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

INTRODUCTION:Adeno-associated virus (AAV)-based gene therapy for haemophilia has shifted therapeutic paradigms by enabling hepatic gene transfer, restoring endogenous clotting factor expression, and reducing reliance on conventional prophylactic treatments. Two products, valoctocogene roxaparvovec (haemophilia A) and etranacogene dezaparvovec (haemophilia B), are now in clinical use, with ongoing development of additional gene therapy modalities. DISCUSSION:The clinical benefits include sustained increases in factor VIII or IX levels, reduction or elimination of bleeding episodes, and improved quality of life. However, significant challenges remain, such as immune-mediated responses leading to hepatocellular inflammation, inter-individual variability in factor expression, and the unresolved durability of therapeutic effects. Comprehensive clinical infrastructure and multidisciplinary coordination-guided by hub-and-spoke models and standardized centre qualification criteria-are essential for the safe delivery of gene therapy. Lifelong post-treatment monitoring is mandatory to detect adverse events such as hepatotoxicity and malignancies, with structured protocols for laboratory testing and imaging now established through international guidelines. CONCLUSIONS:Despite its transformative potential, slow real-world adoption is observed, constrained by scientific, operational, and reimbursement challenges. Ongoing data collection via registries and harmonized monitoring pathways will be vital for optimizing outcomes and delineating long-term safety profiles for gene therapy in haemophilia clinical practice.

BACKGROUND:Mim8 (denecimig), a bispecific antibody mimicking activated factor VIII, was developed for bleeding prophylaxis in patients with hemophilia A with or without factor VIII inhibitors. METHODS:In this phase 3, randomized trial, we assigned patients 12 years of age or older with hemophilia A with or without inhibitors to receive subcutaneous Mim8 once weekly or once monthly at a dose tiered according to body weight and given in a fixed injection volume (0.8 ml). Patients who had been receiving on-demand treatment before the trial were assigned in a 1:1:1 ratio to continue on-demand treatment (group 1) or receive Mim8 once weekly (group 2a) or once monthly (group 2b). Patients who had been receiving clotting factor concentrates during a run-in phase were assigned in a 1:1 ratio to receive Mim8 once weekly (group 3) or once monthly (group 4). The first primary end point was the annualized rate of treated bleeding events (those treated with a coagulation factor product) in an evaluation of Mim8 in group 2a and Mim8 in group 2b as compared with on-demand treatment in group 1. The second was the annualized rate of treated bleeding events in an intrapatient evaluation of Mim8 in group 3 and Mim8 in group 4 as compared with clotting factor concentrate prophylaxis during the run-in phase. RESULTS:Of the 58 patients in the pretrial on-demand treatment cohort, 17 were assigned to group 1, 21 to group 2a, and 20 to group 2b. The estimated mean annualized rate of treated bleeding events was 0.57 (95% confidence interval [CI], 0.25 to 1.30) in group 2a and 0.20 (95% CI, 0.06 to 0.71) in group 2b, as compared with 15.76 (95% CI, 10.70 to 23.20) in group 1 (relative decrease, 96.4% and 98.7%, respectively; P<0.001 for both comparisons). Of the 196 patients in the pretrial prophylaxis cohort, 98 each were assigned to group 3 or group 4. The estimated mean annualized rate of treated bleeding events was 2.25 (95% CI, 1.37 to 3.71) in group 3, as compared with 4.90 (95% CI, 3.65 to 6.56) during the run-in phase (relative decrease, 54.0%; P = 0.006), and 1.78 (95% CI, 1.18 to 2.71) in group 4, as compared with 3.12 (95% CI, 2.25 to 4.32) (relative decrease, 42.8%; P = 0.006). Injection-site reactions were reported in 103 of 4005 injections (2.6%). No patient was reported to have a thromboembolic event or clinical evidence of neutralizing anti-Mim8 antibodies. CONCLUSIONS:Among patients with hemophilia A with or without inhibitors, Mim8 prophylaxis was superior to on-demand treatment and clotting factor concentrate prophylaxis regarding the annualized rate of treated bleeding events. (Funded by Novo Nordisk; FRONTIER2 ClinicalTrials.gov number, NCT05053139.).

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.

Introduction Mim8 (denecimig) is a new-generation, bispecific antibody, activated factor VIII mimetic in clinical development for subcutaneous prophylaxis (PPX) for hemophilia A (HA) with or without inhibitors. The 26-week main phase of the phase 3 FRONTIER2 study (NCT05053139) demonstrated superiority of once-every-week (QW) and once-every-month (QM) Mim8 PPX in reducing annualized bleeding rates (ABRs) for treated bleeds versus on-demand therapy or prior clotting factor concentrate (CFC) PPX. Aim To assess 52-week efficacy and safety of Mim8 PPX in adults and adolescents (aged ≥12 years) with HA with or without inhibitors from the FRONTIER2 extension phase. Methods In the 26-week main phase, participants were randomized to Mim8 QW or QM, or continued on-demand standard-of-care treatment. Participants were grouped by prior treatment regimen: on-demand or CFC PPX. In the 26-week extension, all on-demand participants switched to Mim8 PPX (QW or QM); others continued their assigned regimen. Mim8 was administered using a tiered-dosing approach. Primary endpoint: number of treated bleeds; selected secondary endpoints: number of injection-site reactions (ISRs) and anti-Mim8 antibodies. ABR was estimated using a negative binomial regression model. Safety and immunogenicity were assessed. Ethics approval and informed consent were obtained. Results Of 281 randomized participants, 97% completed the main phase and 96% the extension. Mean (min; max) age at baseline was 32 (13;64) years for the pre-study on-demand group (n=61) and 31 (12;69) years for the pre-study CFC PPX group (n=220). In the pre-study CFC PPX group vs the pre-study on-demand group, there was a higher proportion of patients with severe HA (86% vs 77%) and lower proportion with inhibitors (2% vs 44%). This analysis includes 27 newly reported participants from China. In the main phase, all participants who continued on-demand treatment (n=18) experienced treated bleeds. Estimated mean ABR (95% confidence interval [CI]) was 16.09 (11.21;23.09). All participants entered the extension, during which 88% (Mim8 QW, n=7/8) and 70% (Mim8 QM, n=7/10) had zero treated bleeds. Estimated mean ABRs (95% CI) were 0.67 (0.13;3.61) and 0.79 (0.19;3.33), respectively. For participants previously treated on-demand: of those randomized to Mim8 QW, 86% (n=19/22) had zero treated bleeds in the main phase and 91% (n=19/21) in the extension, with estimated mean ABRs (95% CI) of 0.43 (0.17;1.07) and 0.45 (0.19;1.08), respectively; of those randomized to Mim8 QM, 91% (n=19/21) had zero treated bleeds in the main phase and 86% (n=18/21) in the extension, with estimated mean ABRs (95% CI) of 0.25 (0.08;0.76) and 0.25 (0.08;0.77), respectively. For participants previously on CFC PPX: of those randomized to Mim8 QW, 67% (n=74/111) had zero treated bleeds in the main phase and 70% (n=73/104) in the extension, with estimated mean ABRs (95% CI) of 2.32 (1.35;3.99) and 1.28 (0.78;2.08), respectively; of those randomized to Mim8 QM, 63% (n=69/109) had zero treated bleeds in the main phase and 69% (n=74/108) in the extension, with estimated mean ABRs (95% CI) of 1.79 (1.22;2.63) and 1.54 (0.92;2.59), respectively. Across main and extension phases, median ABR was 0 in all Mim8-treated arms. Adverse events (AEs) were reported in 74% (n=104) of Mim8 QW and 71% (n=100) of Mim8 QM participants. Most AEs were mild: 84% (399/475) of events with Mim8 QW and 82% (321/390) with Mim8 QM. Overall, ISRs occurred in 12% (n=17) of QW and 9% (n=12) of QM participants, accounting for 1.81% and 1.34% of injections, respectively. Overall, anti-Mim8 antibodies were detected in 21 (7%) recipients without clinical evidence of neutralizing activity; all were low (95%) or medium (5%) titer. No thromboembolic events, hypersensitivity reactions, or clinically relevant laboratory abnormalities were observed, including coagulation parameters. Conclusion Over 52 weeks, Mim8 QW and QM PPX provided sustained bleed protection in adults and adolescents with HA, with or without inhibitors, supporting its use as a long-term prophylactic option. During the extension, Mim8 was well tolerated, with infrequent ISRs, few serious AEs, no thromboembolic events or hypersensitivity reactions, and no anti-Mim8 antibodies with clinical impact. Participants completing FRONTIER2 are eligible for the open-label extension, FRONTIER4 (NCT05685238). Mim8 may offer an effective and convenient approach to reducing disease and treatment burden in this population.

Introduction:Elbow arthroscopy is a treatment option for advanced symptomatic arthropathy with few outcomes reported in the literature. Aim:This study determines the safety and short to long-term outcome of therapeutic elbow arthroscopy in haemophilic arthropathy of the elbow. Methods:Patients undergoing arthroscopy between 2005 and 2023 were included. Patients were treated by a multidisciplinary team comprising orthopaedic surgeon, haematologists, physiotherapists and allied professionals. All patients were assessed pre-operatively, intra-operatively and post-operatively with pain, range of motion (ROM), Haemophilia Joint Health Score (HJHS) and EQ5D. Results:Fifteen elbows in 13 patients were managed with arthroscopy for symptomatic haemophilic arthropathy. Mean age was 44.1 ± 13.1 years. The median follow-up was seven years. Intra-operatively, flexion-extension and prono-supination improved by 35° and 26°, respectively. This gradually deteriorated with time, returning to pre-operative levels at approximately 2-5 years. HJHS improved by 2.5 points at six months, 1.67 at 12 months and returned to pre-operative levels at 2-5 years. EQ-VAS score deteriorated by 10.5 points at six months but improved by 19.1 at 12 months, by 10.1 at 2 years and by 14.4 at five years. There were no perioperative complications, the commonest complication was recurrence of stiffness, and two required arthroplasty in long term. Conclusion:Therapeutic arthroscopy is safe in advanced haemophilic elbow arthropathy. It shows potential benefit for function and quality of life in the short to medium term. Though there is a 33% risk of further surgery within 10 years, it should be considered an important adjunct to the multidisciplinary musculoskeletal care pathway in haemophilic elbow arthropathy, especially amongst a young patient cohort.

BACKGROUND AND AIMS:Despite recent progress, advanced non-small cell lung cancer (NSCLC) has poor survival outcomes, necessitating the development of novel therapies. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces cancer cell death and can be delivered to tumors by mesenchymal stromal cells (MSCs) due to the cells' migratory properties. This first-in-human phase I trial assessed safety and dose of umbilical cord-derived MSCs expressing TRAIL (UC-MSCTRAIL) alongside standard NSCLC therapy. METHODS:Participants performance status 0-1 with treatment-naïve, inoperable stage IIIB/IV NSCLC received UC-MSCTRAIL infusions with each cycle of chemotherapy and immunotherapy, up to 3 cycles. A dose de-escalation design was used. Exploratory in vitro and in vivo studies further characterized UC-MSCTRAIL properties. RESULTS:Six participants enrolled; four received 4 × 10⁸ cells/infusion (median 5.4 × 106 cells/kg), and two received 2 × 10⁸ cells/infusion (median 2.4 × 106 cells/kg). Early termination occurred due to asymptomatic pulmonary emboli (N = 5), which included two patients that were anticoagulated as a protocol amendment with prophylactic low molecular weight heparin (enoxaparin 40 mg) and rivaroxaban 20 mg, respectively. Exploratory analyses found no clear pro-coagulant or immunogenic mechanisms, though participants receiving UC-MSCTRAIL had elevated inflammatory markers. CONCLUSION:This first-in-human study of UC-MSCTRAIL in advanced lung cancer was terminated early due to high prevelance of pulmonary embolism. THough exact mechanism remains unclear, UC-MSCTRAIL may have contributed to a pro-inflammatory environment in participants already at elevated risk of thrombosis due to malignancy. Future MSC-based therapies should incorporate close monitoring for asymptomatic thrombosis and follow a dose escalation design for safety. Safety concerns underscore the need for further research.

Summary What is this summary about? This is a summary of the results from a study that looked at the treatment preferences of people with hemophilia and caregivers of children with hemophilia in the US and UK. The study was published in a research journal called Haemophilia. People with hemophilia need regular treatments to help their blood clot properly and to prevent bleeding. Treatments to prevent bleeding are often injected into a vein. For some people, the injections can be painful or hard to use. If treatments are hard to use, people may be less likely to stick to their treatment plan. This can make it harder for them to manage their hemophilia. New treatments that work in a different way can be given as an injection under the skin instead of into a vein. These treatments may be easier for people to use. Newer treatments have different benefits and risks compared with earlier types of treatment, so researchers wanted to understand what features of treatments are most important to people with hemophilia and caregivers What were the results of the study? Adults with hemophilia and caregivers of children with hemophilia in the US and UK took an online survey. They were asked to choose between made-up (hypothetical) treatments with different benefits, risks, and ways of administration (how the treatment is delivered into the body). The study showed that people with hemophilia and caregivers had mostly the same preferences for treatments to prevent bleeds. People cared most about having a treatment they can take less often. People were willing to accept some additional risks or lower treatment benefits if they could have injections under the skin instead of into a vein. What do the results mean? People with hemophilia and caregivers found some treatment features more important than others. It is important for healthcare teams to know which treatment features are most important to people. If treatments match people’s preferences, they are more likely to be satisfied. For example, if people prefer injections under the skin, they may be more likely to stick to their treatment plan if they use a treatment delivered under the skin instead of into a vein. People who stick to their treatment plan are likely to have better health outcomes.

Background:Efanesoctocog alfa is a first-in-class high-sustained factor VIII (FVIII) replacement therapy. In the phase III XTEND-1 (NCT04161495) study, once-weekly efanesoctocog alfa prophylaxis (50 IU/kg) was well-tolerated and achieved high-sustained factor levels in the normal to near-normal range (>40%) for most of the week. Objective:To report outcomes in previously treated participants with severe haemophilia A aged ⩾12 years from an observational study who switched to efanesoctocog alfa prophylaxis during XTEND-1. Design:Paired assessment of participants from an observational study who enrolled in the phase III XTEND-1 study. Methods:Seventy-eight participants switched from marketed standard half-life (SHL) or extended half-life (EHL) FVIII prophylaxis to once-weekly efanesoctocog alfa prophylaxis (50 IU/kg). Endpoints included annualized bleed rates (ABRs), treatment of bleeding episodes, injection frequency and FVIII consumption. Results:Pre-study, 44 (56%) and 34 (44%) participants received SHL FVIII or EHL FVIII prophylaxis, respectively. In the overall population, a significant reduction in ABR from 2.96 to 0.69 (p < 0.0001) was observed following the switch to efanesoctocog alfa prophylaxis as well as reductions in spontaneous, traumatic, joint and spontaneous joint ABRs (p < 0.0001). Significant reductions in mean weekly injection frequency were observed, from 2.8 to 1.0 in the SHL FVIII cohort (p < 0.0001) and from 1.8 to 1.0 in the EHL FVIII cohort (p < 0.0001). Mean annualized factor consumption reduced by 47% in the SHL FVIII cohort and 30% in the EHL FVIII cohort. Conclusion:Collectively, the results of this post hoc analysis demonstrate the benefits of once-weekly efanesoctocog alfa prophylaxis over SHL or EHL FVIII prophylaxis on bleed rates, injection frequency and consumption. Trial registration:Observational study: 242HA201/OBS16221; XTEND-1: NCT04161495 (https://clinicaltrials.gov/study/NCT04161495).

BACKGROUND:Between 1970 and 1991, when viral inhibition reduced the risk, people with a bleeding disorder in the United Kingdom had their missing clotting factors replaced with plasma products derived from donated plasma at risk of infection. We analyzed longer-term survival of people with bleeding disorders exposed to plasma products. METHODS:The National Haemophilia Database documents people with bleeding disorders registered, treated before, and alive on 1 January 1992. We estimated all-cause mortality proportional hazard ratios for exposure groups (Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) coinfected, HCV-diagnosed, and HCV-status unknown) versus HCV antibody negative, within distinct epochs: 1992-1999; 2000-2009; 2010-2019. We estimated years of life lost by epoch and exposure group versus UK general population lifetables or via parametric survival models compared with people with bleeding disorders negative or unknown for HCV antibodies. Models were adjusted for sex, age band at 1 January 1992, bleeding disorder, and severity. RESULTS:Of 6282 people with bleeding disorders who met inclusion criteria, 15% were HIV/HCV coinfected, 32% HCV antibody positive, and 28% HCV antibody negative. Compared with HCV-negative, those HIV/HCV coinfected had an all-cause mortality hazard ratio of 4.2 (95% confidence interval: 2.9, 6.0) and HCV+ of 2.2 (1.7, 2.8) in 2010 to 2019. Years of life lost for 2014 to 2019 were 740 (95% confidence interval: 440, 1030) for HCV+ persons and 270 (130, 400) for HIV/HCV coinfected persons, compared with HCV unknown or negative persons. CONCLUSIONS:People with bleeding disorders in the United Kingdom infected before, but alive at, 1 January 1992, were still at increased risk of death 3 decades postimplementation of HCV screening of blood supplies.

BACKGROUND:Rotational thromboelastometry (ROTEM) aims to measure the coagulation potential in whole blood. Concizumab, an anti-tissue factor pathway inhibitor (TFPI) antibody for prophylaxis in haemophilia, enhances tissue factor (TF)-initiated coagulation by preventing inhibition of activated factor X (FXa), thus increasing thrombin generation. OBJECTIVES:To evaluate a modified ROTEM assay for monitoring patients on concizumab prophylaxis. METHODS:The TF reagent (r_exTEM) was diluted 50,000-fold to make the ROTEM assay sensitive to haemophilia and to concizumab. The effect of concizumab was evaluated in the modified ROTEM in haemophilia A (HA)-like blood (normal blood with added anti-FVIII antibody). ROTEM analysis was performed in blood from patients participating in the explorer7/8 trials during 24 weeks of concizumab prophylaxis. Rotrol N plasma was used as quality control. RESULTS:In vitro experiments showed concizumab concentration-dependent reduction in clot time (CT) and increase in clot development (α-angle) in HA-like blood. At three of four clinical sites, CT and clot development were stable, variance of the control plasma was ≤12.4% and TF content of the diluted reagent (r_exTEM) was consistent. At these three sites, the correlation between CT versus concizumab exposure, free TFPI and thrombin generation assay parameters was weak (-0.508 to +0.359). Prothrombin time positively correlated with CT (0.523) and negatively correlated with α-angle (-0.659). CONCLUSION:Due to the poor correlation between ROTEM parameters, concizumab exposure, free TFPI and thrombin generation parameters and the lack of consistent and reliable performance of the modified ROTEM assay, it cannot be recommended for general monitoring of patients on concizumab prophylaxis.

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.

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.

ABSTRACT:Factor VIII (FVIII) replacement remains central to the management of hemophilia A. Extended half-life (EHL)-FVIII concentrates, developed through Fc-fusion or PEGylation, extend terminal half-life and overall exposure area under the curve (AUC) by ∼30% compared with standard half-life (SHL) products but remain limited by the von Willebrand factor (VWF)-imposed half-life ceiling. A newly engineered high-sustained-activity/ultralong half-life FVIII (HSA/UL-FVIII) eliminates VWF binding through multiple structural modifications, achieving a fourfold longer half-life, a sixfold greater AUC than SHL-FVIII, and FVIII activity within the nonhemophilia range for several days following once-weekly dosing. Using population pharmacokinetic (PK) modeling, we simulated single-dose and steady-state FVIII activity-time profiles in 1000 virtual patients treated with SHL-, EHL-, or HSA/UL-FVIII. Time spent and area above clinically relevant FVIII thresholds clearly differentiated HSA/UL-FVIII from EHL products. These data support updating FVIII product classification and highlight the value of new PK-based metrics, including time-above-threshold and segmented AUC, in evaluating next-generation FVIII therapies.