RARE DISEASE
Severe hemophilia A
Severe hemophilia A
Severe hemophilia A
Synonyms: Severe congenital F8 deficiency, Severe congenital factor VIII deficiency
Synonyms: Severe congenital F8 deficiency, Severe congenital factor VIII deficiency
Synonyms: Severe congenital F8 deficiency, Severe congenital factor VIII deficiency
Drug discovery
1
drug
With orphan designation
Overview
Severe Hemophilia A is an X-linked bleeding disorder characterized by factor VIII levels <1% of normal, resulting in spontaneous bleeding into joints, muscles, and soft tissues. Lifelong management focuses on preventing/treating bleeds through factor replacement or non-factor therapies. Complications include chronic arthropathy, inhibitor development, and substantial quality-of-life impairments [1][6][11][12].
Therapies
Prophylaxis: Regular FVIII infusions (plasma-derived or recombinant) to maintain levels ≥1% [1][18].
Non-factor therapies: Subcutaneous emicizumab (bispecific antibody mimicking FVIII) reduces bleed frequency [3][6].
Immune tolerance induction: High-dose FVIII regimens for inhibitor eradication [8].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
3,207 drug discovery papers about Severe hemophilia A, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,207 drug discovery papers about Severe hemophilia A, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-29 | Genetically confirmed severe hemophilia A in a preterm infant: a case report.
Severe hemophilia A is exceptionally rare among preterm infants. Qwing to immature coagulation system and nonspecific bleeding manifestations, the condition is readily misdiagnosed as other neonatal hemorrhagic disorders, such as vitamin K deficiency, neonatal sepsis and thrombocytopenia. Delayed diagnosis will greatly increase the risk of severe complications, particularly intracranial hemorrhage. Herein, we report a case of genetically confirmed severe hemophilia A in a 34-week preterm infant without family history of hemophilia. Treatment comprised sequential adminnistration of coagulation factor VIII repalcement and emicizumab. We futher analyze the clinical characteristics, diagnostic difficulties and standardized management principles of hemophilia A in preterm infants, so as to improve clinicians' awareness, reduce misdiagnosis and missed diagnosis, and optimize the long-term prognosis of affected infants.
2026-09-13 | FRONTIER5: Safety and patient experience of a direct switch from emicizumab to denecimig (Mim8) in patients with haemophilia A with or without inhibitors.
Denecimig (Mim8) is an activated factor VIII mimetic, fully human, bispecific IgG4 antibody in development for subcutaneous prophylaxis in patients with haemophilia A (HA) with/without inhibitors. To evaluate the safety and patient experience of a direct switch from emicizumab to denecimig prophylaxis without a washout period or loading dose. FRONTIER5 (NCT05878938) was a 26-week, single-arm, open-label, phase 3b study in patients aged ≥12 years with HA with or without factor VIII inhibitors. Patients transitioned directly from emicizumab to denecimig maintenance doses administered subcutaneously once-every week, once-every-two-weeks, or once-every-month by a pen-injector. The primary endpoint was the number of treatment-emergent adverse events (TEAEs); secondary and exploratory endpoints included thrombin generation, and patient-reported pen-injector experience, treatment burden, joint pain, and physical activity. All 61 enrolled patients completed the study. TEAEs occurred in 70.5% of patients (3.48 per patient-year of exposure). Most TEAEs were mild or moderate in severity and not treatment-related. No thromboembolic events, hypersensitivity reactions, or clinical evidence of neutralising anti-denecimig antibodies were observed. Injection-site reactions were observed in 15/990 (1.5%) injections. Thrombin generation with denecimig increased into the normal reference range by week 1, without exaggerated haemostatic response. Without a loading dose, denecimig reached steady-state plasma concentrations by week 16. Most participants (98.3%) rated the denecimig pen-injector as 'easy' or 'very easy' to use. The direct switch from emicizumab to denecimig without a washout period was well tolerated in adolescents and adults with HA with or without inhibitors. No new safety concerns were observed.
2026-09-09 | Evaluating Costs and Efficacy of rFVIII Prophylaxis Using Matching-Adjusted Indirect Comparisons in Hemophilia A.
Introduction Prophylaxis with factor VIII (FVIII) is the standard of care for individuals with severe hemophilia A, but it is associated with a substantial economic burden. This analysis compared the efficacy, dosing, and annual treatment costs of simoctocog alfa (Nuwiq, a recombinant FVIII [rFVIII]) with five extended half-life (EHL) rFVIII concentrate products. Methods Matching-adjusted indirect comparisons (MAICs) were performed to compare simoctocog alfa with efanesoctocog alfa (ALTUVIIIO) and turoctocog alfa pegol (Esperoct), and results were integrated with a previously published MAIC comparing simoctocog alfa with efmoroctocog alfa (ELOCTATE), damoctocog alfa pegol (JIVI), and rurioctocog alfa pegol (ADYNOVATE). These MAIC-adjusted populations were used to develop a cost model from a United States payer perspective. Results Annual total costs per person were $147,058 to $492,090 lower with simoctocog alfa compared with EHL rFVIII products, corresponding to a 21% to 46% cost reduction, primarily driven by lower drug acquisition costs. Outcomes were comparable or favorable to simoctocog alfa versus turoctocog alfa pegol, efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol. In comparison with efanesoctocog alfa (Group A), no significant differences were observed in the proportion of individuals with zero bleeds, whereas treated total annualized bleeding rate (ABR) and treated spontaneous ABR favored efanesoctocog alfa. Conclusion This indirect comparison suggests that personalized prophylaxis with simoctocog alfa may offer economic advantages versus EHL rFVIII products in individuals with severe hemophilia A. Clinical outcomes were broadly comparable across comparators, although treated total and spontaneous ABRs were significantly lower with efanesoctocog alfa (Group A).
2026-08-30 | Coagulation potential of concomitant factor VIII administration in people with hemophilia A receiving emicizumab prophylaxis (CAGUYAMA study): a multicenter, open-label, nonrandomized clinical trial.
Emicizumab prophylaxis reduces bleeding in people with hemophilia A. However, factor (F)VIII is still required to manage breakthrough bleeding and for surgical procedures. The optimal additional FVIII dose during such events remains unclear because of emicizumab's baseline hemostatic activity. To assess FVIII-induced changes in global coagulation potential in people with hemophilia A without inhibitors treated with emicizumab and to inform FVIII dosing during prophylaxis. The multicenter "Coagulation potential of concomitant factor VIII administration in people with hemophilia A receiving emicizumab prophylaxis" study enrolled 100 people with hemophilia A (aged ≥4 years) receiving emicizumab at 13 centers in Japan. For eligible bleeding or surgical events, FVIII (standard or extended half-life) was administered at a target dose of 30 IU/kg (allowable range, 25-35 IU/kg). Paired blood samples were obtained pre- and post-FVIII administration. The primary endpoint was the change in clot waveform analysis-adjusted maximum coagulation rate, expressed as IMCR% relative to pooled normal plasma and untreated severe hemophilia A plasma. Secondary endpoints included peak thrombin in the thrombin generation assay, rotational thromboelastometry, clinical hemostasis, and safety. Anti-emicizumab antibodies were used in vitro to isolate the effects of FVIII. Thirty-two FVIII-treated events in 24 people with hemophilia A (15 bleeding events and 17 surgical events) were analyzed. The clot waveform analysis-adjusted maximum coagulation rate increased from 39.4% to 92.1% post-FVIII and from 3.2% to 78.6% under anti-emicizumab conditions. Peak thrombin in the thrombin generation assay increased from 249 to 348 nM (IMCR%: from 55.4% to 88.0%) and from 6.4% to 74.6% under anti-emicizumab conditions. All events achieved effective hemostasis. No thromboembolic events, thrombotic microangiopathy, or hypersensitivity reactions were reported. FVIII administered at a target dose of 30 IU/kg (allowable range, 25-35 IU/kg) improved global coagulation parameters and achieved effective hemostasis without thrombotic complications, warranting evaluation as part of emicizumab prophylaxis.
2026-08-28 | Successful immune tolerance induction using efanesoctocog alfa in severe hemophilia A: A case series.
The development of neutralizing factor VIII (FVIII) inhibitors remains a major therapeutic challenge in severe hemophilia A. We report two patients with complex inhibitor histories who achieved rapid and sustained inhibitor eradication using efanesoctocog alfa. Immune tolerance induction (ITI) was initiated at 100 units (U)/kg 3 times weekly, with subsequent dose reduction after inhibitor clearance. Inhibitor titers declined to undetectable levels (<0.5 Bethesda units [BU]) within 6 weeks in one case and 3 months in the other, with FVIII recovery exceeding 90%. Transition to once-weekly individualized prophylaxis maintained functional FVIII activity and therapeutic FVIII trough levels (4%-6%), allowing discontinuation of emicizumab. Sustained bleed-free outcomes were achieved with individualized prophylactic dosing without inhibitor recurrence. These cases support efanesoctocog alfa-based ITI as a promising strategy for rescue and retreatment patients with complex inhibitor histories.
small molecules
2026-09-19 | The outcome of chemical synovectomy with Rifampicin in chronic hemophilic synovitis: The Syrian experience.
Chronic arthropathy is the most common complication of moderate to severe hemophilia. Chemical synovectomy with Rifampicin offers a cost-effective alternative to radioactive synovectomy, especially in resource-limited settings like Syria. A retrospective study was conducted at the Syrian Hemophilia Society (2020-2024), involving 50 patients (69 target joints) with hemophilic synovitis. Outcomes were assessed using the Hemophilia Joint Health Score visual analogue scale (VAS) for pain, range of motion (ROM), Arnold-Hilgartner classification, and annual bleeding rate,pre- and post-intervention. Participants were predominantly young (mean age 18.99 ± 6.51 years), with hemophilia A (80%). A significant delay was noted between target joint onset and intervention (mean 40.30 months). The knees were most affected (72%), with moderate joint involvement (Arnold-Hilgartner Class II-III). Regional disparities emerged: Damascus patients showed better outcomes (HJHS: 2.33 vs 7.04; VAS: 1.11 vs 3.27, P < .001). Most patients improved significantly (P < .05), except those with mild phenotypes (no HJHS/VAS improvement), ankle involvement (no ROM improvement), and Arnold score 0 (no ROM improvement). Findings underscored inequities in care access across regions. Rifampicin-based chemical synovectomy is a viable, accessible treatment for hemophilic synovitis in low-resource settings. It led to significant improvements in pain, bleeding episodes, joint health, and mobility. However, regional healthcare disparities and delayed interventions remain key challenges affecting outcomes.
2026-09-11 | Neutrophil-dependent interferonopathy contributes to joint damage in hemophilia.
Patients with severe hemophilia A suffer from recurrent bleeding in synovial joints, which leads to development of hemophilic arthropathy, a progressive condition characterized by permanent joint damage, chronic pain and poor quality of life. Current treatment with factor VIII replacement or factor VIII mimetic therapy provides only partial protection from joint bleeding. Unfortunately, targeted therapies to prevent the development of hemophilic arthropathy remain an unmet clinical need, and the etiological mechanism underlying joint damage in hemophilia is still poorly understood. Using the experimental model of hemophilic arthropathy in Factor 8 total knockout (F8TKO) mice and blood samples from hemophilia A patients with or without active joint bleeding, we show that acute joint bleeding promotes an inflammatory milieu in hemophilia, which triggers the type-I interferon response and downstream signaling in neutrophils, leading to systemic shedding of neutrophil extracellular traps (NETs). Remarkably, therapeutic inhibition of type-I interferon receptor attenuates shedding of NETs and reduces the severity of joint damage in F8TKO mice. The current study is the first to identify a role for NETs in the pathogenesis of hemophilic arthropathy and demonstrates the therapeutic potential of targeting neutrophil-dependent type-I interferon signaling to attenuate the progression of joint damage in hemophilia.
2026-07-02 | Biopsy-proven immune-mediated hepatitis after valoctocogene roxaparvovec.
Valoctogene roxaparvovec is an approved and efficacious gene therapy (GT) for severe hemophilia A (HA), however alanine aminotransferase (ALT) elevation after dosing raises safety concerns. Corticosteroids are the first-line therapy for ALT>1.5X the baseline value, but this indication requires further pathological characterization in humans. We explored mechanisms of ALT elevation to personalize corticosteroid therapy. Follow-up data on real-life experience with valoctogene roxaparvovec were collected. Transjugular liver biopsy for histology, transmission electron microscopy and immunophenotype characterization were compared with positive/negative controls. Five severe HA patients were treated with valoctogene roxaparvovec. Four (80%) had ALT>1.5X the baseline value but two had transaminase above the normal range (59 U/L) and lowering of transgene expression and were treated with prednisone. Liver biopsy from these two cases before starting prednisone revealed acute immunemediated hepatitis and abnormal enlargement of the smooth endoplasmic reticulum of hepatocytes. ALT normalized along with preservation of transgene expression after a personalized schedule of oral prednisone. High T-cytotoxic and low T-regulatory activity was observed during acute hepatitis. The median transgene expression at the end of the follow-up was 83(12-206)% (chromogenic assay), but it was highly variable regardless the exposure to prednisone: 48(12-83)% in patients treated with prednisone and 194(20-206)% in patients not treated with prednisone. Immune-mediated hepatitis can cause ALT elevations in HA after valoctogene roxaparvovec and, in selected cases, a biopsy-proven diagnosis could support a safer and more effective therapeutic course of prednisone to maintain optimal transgene expression.
2026-04-09 | Screening chemical libraries for the development of oral treatments for bleeding disorders.
Hemophilia is a rare bleeding disorder due to factor VIII (FVIII) or FIX deficiency involved in hemophilia A (HA) or HB, respectively. Treatment has long relied on invasive IV infusions of the missing factor for prophylaxis or bleeding treatments. Despite significant progress in patient care, there is still no oral procoagulant drug available for people with hemophilia. Such an oral procoagulant could provide benefits to other inherited and acquired bleeding disorders, as well as anticoagulant-induced bleeding. To find chemical compounds that could become potential future orally administered procoagulants, we designed a hierarchical high-throughput screening protocol combining 2 successive screening filters: a miniaturized fibrin formation assay, followed by a thrombin generation assay, both on severe HA plasma. We screened 3 chemical collections totaling > 2300 chemical compounds; we identified adapalene, a commercialized antiacneic compound (Differin), which is strongly hydrophobic. To design a drug that could be orally administered, we developed a series of chemical analogs of adapalene, and 3 of them, with similar procoagulant activities in FVIII-deficient plasma, showed improved solubilities. The mechanism of action was thoroughly investigated by a series of thrombin generation and enzymatic assays. These studies conclude that the procoagulant activity of the chemical compounds in FVIII-deficient plasma is due to the activation of FXII.
2026-02-28 | Machine learning estimation of FVIII pharmacokinetic parameters in Chinese children with severe Hemophilia A.
Hemophilia A is a rare inherited bleeding disorder typically managed with coagulation factor VIII (FVIII) replacement therapy. Designing personalized prophylactic regimens requires accurate pharmacokinetic (PK) characterization; current population PK (popPK) and Bayesian approaches provide a principled framework for individualized dosing, but their routine clinical implementation may still be constrained by model specification requirements and practical considerations in data collection and analysis. Here we present a machine learning (ML) framework, incorporating state-of-the-art language models, to predict individual FVIII PK parameters in pediatric patients. Using minimal sampling and routinely collected clinical data, our approach achieves superior performance over the widely adopted WAPPS-Hemo platform in predicting in vivo recovery (IVR) and FVIII half-life. These findings highlight the potential of AI-driven methods to reduce patient burden while improving accuracy in individualized treatment planning for children with severe hemophilia A.
antibodies
2026-09-23 | Emicizumab enables rapid tolerance, reducing bleeding during low-dose ITI in pediatric hemophilia A.
Immune tolerance induction (ITI) remains the only proven strategy for eradicating factor VIII (FVIII) inhibitors in severe hemophilia A, yet low-dose regimens are associated with prolonged treatment and significant bleeding. Emicizumab provides FVIII-independent hemostatic protection and may permit antigen exposure under conditions of reduced bleeding and inflammation during ITI. We conducted a single-center cohort study with historical controls to evaluate the impact of emicizumab on low-dose ITI (LD-ITI) outcomes in pediatric patients (aged <14 years) with severe hemophilia A and high-responding inhibitors undergoing their first LD-ITI (50 IU/kg, 3× per week). Twenty-three patients were included. Patients treated with LD-ITI alone (2010-2020; n = 14) were compared with those receiving LD-ITI plus emicizumab prophylaxis (LD-ITI+EMI; 2021-2023; n = 9). Complete ITI success occurred in 7 of 9 patients (78%) of the LD-ITI+EMI cohort vs 5 of 14 patients (36%) of the LD-ITI cohort (P = .09). Median time to tolerance was shorter with emicizumab (9 vs 19 months; P = .003). Time-to-event analysis confirmed faster tolerance with emicizumab (hazard ratio of 3.89; P = .02). Treated bleeds during ITI were drastically reduced in the emicizumab cohort (median annualized treated bleeding rate, 0.0 vs 5.1; P < .0001), and a higher bleeding burden was associated with delayed tolerance. No thrombotic complications were observed. Median direct treatment costs were comparable between cohorts. In this pediatric cohort, LD-ITI combined with emicizumab was associated with faster tolerance achievement, bleeding reduction, and no increase in direct costs. These findings suggest that ITI associated with emicizumab may provide a more efficient and clinically manageable approach to inhibitor eradication in pediatric patients.
2026-09-18 | Plasma emicizumab concentrations and bleeding rates in children and adults with severe hemophilia A.
Emicizumab has been in clinical use for less than 10 years. Real-world experience is still needed to guide its use for optimal safety, efficacy, and resource efficiency. Recent data suggest that conventional weight-based dosing may be excessive for many patients. More data on the correlation between bleeding events and plasma emicizumab concentation will help to clarify optimal dosing regimens. To determine bleeding rates and their correlation with drug levels in patients without inhibitors using prophylactic emicizumab. We conducted an observational study in a large cohort of adult and pediatric persons with severe hemophilia A without inhibitors to determine the rate of bleeding events during emicizumab prophylaxis and the correlation between plasma emicizumab concentration and bleeding rates. Among the 73 patients followed for a mean of 69.0 weeks, 47.9% had 0 treated bleeds and 80.8% had 0 spontaneous bleeds. The mean and median annualized treated bleed rates were 1.12 and 0.57, and the mean and median annualized joint bleed rates were 0.51 and 0. The mean factor VIII concentrate used to treat bleeds was 63.0 IU/kg/y per patient (median, 23.1 IU/kg/y). Steady-state plasma emicizumab concentration did not correlate with total or spontaneous annualized treated bleed rate and annualized joint bleed rate or with patient age at enrolment, body weight, or body mass index. Dose capping at 150 mg/wk did not result in lower emicizumab concentrations in the 9 patients with body weight >100 kg. Emicizumab provided highly effective prophylaxis in persons with severe hemophilia A across the age spectrum. The lack of correlation of bleed outcomes with plasma emicizumab concentration suggests that minimal effective drug concentrations should be reconsidered. Studies to rationalize and personalize therapy should be explored.
2026-09-09 | Discovery and development of a bispecific antibody for the treatment of hemophilia.
The 2026 Lasker~DeBakey Clinical Medical Research Award has been awarded to Kunihiro Hattori, Takehisa Kitazawa, and Tomoyuki Igawa (Chugai Pharmaceuticals, Tokyo, Japan) for invention of a bispecific antibody that joins blood clotting Factors IXa (FIXa) and X (FX), restoring deficient Factor VIII (FVIII) activity in patients with hemophilia A and preventing severe bleeding in this hereditary disorder. Starting from the 1960s, types of FVIII-replacement therapy remarkably improved on-demand hemostatic treatment for ongoing bleeds and enabled prophylactic reduction of bleeding episodes. However, these agents required burdensome intravenous infusions multiple times per week, and ~30% of patients developed neutralizing anti-FVIII antibodies (FVIII inhibitors). To address these unmet medical needs, in 2000, Hattori-a molecular and hematology biologist, Kitazawa-a hematology biologist and translational researcher, and Igawa-a biochemist and protein engineer, conceived, designed, and created over the span of 10 y a novel FVIII-mimetic. Instead of a native protein construct, they engineered a bispecific IgG antibody against FIXa and FX, circumventing the need for FVIII and enabling subcutaneous administration up to once per month. Importantly, they identified the biophysical requirements for the bispecific to mimic FVIII function effectively and safely, and their breakthrough protein engineering design made possible favorable pharmacokinetics and physicochemical properties with efficient manufacturability. Their collective research efforts demonstrate how imagination, determination, and multidisciplinary scientific research come together to improve patients' lives.
2026-09-09 | Emicizumab and shared medical decision in patients living with hemophilia A.
Emicizumab is a new prophylactic treatment for patients with severe hemophilia A. This study evaluated patient decisional conflict and physician decisional comfort regarding the switch to emicizumab, identifying the criteria that drive this choice. This is an observational, non-interventional, multicenter, retrospective and exploratory study of hemophilia A patients at seven centers in France. The evaluation used the patient's decisional conflict scale and the physician's decisional comfort scale, as well as a questionnaire to determine the criteria for choosing whether to switch to emicizumab. A cluster approach was applied to identify patient subgroups with distinct decisional profiles. A total of 53 patients and their physicians were included in this study: 34 in the emicizumab arm and 19 in the factor VIII arm. Patients in the factor VIII arm reported higher remorse, while physicians in this group felt significantly less comfortable with the decision. While factors influencing the decision were similar between both patients and physicians, illustrating good mutual understanding. Cluster analysis identified a specific subgroup (23%) in the total cohort experiencing high decisional conflict despite their final choice, highlighting a need for targeted clinical support. This study highlights the importance of shared decision-making in hemophilia treatment, encouraging open communication between patients and physicians for more personalized care.
2026-09-03 | Real-World Experience With Emicizumab for Haemophilia A From the Physician Perspective in a Real-World Clinical Setting.
Emicizumab is a bispecific antibody approved for prophylaxis in people with haemophilia A (PwHA). To describe from the physician perspective the characteristics and treatment experiences of PwHA receiving emicizumab. The Adelphi Real World Haemophilia Disease Specific Programme is a cross-sectional, retrospective data collection from US haematology and haematology-oncology specialists between July 2023 and April 2024. Male PwHA with or without inhibitors were included if they had baseline factor VIII levels <5% and were not currently participating in a clinical trial. Surveys captured demographic characteristics and clinical outcomes, including bleeding events. Fifty-four physicians provided data for 293 PwHA, of which 115 were seen outside federally funded haemophilia treatment centres (HTCs), 77 were treated with emicizumab and 49 had pre- and post-emicizumab initiation data available. More Black, African American, African or Caribbean PwHA received emicizumab outside federally funded HTCs than at federally funded HTCs (46.2% vs. 16.7%). Most emicizumab doses were taken on time (mean [SD], 90.7% [14.6%]), and 64.0% of PwHA took >80% of the prescribed dose. More PwHA had zero treated bleeds (76.9% vs. 42.9%), with fewer bleeding events (mean [SD], 1.3 [1.9] vs. 0.4 [1.1]; p = 0.0001) during the post-emicizumab period (median [IQR] follow-up, 12.0 [1.3-12.0] months) than in the 12 months pre-emicizumab. Post-emicizumab outcomes were similarly improved across settings, whether at federally funded HTCs or elsewhere. Among PwHA receiving emicizumab, rates and severity of bleeds decreased after emicizumab initiation, regardless of the clinical setting.
gene therapies
2026-08-21 | Evaluation of early prophylactic corticosteroid administration on early safety and efficacy outcomes of adeno-associated virus gene therapy in the hemophilia dog model.
Prior to commercial withdrawal, adeno-associated virus (AAV) gene therapy was approved for the treatment of adults with severe hemophilia A. Mechanisms underlying variability, durability, and liver transaminitis are largely uncharacterized. To evaluate the effects of prophylactic corticosteroid administration on AAV gene therapy outcomes in dogs with severe hemophilia A. Seven dogs with hemophilia A received 6e13 vector genomes/kg of AAV5-canine factor (F)VIII. Four dogs received oral prednisolone (1 mg/kg/day) starting 3 hours preinfusion with dose-tapering over 6 weeks; three control dogs received no corticosteroids. Percutaneous liver biopsies were performed on detection of alanine aminotransferase (ALT) >2-fold the upper limit of normal. All dogs expressed therapeutic FVIII:C (8.7-56.1%), improved whole blood clot time, and decreased bleeding rates (pre = 6.11 vs post = 1.42 bleeds/year, P = .016) over 2 years post-AAV5-canine FVIII. Corticosteroid-treated dogs demonstrated a modest increase in mean FVIII:C at 2 years by chromogenic substrate assay (39.1%) compared with controls (29.5%), driven by one female with markedly elevated FVIII:C from day 54 onward. When analyzed by sex, all female dogs exhibited increased mean FVIII:C chromogenic substrate assay at 2 years (49.3%) compared with males (9.1%), regardless of prophylactic corticosteroid use. Prophylactic corticosteroids did not impact transient posttreatment elevations of proinflammatory cytokines, anti-AAV antibody formation, or ALT levels. One corticosteroid-treated dog experienced ALT > 4.3-fold the upper limit of normal at 18 weeks without impacting long-term FVIII:C expression. A liver biopsy showed diffuse, minimal periportal lymphocyte and neutrophil infiltration, consistent with nonspecific minimal hepatitis. Prophylactic corticosteroids were not clearly associated with increased transgene expression in dogs with hemophilia A.
2026-06-03 | Real-world provider experiences with hemophilia A gene therapy: administration of valoctocogene roxaparvovec.
Severe hemophilia A is a bleeding condition caused by a deficiency in clotting factor VIII (FVIII ≤1 IU/dL) that results in spontaneous and excessive posttraumatic bleeding. The current standard of care is prophylaxis with exogenous FVIII or bispecific antibodies that mimic FVIII function. Valoctocogene roxaparvovec is a gene therapy approved for adults with severe hemophilia A that enables endogenous FVIII production to protect against bleeding. As a newer treatment modality, workflows for gene therapy administration and postinfusion care are still unfamiliar to many health care professionals and may be perceived as implementation barriers. We are 10 hemophilia gene therapy providers across the United States, Italy, and Germany sharing our experiences of administering valoctocogene roxaparvovec in clinical practice to >25 patients with severe hemophilia A. In this study, we provide our insights into patient preparation, establishment of treatment centers and multidisciplinary teams, postinfusion management, and patient follow-up to facilitate open communication and collaboration among the treatment community.
2026-05-07 | Gait Pattern at Different Speeds in Persons With Haemophilia.
Persons with haemophilia (PwH) have a risk of bleeding in joints, especially in elbow, knee and ankle. In the long term, this leads to haemophilic arthropathy (HA), which results in joint deformities. This study aims to examine how walking speed and HA affect (1) foot pressure distribution, (2) average vertical peak pressure, and (3) knee and ankle joint angles during walking. Using a motion analysis system (DIERS 4DmotionLab), 30 PwH and 31 healthy controls (CG) were examined at speeds of 3, 4, and 5 km/h. Groups were additionally divided according to the severity of HA, in the subgroups PwH(major) and PwH(minor). Regarding different gait speeds, no differences were found between PwH and CG in peak pressure distribution. However, pedobarography showed a significant reduction in average vertical peak pressure in the second half of the stance phase in PwH(major) compared to CG (p < 0.007). Joint angle measurements showed reduced plantar flexion (p = 0.041), dorsiflexion (p = 0.011), and descriptive, non-significant knee flexion in PwH(major) at different speeds. Knee extension did not differ between groups. The study confirms that PwH, especially those with advanced HA, show impaired gait pattern. While different walking speeds had no impact on peak pressure values compared to CG, force transmission was reduced in PwH in the second half of the stance phase. This, in conjunction with reduced mobility in the ankle joints, indicates impaired power transmission in the propulsion phase which is well compensated.
2026-05-01 | Correlation between Factor VIII chromogenic activity and antigen levels in patients treated with adeno-associated virus 5-mediated gene therapy for hemophilia A.
Gene therapy for hemophilia A with valoctocogene roxaparvovec, an adeno-associated virus (AAV) vector encoding B-domain-deleted factor (F)VIII, enables sustained endogenous FVIII expression and long-term bleed protection. FVIII activity is commonly measured using a one-stage clotting assay (OSA) or a chromogenic assay (CA), which yield discrepant results. Data on FVIII transgene expression, assessed by antigen measurements after gene therapy in humans, remain limited. To evaluate the correlation between FVIII activity assessed by OSA and CA and FVIII antigen levels after valoctocogene roxaparvovec administration. Four adult patients with severe hemophilia A received a single infusion of valoctocogene roxaparvovec (6 × 1013 vg/kg). FVIII activity was measured by OSA and CA methods; FVIII antigen was quantified using an enzyme-linked immunosorbent assay optimized for B-domain-deleted FVIII. A total of 182 plasma samples were collected at multiple time points post-AAV5 FVIII dosing. The median follow-up time for patients was 61 weeks (IQR, 52.5-115.7). The OSA consistently showed FVIII activity 1.6- to 2-fold higher than the CA, consistent with observations from previous clinical trials. Transgenic FVIII antigen levels positively correlated with FVIII activity measured by the CA, indicating effective transcription and translation of the FVIII transgene. FVIII antigen levels showed strong concordance with CA results following AAV-mediated gene therapy. These findings support the CA as the preferred method for monitoring therapeutic FVIII expression in patients treated with gene therapy for hemophilia A. Multiassay strategies remain essential for comprehensive assessment of transgene expression and clinical management after gene therapy.
2026-05-01 | Durability of efficacy, safety, and quality of life 5 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A: final phase 3 GENEr8-1 trial results.
Valoctocogene roxaparvovec, a gene therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) expression and confers bleed control. To present the final 5-year efficacy and safety results from the phase 3 GENEr8-1 trial. Adult men (N = 134) with severe hemophilia A without inhibitors who were using FVIII prophylaxis received one 6 × 1013 vg/kg infusion of valoctocogene roxaparvovec. End points included annualized bleeding rate (ABR), FVIII infusion rate, FVIII activity, Haemophilia-Specific Quality of Life Questionnaire for Adults, adverse events, and immunosuppressant use. Median follow-up was 261.1 weeks; 128 of 134 participants completed the study. For the 112 participants who enrolled from a previous noninterventional study (rollover population), mean ABR for treated bleeds declined by 83.3% (P < .0001), mean FVIII infusion rate declined by 94.9% (P < .0001), and mean ABR for all bleeds declined by 78.1% in the 5-year efficacy evaluation period vs baseline. In 132 modified intention-to-treat participants, mean and median FVIII activity at week 260 was 13.7 and 6.2 IU/dL, respectively (chromogenic assay). In year 5, 77.8% of rollover participants had 0 treated bleeds. One participant resumed prophylaxis since the 4-year data cutoff (25/134 across all follow-up). Haemophilia-Specific Quality of Life Questionnaire for Adults total score was improved from baseline at year 5. In year 5, alanine aminotransferase elevations occurred in 51 of 129 participants who entered year 5. Immunosuppressants were not used to manage them. No serious treatment-related adverse events occurred after year 1. Valoctocogene roxaparvovec provides durable hemostatic efficacy, FVIII activity, and improved health-related quality of life for ≥5 years, with no new safety signals.
other
2026-01-13 | Impact of antiplatelet therapy on the hemostatic efficacy of platelet-targeted FVIII gene therapy in hemophilia A mice.
Platelet-targeted factor VIII (FVIII) (2bF8) gene therapy offers promising hemostatic correction in hemophilia A (HA), even in the presence of FVIII inhibitors. Because platelet-derived FVIII is released from platelet α-granules upon activation at injury sites, it is essential to evaluate whether antiplatelet agents would compromise its therapeutic efficacy. Here, we investigated the effect of antiplatelet agents on the efficacy of platelet-FVIII in HA mice. 2bF8Tg mice express FVIII in platelets controlled by the αIIb promoter and were treated with aspirin, clopidogrel, or the αIIbβ3-blocking antibody Leo.H4. Hemostatic function was evaluated through tail-bleeding models and in vitro assays. We found that all antiplatelet agents impaired platelet-FVIII-mediated hemostasis in vivo. Leo.H4 treatment caused severe bleeding in both the tail tip and tail vein transection injury models, consistent with its inhibition of platelet aggregation. Clopidogrel-treated 2bF8Tg mice exhibited 10 to 14 times more blood loss than controls, with extended bleeding; however, they still showed improvement compared to FVIIInull controls. Notably, platelet-FVIII retained superior efficacy compared to plasma-derived FVIII in clopidogrel-treated mice, despite having only 24% of normal FVIII activity. Aspirin also impaired hemostasis but to a lesser extent. In vitro rotational thromboelastometry and whole-blood thrombin generation assays showed no significant differences between aspirin- or clopidogrel-treated and control mice, suggesting that these assays may not fully capture platelet-FVIII dynamics. Our results indicate that platelet aggregation is crucial for the efficacy of platelet-FVIII. Although antiplatelet agents hinder its function, platelet-FVIII remains preferable to plasma-FVIII, highlighting its clinical potential and the importance of considering concomitant therapies in future applications.
2025-11-14 | [RNA Sequencing Reveals Molecular Alternations of Splenocytes Associated with Anti-FⅧ Immune Response in Hemophilia A Murine Model].
To investigate the molecular alterations of splenocytes associated with anti-factor Ⅷ (FⅧ) immune response and the underlying mechanisms based on hemophilia A (HA) murine model via RNA sequencing (RNA-seq) technology. Severe HA mice were immunized with recombinant human factor Ⅷ (rhF8) weekly for 4 weeks to establish an FⅧ inhibitor model. High quality raw data were obtained by using bulk RNA-seq and CASAVA base identification technology, and the differentially expressed genes (DEGs) were identified. The DEGs were statistically classified by gene ontology (GO) annotation to obtain information on the major signaling pathways and biological processes involved in anti-FⅧ immune response in HA mouse splenocytes. The cell clusters, genes, and signaling pathway datasets were comprehensively analyzed by GO, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and single cell RNA-seq (ScRNA-seq) analysis, respectively. Flow cytometry analysis was used to verify the changes in T follicular helper cells (Tfh) and regulatory T cells (Treg). A total of 3731 DEGs was identified, including 2275 genes with up-regulated expression and 1456 genes with down-regulated expression. The DEGs were enriched in helper T cell differentiation, cytokine receptor, T cell receptor signaling pathway, ferroptosis, etc. Uniform Manifold Approximation and Project (UMAP) downscaling and visualization analysis yielded a total number of 11 T/NK cell subsets, visualizing the overall expression distribution of C-X-C chemokine-specific receptor gene cxcr5 among these T/NK cell subsets. Higher expression of cxcr5 was found in activated Tfh from FⅧ inhibitor mice, in comparison to the control group. The visualization using Upset plot R language showed a close interaction between Tfh and Treg. Moreover, the increased frequencies of Tfh and the decreased frequencies of Treg in inhibitor mouse splenocytes were further verified by flow cytometry analysis. Multiple immune cell subsets, signaling pathways, and characteristic genes may be involved in the process of anti-FⅧ immune response in HA mouse splenocytes. The molecules involved in the regulation of Tfh/Treg may play key roles, which provide potential biological targets and therapeutic strategies for HA patients with inhibitors in the future.
2025-11-03 | Efficacy and safety of fitusiran prophylaxis in people with haemophilia a or haemophilia B: A systematic review and meta-analysis
Abstract Background: Prophylaxis is the standard of care for people with severe hemophilia A or B to prevent bleeding, but the treatment burden can be high, and breakthrough bleeding can still occur, particularly in patients with inhibitors. Fitusiran, a small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis, offering a novel prophylactic approach. This systematic review and meta-analysis aim to evaluate the efficacy and safety of Fitusiran prophylaxis in this population. Aim: To systematically review and meta-analyze the efficacy and safety of Fitusiran prophylaxis compared to control in people with hemophilia A or B, with or without inhibitors. Methods: A systematic literature search was conducted across PubMed, Cochrane, ScienceDirect, Web of Science, and Scopus to identify randomized controlled trials (RCTs) comparing Fitusiran with control (placebo or bypassing agents on-demand) in patients with hemophilia A or B. The primary efficacy outcomes were the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR), and annualized joint bleeding rate (AjBR). Safety outcomes included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent severe adverse events (TESAEs), and specific adverse events of interest such as elevated liver enzymes. Data from RCTs were pooled using a random-effects model. Mean difference (MD) was used for continuous outcomes and odds ratio (OR) for dichotomous outcomes, with 95% confidence intervals (CI). Heterogeneity was assessed using the I² statistic. Results: Three RCTs were included in this meta-analysis, ATLAS-INH 2023, ATLAS-PPX 2024, and ATLAS A/B 2023, with a combined sample size of (N=311). In patients with inhibitors, Fitusiran significantly reduced ABR (MD: -11.70, 95% CI: [-18.55, -4.85]; P=0.0008), AsBR (MD: -9.40, 95% CI: [-18.63, -0.18]; P=0.05), and AjBR (MD: -8.49, 95% CI: [-14.92, -2.05]; P=0.01). In patients without inhibitors, no statistically significant reduction was observed for ABR (P=0.25), AsBR (P=0.26), or AjBR (P=0.28). Fitusiran was associated with a significantly higher odds of any TEAE (OR: 5.11, 95% CI: [3.05, 8.56]; P<0.00001) and increased alanine aminotransferase (ALT) (OR: 17.80, 95% CI: [4.88, 64.92]; P<0.0001). There was no statistically significant difference in the odds of increased aspartate aminotransferase (AST) (P=0.06), upper respiratory tract infection (P=0.12), arthralgia (P=0.23), nasopharyngitis (P=0.15), or TESAEs (OR: 0.84, 95% CI: [0.35, 2.00]; P=0.69). Heterogeneity for all outcomes was low. Conclusion: Fitusiran prophylaxis is an effective therapy for reducing bleeding rates in patients with hemophilia A or B with inhibitors. While a similar trend was observed in patients without inhibitors, the result was not statistically significant. The safety profile indicates an increased risk of TEAEs, most notably transient elevations in ALT, but not an increase in severe adverse events. These findings support Fitusiran as a promising prophylactic option, especially for the difficult-to-treat inhibitor population and underscore the importance of monitoring liver function during treatment.
2025-08-05 | PO47 | Hemophilia A and antithrombin deficiency: a case of natural hemostatic rebalancing
Background: Hemostasis is governed by a dynamic balance between procoagulant and anticoagulant forces. While inherited bleeding and thrombotic disorders are typically studied as discrete entities, rare cases of co-inheritance may produce unique clinical phenotypes due to compensatory interactions. Among these, hemophilia A and antithrombin (AT) deficiency represent prototypical yet contrasting conditions: patients with severe hemophilia A often experience spontaneous joint and muscle bleeding, requiring lifelong prophylaxis or on-demand therapy with FVIII concentrates, whereas AT deficiency is associated with a markedly increased risk of venous thromboembolism (VTE), particularly in high-risk situations such as surgery, trauma, or prolonged immobilization. Understanding how opposing defects interact within the same individual may inform individualized management and therapeutic innovation. Case Report: We describe the case of a 19-year-old male with severe hemophilia A (FVIII <1%, no inhibitors), carrying a mutation in exon 3 of the F8 gene (NM_000132.4:c.296A>G, resulting in p.His99Arg), co-inherited with congenital AT deficiency (~50% activity). At birth, neonatal screening was prompted by a maternal family history of hemophilia A and a paternal history of thrombophilia. The patient’s father had been diagnosed with AT deficiency following a life-threatening episode of VTE involving extensive ilio-caval thrombosis and pulmonary embolism. Despite the severe FVIII deficiency, the patient has remained asymptomatic, with an annual bleeding rate (ABR) of zero and no history of spontaneous hemorrhage. He has only received perioperative FVIII prophylaxis and has remained free of thrombotic complications. Thrombin generation assay (TGA) showed delayed initiation and propagation, reduced peak and velocity index, but preserved endogenous thrombin potential (ETP), suggesting a compensatory procoagulant effect from AT deficiency (Figure 1). Although the patient demonstrated impaired thrombin amplification – consistent with FVIII deficiency – the preserved ETP suggests that decreased anticoagulant activity due to AT deficiency provides sufficient compensatory procoagulant effect to maintain clinical hemostasis. This dynamic interplay reflects a finely tuned compensatory mechanism that may alter the clinical expression of inherited bleeding disorders. Conclusions: This case exemplifies a naturally rebalanced hemostatic state resulting from the dual inheritance of opposing coagulation traits, and aligns with previously reported cases. The preserved ETP despite FVIII deficiency supports the concept of compensatory interplay and provides a rationale for rebalancing therapies such as Fitusiran, a small interfering RNA (siRNA) agent that suppresses hepatic AT production. By mimicking this compensatory mechanism, Fitusiran enhances thrombin generation and may improve coagulation in hemophilia patients, including those with inhibitors. Recognition of such rare but informative genetic constellations not only improves diagnostic accuracy, but also has significant implications for therapeutic decision-making. Comprehensive coagulation profiling, including genetic and functional assays, is essential for characterizing atypical presentations and guiding personalized treatment strategies.
2024-12-06 | 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 a 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 (ClinicalTrials.gov identifier: NCT02035605) were enrolled. Participants received monthly subcutaneous fitusiran (50 or 80 mg) under the original dose regimen until a voluntary dosing pause in 2020, after which the AT-based dose regimen was introduced, targeting the recommended AT activity levels of 15% to 35%. Thirty-four participants (hemophilia A, n = 27; hemophilia B, n = 7) were enrolled in the phase 2 study and treated with fitusiran for a median exposure of 4.1 years. Adverse events reported on the original and the AT-based dose regimen were consistent with the identified risks of fitusiran. After implementation of the AT-based dose regimen, there were no thrombotic events, and a reduction in the incidence of elevated transaminases and biliary events was reported. The observed median annualized bleed rate (ABR) on the AT-based dose regimen (0.87) was comparable with the ABR under the original dose regimen (0.70). Furthermore, fitusiran prophylaxis was associated with improved health-related quality of life compared with baseline and provided successful hemostatic control during surgical procedures and invasive interventions. Overall, fitusiran was well tolerated, and effective bleeding control was maintained on an AT-based dose regimen. This trial was registered at www.clinicaltrials.gov as #NCT02554773.
proteins
2026-09-29 | Genetically confirmed severe hemophilia A in a preterm infant: a case report.
Severe hemophilia A is exceptionally rare among preterm infants. Qwing to immature coagulation system and nonspecific bleeding manifestations, the condition is readily misdiagnosed as other neonatal hemorrhagic disorders, such as vitamin K deficiency, neonatal sepsis and thrombocytopenia. Delayed diagnosis will greatly increase the risk of severe complications, particularly intracranial hemorrhage. Herein, we report a case of genetically confirmed severe hemophilia A in a 34-week preterm infant without family history of hemophilia. Treatment comprised sequential adminnistration of coagulation factor VIII repalcement and emicizumab. We futher analyze the clinical characteristics, diagnostic difficulties and standardized management principles of hemophilia A in preterm infants, so as to improve clinicians' awareness, reduce misdiagnosis and missed diagnosis, and optimize the long-term prognosis of affected infants.
2026-09-13 | FRONTIER5: Safety and patient experience of a direct switch from emicizumab to denecimig (Mim8) in patients with haemophilia A with or without inhibitors.
Denecimig (Mim8) is an activated factor VIII mimetic, fully human, bispecific IgG4 antibody in development for subcutaneous prophylaxis in patients with haemophilia A (HA) with/without inhibitors. To evaluate the safety and patient experience of a direct switch from emicizumab to denecimig prophylaxis without a washout period or loading dose. FRONTIER5 (NCT05878938) was a 26-week, single-arm, open-label, phase 3b study in patients aged ≥12 years with HA with or without factor VIII inhibitors. Patients transitioned directly from emicizumab to denecimig maintenance doses administered subcutaneously once-every week, once-every-two-weeks, or once-every-month by a pen-injector. The primary endpoint was the number of treatment-emergent adverse events (TEAEs); secondary and exploratory endpoints included thrombin generation, and patient-reported pen-injector experience, treatment burden, joint pain, and physical activity. All 61 enrolled patients completed the study. TEAEs occurred in 70.5% of patients (3.48 per patient-year of exposure). Most TEAEs were mild or moderate in severity and not treatment-related. No thromboembolic events, hypersensitivity reactions, or clinical evidence of neutralising anti-denecimig antibodies were observed. Injection-site reactions were observed in 15/990 (1.5%) injections. Thrombin generation with denecimig increased into the normal reference range by week 1, without exaggerated haemostatic response. Without a loading dose, denecimig reached steady-state plasma concentrations by week 16. Most participants (98.3%) rated the denecimig pen-injector as 'easy' or 'very easy' to use. The direct switch from emicizumab to denecimig without a washout period was well tolerated in adolescents and adults with HA with or without inhibitors. No new safety concerns were observed.
2026-09-09 | Evaluating Costs and Efficacy of rFVIII Prophylaxis Using Matching-Adjusted Indirect Comparisons in Hemophilia A.
Introduction Prophylaxis with factor VIII (FVIII) is the standard of care for individuals with severe hemophilia A, but it is associated with a substantial economic burden. This analysis compared the efficacy, dosing, and annual treatment costs of simoctocog alfa (Nuwiq, a recombinant FVIII [rFVIII]) with five extended half-life (EHL) rFVIII concentrate products. Methods Matching-adjusted indirect comparisons (MAICs) were performed to compare simoctocog alfa with efanesoctocog alfa (ALTUVIIIO) and turoctocog alfa pegol (Esperoct), and results were integrated with a previously published MAIC comparing simoctocog alfa with efmoroctocog alfa (ELOCTATE), damoctocog alfa pegol (JIVI), and rurioctocog alfa pegol (ADYNOVATE). These MAIC-adjusted populations were used to develop a cost model from a United States payer perspective. Results Annual total costs per person were $147,058 to $492,090 lower with simoctocog alfa compared with EHL rFVIII products, corresponding to a 21% to 46% cost reduction, primarily driven by lower drug acquisition costs. Outcomes were comparable or favorable to simoctocog alfa versus turoctocog alfa pegol, efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol. In comparison with efanesoctocog alfa (Group A), no significant differences were observed in the proportion of individuals with zero bleeds, whereas treated total annualized bleeding rate (ABR) and treated spontaneous ABR favored efanesoctocog alfa. Conclusion This indirect comparison suggests that personalized prophylaxis with simoctocog alfa may offer economic advantages versus EHL rFVIII products in individuals with severe hemophilia A. Clinical outcomes were broadly comparable across comparators, although treated total and spontaneous ABRs were significantly lower with efanesoctocog alfa (Group A).
2026-08-30 | Coagulation potential of concomitant factor VIII administration in people with hemophilia A receiving emicizumab prophylaxis (CAGUYAMA study): a multicenter, open-label, nonrandomized clinical trial.
Emicizumab prophylaxis reduces bleeding in people with hemophilia A. However, factor (F)VIII is still required to manage breakthrough bleeding and for surgical procedures. The optimal additional FVIII dose during such events remains unclear because of emicizumab's baseline hemostatic activity. To assess FVIII-induced changes in global coagulation potential in people with hemophilia A without inhibitors treated with emicizumab and to inform FVIII dosing during prophylaxis. The multicenter "Coagulation potential of concomitant factor VIII administration in people with hemophilia A receiving emicizumab prophylaxis" study enrolled 100 people with hemophilia A (aged ≥4 years) receiving emicizumab at 13 centers in Japan. For eligible bleeding or surgical events, FVIII (standard or extended half-life) was administered at a target dose of 30 IU/kg (allowable range, 25-35 IU/kg). Paired blood samples were obtained pre- and post-FVIII administration. The primary endpoint was the change in clot waveform analysis-adjusted maximum coagulation rate, expressed as IMCR% relative to pooled normal plasma and untreated severe hemophilia A plasma. Secondary endpoints included peak thrombin in the thrombin generation assay, rotational thromboelastometry, clinical hemostasis, and safety. Anti-emicizumab antibodies were used in vitro to isolate the effects of FVIII. Thirty-two FVIII-treated events in 24 people with hemophilia A (15 bleeding events and 17 surgical events) were analyzed. The clot waveform analysis-adjusted maximum coagulation rate increased from 39.4% to 92.1% post-FVIII and from 3.2% to 78.6% under anti-emicizumab conditions. Peak thrombin in the thrombin generation assay increased from 249 to 348 nM (IMCR%: from 55.4% to 88.0%) and from 6.4% to 74.6% under anti-emicizumab conditions. All events achieved effective hemostasis. No thromboembolic events, thrombotic microangiopathy, or hypersensitivity reactions were reported. FVIII administered at a target dose of 30 IU/kg (allowable range, 25-35 IU/kg) improved global coagulation parameters and achieved effective hemostasis without thrombotic complications, warranting evaluation as part of emicizumab prophylaxis.
2026-08-28 | Successful immune tolerance induction using efanesoctocog alfa in severe hemophilia A: A case series.
The development of neutralizing factor VIII (FVIII) inhibitors remains a major therapeutic challenge in severe hemophilia A. We report two patients with complex inhibitor histories who achieved rapid and sustained inhibitor eradication using efanesoctocog alfa. Immune tolerance induction (ITI) was initiated at 100 units (U)/kg 3 times weekly, with subsequent dose reduction after inhibitor clearance. Inhibitor titers declined to undetectable levels (<0.5 Bethesda units [BU]) within 6 weeks in one case and 3 months in the other, with FVIII recovery exceeding 90%. Transition to once-weekly individualized prophylaxis maintained functional FVIII activity and therapeutic FVIII trough levels (4%-6%), allowing discontinuation of emicizumab. Sustained bleed-free outcomes were achieved with individualized prophylactic dosing without inhibitor recurrence. These cases support efanesoctocog alfa-based ITI as a promising strategy for rescue and retreatment patients with complex inhibitor histories.
small molecules
2026-09-19 | The outcome of chemical synovectomy with Rifampicin in chronic hemophilic synovitis: The Syrian experience.
Chronic arthropathy is the most common complication of moderate to severe hemophilia. Chemical synovectomy with Rifampicin offers a cost-effective alternative to radioactive synovectomy, especially in resource-limited settings like Syria. A retrospective study was conducted at the Syrian Hemophilia Society (2020-2024), involving 50 patients (69 target joints) with hemophilic synovitis. Outcomes were assessed using the Hemophilia Joint Health Score visual analogue scale (VAS) for pain, range of motion (ROM), Arnold-Hilgartner classification, and annual bleeding rate,pre- and post-intervention. Participants were predominantly young (mean age 18.99 ± 6.51 years), with hemophilia A (80%). A significant delay was noted between target joint onset and intervention (mean 40.30 months). The knees were most affected (72%), with moderate joint involvement (Arnold-Hilgartner Class II-III). Regional disparities emerged: Damascus patients showed better outcomes (HJHS: 2.33 vs 7.04; VAS: 1.11 vs 3.27, P < .001). Most patients improved significantly (P < .05), except those with mild phenotypes (no HJHS/VAS improvement), ankle involvement (no ROM improvement), and Arnold score 0 (no ROM improvement). Findings underscored inequities in care access across regions. Rifampicin-based chemical synovectomy is a viable, accessible treatment for hemophilic synovitis in low-resource settings. It led to significant improvements in pain, bleeding episodes, joint health, and mobility. However, regional healthcare disparities and delayed interventions remain key challenges affecting outcomes.
2026-09-11 | Neutrophil-dependent interferonopathy contributes to joint damage in hemophilia.
Patients with severe hemophilia A suffer from recurrent bleeding in synovial joints, which leads to development of hemophilic arthropathy, a progressive condition characterized by permanent joint damage, chronic pain and poor quality of life. Current treatment with factor VIII replacement or factor VIII mimetic therapy provides only partial protection from joint bleeding. Unfortunately, targeted therapies to prevent the development of hemophilic arthropathy remain an unmet clinical need, and the etiological mechanism underlying joint damage in hemophilia is still poorly understood. Using the experimental model of hemophilic arthropathy in Factor 8 total knockout (F8TKO) mice and blood samples from hemophilia A patients with or without active joint bleeding, we show that acute joint bleeding promotes an inflammatory milieu in hemophilia, which triggers the type-I interferon response and downstream signaling in neutrophils, leading to systemic shedding of neutrophil extracellular traps (NETs). Remarkably, therapeutic inhibition of type-I interferon receptor attenuates shedding of NETs and reduces the severity of joint damage in F8TKO mice. The current study is the first to identify a role for NETs in the pathogenesis of hemophilic arthropathy and demonstrates the therapeutic potential of targeting neutrophil-dependent type-I interferon signaling to attenuate the progression of joint damage in hemophilia.
2026-07-02 | Biopsy-proven immune-mediated hepatitis after valoctocogene roxaparvovec.
Valoctogene roxaparvovec is an approved and efficacious gene therapy (GT) for severe hemophilia A (HA), however alanine aminotransferase (ALT) elevation after dosing raises safety concerns. Corticosteroids are the first-line therapy for ALT>1.5X the baseline value, but this indication requires further pathological characterization in humans. We explored mechanisms of ALT elevation to personalize corticosteroid therapy. Follow-up data on real-life experience with valoctogene roxaparvovec were collected. Transjugular liver biopsy for histology, transmission electron microscopy and immunophenotype characterization were compared with positive/negative controls. Five severe HA patients were treated with valoctogene roxaparvovec. Four (80%) had ALT>1.5X the baseline value but two had transaminase above the normal range (59 U/L) and lowering of transgene expression and were treated with prednisone. Liver biopsy from these two cases before starting prednisone revealed acute immunemediated hepatitis and abnormal enlargement of the smooth endoplasmic reticulum of hepatocytes. ALT normalized along with preservation of transgene expression after a personalized schedule of oral prednisone. High T-cytotoxic and low T-regulatory activity was observed during acute hepatitis. The median transgene expression at the end of the follow-up was 83(12-206)% (chromogenic assay), but it was highly variable regardless the exposure to prednisone: 48(12-83)% in patients treated with prednisone and 194(20-206)% in patients not treated with prednisone. Immune-mediated hepatitis can cause ALT elevations in HA after valoctogene roxaparvovec and, in selected cases, a biopsy-proven diagnosis could support a safer and more effective therapeutic course of prednisone to maintain optimal transgene expression.
2026-04-09 | Screening chemical libraries for the development of oral treatments for bleeding disorders.
Hemophilia is a rare bleeding disorder due to factor VIII (FVIII) or FIX deficiency involved in hemophilia A (HA) or HB, respectively. Treatment has long relied on invasive IV infusions of the missing factor for prophylaxis or bleeding treatments. Despite significant progress in patient care, there is still no oral procoagulant drug available for people with hemophilia. Such an oral procoagulant could provide benefits to other inherited and acquired bleeding disorders, as well as anticoagulant-induced bleeding. To find chemical compounds that could become potential future orally administered procoagulants, we designed a hierarchical high-throughput screening protocol combining 2 successive screening filters: a miniaturized fibrin formation assay, followed by a thrombin generation assay, both on severe HA plasma. We screened 3 chemical collections totaling > 2300 chemical compounds; we identified adapalene, a commercialized antiacneic compound (Differin), which is strongly hydrophobic. To design a drug that could be orally administered, we developed a series of chemical analogs of adapalene, and 3 of them, with similar procoagulant activities in FVIII-deficient plasma, showed improved solubilities. The mechanism of action was thoroughly investigated by a series of thrombin generation and enzymatic assays. These studies conclude that the procoagulant activity of the chemical compounds in FVIII-deficient plasma is due to the activation of FXII.
2026-02-28 | Machine learning estimation of FVIII pharmacokinetic parameters in Chinese children with severe Hemophilia A.
Hemophilia A is a rare inherited bleeding disorder typically managed with coagulation factor VIII (FVIII) replacement therapy. Designing personalized prophylactic regimens requires accurate pharmacokinetic (PK) characterization; current population PK (popPK) and Bayesian approaches provide a principled framework for individualized dosing, but their routine clinical implementation may still be constrained by model specification requirements and practical considerations in data collection and analysis. Here we present a machine learning (ML) framework, incorporating state-of-the-art language models, to predict individual FVIII PK parameters in pediatric patients. Using minimal sampling and routinely collected clinical data, our approach achieves superior performance over the widely adopted WAPPS-Hemo platform in predicting in vivo recovery (IVR) and FVIII half-life. These findings highlight the potential of AI-driven methods to reduce patient burden while improving accuracy in individualized treatment planning for children with severe hemophilia A.
antibodies
2026-09-23 | Emicizumab enables rapid tolerance, reducing bleeding during low-dose ITI in pediatric hemophilia A.
Immune tolerance induction (ITI) remains the only proven strategy for eradicating factor VIII (FVIII) inhibitors in severe hemophilia A, yet low-dose regimens are associated with prolonged treatment and significant bleeding. Emicizumab provides FVIII-independent hemostatic protection and may permit antigen exposure under conditions of reduced bleeding and inflammation during ITI. We conducted a single-center cohort study with historical controls to evaluate the impact of emicizumab on low-dose ITI (LD-ITI) outcomes in pediatric patients (aged <14 years) with severe hemophilia A and high-responding inhibitors undergoing their first LD-ITI (50 IU/kg, 3× per week). Twenty-three patients were included. Patients treated with LD-ITI alone (2010-2020; n = 14) were compared with those receiving LD-ITI plus emicizumab prophylaxis (LD-ITI+EMI; 2021-2023; n = 9). Complete ITI success occurred in 7 of 9 patients (78%) of the LD-ITI+EMI cohort vs 5 of 14 patients (36%) of the LD-ITI cohort (P = .09). Median time to tolerance was shorter with emicizumab (9 vs 19 months; P = .003). Time-to-event analysis confirmed faster tolerance with emicizumab (hazard ratio of 3.89; P = .02). Treated bleeds during ITI were drastically reduced in the emicizumab cohort (median annualized treated bleeding rate, 0.0 vs 5.1; P < .0001), and a higher bleeding burden was associated with delayed tolerance. No thrombotic complications were observed. Median direct treatment costs were comparable between cohorts. In this pediatric cohort, LD-ITI combined with emicizumab was associated with faster tolerance achievement, bleeding reduction, and no increase in direct costs. These findings suggest that ITI associated with emicizumab may provide a more efficient and clinically manageable approach to inhibitor eradication in pediatric patients.
2026-09-18 | Plasma emicizumab concentrations and bleeding rates in children and adults with severe hemophilia A.
Emicizumab has been in clinical use for less than 10 years. Real-world experience is still needed to guide its use for optimal safety, efficacy, and resource efficiency. Recent data suggest that conventional weight-based dosing may be excessive for many patients. More data on the correlation between bleeding events and plasma emicizumab concentation will help to clarify optimal dosing regimens. To determine bleeding rates and their correlation with drug levels in patients without inhibitors using prophylactic emicizumab. We conducted an observational study in a large cohort of adult and pediatric persons with severe hemophilia A without inhibitors to determine the rate of bleeding events during emicizumab prophylaxis and the correlation between plasma emicizumab concentration and bleeding rates. Among the 73 patients followed for a mean of 69.0 weeks, 47.9% had 0 treated bleeds and 80.8% had 0 spontaneous bleeds. The mean and median annualized treated bleed rates were 1.12 and 0.57, and the mean and median annualized joint bleed rates were 0.51 and 0. The mean factor VIII concentrate used to treat bleeds was 63.0 IU/kg/y per patient (median, 23.1 IU/kg/y). Steady-state plasma emicizumab concentration did not correlate with total or spontaneous annualized treated bleed rate and annualized joint bleed rate or with patient age at enrolment, body weight, or body mass index. Dose capping at 150 mg/wk did not result in lower emicizumab concentrations in the 9 patients with body weight >100 kg. Emicizumab provided highly effective prophylaxis in persons with severe hemophilia A across the age spectrum. The lack of correlation of bleed outcomes with plasma emicizumab concentration suggests that minimal effective drug concentrations should be reconsidered. Studies to rationalize and personalize therapy should be explored.
2026-09-09 | Discovery and development of a bispecific antibody for the treatment of hemophilia.
The 2026 Lasker~DeBakey Clinical Medical Research Award has been awarded to Kunihiro Hattori, Takehisa Kitazawa, and Tomoyuki Igawa (Chugai Pharmaceuticals, Tokyo, Japan) for invention of a bispecific antibody that joins blood clotting Factors IXa (FIXa) and X (FX), restoring deficient Factor VIII (FVIII) activity in patients with hemophilia A and preventing severe bleeding in this hereditary disorder. Starting from the 1960s, types of FVIII-replacement therapy remarkably improved on-demand hemostatic treatment for ongoing bleeds and enabled prophylactic reduction of bleeding episodes. However, these agents required burdensome intravenous infusions multiple times per week, and ~30% of patients developed neutralizing anti-FVIII antibodies (FVIII inhibitors). To address these unmet medical needs, in 2000, Hattori-a molecular and hematology biologist, Kitazawa-a hematology biologist and translational researcher, and Igawa-a biochemist and protein engineer, conceived, designed, and created over the span of 10 y a novel FVIII-mimetic. Instead of a native protein construct, they engineered a bispecific IgG antibody against FIXa and FX, circumventing the need for FVIII and enabling subcutaneous administration up to once per month. Importantly, they identified the biophysical requirements for the bispecific to mimic FVIII function effectively and safely, and their breakthrough protein engineering design made possible favorable pharmacokinetics and physicochemical properties with efficient manufacturability. Their collective research efforts demonstrate how imagination, determination, and multidisciplinary scientific research come together to improve patients' lives.
2026-09-09 | Emicizumab and shared medical decision in patients living with hemophilia A.
Emicizumab is a new prophylactic treatment for patients with severe hemophilia A. This study evaluated patient decisional conflict and physician decisional comfort regarding the switch to emicizumab, identifying the criteria that drive this choice. This is an observational, non-interventional, multicenter, retrospective and exploratory study of hemophilia A patients at seven centers in France. The evaluation used the patient's decisional conflict scale and the physician's decisional comfort scale, as well as a questionnaire to determine the criteria for choosing whether to switch to emicizumab. A cluster approach was applied to identify patient subgroups with distinct decisional profiles. A total of 53 patients and their physicians were included in this study: 34 in the emicizumab arm and 19 in the factor VIII arm. Patients in the factor VIII arm reported higher remorse, while physicians in this group felt significantly less comfortable with the decision. While factors influencing the decision were similar between both patients and physicians, illustrating good mutual understanding. Cluster analysis identified a specific subgroup (23%) in the total cohort experiencing high decisional conflict despite their final choice, highlighting a need for targeted clinical support. This study highlights the importance of shared decision-making in hemophilia treatment, encouraging open communication between patients and physicians for more personalized care.
2026-09-03 | Real-World Experience With Emicizumab for Haemophilia A From the Physician Perspective in a Real-World Clinical Setting.
Emicizumab is a bispecific antibody approved for prophylaxis in people with haemophilia A (PwHA). To describe from the physician perspective the characteristics and treatment experiences of PwHA receiving emicizumab. The Adelphi Real World Haemophilia Disease Specific Programme is a cross-sectional, retrospective data collection from US haematology and haematology-oncology specialists between July 2023 and April 2024. Male PwHA with or without inhibitors were included if they had baseline factor VIII levels <5% and were not currently participating in a clinical trial. Surveys captured demographic characteristics and clinical outcomes, including bleeding events. Fifty-four physicians provided data for 293 PwHA, of which 115 were seen outside federally funded haemophilia treatment centres (HTCs), 77 were treated with emicizumab and 49 had pre- and post-emicizumab initiation data available. More Black, African American, African or Caribbean PwHA received emicizumab outside federally funded HTCs than at federally funded HTCs (46.2% vs. 16.7%). Most emicizumab doses were taken on time (mean [SD], 90.7% [14.6%]), and 64.0% of PwHA took >80% of the prescribed dose. More PwHA had zero treated bleeds (76.9% vs. 42.9%), with fewer bleeding events (mean [SD], 1.3 [1.9] vs. 0.4 [1.1]; p = 0.0001) during the post-emicizumab period (median [IQR] follow-up, 12.0 [1.3-12.0] months) than in the 12 months pre-emicizumab. Post-emicizumab outcomes were similarly improved across settings, whether at federally funded HTCs or elsewhere. Among PwHA receiving emicizumab, rates and severity of bleeds decreased after emicizumab initiation, regardless of the clinical setting.
gene therapies
2026-08-21 | Evaluation of early prophylactic corticosteroid administration on early safety and efficacy outcomes of adeno-associated virus gene therapy in the hemophilia dog model.
Prior to commercial withdrawal, adeno-associated virus (AAV) gene therapy was approved for the treatment of adults with severe hemophilia A. Mechanisms underlying variability, durability, and liver transaminitis are largely uncharacterized. To evaluate the effects of prophylactic corticosteroid administration on AAV gene therapy outcomes in dogs with severe hemophilia A. Seven dogs with hemophilia A received 6e13 vector genomes/kg of AAV5-canine factor (F)VIII. Four dogs received oral prednisolone (1 mg/kg/day) starting 3 hours preinfusion with dose-tapering over 6 weeks; three control dogs received no corticosteroids. Percutaneous liver biopsies were performed on detection of alanine aminotransferase (ALT) >2-fold the upper limit of normal. All dogs expressed therapeutic FVIII:C (8.7-56.1%), improved whole blood clot time, and decreased bleeding rates (pre = 6.11 vs post = 1.42 bleeds/year, P = .016) over 2 years post-AAV5-canine FVIII. Corticosteroid-treated dogs demonstrated a modest increase in mean FVIII:C at 2 years by chromogenic substrate assay (39.1%) compared with controls (29.5%), driven by one female with markedly elevated FVIII:C from day 54 onward. When analyzed by sex, all female dogs exhibited increased mean FVIII:C chromogenic substrate assay at 2 years (49.3%) compared with males (9.1%), regardless of prophylactic corticosteroid use. Prophylactic corticosteroids did not impact transient posttreatment elevations of proinflammatory cytokines, anti-AAV antibody formation, or ALT levels. One corticosteroid-treated dog experienced ALT > 4.3-fold the upper limit of normal at 18 weeks without impacting long-term FVIII:C expression. A liver biopsy showed diffuse, minimal periportal lymphocyte and neutrophil infiltration, consistent with nonspecific minimal hepatitis. Prophylactic corticosteroids were not clearly associated with increased transgene expression in dogs with hemophilia A.
2026-06-03 | Real-world provider experiences with hemophilia A gene therapy: administration of valoctocogene roxaparvovec.
Severe hemophilia A is a bleeding condition caused by a deficiency in clotting factor VIII (FVIII ≤1 IU/dL) that results in spontaneous and excessive posttraumatic bleeding. The current standard of care is prophylaxis with exogenous FVIII or bispecific antibodies that mimic FVIII function. Valoctocogene roxaparvovec is a gene therapy approved for adults with severe hemophilia A that enables endogenous FVIII production to protect against bleeding. As a newer treatment modality, workflows for gene therapy administration and postinfusion care are still unfamiliar to many health care professionals and may be perceived as implementation barriers. We are 10 hemophilia gene therapy providers across the United States, Italy, and Germany sharing our experiences of administering valoctocogene roxaparvovec in clinical practice to >25 patients with severe hemophilia A. In this study, we provide our insights into patient preparation, establishment of treatment centers and multidisciplinary teams, postinfusion management, and patient follow-up to facilitate open communication and collaboration among the treatment community.
2026-05-07 | Gait Pattern at Different Speeds in Persons With Haemophilia.
Persons with haemophilia (PwH) have a risk of bleeding in joints, especially in elbow, knee and ankle. In the long term, this leads to haemophilic arthropathy (HA), which results in joint deformities. This study aims to examine how walking speed and HA affect (1) foot pressure distribution, (2) average vertical peak pressure, and (3) knee and ankle joint angles during walking. Using a motion analysis system (DIERS 4DmotionLab), 30 PwH and 31 healthy controls (CG) were examined at speeds of 3, 4, and 5 km/h. Groups were additionally divided according to the severity of HA, in the subgroups PwH(major) and PwH(minor). Regarding different gait speeds, no differences were found between PwH and CG in peak pressure distribution. However, pedobarography showed a significant reduction in average vertical peak pressure in the second half of the stance phase in PwH(major) compared to CG (p < 0.007). Joint angle measurements showed reduced plantar flexion (p = 0.041), dorsiflexion (p = 0.011), and descriptive, non-significant knee flexion in PwH(major) at different speeds. Knee extension did not differ between groups. The study confirms that PwH, especially those with advanced HA, show impaired gait pattern. While different walking speeds had no impact on peak pressure values compared to CG, force transmission was reduced in PwH in the second half of the stance phase. This, in conjunction with reduced mobility in the ankle joints, indicates impaired power transmission in the propulsion phase which is well compensated.
2026-05-01 | Correlation between Factor VIII chromogenic activity and antigen levels in patients treated with adeno-associated virus 5-mediated gene therapy for hemophilia A.
Gene therapy for hemophilia A with valoctocogene roxaparvovec, an adeno-associated virus (AAV) vector encoding B-domain-deleted factor (F)VIII, enables sustained endogenous FVIII expression and long-term bleed protection. FVIII activity is commonly measured using a one-stage clotting assay (OSA) or a chromogenic assay (CA), which yield discrepant results. Data on FVIII transgene expression, assessed by antigen measurements after gene therapy in humans, remain limited. To evaluate the correlation between FVIII activity assessed by OSA and CA and FVIII antigen levels after valoctocogene roxaparvovec administration. Four adult patients with severe hemophilia A received a single infusion of valoctocogene roxaparvovec (6 × 1013 vg/kg). FVIII activity was measured by OSA and CA methods; FVIII antigen was quantified using an enzyme-linked immunosorbent assay optimized for B-domain-deleted FVIII. A total of 182 plasma samples were collected at multiple time points post-AAV5 FVIII dosing. The median follow-up time for patients was 61 weeks (IQR, 52.5-115.7). The OSA consistently showed FVIII activity 1.6- to 2-fold higher than the CA, consistent with observations from previous clinical trials. Transgenic FVIII antigen levels positively correlated with FVIII activity measured by the CA, indicating effective transcription and translation of the FVIII transgene. FVIII antigen levels showed strong concordance with CA results following AAV-mediated gene therapy. These findings support the CA as the preferred method for monitoring therapeutic FVIII expression in patients treated with gene therapy for hemophilia A. Multiassay strategies remain essential for comprehensive assessment of transgene expression and clinical management after gene therapy.
2026-05-01 | Durability of efficacy, safety, and quality of life 5 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A: final phase 3 GENEr8-1 trial results.
Valoctocogene roxaparvovec, a gene therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) expression and confers bleed control. To present the final 5-year efficacy and safety results from the phase 3 GENEr8-1 trial. Adult men (N = 134) with severe hemophilia A without inhibitors who were using FVIII prophylaxis received one 6 × 1013 vg/kg infusion of valoctocogene roxaparvovec. End points included annualized bleeding rate (ABR), FVIII infusion rate, FVIII activity, Haemophilia-Specific Quality of Life Questionnaire for Adults, adverse events, and immunosuppressant use. Median follow-up was 261.1 weeks; 128 of 134 participants completed the study. For the 112 participants who enrolled from a previous noninterventional study (rollover population), mean ABR for treated bleeds declined by 83.3% (P < .0001), mean FVIII infusion rate declined by 94.9% (P < .0001), and mean ABR for all bleeds declined by 78.1% in the 5-year efficacy evaluation period vs baseline. In 132 modified intention-to-treat participants, mean and median FVIII activity at week 260 was 13.7 and 6.2 IU/dL, respectively (chromogenic assay). In year 5, 77.8% of rollover participants had 0 treated bleeds. One participant resumed prophylaxis since the 4-year data cutoff (25/134 across all follow-up). Haemophilia-Specific Quality of Life Questionnaire for Adults total score was improved from baseline at year 5. In year 5, alanine aminotransferase elevations occurred in 51 of 129 participants who entered year 5. Immunosuppressants were not used to manage them. No serious treatment-related adverse events occurred after year 1. Valoctocogene roxaparvovec provides durable hemostatic efficacy, FVIII activity, and improved health-related quality of life for ≥5 years, with no new safety signals.
other
2026-01-13 | Impact of antiplatelet therapy on the hemostatic efficacy of platelet-targeted FVIII gene therapy in hemophilia A mice.
Platelet-targeted factor VIII (FVIII) (2bF8) gene therapy offers promising hemostatic correction in hemophilia A (HA), even in the presence of FVIII inhibitors. Because platelet-derived FVIII is released from platelet α-granules upon activation at injury sites, it is essential to evaluate whether antiplatelet agents would compromise its therapeutic efficacy. Here, we investigated the effect of antiplatelet agents on the efficacy of platelet-FVIII in HA mice. 2bF8Tg mice express FVIII in platelets controlled by the αIIb promoter and were treated with aspirin, clopidogrel, or the αIIbβ3-blocking antibody Leo.H4. Hemostatic function was evaluated through tail-bleeding models and in vitro assays. We found that all antiplatelet agents impaired platelet-FVIII-mediated hemostasis in vivo. Leo.H4 treatment caused severe bleeding in both the tail tip and tail vein transection injury models, consistent with its inhibition of platelet aggregation. Clopidogrel-treated 2bF8Tg mice exhibited 10 to 14 times more blood loss than controls, with extended bleeding; however, they still showed improvement compared to FVIIInull controls. Notably, platelet-FVIII retained superior efficacy compared to plasma-derived FVIII in clopidogrel-treated mice, despite having only 24% of normal FVIII activity. Aspirin also impaired hemostasis but to a lesser extent. In vitro rotational thromboelastometry and whole-blood thrombin generation assays showed no significant differences between aspirin- or clopidogrel-treated and control mice, suggesting that these assays may not fully capture platelet-FVIII dynamics. Our results indicate that platelet aggregation is crucial for the efficacy of platelet-FVIII. Although antiplatelet agents hinder its function, platelet-FVIII remains preferable to plasma-FVIII, highlighting its clinical potential and the importance of considering concomitant therapies in future applications.
2025-11-14 | [RNA Sequencing Reveals Molecular Alternations of Splenocytes Associated with Anti-FⅧ Immune Response in Hemophilia A Murine Model].
To investigate the molecular alterations of splenocytes associated with anti-factor Ⅷ (FⅧ) immune response and the underlying mechanisms based on hemophilia A (HA) murine model via RNA sequencing (RNA-seq) technology. Severe HA mice were immunized with recombinant human factor Ⅷ (rhF8) weekly for 4 weeks to establish an FⅧ inhibitor model. High quality raw data were obtained by using bulk RNA-seq and CASAVA base identification technology, and the differentially expressed genes (DEGs) were identified. The DEGs were statistically classified by gene ontology (GO) annotation to obtain information on the major signaling pathways and biological processes involved in anti-FⅧ immune response in HA mouse splenocytes. The cell clusters, genes, and signaling pathway datasets were comprehensively analyzed by GO, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and single cell RNA-seq (ScRNA-seq) analysis, respectively. Flow cytometry analysis was used to verify the changes in T follicular helper cells (Tfh) and regulatory T cells (Treg). A total of 3731 DEGs was identified, including 2275 genes with up-regulated expression and 1456 genes with down-regulated expression. The DEGs were enriched in helper T cell differentiation, cytokine receptor, T cell receptor signaling pathway, ferroptosis, etc. Uniform Manifold Approximation and Project (UMAP) downscaling and visualization analysis yielded a total number of 11 T/NK cell subsets, visualizing the overall expression distribution of C-X-C chemokine-specific receptor gene cxcr5 among these T/NK cell subsets. Higher expression of cxcr5 was found in activated Tfh from FⅧ inhibitor mice, in comparison to the control group. The visualization using Upset plot R language showed a close interaction between Tfh and Treg. Moreover, the increased frequencies of Tfh and the decreased frequencies of Treg in inhibitor mouse splenocytes were further verified by flow cytometry analysis. Multiple immune cell subsets, signaling pathways, and characteristic genes may be involved in the process of anti-FⅧ immune response in HA mouse splenocytes. The molecules involved in the regulation of Tfh/Treg may play key roles, which provide potential biological targets and therapeutic strategies for HA patients with inhibitors in the future.
2025-11-03 | Efficacy and safety of fitusiran prophylaxis in people with haemophilia a or haemophilia B: A systematic review and meta-analysis
Abstract Background: Prophylaxis is the standard of care for people with severe hemophilia A or B to prevent bleeding, but the treatment burden can be high, and breakthrough bleeding can still occur, particularly in patients with inhibitors. Fitusiran, a small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis, offering a novel prophylactic approach. This systematic review and meta-analysis aim to evaluate the efficacy and safety of Fitusiran prophylaxis in this population. Aim: To systematically review and meta-analyze the efficacy and safety of Fitusiran prophylaxis compared to control in people with hemophilia A or B, with or without inhibitors. Methods: A systematic literature search was conducted across PubMed, Cochrane, ScienceDirect, Web of Science, and Scopus to identify randomized controlled trials (RCTs) comparing Fitusiran with control (placebo or bypassing agents on-demand) in patients with hemophilia A or B. The primary efficacy outcomes were the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR), and annualized joint bleeding rate (AjBR). Safety outcomes included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent severe adverse events (TESAEs), and specific adverse events of interest such as elevated liver enzymes. Data from RCTs were pooled using a random-effects model. Mean difference (MD) was used for continuous outcomes and odds ratio (OR) for dichotomous outcomes, with 95% confidence intervals (CI). Heterogeneity was assessed using the I² statistic. Results: Three RCTs were included in this meta-analysis, ATLAS-INH 2023, ATLAS-PPX 2024, and ATLAS A/B 2023, with a combined sample size of (N=311). In patients with inhibitors, Fitusiran significantly reduced ABR (MD: -11.70, 95% CI: [-18.55, -4.85]; P=0.0008), AsBR (MD: -9.40, 95% CI: [-18.63, -0.18]; P=0.05), and AjBR (MD: -8.49, 95% CI: [-14.92, -2.05]; P=0.01). In patients without inhibitors, no statistically significant reduction was observed for ABR (P=0.25), AsBR (P=0.26), or AjBR (P=0.28). Fitusiran was associated with a significantly higher odds of any TEAE (OR: 5.11, 95% CI: [3.05, 8.56]; P<0.00001) and increased alanine aminotransferase (ALT) (OR: 17.80, 95% CI: [4.88, 64.92]; P<0.0001). There was no statistically significant difference in the odds of increased aspartate aminotransferase (AST) (P=0.06), upper respiratory tract infection (P=0.12), arthralgia (P=0.23), nasopharyngitis (P=0.15), or TESAEs (OR: 0.84, 95% CI: [0.35, 2.00]; P=0.69). Heterogeneity for all outcomes was low. Conclusion: Fitusiran prophylaxis is an effective therapy for reducing bleeding rates in patients with hemophilia A or B with inhibitors. While a similar trend was observed in patients without inhibitors, the result was not statistically significant. The safety profile indicates an increased risk of TEAEs, most notably transient elevations in ALT, but not an increase in severe adverse events. These findings support Fitusiran as a promising prophylactic option, especially for the difficult-to-treat inhibitor population and underscore the importance of monitoring liver function during treatment.
2025-08-05 | PO47 | Hemophilia A and antithrombin deficiency: a case of natural hemostatic rebalancing
Background: Hemostasis is governed by a dynamic balance between procoagulant and anticoagulant forces. While inherited bleeding and thrombotic disorders are typically studied as discrete entities, rare cases of co-inheritance may produce unique clinical phenotypes due to compensatory interactions. Among these, hemophilia A and antithrombin (AT) deficiency represent prototypical yet contrasting conditions: patients with severe hemophilia A often experience spontaneous joint and muscle bleeding, requiring lifelong prophylaxis or on-demand therapy with FVIII concentrates, whereas AT deficiency is associated with a markedly increased risk of venous thromboembolism (VTE), particularly in high-risk situations such as surgery, trauma, or prolonged immobilization. Understanding how opposing defects interact within the same individual may inform individualized management and therapeutic innovation. Case Report: We describe the case of a 19-year-old male with severe hemophilia A (FVIII <1%, no inhibitors), carrying a mutation in exon 3 of the F8 gene (NM_000132.4:c.296A>G, resulting in p.His99Arg), co-inherited with congenital AT deficiency (~50% activity). At birth, neonatal screening was prompted by a maternal family history of hemophilia A and a paternal history of thrombophilia. The patient’s father had been diagnosed with AT deficiency following a life-threatening episode of VTE involving extensive ilio-caval thrombosis and pulmonary embolism. Despite the severe FVIII deficiency, the patient has remained asymptomatic, with an annual bleeding rate (ABR) of zero and no history of spontaneous hemorrhage. He has only received perioperative FVIII prophylaxis and has remained free of thrombotic complications. Thrombin generation assay (TGA) showed delayed initiation and propagation, reduced peak and velocity index, but preserved endogenous thrombin potential (ETP), suggesting a compensatory procoagulant effect from AT deficiency (Figure 1). Although the patient demonstrated impaired thrombin amplification – consistent with FVIII deficiency – the preserved ETP suggests that decreased anticoagulant activity due to AT deficiency provides sufficient compensatory procoagulant effect to maintain clinical hemostasis. This dynamic interplay reflects a finely tuned compensatory mechanism that may alter the clinical expression of inherited bleeding disorders. Conclusions: This case exemplifies a naturally rebalanced hemostatic state resulting from the dual inheritance of opposing coagulation traits, and aligns with previously reported cases. The preserved ETP despite FVIII deficiency supports the concept of compensatory interplay and provides a rationale for rebalancing therapies such as Fitusiran, a small interfering RNA (siRNA) agent that suppresses hepatic AT production. By mimicking this compensatory mechanism, Fitusiran enhances thrombin generation and may improve coagulation in hemophilia patients, including those with inhibitors. Recognition of such rare but informative genetic constellations not only improves diagnostic accuracy, but also has significant implications for therapeutic decision-making. Comprehensive coagulation profiling, including genetic and functional assays, is essential for characterizing atypical presentations and guiding personalized treatment strategies.
2024-12-06 | 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 a 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 (ClinicalTrials.gov identifier: NCT02035605) were enrolled. Participants received monthly subcutaneous fitusiran (50 or 80 mg) under the original dose regimen until a voluntary dosing pause in 2020, after which the AT-based dose regimen was introduced, targeting the recommended AT activity levels of 15% to 35%. Thirty-four participants (hemophilia A, n = 27; hemophilia B, n = 7) were enrolled in the phase 2 study and treated with fitusiran for a median exposure of 4.1 years. Adverse events reported on the original and the AT-based dose regimen were consistent with the identified risks of fitusiran. After implementation of the AT-based dose regimen, there were no thrombotic events, and a reduction in the incidence of elevated transaminases and biliary events was reported. The observed median annualized bleed rate (ABR) on the AT-based dose regimen (0.87) was comparable with the ABR under the original dose regimen (0.70). Furthermore, fitusiran prophylaxis was associated with improved health-related quality of life compared with baseline and provided successful hemostatic control during surgical procedures and invasive interventions. Overall, fitusiran was well tolerated, and effective bleeding control was maintained on an AT-based dose regimen. This trial was registered at www.clinicaltrials.gov as #NCT02554773.
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Drug Discovery Landscape
1 orphan drug designation for Severe hemophilia A.
1 orphan drug designation for Severe hemophilia A.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
an autologous gene therapy consisting of CD34+ hematopoietic stem and progenitor cells transduced ex-vivo with the CD68-ET3-LV lentiviral vector | gene therapies | FDA | Expression Therapeutics LLC |
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