: HA, n = 9; HB, n = 12), 42 to concizumab (group 2: HA, n = 18; HB, n = 24), and 85 to the nonrandomized concizumab groups (groups 3 and 4: HA, n = 55; HB, n = 30). After ≥24 weeks of treatment, 17 patients in group 1 switched to concizumab. Low median annualized bleeding rates for treated spontaneous and traumatic bleeding episodes were maintained at the 56-week cutoff in patients receiving concizumab (HA, 1.7 [interquartile range (IQR), 0.0-4.5]; HB, 2.8 [IQR, 0.0-6.4]), consistent with 32-week cutoff results. Concizumab plasma concentration remained stable, with no new safety concerns. Concizumab showed longer-term efficacy in patients with HA/HB at the 56-week cutoff and was considered safe and well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT04082429.

It might take years for previously untreated patients (PUPs) with hemophilia A on emicizumab prophylaxis to receive 50 factor VIII (FVIII) exposures. This corresponds to the time at risk for FVIII inhibitors under conventional FVIII prophylaxis. During emicizumab prophylaxis, it is unknown whether additional treatment with regular FVIII doses promotes FVIII tolerance, unmasks inhibitors, or rather, induces them. Therefore, we conducted a survey to describe the current global perspectives and practices of hemophilia health care providers (HCPs) in PUPs with severe hemophilia A receiving emicizumab prophylaxis. In 2024, a survey was sent by email to 1193 hemophilia treatment centers, addressing the perceived inhibitor risk with emicizumab, the potential need for concomitant regular FVIII infusions, and the perceived parental willingness to use concomitant FVIII. In total, 102 pediatric HCPs (85% physicians, 13% nurses) from 38 countries participated. Perceived inhibitor risk data were available for 63 HCPs (62%). Compared with FVIII prophylaxis, the inhibitor risk on emicizumab was estimated to be higher by 13%, equal by 41%, lower by 32%, and unknown by 14%. Among 57 of 102 HCPs with clinical access to emicizumab for children with severe hemophilia A without inhibitors, 30 (53%) offered regular concomitant FVIII infusions. However, in the experience of the HCPs, approximately 45% of parents rejected this option due to concerns about intravenous access. Ultimately, global perspectives on FVIII inhibitor risk and concomitant FVIII use in PUPs on emicizumab prophylaxis are heterogeneous due to lack of evidence, indicating the need for further research to guide treatment strategies.

ABSTRACT:Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia. This phase 3 open-label extension study (ATLAS-OLE) evaluated safety and efficacy of an AT-based dose regimen (AT-DR) in males aged ≥12 years with severe hemophilia A/B, with/without inhibitors. The original dose regimen (ODR) of 80 mg monthly was optimized to AT-DR targeting AT activity levels 15% to 35% to mitigate thrombotic risk (starting dose of 50 mg once every 2 months, individually adjusted to 20 mg once every 2 months, or 20/50/80 mg monthly as needed). Primary and secondary end points were safety and efficacy, respectively. Integrated safety analyses assessed safety of AT-DR and ODR across all fitusiran studies and integrated efficacy analyses compared efficacy of AT-DR in ATLAS-OLE with phase 3 parent study control groups. At interim data cutoff, 213 participants were enrolled on AT-DR (78% on regimens of once every 2 months). Integrated safety analyses of participants receiving AT-DR (n = 286) demonstrated that AT-DR was well tolerated. In ATLAS-OLE, median observed annualized bleeding rate (ABR) with AT-DR was 3.7 (interquartile range, 0.0-7.5). Integrated efficacy analyses demonstrated superiority of AT-DR over on-demand clotting factor concentrates (CFCs; 71% mean ABR reduction; P < .0001), and on-demand bypassing agents (BPAs; 73% mean ABR reduction; P = .0006); improvement over BPA prophylaxis (70% mean ABR reduction); and ABR comparable with that observed with CFC prophylaxis. Fitusiran AT-DR was well tolerated and maintained bleed protection with as few as 6 injections per year. This trial was registered at www.ClinicalTrials.gov as #NCT03754790.

Severe bleeding episodes (BEs) in persons with hemophilia A or B and inhibitors (PwHABIs) represent challenging clinical situations and can require treatment regimens lasting days or weeks before hemostatic control is achieved. Eptacog beta is a recombinant activated human factor VII bypassing agent approved for treating and controlling bleeding in PwHABIs aged ≥12 years. The aim of this study is to assess the efficacy and safety of eptacog beta for severe bleed treatment in PwHABIs during 2 phase 3 trials (PERSEPT 1 and PERSEPT 2). Patients could treat severe BEs with initial doses of 75 or 225 μg/kg eptacog beta at home, followed by subsequent 75 μg/kg eptacog beta infusions administered at predefined intervals in a hospital or hemophilia treatment center. Satisfactory treatment responses to eptacog beta were typically defined in this post hoc analysis by physician- and patient-reported hemostasis evaluations of "excellent" or "good." Hemostatic control of an intracranial hemorrhage (ICH) in 1 patient was assessed by computed tomography. Seven PwHABIs (aged 1-50 years) treated 8 BEs considered severe or otherwise life threatening with eptacog beta during PERSEPT 1 and PERSEPT 2. Hemostatic control of 7 of these BEs (including 3 ICH events) was achieved. Eptacog beta treatment durations ranged from 25 minutes to 96 hours. No thrombotic events were reported, and eptacog beta was well tolerated. Most severe BEs resolved with eptacog beta treatment during PERSEPT 1 and PERSEPT 2. The PERSEPT 1 and PERSEPT 2 trials were registered at www.clinicaltrials.gov as #NCT02020369 and #NCT02448680, respectively.

BACKGROUND:Extended-phase anticoagulation of venous thromboembolism in children is not well documented nor systematically reported. Previously, we reported on recurrent venous thromboembolism and bleeding during acute-phase anticoagulation in EINSTEIN-Jr, a randomised controlled study in 500 children with venous thromboembolism comparing rivaroxaban to standard anticoagulants. The aim of the present study was to evaluate the efficacy and safety of extended-phase anticoagulant therapy in children and to characterise factors associated with the decision to extend anticoagulation. METHODS:Children aged 17 years or younger, who were enrolled in the EINSTEIN-Jr trial (NCT02234843) from 107 paediatric hospitals in 28 countries, and who had previously completed a 3-month acute anticoagulation treatment phase (1-month in children <2 years with catheter-related venous thromboembolism) for acute venous thromboembolism within the trial were included in this cohort study. After completion of the preceding acute anticoagulation treatment phase, children could extend study treatment for up to 9 months (or up to 2 months for children <2 years with catheter-related venous thromboembolism). Study anticoagulants were bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20 mg equivalent dose or standard anticoagulants (heparin or vitamin K antagonist). The main outcomes were suspected recurrent venous thromboembolism (primary efficacy outcome) and clinically relevant bleeding (principal safety outcome), both confirmed or refuted by appropriate objective testing. Cumulative incidences of efficacy and safety outcomes are reported for children who received extended anticoagulation within the framework of the study. We also compared demographic and clinical characteristics of those administered any extended-phase anticoagulation (whether within or outside the framework of the study) with those not administered extended-phase anticoagulation, applying multivariable logistic regression. FINDINGS:248 (51%) children received extended-phase anticoagulation between Nov 14, 2014, and Jan 15, 2019, 214 within the study and 34 outside the framework of the study. During extended-phase anticoagulant treatment, recurrent venous thromboembolism occurred in three (1%) of the 214 children within the study (cumulative incidence 3·0%; 95% CI 0·9-9·8). Clinically relevant non-major bleeding occurred in four (2%) of 214 children (3·3%; 1·2-9·2). Fatal venous thromboembolism or major bleeding did not occur. Outcome rates were similar with rivaroxaban or standard anticoagulants. Symptomatic index venous thromboembolism (odds ratio 1·88; 95% CI 1·14-3·11), unprovoked venous thromboembolism or persistent risk factor (2·16; 1·46-3·19), and residual thrombosis on repeat imaging (3·79; 2·52-5·71) were associated with the decision to extend anticoagulation. INTERPRETATION:Incidences of recurrent venous thromboembolism and bleeding during extended-phase anticoagulant treatment were low and similar to those observed during acute-phase treatment and adult studies on extended-phase anticoagulant treatment, providing valuable information for clinical practice on extended anticoagulation in children. FUNDING:Bayer and Janssen Research & Development.

Abstract 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. This approach is effective ∼65% of the time, leaving at least a third of patients who develop inhibitors with this lifelong problem. Although emicizumab has greatly improved the quality of life of inhibitor patients, eradicating the inhibitor remains an important treatment goal. Animal models have shown the potential for gene therapy to induce tolerance. A recent abstract describing a study in humans demonstrated the potential for successful tolerance induction. This article will describe the rationale for using gene therapy to induce tolerance and provide this author's viewpoint on the importance and possible historic significance of attempting to eradicate inhibitors with this approach.

INTRODUCTION:Accurate and reproducible measures of factor activity are required to guide clinical decision-making following gene therapy for haemophilia B (HB). Highly significant discrepancies have been observed in measurements of various factor IX (FIX) concentrates that carry molecular modifications to extend their half-life, arguing for the need for careful analysis of new HB treatment modalities with respect to FIX assay performance. AIM:To further characterise variability in FIX activity measured using different one-stage assays (OSAs) and chromogenic assays (CAs) in patients with HB receiving gene therapy utilising the FIX Padua variant and to assess whether assay differences were due to the FIX-Padua variant. METHODS:FIX activity was assessed centrally (OSA and CA) and locally (OSA only) using plasma samples collected from a phase 2b and phase 3 study of etranacogene dezaparvovec and in an in vitro study of wild-type (wt) recombinant human FIX (rhFIX) and rhFIX-Padua. RESULTS:Lower CA than OSA FIX activity for plasma samples from the phase 3 trial was observed (CA:OSA ratio: 0.408 [±0.049]-0.547 [±0.062]). Local OSA:central OSA FIX activity ratios were 0.789 (±0.314)-1.021 (±0.159). Local OSA:central OSA FIX activity ratios across methods and/or reagents were 0.81 (±0.02)-1.28 (±0.04) for rhFIX-wt-spiked samples and 0.67 (±0.02)-1.13 (±0.09) for rhFIX-Padua-spiked samples. CONCLUSION:FIX activity differences between central and local OSAs were modest; similar differences were observed in vitro with rhFIX-wt versus rhFIX-Padua. Commonly available OSAs can be used to monitor patients post-etranacogene dezaparvovec administration; we recommend using the same assay platform throughout the post-treatment period.

Critically ill children have a high risk of hospital associated venous thromboembolism (HA-VTE). Developing a validated risk assessment model (RAM) to identify children who may benefit from thromboprophylaxis is essential. We aimed to prospectively validate the Children's Healthcare Advancements in Thrombosis (CHAT) intensive care unit (ICU) VTE RAM containing five clinically significant variables: CVC, immobility, congenital heart disease, autoimmune or inflammatory conditions and hospital stay of ≥3 days in a multicenter cohort study. Randomly selected patients aged 0-21 years admitted to a pediatric ICU (PICU) at 32 institutions were monitored via medical record review for HA-VTE. Discrimination was assessed using the area under the receiver operating characteristic (AUROC) curve. Calibration was assessed using calibration plots. Complete case and imputed analyses were performed and model risk scores were generated along with post-test probability. The RAM was validated in 4,674 patients with an AUROC of 0.71 [95% CI:0.64-0.78], calibration slope of 1.0 (95% CI:0.87-1.14) and intercept of 1.81x10-5 (95% CI: -5.40x10-3-5.44x10- 3). The AUROC for the imputed model was 0.69 (95% CI:0.68-0.70) with the calibration slope of 1.03 (95% CI: 0.85-1.21) and intercept of 1.22x10-3 (95% CI: -7.80x10-3-5.36x10-3). Calculated risk scores were 1 or 2 for each variable in the RAM with a total risk score ranging from 0 to 6. The estimated probability for developing HA-VTE ranged from 1% to 17.4% depending on the total score. In conclusion, the CHAT-ICU RAM has good discriminatory validity, is well-calibrated and reliably identifies children in the PICU at high and low risk of HA-VTE.

Valoctocogene roxaparvovec is the only factor VIII (FVIII) gene therapy currently approved for adults with severe hemophilia A in Europe and the USA. Elevated alanine transaminase (transaminitis) has been the most common adverse event observed during valoctocogene roxaparvovec clinical trials. Typically mild and transient, this marker of hepatocyte injury coincides, in some patients, with reduced FVIII levels and is generally managed with a reactive course of corticosteroids. An essential step in optimizing outcomes for patients who receive valoctocogene roxaparvovec is reviewing the extensive evidence currently available on this topic to determine practices for managing transaminitis, if it occurs. This forum article provides practical guidance based on the available clinical data and expert opinion for evaluating and managing transaminitis with corticosteroids to mitigate potential declines in FVIII activity levels in adults with severe hemophilia A who have received valoctocogene roxaparvovec.