RARE DISEASE
Mild hemophilia A
Mild hemophilia A
Mild hemophilia A
Synonyms: Mild congenital F8 deficiency, Mild congenital factor VIII deficiency
Synonyms: Mild congenital F8 deficiency, Mild congenital factor VIII deficiency
Synonyms: Mild congenital F8 deficiency, Mild congenital factor VIII deficiency
Drug discovery
639
papers
On emerging therapies
Overview
Mild hemophilia A is an inherited bleeding disorder characterized by factor VIII levels between 5%–40% (0.05–0.40 IU/mL), leading to trauma- or procedure-related bleeding rather than spontaneous episodes [1][12][17]. Diagnosis is often delayed until surgical or injury-related bleeding occurs due to low clinical awareness, even among families [1][18]. Management focuses on preventing and controlling acute bleeds, with risks including underrecognized joint damage and inhibitor development [1][9].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
639 drug discovery papers about Mild hemophilia A. Recent publications:
639 drug discovery papers about Mild hemophilia A. Recent publications:
categories:
Small molecules
proteins
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.
2026-09-03 | Prophylaxis in patients with moderate and mild haemophilia: experience from a single centre
Introduction: Prophylaxis in hemophilia as a gold standard of treatment was classically restricted to patients with severe forms.Objective: To evaluate the implementation of prophylaxis in patients with moderate and mild hemophilia, addressing its impact on the reduction of bleeding and quality of life.Material and methods: Nine patients were included, analyzing retrospective data 12 months before and after starting prophylaxis collected from their electronic medical records.Results: It's observed a significant reduction in annualized bleeding rate by 96.78% for hemophilia A and 91.67% for hemophilia B. Concentrates of factors VIII and IX were used with different infusion regimens.Prophylaxis improved hospital independence and decreased joint bleeding, although with a burden associated with treatment.Conclusions: The need for early follow-up and adoption of prophylaxis in non-severe patients to prevent arthropathies and improve quality of life is highlighted, in line with international recommendations.
2026-08-19 | Substitution-induced allosteric activation of coagulation factor IX as a potential alternative hemophilia A treatment strategy.
Cofactor-independent activity of FIX has previously been achieved in FIX-IDAV and FIX-FIAV variants containing L6F, V181I, E185D, K265A, and I383V substitutions. Cofactor-dependent FIX hyperactivity was attained through the V10K, R338L, and S377W (KLW) modifications. We evaluated whether combining IDAV/FIAV and KLW substitutions could enhance cofactor-independent activity and elucidated the biochemical mechanisms underlying FVIII-independent FIX-FIAV function. Recombinant FIX variants, expressed in HEK293 cells, were analyzed for FIX-specific and FVIII-equivalent clotting activities. Highly purified FIX-FIAV was characterized using purified component assays and FXIa-triggered thrombin generation in FVIII-deficient plasma. FIX-IDAV-KLW and FIX-FIAV-KLW exhibited 20-28-fold higher FIX-specific activity and a modest twofold increase in FVIII-equivalent clotting activity. Owing to thrombotic safety concerns, KLW combinations were not further pursued. FIX-FIAV displayed normal FIX-specific activity and fourfold enhanced FVIII-equivalent clotting activity. The FIAV substitutions did not alter activation by the extrinsic (TF-FVIIa) or intrinsic (FXIa) pathways, nor cofactor-dependent FX activation, but conferred FVIII-independent FX conversion. Kinetic analyses revealed a modified active site conformation with a trend toward reduced antithrombin inhibition. In FVIII-deficient plasma, FIX-FIAV dose-dependently increased FXIa-triggered thrombin generation by shortening the lag time and time to peak and shifted coagulation phenotype categories based on FVIII-equivalent thrombin generation (TG) activity from severe toward moderate/mild ranges in plasma-based models, without exceeding normal FVIII-equivalent TG activity. FIX-FIAV represents a FIX variant with FVIII-independent activity, normal FIX-specific activity, and reduced inactivation by antithrombin. Targeted modification of regions surrounding the FIXa active site enables allosteric activation, providing a potential foundation for novel bypassing strategies in hemophilia A therapy.
2026-06-17 | Innovations in Hemorrhage Management: Calcium Alginate, Celox, and Desmopressin as Next-generation Hemostatic Agents.
Hemorrhage continues to be the primary preventable cause of death, accounting for 87% of military deaths and 62% of civilian deaths. In war zones, delayed evacuation exacerbates the situation. The need for safer, more efficient substitutes is highlighted by the fact that conventional therapies, such as bone wax and vancomycin, can cause infection or systemic toxicity. Recent developments in hemostatic technologies, including biodegradable waxes, chitosan-based agents, commercial dressings, calcium alginates, pharmaceutical alternatives, and plant-derived formulations, were studied. The hemostatic performance, biocompatibility, regeneration potential, and field applicability of these studies were evaluated. Comparative studies established QuikClot Combat Gauze (QCG) as superior to Celox Rapid (CR), achieving 100% immediate hemostasis versus 70% and reducing blood loss by 162 ± 48 mL. Calcium alginates provided multifunctionality by absorbing >500% of fluid, maintaining wound hydration, and supporting tissue regeneration. Desmopressin offered systemic hemostatic effects in von Willebrand disease and mild hemophilia A, although its broader utility was limited. Despite decades of research, hemorrhage remains the leading cause of preventable death, driving innovation in biodegradable hemostatic agents and safer alternatives to traditional treatments. Traditional bone wax increases infection rates, necessitating safer alternatives. New biodegradable wax formulations show dual hemostatic and regenerative properties. Chitosanbased agents demonstrate superior biocompatibility and effectiveness. Significant strides have been made toward safer, regenerative hemostatic treatments through the development of biodegradable and biocompatible agents. However, effectively translating laboratory advancements into trauma treatment and reducing hemorrhage-related mortality requires the integration of these technologies with improved evacuation infrastructure, evidencebased adoption, and enhanced field training.
2026-05-31 | The biomarkers uCTX-II, CS846 and IGF-1 are associated with clinical and ultrasound scores in haemophilic arthropathy: a cross-sectional study.
Haemophilic arthropathy (HA) leads to progressive joint damage. Biomarkers may support early detection and monitoring of disease severity. To assess the association of cartilage and bone turnover biomarkers uCTX-II, CS846, OC, bALP, CTX-I, IGF-1, and CTSG with HA severity in severe and mild haemophilia, as evaluated by clinical and ultrasound scoring. Fifty-three adult patients with severe (n = 27) or mild (n = 26) haemophilia and 52 healthy controls were enrolled. Biomarkers were measured in serum and urine. Joints were assessed using the WFH Physical Examination and HEAD-US scores. uCTX-II was the only biomarker significantly elevated in haemophilia patients and increased progressively with disease severity (median 192.99, 243.34, and 422.88 ng/mmol in controls, mild, and severe haemophilia, respectively; p < 0.001), correlating with both clinical (rho = 0.327, p = 0.028) and HEAD-US (rho = 0.308, p = 0.040) scores in the overall haemophilia group. CS846 levels negatively correlated with clinical (rho = -0.514, p = 0.012) and HEAD-US (rho=-0.609, p = 0.002) scores in mild haemophilia. IGF-1 negatively correlated with clinical (rho=-0.621, p = 0.003) and HEAD-US (rho=-0.646, p = 0.002) scores in severe haemophilia. No significant group differences or associations were observed for OC, bALP, CTX-I, and CTSG. uCTX-II levels increased with HA severity and correlated with joint scores, suggesting its potential as a biomarker of joint damage. Negative correlations with joint scores were observed for CS846 in mild haemophilia, and for IGF-1 in severe haemophilia. CTSG and bone turnover markers showed no association with HA severity. These findings identify uCTX-II, CS846, and IGF-1 as candidate biomarkers for assessing HA severity; longitudinal studies are needed to confirm their clinical utility.
small molecules
2026-07-25 | Blunt Splenic Injury in Hemophilia A: Embolic Agent Selection When Hemostasis Cannot be Assumed.
Blunt splenic injury in a patient with hemophilia A presents a dilemma that has traditionally been settled by splenectomy. Removing the spleen leaves a patient already prone to bleeding without its immune function, and the factor VIII (FVIII) exposure that open surgery requires is itself a recognized trigger for inhibitor formation. In the general trauma population, nonoperative management is now the standard for hemodynamically stable patients: observation suffices in most, and splenic artery embolization is reserved for higher-risk injuries. Patients with inherited coagulopathy, however, sit outside the trials and guidelines that built this paradigm. We present a 66-year-old man with mild hemophilia A (FVIII activity 13%), cardiac comorbidity, and a plasma allergy who sustained a blunt splenic laceration graded as American Association for the Surgery of Trauma (AAST) Grade II. No interim computed tomography was obtained; by hospital day 3, selective angiography showed an arteriovenous fistula that had been absent at presentation, a delayed vascular complication of the original injury. Coils and particulate agents failed to achieve occlusion, whereas a 1:3 N-butyl cyanoacrylate (NBCA)-lipiodol mixture produced immediate and complete vessel sealing via coagulation-independent polymerization. Using this case as an anchor, we review nonoperative management of splenic injury across inherited and acquired coagulopathy, compare coagulation-dependent and coagulation-independent embolic agents, and propose a multidisciplinary approach spanning factor replacement, agent selection, and immunoprophylaxis for this underserved population.
2026-06-01 | Effect of marstacimab in young people living with severe hemophilia A or moderate to severe hemophilia B without inhibitors: A plain language summary from the BASIS study.
What is this summary about? This summary describes a study that looked at how well the study treatment (marstacimab) works in people living with hemophilia. The summary describes how well marstacimab reduced bleeding episodes in young people (adolescents) 12 to 17 years old. Hemophilia is a condition that causes people to bleed more easily because their blood is unable to clot properly. Clotting is when blood turns from liquid into gel to stop bleeding. Hemophilia is caused by not having enough blood clotting factors, which are proteins found in the blood that help in forming a clot and stop bleeding. People living with hemophilia either don't make these proteins, have low amounts of these proteins, or their proteins do not work well. There are different types of hemophilia, depending on which clotting factor is affected. For example, people living with hemophilia A lack clotting factor 8, and people living with hemophilia B lack clotting factor 9. Some treatments for hemophilia work by replacing clotting factors. These treatments are called factor replacement therapy, and are given directly into a vein (called intravenous, or IV for short). They are given frequently, sometimes even more than once a week. In some people living with hemophilia, the body develops antibodies called inhibitors that block replacement clotting factors from working properly. Not all people living with hemophilia produce these antibodies - those who don't are classified as having hemophilia without inhibitors. A different way to treat people living with hemophilia is by using treatment called non-factor replacement therapy. One type of non-factor treatment called marstacimab is given as a regular preventive treatment (called prophylaxis). It works without replacing the missing clotting factors but brings blood clotting and bleeding back to a normal balance. Marstacimab is given once a week as a flat-dose (not based on body weight) injection under the skin (called subcutaneous) using an auto-injector device. This injection is sometimes called a shot and can be easier than injecting directly into a vein. In some cases, marstacimab can be taken less often than clotting factors. Marstacimab offers a new way to treat people living with hemophilia A or B without inhibitors. What were the results of the study? In this study, young people treated with marstacimab for 1 year had on average fewer bleeding episodes than on previous clotting factor replacement treatment. Marstacimab was well tolerated in young people (similar to adults), which means that most side effects that people had were mild to moderate and resolved by the end of the study. What do the results mean? This study showed that a once weekly injection of marstacimab could help reduce bleeding episodes in young people living with hemophilia A or B, without inhibitors.
2026-03-18 | FIXa-triggered thrombin generation correlates with FVIII levels less than 1% in reconstituted plasma mimicking samples obtained from patients with severe hemophilia A.
More than 10% of severe hemophilia A patients are paradoxically mild bleeders despite factor VIII (FVIII) levels being <1 IU/dl. Quantitation of FVIII levels <1 IU/dl is a challenge due to the detection limits of traditional one-stage activated partial thromboplastin time, two-stage chromogenic assay, and tissue factor-initiated thrombin generation assay (TF-TGA), impeding a precise characterization of the bleeding phenotype in severe hemophilia patients. The study aimed to enhance the sensitivity of TGA by modifying the trigger reagent for FVIII measurement. We optimized the fluorometric quantitation of thrombin generation triggered by factor IXa (FIXa) in artificial reconstituted plasma by blending varying proportions of normal pooled plasma (NPP) and FVIII-immunodepleted plasma containing a normal level of von Willebrand factor. FIXa-initiated thrombin generation depended on FVIII level, while TF could bypass FVIII deficiency to activate thrombin, making TF-TGA incapable of quantifying low levels of FVIII. When triggering with 0.6 nM FIXa, in the presence of 4 μM phospholipids and 40 μg/ml corn trypsin inhibitor, thrombin generation was highly dependent on FVIII levels even below 1 IU/dl. Among the five routinely used TGA parameters, peak thrombin, endogenous thrombin potential, and velocity index demonstrated the strongest linear correlation with FVIII levels down to 0.1 IU/dl. The study evaluated the performance of a modified TGA activated with FIXa. In addition to traditional TF-TGA, FIXa-TGA may provide additional information when assessing the bleeding tendency of patients with severe hemophilia A, facilitating personalized factor replacement therapy.
2026-01-01 | Evidence-based dental management strategies for individuals with congenital hemophilia: a systematic review
Abstract Background People with hemophilia commonly present with a range of bleeding symptoms, from minor oral cavity bleeds to life-threatening events such as intracranial hemorrhage. People with hemophilia often exhibit poor oral health, attributed to disease-specific barriers and a fear of dental procedures, which may exacerbate their oral disease burden. This systematic review aimed to evaluate the various dental procedures performed in patients with hemophilia and the corresponding clotting factor concentrate replacement regimens used for individuals with mild, moderate, and severe forms of the disease. Methods An electronic database search was carried out using MEDLINE by PubMed, Scopus, Google Scholar, Web of Science, ProQuest, CINAHL, EBSCO Dental collection and EMBASE databases from inception to March 2025 for studies published in English language. The search strategy terms included were “hemophilia A”, “hemophilia A”, “hemophilia B”, “hemophilia B”, “dental care”, “oral surgery”, “complications”, “bleeding”. Case control studies, randomized controlled trials, observational studies and case reports addressing the dental treatments for people with hemophilia A/hemophilia B were included. Cases of acquired hemophilia and cases of hemophilia who are inhibitor positive were excluded. Results A total of 23 studies were included for the final review. Majority of the studies have ensured to achieve 30% to 50% factor correction for dental procedures. Routine dental care procedures like restoration and dental scaling with the necessary technical specifications can be safely performed. Dental extractions can be safely performed using local infiltration anesthesia; however, administering nerve blocks typically necessitates prior administration of clotting factors due to the elevated bleeding risk. Adjuvant systemic anti-fibrinolytics like Epsilon-aminocaproic acid (EACA) and tranexamic acid greatly reduces the need for additional factor infusion. Conclusions The use of prophylactic clotting factors during dental interventions in hemophilia patients showed notable inconsistencies across studies. This inconsistency underscores the importance of conducting larger, prospective clinical studies to better understand the rationale behind clotting factor use and its effects on dental treatment outcomes in patients with varying degrees of hemophilia severity.
2025-12-12 | Mechanisms of thrombin inhibition by protein S and the TFPIα-fVshort-protein S complex
Protein S (PS) is a notable anticoagulant implicated in both bleeding and thrombotic disorders, making it a promising drug target. Importantly, PS enhances the anticoagulant function of TFPI$α$, likely circulating in the bloodstream together with TFPI$α$ and a truncated form of factor V (fVshort) in the trimolecular complex, TFPI$α$-fVshort-PS, which we call protein S complex (PSC). PSC has been proposed to strongly inhibit thrombin production by enhancing the ability of TFPI$α$ to inhibit clotting factor Xa up to 100-fold and by localizing to platelet membranes, limiting fXa activity shortly after coagulation starts. Yet, exactly how PS functions with TFPI$α$ as an anticoagulant remains poorly understood. To investigate, we extend an experimentally validated mathematical model of blood coagulation to include PSC and free PS (not part of PSC) in the plasma, as well as free PS and TFPI$α$ in platelets. We find that shortly after coagulation initiation, PSC strongly inhibits thrombin production. We find that the (unknown) magnitude of the enhanced affinity of PSC binding to inhibit fXa critically regulates PSC's impact on thrombin production. We find that under flow, PSC can unexpectedly accumulate on platelets to concentrations ~50 times higher than in the plasma. We also find that PSC limits thrombin production by occupying fV-specific binding sites on platelets. Our results show that changes in PSC can dramatically impact severity of pathological bleeding disorders. For the east Texas bleeding disorder, elevated PSC concentrations eliminate thrombin bursts, leading to bleeding. With fV deficiency, reducing PSC rescues thrombin production in severe fV deficiency and returns thrombin production due to mild fV deficiency to normal. Finally, thrombin production in severe hemophilia A can be substantially improved by blocking PSC's anticoagulant function.
antibodies
2026-09-05 | Clinical Pharmacokinetics and Pharmacodynamics of Marstacimab, an Anti-tissue Factor Pathway Inhibitor Monoclonal Antibody, in Adolescent and Adult Participants with Hemophilia.
Marstacimab, a monoclonal antibody that targets tissue factor pathway inhibitor (TFPI), was developed for prophylactic treatment of hemophilia, with or without inhibitors. A nonlinear mixed-effects modeling approach was used to characterize plasma marstacimab and TFPI concentrations and identify covariates impacting marstacimab concentration. Population modeling using nonlinear mixed-effects modeling (NONMEM) 7.5.0 software was performed with marstacimab and total TFPI concentration data pooled from 213 participants across 6 clinical trials including healthy volunteers (n = 63) and participants with hemophilia (n = 150). Participants received subcutaneous marstacimab at doses ranging from 30 mg to 450 mg. Plasma samples to determine marstacimab and total TFPI were analyzed using validated assays. An Emax pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to link model-predicted free TFPI concentrations to peak thrombin. Marstacimab and total TFPI concentrations were adequately described with a target mediated drug disposition (TMDD) model with nonlinear clearance. Body weight was the key structural covariate. After adjusting for body weight, no clinically relevant effect of age (adolescent vs adult), race (Asian vs non-Asian), participant status (healthy vs hemophilia) or mild hepatic impairment was seen. There was good agreement between observed and model-predicted peak thrombin levels in adults and adolescents, with no clinically relevant differences between the populations. A TMDD model with first-order absorption and quasi-steady-state approximation adequately characterized marstacimab PK and total TFPI concentrations. An Emax model adequately described the relationship between model-predicted free TFPI and peak thrombin. The PK/PD simulation indicated that no changes in dosing regimen based on age or body weight were warranted. ClinicalTrials.gov: NCT02531815, NCT02974855, NCT03363321, NCT03938792, NCT04832139, NCT04878731.
2026-09-01 | Concizumab for the Management of Heavy Menstrual Bleeding in a Woman with Mild Hemophilia A
Background Heavy menstrual bleeding (HMB) is a common bleeding manifestation in women with hemophilia A and may impair quality of life. Key Clinical Question Can concizumab control refractory HMB in a woman with mild hemophilia A who cannot tolerate conventional therapies? Clinical Approach An 18-year-old woman with mild hemophilia A had prolonged menstruation. Combined oral contraceptives improved bleeding but were discontinued because of mood-related adverse effects. Extended half-life factor VIII (FVIII) concentrates shortened menstruation but caused significant burden due to repeated venipuncture. Following shared decision-making, subcutaneous concizumab was initiated. During concizumab treatment, menstrual duration was generally maintained at 7–11 days per cycle. Menstrual control deteriorated after temporary concizumab dose reduction and remained inadequate despite the addition of tranexamic acid (TXA), prompting restoration of the previous concizumab dose. Subsequent concizumab concentration and D-dimer levels were within their respective target or reference ranges. Conclusions Concizumab provided menstrual bleeding control broadly comparable to intravenous FVIII replacement while reducing treatment burden. This single case does not establish concizumab as a treatment for HMB in women with mild hemophilia A, but its potential role in carefully selected patients warrants further investigation.
2026-04-16 | Expanding the Toolbox With Non-Factor Therapies.
Prophylaxis is the standard of care for people living with haemophilia (PwH) as it is able to prevent majority of bleeding episodes, including joint bleeds and life-threatening bleeds (i.e., intracranial haemorrhage). However, despite undeniable advantages, prophylaxis has limitations including need for frequent intravenous infusions and cost. Adherence to long-term treatment regimens based on multiple weekly intravenous injections of standard half-life products is challenging, and it is highly likely that injections are skipped or delayed with great impact on efficacy due to the rather rapid clearance of the drug from the body. The advent of extended half-life products allowed for greater flexibility and easier treatment personalization with the possibility to improve protection as well as to reduce number of intravenous injections. For people living with haemophilia A and inhibitors the advent of the first non-replacement therapy, emicizumab, made a turning point offering for the first time an effective prophylaxis with the additional advantage of a consistent steady state of haemostatic effect across different ages and body weights and of subcutaneous route of administration. However, during emicizumab prophylaxis breakthrough bleeds might occur due to the limited haemostatic potential which stays in the mild haemophilia range with some interindividual variability and not clearly definable FVIII equivalence. More recently the toolbox for haemophilia care has further expanded with several non-factor therapies that will offer the opportunity of effective prophylaxis to people with haemophilia B with inhibitors, subcutaneous prophylaxis for all PwH and the promise of protection in the non-haemophilia range.
2026-02-05 | NXTAGE: a phase 1/2 study of NXT007 to assess safety, pharmacokinetics, and efficacy in hemophilia A without inhibitors.
NXT007 is a next-generation, activated factor VIII (FVIIIa)-mimetic bispecific antibody under investigation in the phase 1/2 NXTAGE trial. Here, we report the primary analysis of the multiple-ascending-dose Part B study in people with hemophilia A (PwHA). Eligible participants were men with severe HA without FVIII inhibitors. Four dose cohorts (B1-B4) were planned, with NXT007 administered subcutaneously at maintenance doses of 0.072 mg/kg, 0.28 mg/kg, 0.70 mg/kg, and 1.08 mg/kg, respectively, every 4 weeks. Primary end points were safety (adverse events [AEs] and serious AEs [SAEs]), tolerability, pharmacokinetics, pharmacodynamics, and efficacy; secondary end points included incidence of anti-drug antibodies (ADAs). Participants in cohorts B1 (n = 10), B2 (n = 6), B3 (n = 6), and B4 (n = 8) had received NXT007 for a median (minimum to maximum) of 114.1 (29-140), 96.4 (88-112), 58.1 (52-72), and 22.2 (4-28) weeks, respectively. Two participants discontinued treatment: NXT007-unrelated AE (n = 1) and complete loss of NXT007 exposure due to ADAs (n = 1). Participants' plasma NXT007 concentration showed a dose-dependent increase, and predicted FVIII-equivalent activity reached a nonhemophilic level (≥40 IU/dL) in B2 onward. NXT007 had a favorable safety profile at all doses. Most AEs were mild/moderate and all 3 SAEs were considered unrelated to NXT007. Mean annualized treated bleed rates were 1.48 (B1), 0.28 (B2), 0.00 (B3), and 0.00 (B4). Two participants had pharmacokinetics-affecting NXT007 ADAs, including the B1 participant who discontinued treatment. NXTAGE Part B demonstrates that NXT007 could provide nonhemophilic coagulation activity in PwHA, with a less burdensome dose regimen than currently available therapies. This trial was registered at Japan Registry of Clinical Trials as jRCT2080224835.
2026-01-19 | Anti-emicizumab antibodies and their relevance in clinical practice.
Emicizumab is licensed for treatment of people with hemophilia A (HA) of all ages, with and without factor (F)VIII inhibitors. It is well tolerated, and most of the treatment-related adverse events are of mild intensity and transient. As for other therapeutic proteins, the potential of emicizumab to induce anti-drug antibodies (ADAs) should be considered when a decrease in treatment efficacy is observed. Data from 7 phase 3/3b pivotal studies showed that 5.1% of treated patients developed ADAs, <1% being activity neutralizing. Among them, 1 case required discontinuation of emicizumab due to loss of treatment efficacy. To date, among several thousands of patients treated with emicizumab, 5 cases of ADAs requiring treatment discontinuation have been reported. Monitoring anti-emicizumab antibodies in 67 subjects with congenital HA who switched to emicizumab prophylaxis from FVIII products or bypassing agents. The anti-emicizumab antibodies were tested, depending on patient availability, at baseline and longitudinally at 5, 10, 20, and 50 weeks after the first dose, as well as when clinically required. ADAs were detected in 4 of 67 cases (5.9%) on at least 2 occasions and were not necessarily associated to significant decreased emicizumab concentration, activated partial thromboplastin time prolongation or bleeding episodes. Only 1 of 4 ADA-positive patients required emicizumab discontinuation due to treatment failure. The present findings confirm that the development of anti-emicizumab antibodies is a rare event, particularly those with neutralizing activity. Routine monitoring should be reserved only for patients with clinical manifestations of bleeding when therapy failure is suspected.
gene therapies
2026-02-19 | Gene therapy in the treatment of hemophilia A: a systematic review and meta-analysis.
Gene therapy (GT) is an emerging one-time treatment for people with hemophilia A (PwHA). We conducted a systematic review and meta-analysis to evaluate the efficacy, effectiveness, and safety of GT versus factor VIII (FVIII) or emicizumab prophylaxis. Searches of MEDLINE/PubMed, Embase, Cochrane Library, LILACS and trial registries were run to Aug/02/2025. Eligible studies enrolled adults with severe/moderately hemophilia A treated with GT. Outcomes involved annualized bleeding rate (ABR), FVIII activity, FVIII/emicizumab consumption, annualized infusion rate, health-related quality of life (HRQoL), and adverse events. Risk of bias was assessed with MINORS. (CRD42024562798). Fourteen publications from five studies evaluated valoctocogene roxaparvovec, giroctocogene fitelparvovec, and dirloctocogene samoparvovec. GT reduced ABR [SMD -0.72 (95% CI: -0.96 to -0.48); p < 0.00001] versus FVIII prophylaxis. Mean FVIII activity rose to 8.3-67.5 IU/dL in year 1, then declined over follow-up. FVIII prophylaxis use decreased by >96% in year 4, with marked improvements HRQoL. Return to prophylaxis after GT ranged from 0%-33%. Adverse events were common but mostly mild to moderate, particularly transient liver enzyme elevations managed with corticosteroids. Risk of bias was moderate. GT offered meaningful reductions in bleeding and treatment burden in PwHA. Durability of FVIII expression and long-term safety require further investigation. This study was prospectively registered at PROSPERO (CRD42024562798).
2025-12-26 | Overview of gene therapy for hemophilia: questions and answers to navigate the innovation.
Hemophilia is a rare inherited bleeding disorder affecting approximately 1.1 million individuals worldwide, characterized by deficiency in clotting factor (F)VIII (hemophilia A) or FIX (hemophilia B). Despite advances in prophylactic factor replacement therapy and nonfactor treatments, persons with hemophilia continue to experience breakthrough bleeding, joint deterioration, and treatment burden, highlighting the need for transformative therapeutic approaches. This educational review provides a comprehensive overview of gene therapy developments for hemophilia, focusing on adenoassociated virus (AAV)-based approaches, their clinical implementation, and multidisciplinary care requirements. Gene therapy represents a paradigm shift in hemophilia treatment by addressing the underlying genetic cause through a potentially 1-time intervention. AAV-based gene therapies have demonstrated sustained factor expression in clinical trials, with persons with hemophilia, achieving factor levels in the normal or mild hemophilia range and significant reductions in bleeding rates. Recent phase III trials of valoctocogene roxaparvovec (hemophilia A) and etranacogene dezaparvovec (hemophilia B) have shown durable factor expression for up to 5 years, with the FIX-Padua variant enhancing treatment efficacy 5- to 8-fold. However, approximately 20% to 90% of persons with hemophilia experience transaminase elevation postinfusion, requiring immunosuppressive management and hepatologic monitoring. Gene therapy for hemophilia has evolved from experimental concept to clinical reality, offering sustained hemostatic protection with reduced treatment burden. While challenges remain regarding long-term durability, immune responses, and standardized care pathways, current AAV-based therapies represent a transformative advance. Future developments including alternative vectors, enhanced factor variants, and gene editing technologies promise to further improve treatment outcomes and expand patient access.
2025-08-05 | CS06 | Patient specific iPSCs-derived sinusoidal endothelial cells for phenotypic correction of haemophilia A
Background and Aims: Hemophilia A (HA) is a rare X-linked recessive bleeding disorder caused by variants in the F8 gene, which encodes coagulation factor VIII (FVIII). It affects approximately one in 6,000 males. The severity of HA is determined by the level of plasma FVIII activity and is classified as severe (<1%), moderate (1%–5%), or mild (5%–40%). In patients with HA, increasing FVIII activity to above 2–5% can significantly improve quality of life. The aim of this study was to restore FVIII levels to prevent spontaneous bleeding by correcting FVIII variants using CRISPR-Cas9 base editing in liver sinusoidal endothelial cells (LSECs), which are recognized as a key FVIII producers’ cells. Methods: Peripheral blood mononuclear cells (PBMC) from 3 HA patient and 2 healthy subjects were isolated and reprogrammed into induced pluripotent stem cells (iPSC) after transduction in a feeder-free culture with a non-integrative system with Sendai virus. The clones obtained were stabilized using an enzymatic method with EDTA and characterised for their pluripotency markers expression. Gene correction of the HA-iPSCs will be carried out using CRISPR-Cas9 DNA base editing technologies with specially target of FVIII variations. The following gene variants NM_000132.4:c.6593G>T, NM_000132.4:c.4285C>T and NM_000132.4:c.5373+ 1G>A were considered. Subsequently, HA-iPSCs will be differentiated into liver sinusoidal endothelial cells (LSECs) and hepatocyte-like cells (HLCs) using an optimized differentiation protocol involving BMP4 and VEGF and others growth factors. Specific cells markers were analysed and the expression of FVIII, LSEC and HLCS markers, were evaluated using immunofluorescence (IF) and real-time PCR (RT-qPCR). Results: Obtained iPSCs was positive for alkaline phosphatase staining and immunofluorescence showed the expression of stem cells markers (Oct4, SeV, Sox2, Klf4, KOS and cMyc). The LSECs and HLCs differentiated obtained cells were stained positive for the expression of CD31, STAB2 and LYVE1 and cytokeratin 18 respectively. Following RT-qPCR and flow cytometry analysis expression of the above markers confirmed the obtained cells phenotype. Furthermore, the expression of FVIII were assessed by IF and flow cytometry in the HA-patients obtained cells before and after gene editing and the correction was confirmed. Conclusions: In this study, we generated specific iPSCs from HA-patients carrying different F8 gene variants, derived from PBMCs. These iPSCs were then differentiated in vitro into LSECs and HLCs using optimized protocols. CRISPR-Cas9 mediated gene correction enabled us to demonstrate that specific disease-causing variants can be effectively repaired, resulting in the restoration of FVIII expression. The LSECs and HLCs obtained through these protocols represent a useful in vitro model for evaluating FVIII restoration in HA-patients with different F8 gene variants. Given the limitations of current treatments, new strategies for a definitive cure are urgently needed. Gene and cell therapies offer promising avenues and could provide a powerful, personalized therapeutic approach to optimize treatment for each individual HA-patient.
2025-07-07 | Plain language summary of 4-year results of the GENEr8-1 clinical trial of valoctocogene roxaparvovec gene therapy for hemophilia A
Plain Language SummaryWhat is this summary about?Factor VIII (‘FVIII’) is a protein important for blood clotting. Hemophilia A occurs when F8–the gene that is required to produce FVIII–is not functional, leading to excessive bleeding. Typically, people with hemophilia A use FVIII concentrate or emicizumab to prevent bleeding. Valoctocogene roxaparvovec (ROCTAVIAN) is the first approved gene therapy for hemophilia A that delivers functional copies of F8 to the liver to enable the body to produce its own FVIII and prevent excessive bleeding.What was the objective of this study?To determine whether valoctocogene roxaparvovec continues to provide people with severe hemophilia A better protection against bleeding than FVIII concentrate 4 years after treatment.What were the results?A total of 134 men with severe hemophilia A enrolled in the GENEr8-1 study and received a single infusion of valoctocogene roxaparvovec. After ending regular FVIII prophylaxis, the average number of bleeds that required treatment dropped 83%, from ∼5 bleeds per year to ∼1 bleed per year. Furthermore, 74% of participants had no bleeds requiring treatment during year 4. The average FVIII level was 16% at the end of year 4. Overall, 110 of 134 participants remain off prophylaxis. Elevated levels of the liver enzyme alanine aminotransferase (a sign of liver inflammation) occurred in 43% of participants in year 4; however, no participants required steroids to treat the elevations during year 4.What do the results mean?A single infusion of valoctocogene roxaparvovec continued to provide better protection against bleeds on average than prophylaxis with regular infusions of FVIII concentrate, and most participants remained off prophylaxis and had mild or non-hemophilia FVIII levels. The risk-benefit balance for valoctocogene roxaparvovec did not change and remains favorable.How to say (download PDF and double click sound icon to play sound)…Valoctocogene roxaparvovec: Val-octo-CO-jeen roxa-PARVO-vekProphylaxis: Pro-fi-lax-isHemophilia: Hee-muh-FIL-ee-uhAdeno-associated virus (AAV): ADD-en-o associated virus (A-A-V)Alanine aminotransferase (ALT): Al-ah-neen ah-mean-oh-trans-fear-aze (A-L-T)Emicizumab: Eh-mih-SIZ-oo-mabGene: A template made of DNA that the body uses to produce proteins.Emicizumab: An antibody that is designed to mimic the ability of FVIII to clot blood; emicizumab is an approved therapy for hemophilia A that is used for prophylaxis against bleeding.Prophylaxis: A treatment aimed at preventing an event from occurring.Participant: A person who meets the criteria to be included in a study and chooses to take part.Alanine aminotransferase (ALT): An enzyme (a type of protein) that is commonly monitored by doctors as a sign of liver inflammation.This is an abstract of the Plain Language Summary of Publication article.View the full Plain Language Summary PDF of this article to read the full-textLink to original article hereClinicalTrials.gov identifier: NCT03370913.
2024-12-24 | A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials.
Haemophilia A is an X-linked bleeding disorder resulting from a deficiency of factor VIII (FVIII). To date, multiple gene therapies have entered clinical trials with the goal of providing durable haemostatic protection from a single dose. TAK 754 (BAX 888) is an investigational AAV8-based gene therapy containing a FVIII transgene. Reduction in CpG motifs was performed to reduce immunogenicity based on prior observations. Here, we describe the results of the first two cohorts treated with TAK 754. To report clinical and translational results of the TAK-754 phase 1/2 AAV gene therapy study for the treatment of haemophilia A. A phase 1/2 single arm open-label dose escalation study of TAK-754 was performed in participants with severe haemophilia A (NCT03370172). Participants were monitored for safety events, endogenous FVIII activity and bleeding rates. Glucocorticoids were implemented to preserve transgene expression. A transcriptomics analysis was performed to evaluate immunogenicity along with additional post-hoc analyses. Four participants were dosed in two cohorts. Infusion of TAK 754 was well-tolerated. All participants developed mild transient transaminase elevation and subsequent loss of FVIII expression within the first 12 months of treatment despite use of glucocorticoids. Transcriptomic analysis did not demonstrate significant changes in immunogenicity signals in peripheral blood. One serious adverse event of hypophosphatemia occurred in the second cohort without obvious risk factors. Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow-up periods.
other
2025-08-06 | Cartilage degeneration in hemophilic arthropathy: to focus on prevention or regeneration?
One of the problems that remain unsolved in people with hemophilia (PwH) is how to regenerate articular cartilage. In this article, we have reviewed the existing information on articular cartilage regeneration in the general population and in PwH. In the general population, it has been reported that the clinical results of different types of commercial products are better than those of microfractures and that the results of products that combined microfractures and allograft products are better than those of autologous chondrocyte products. In PwH iron chelators, anti-inflammatory drugs, and anti-fibrinolytics drugs have shown beneficial effects, predominantly in preclinical studies. Hemarthrosis models have shown that mesenchymal stem cells (MSCs) intraarticular injections have some beneficial effects on cartilage structure and function. An in vitro preliminary study has highlighted the opportunity of using hemophilic chondrocytes for autologous cartilage implants in PwH. In a clinical study, bone marrow-derived cells transplantation (BMDCT) seemed to be a promising regenerative treatment for osteochondral lesions in mild ankle hemophilic arthropathy in PwH. Today it is not possible to regenerate articular cartilage. It is essential to perform primary hematologic prophylaxis throughout the life of PwH to prevent the articular cartilage from degeneration.
2025-08-05 | CO32 | Major surgery in patients with severe hemophilia A without inhibitors receiving prophylaxis with fitusiran
Background and Aims: Fitusiran is an RNA interference therapy that lowers antithrombin (AT) levels, thereby restoring hemostatic balance in patients with hemophilia A or B, regardless of inhibitor status. However, clinical experience with perioperative management of major surgery in patients receiving fitusiran is still limited. We report three major surgical procedures performed in two patients with severe hemophilia A without inhibitors, treated with fitusiran, focusing on coagulation parameters and clinical outcomes. Methods: Two adult patients with severe hemophilia A without inhibitors, enrolled in the ATLAS-OLE trial and receiving monthly prophylaxis with subcutaneous fitusiran dat a dosage of 80 mg or 20 mg every 2 months as part of an investigational therapy, underwent the following major surgical procedures: (1) Patient 1 underwent a robot-assisted sigmoidectomy with colorectal anastomosis using the Knight-Griffen technique for the treatment of sigmoid adenocarcinoma; (2) Patient 2 underwent total right knee arthroplasty, followed by (3) joint revision, arthrolysis, and patellar resurfacing. We decided not to discontinue Fitusiran treatment prior to surgery, and also chose not to administer antithrombin to normalize antithrombin levels. Perioperative prophylaxis was conducted using low-dose FVIII, 10 IU/kg/day. Perioperative monitoring included antithrombin (AT, %), hemoglobin (Hb), prothrombin time (PT), activated partial thromboplastin time (aPTT), and factor VIII (FVIII) levels. Results: The three major surgeries (two orthopedic and one abdominal) in patients with hemophilia A without inhibitors, with a mean age of 50.7 years (±17.7 years), receiving prophylaxis with fitusiran, were completed without perioperative complications. The last administration of fitusiran occurred 15, 56, and 77 days before the surgery and the antithrombin (AT) activity level on the day of surgery were 14%, 23.1%, and 21.5%, respectively. A total dose of FVIII (Beriate) ranging from 65 to 90 IU/kg was administered throughout the hospitalization. The median FVIII levels during hospitalization were 27.4%, 13.6%, and 13.4%. Hemoglobin (Hb) values showed a mild/moderate decrease at discharge, with reductions of 0.6 g/L, 0.7 g/L, and 2.1 g/L in the three cases, without signs of active bleeding (Tab 1). Excellent hemostatic control was achieved in all surgeries, with minimal blood loss, and no patient required transfusions or showed signs of significant anemia. No antithrombotic prophylaxis was administered, and no clinical signs of thrombosis were observed during the entire course of treatment. The administration times of fitusiran were maintained according to protocol in the postoperative period. Conclusions: In patients with severe hemophilia A without inhibitors undergoing fitusiran prophylaxis, major surgeries can be safely and effectively performed using low daily doses of FVIII. The use of fitusiran in this context has demonstrated its ability to provide adequate hemostasis throughout the perioperative period. It is important to emphasize that the absence of bleeding complications, the lack of significant anemia, and the absence of thrombotic events during the perioperative course further highlight the safety of this therapeutic strategy.
2023-04-01 | RNAi for the Treatment of People with Hemophilia: Current Evidence and Patient Selection
Severe hemophilia is associated with spontaneous, prolonged and recurrent bleeding.Inadequate prevention and treatment of bleeding can lead to serious morbidity and mortality.Due to the limitations of intravenous clotting factor replacement, including the risk of inhibitory antibodies, innovative novel therapies have been developed that have dramatically changed the landscape of hemophilia therapy.Ribonucleic acid interference (RNAi) has brought the opportunity for multiple strategies to manipulate the hemostatic system and ameliorate the bleeding phenotype in severe bleeding disorders.Fitusiran is a RNAi therapeutic that inhibits the expression of the natural anticoagulant serpin antithrombin.Reduction in antithrombin is known to cause thrombosis if coagulation parameters are otherwise normal and can rebalance hemostasis in severe hemophilia.Reports from late stage clinical trials of fitusiran in hemophilia A and B participants, with and without inhibitory antibodies to exogenous clotting factor, have demonstrated efficacy in preventing bleeding events showing promise for a future "universal" prophylactic treatment of individuals with moderate-severe hemophilia.
2020-09-07 | Clinical manifestation of hemophilia A in the absence of mutations in the F8 gene that encodes FVIII: role of microRNAs.
Hemophilia A (HA) is associated with mutations in the F8 gene that expresses factor VIII (FVIII). Unexpectedly, HA also manifests in a small subset of individuals with no mutations (exonic or intronic) in their F8 gene. MicroRNAs (miRNAs) cause translational interference, affecting protein quality and stoichiometry. Here, by analyzing miRNAs of two patients from this subset, we evaluated miRNA-based FVIII suppression as a testable hypothesis to explain FVIII deficiency in patients with HA with no F8 gene mutations. To test the hypothesis, miRNA sequencing from two patients with mild and moderate HA with no mutations in their F8 gene, followed by experimental verification, was used to identify a group of upregulated miRNAs in patients with HA compared to normal controls; with binding sites in the 3' untranslated region (UTR) of F8 messenger RNA (mRNA), a prerequisite for miRNA-based gene regulation. From this pool, miR-374b-5p and miR-30c-5p, known to be expressed in human liver, where FVIII is expressed, were subjected to extensive characterization. In two cell lines that constitutively express FVIII, we demonstrated that overexpression of miR-374b or miR-30c decreased FVIII expression, while an miR-30c inhibitor partially restored FVIII expression. These data support a role for microRNAs in fine-tuning F8 gene regulation. Based on our findings, our current model suggests that in HA cases where the F8 gene is normal and is predicted to express normal levels of FVIII, F8 mRNA 3' UTR targeting miRNAs may be responsible for a FVIII-deficiency phenotype clinically manifesting as HA.
2020-05-06 | Maternal microchimerism protects hemophilia A patients from inhibitor development
Key Points Deleterious F8 mutations do not necessarily lead to the incidence of inhibitors in hemophilia A patients receiving replacement therapy. Maternal chimeric cells migrated into a fetus with hemophilia A during pregnancy could induce tolerance toward FVIII.
proteins
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.
2026-09-03 | Prophylaxis in patients with moderate and mild haemophilia: experience from a single centre
Introduction: Prophylaxis in hemophilia as a gold standard of treatment was classically restricted to patients with severe forms.Objective: To evaluate the implementation of prophylaxis in patients with moderate and mild hemophilia, addressing its impact on the reduction of bleeding and quality of life.Material and methods: Nine patients were included, analyzing retrospective data 12 months before and after starting prophylaxis collected from their electronic medical records.Results: It's observed a significant reduction in annualized bleeding rate by 96.78% for hemophilia A and 91.67% for hemophilia B. Concentrates of factors VIII and IX were used with different infusion regimens.Prophylaxis improved hospital independence and decreased joint bleeding, although with a burden associated with treatment.Conclusions: The need for early follow-up and adoption of prophylaxis in non-severe patients to prevent arthropathies and improve quality of life is highlighted, in line with international recommendations.
2026-08-19 | Substitution-induced allosteric activation of coagulation factor IX as a potential alternative hemophilia A treatment strategy.
Cofactor-independent activity of FIX has previously been achieved in FIX-IDAV and FIX-FIAV variants containing L6F, V181I, E185D, K265A, and I383V substitutions. Cofactor-dependent FIX hyperactivity was attained through the V10K, R338L, and S377W (KLW) modifications. We evaluated whether combining IDAV/FIAV and KLW substitutions could enhance cofactor-independent activity and elucidated the biochemical mechanisms underlying FVIII-independent FIX-FIAV function. Recombinant FIX variants, expressed in HEK293 cells, were analyzed for FIX-specific and FVIII-equivalent clotting activities. Highly purified FIX-FIAV was characterized using purified component assays and FXIa-triggered thrombin generation in FVIII-deficient plasma. FIX-IDAV-KLW and FIX-FIAV-KLW exhibited 20-28-fold higher FIX-specific activity and a modest twofold increase in FVIII-equivalent clotting activity. Owing to thrombotic safety concerns, KLW combinations were not further pursued. FIX-FIAV displayed normal FIX-specific activity and fourfold enhanced FVIII-equivalent clotting activity. The FIAV substitutions did not alter activation by the extrinsic (TF-FVIIa) or intrinsic (FXIa) pathways, nor cofactor-dependent FX activation, but conferred FVIII-independent FX conversion. Kinetic analyses revealed a modified active site conformation with a trend toward reduced antithrombin inhibition. In FVIII-deficient plasma, FIX-FIAV dose-dependently increased FXIa-triggered thrombin generation by shortening the lag time and time to peak and shifted coagulation phenotype categories based on FVIII-equivalent thrombin generation (TG) activity from severe toward moderate/mild ranges in plasma-based models, without exceeding normal FVIII-equivalent TG activity. FIX-FIAV represents a FIX variant with FVIII-independent activity, normal FIX-specific activity, and reduced inactivation by antithrombin. Targeted modification of regions surrounding the FIXa active site enables allosteric activation, providing a potential foundation for novel bypassing strategies in hemophilia A therapy.
2026-06-17 | Innovations in Hemorrhage Management: Calcium Alginate, Celox, and Desmopressin as Next-generation Hemostatic Agents.
Hemorrhage continues to be the primary preventable cause of death, accounting for 87% of military deaths and 62% of civilian deaths. In war zones, delayed evacuation exacerbates the situation. The need for safer, more efficient substitutes is highlighted by the fact that conventional therapies, such as bone wax and vancomycin, can cause infection or systemic toxicity. Recent developments in hemostatic technologies, including biodegradable waxes, chitosan-based agents, commercial dressings, calcium alginates, pharmaceutical alternatives, and plant-derived formulations, were studied. The hemostatic performance, biocompatibility, regeneration potential, and field applicability of these studies were evaluated. Comparative studies established QuikClot Combat Gauze (QCG) as superior to Celox Rapid (CR), achieving 100% immediate hemostasis versus 70% and reducing blood loss by 162 ± 48 mL. Calcium alginates provided multifunctionality by absorbing >500% of fluid, maintaining wound hydration, and supporting tissue regeneration. Desmopressin offered systemic hemostatic effects in von Willebrand disease and mild hemophilia A, although its broader utility was limited. Despite decades of research, hemorrhage remains the leading cause of preventable death, driving innovation in biodegradable hemostatic agents and safer alternatives to traditional treatments. Traditional bone wax increases infection rates, necessitating safer alternatives. New biodegradable wax formulations show dual hemostatic and regenerative properties. Chitosanbased agents demonstrate superior biocompatibility and effectiveness. Significant strides have been made toward safer, regenerative hemostatic treatments through the development of biodegradable and biocompatible agents. However, effectively translating laboratory advancements into trauma treatment and reducing hemorrhage-related mortality requires the integration of these technologies with improved evacuation infrastructure, evidencebased adoption, and enhanced field training.
2026-05-31 | The biomarkers uCTX-II, CS846 and IGF-1 are associated with clinical and ultrasound scores in haemophilic arthropathy: a cross-sectional study.
Haemophilic arthropathy (HA) leads to progressive joint damage. Biomarkers may support early detection and monitoring of disease severity. To assess the association of cartilage and bone turnover biomarkers uCTX-II, CS846, OC, bALP, CTX-I, IGF-1, and CTSG with HA severity in severe and mild haemophilia, as evaluated by clinical and ultrasound scoring. Fifty-three adult patients with severe (n = 27) or mild (n = 26) haemophilia and 52 healthy controls were enrolled. Biomarkers were measured in serum and urine. Joints were assessed using the WFH Physical Examination and HEAD-US scores. uCTX-II was the only biomarker significantly elevated in haemophilia patients and increased progressively with disease severity (median 192.99, 243.34, and 422.88 ng/mmol in controls, mild, and severe haemophilia, respectively; p < 0.001), correlating with both clinical (rho = 0.327, p = 0.028) and HEAD-US (rho = 0.308, p = 0.040) scores in the overall haemophilia group. CS846 levels negatively correlated with clinical (rho = -0.514, p = 0.012) and HEAD-US (rho=-0.609, p = 0.002) scores in mild haemophilia. IGF-1 negatively correlated with clinical (rho=-0.621, p = 0.003) and HEAD-US (rho=-0.646, p = 0.002) scores in severe haemophilia. No significant group differences or associations were observed for OC, bALP, CTX-I, and CTSG. uCTX-II levels increased with HA severity and correlated with joint scores, suggesting its potential as a biomarker of joint damage. Negative correlations with joint scores were observed for CS846 in mild haemophilia, and for IGF-1 in severe haemophilia. CTSG and bone turnover markers showed no association with HA severity. These findings identify uCTX-II, CS846, and IGF-1 as candidate biomarkers for assessing HA severity; longitudinal studies are needed to confirm their clinical utility.
small molecules
2026-07-25 | Blunt Splenic Injury in Hemophilia A: Embolic Agent Selection When Hemostasis Cannot be Assumed.
Blunt splenic injury in a patient with hemophilia A presents a dilemma that has traditionally been settled by splenectomy. Removing the spleen leaves a patient already prone to bleeding without its immune function, and the factor VIII (FVIII) exposure that open surgery requires is itself a recognized trigger for inhibitor formation. In the general trauma population, nonoperative management is now the standard for hemodynamically stable patients: observation suffices in most, and splenic artery embolization is reserved for higher-risk injuries. Patients with inherited coagulopathy, however, sit outside the trials and guidelines that built this paradigm. We present a 66-year-old man with mild hemophilia A (FVIII activity 13%), cardiac comorbidity, and a plasma allergy who sustained a blunt splenic laceration graded as American Association for the Surgery of Trauma (AAST) Grade II. No interim computed tomography was obtained; by hospital day 3, selective angiography showed an arteriovenous fistula that had been absent at presentation, a delayed vascular complication of the original injury. Coils and particulate agents failed to achieve occlusion, whereas a 1:3 N-butyl cyanoacrylate (NBCA)-lipiodol mixture produced immediate and complete vessel sealing via coagulation-independent polymerization. Using this case as an anchor, we review nonoperative management of splenic injury across inherited and acquired coagulopathy, compare coagulation-dependent and coagulation-independent embolic agents, and propose a multidisciplinary approach spanning factor replacement, agent selection, and immunoprophylaxis for this underserved population.
2026-06-01 | Effect of marstacimab in young people living with severe hemophilia A or moderate to severe hemophilia B without inhibitors: A plain language summary from the BASIS study.
What is this summary about? This summary describes a study that looked at how well the study treatment (marstacimab) works in people living with hemophilia. The summary describes how well marstacimab reduced bleeding episodes in young people (adolescents) 12 to 17 years old. Hemophilia is a condition that causes people to bleed more easily because their blood is unable to clot properly. Clotting is when blood turns from liquid into gel to stop bleeding. Hemophilia is caused by not having enough blood clotting factors, which are proteins found in the blood that help in forming a clot and stop bleeding. People living with hemophilia either don't make these proteins, have low amounts of these proteins, or their proteins do not work well. There are different types of hemophilia, depending on which clotting factor is affected. For example, people living with hemophilia A lack clotting factor 8, and people living with hemophilia B lack clotting factor 9. Some treatments for hemophilia work by replacing clotting factors. These treatments are called factor replacement therapy, and are given directly into a vein (called intravenous, or IV for short). They are given frequently, sometimes even more than once a week. In some people living with hemophilia, the body develops antibodies called inhibitors that block replacement clotting factors from working properly. Not all people living with hemophilia produce these antibodies - those who don't are classified as having hemophilia without inhibitors. A different way to treat people living with hemophilia is by using treatment called non-factor replacement therapy. One type of non-factor treatment called marstacimab is given as a regular preventive treatment (called prophylaxis). It works without replacing the missing clotting factors but brings blood clotting and bleeding back to a normal balance. Marstacimab is given once a week as a flat-dose (not based on body weight) injection under the skin (called subcutaneous) using an auto-injector device. This injection is sometimes called a shot and can be easier than injecting directly into a vein. In some cases, marstacimab can be taken less often than clotting factors. Marstacimab offers a new way to treat people living with hemophilia A or B without inhibitors. What were the results of the study? In this study, young people treated with marstacimab for 1 year had on average fewer bleeding episodes than on previous clotting factor replacement treatment. Marstacimab was well tolerated in young people (similar to adults), which means that most side effects that people had were mild to moderate and resolved by the end of the study. What do the results mean? This study showed that a once weekly injection of marstacimab could help reduce bleeding episodes in young people living with hemophilia A or B, without inhibitors.
2026-03-18 | FIXa-triggered thrombin generation correlates with FVIII levels less than 1% in reconstituted plasma mimicking samples obtained from patients with severe hemophilia A.
More than 10% of severe hemophilia A patients are paradoxically mild bleeders despite factor VIII (FVIII) levels being <1 IU/dl. Quantitation of FVIII levels <1 IU/dl is a challenge due to the detection limits of traditional one-stage activated partial thromboplastin time, two-stage chromogenic assay, and tissue factor-initiated thrombin generation assay (TF-TGA), impeding a precise characterization of the bleeding phenotype in severe hemophilia patients. The study aimed to enhance the sensitivity of TGA by modifying the trigger reagent for FVIII measurement. We optimized the fluorometric quantitation of thrombin generation triggered by factor IXa (FIXa) in artificial reconstituted plasma by blending varying proportions of normal pooled plasma (NPP) and FVIII-immunodepleted plasma containing a normal level of von Willebrand factor. FIXa-initiated thrombin generation depended on FVIII level, while TF could bypass FVIII deficiency to activate thrombin, making TF-TGA incapable of quantifying low levels of FVIII. When triggering with 0.6 nM FIXa, in the presence of 4 μM phospholipids and 40 μg/ml corn trypsin inhibitor, thrombin generation was highly dependent on FVIII levels even below 1 IU/dl. Among the five routinely used TGA parameters, peak thrombin, endogenous thrombin potential, and velocity index demonstrated the strongest linear correlation with FVIII levels down to 0.1 IU/dl. The study evaluated the performance of a modified TGA activated with FIXa. In addition to traditional TF-TGA, FIXa-TGA may provide additional information when assessing the bleeding tendency of patients with severe hemophilia A, facilitating personalized factor replacement therapy.
2026-01-01 | Evidence-based dental management strategies for individuals with congenital hemophilia: a systematic review
Abstract Background People with hemophilia commonly present with a range of bleeding symptoms, from minor oral cavity bleeds to life-threatening events such as intracranial hemorrhage. People with hemophilia often exhibit poor oral health, attributed to disease-specific barriers and a fear of dental procedures, which may exacerbate their oral disease burden. This systematic review aimed to evaluate the various dental procedures performed in patients with hemophilia and the corresponding clotting factor concentrate replacement regimens used for individuals with mild, moderate, and severe forms of the disease. Methods An electronic database search was carried out using MEDLINE by PubMed, Scopus, Google Scholar, Web of Science, ProQuest, CINAHL, EBSCO Dental collection and EMBASE databases from inception to March 2025 for studies published in English language. The search strategy terms included were “hemophilia A”, “hemophilia A”, “hemophilia B”, “hemophilia B”, “dental care”, “oral surgery”, “complications”, “bleeding”. Case control studies, randomized controlled trials, observational studies and case reports addressing the dental treatments for people with hemophilia A/hemophilia B were included. Cases of acquired hemophilia and cases of hemophilia who are inhibitor positive were excluded. Results A total of 23 studies were included for the final review. Majority of the studies have ensured to achieve 30% to 50% factor correction for dental procedures. Routine dental care procedures like restoration and dental scaling with the necessary technical specifications can be safely performed. Dental extractions can be safely performed using local infiltration anesthesia; however, administering nerve blocks typically necessitates prior administration of clotting factors due to the elevated bleeding risk. Adjuvant systemic anti-fibrinolytics like Epsilon-aminocaproic acid (EACA) and tranexamic acid greatly reduces the need for additional factor infusion. Conclusions The use of prophylactic clotting factors during dental interventions in hemophilia patients showed notable inconsistencies across studies. This inconsistency underscores the importance of conducting larger, prospective clinical studies to better understand the rationale behind clotting factor use and its effects on dental treatment outcomes in patients with varying degrees of hemophilia severity.
2025-12-12 | Mechanisms of thrombin inhibition by protein S and the TFPIα-fVshort-protein S complex
Protein S (PS) is a notable anticoagulant implicated in both bleeding and thrombotic disorders, making it a promising drug target. Importantly, PS enhances the anticoagulant function of TFPI$α$, likely circulating in the bloodstream together with TFPI$α$ and a truncated form of factor V (fVshort) in the trimolecular complex, TFPI$α$-fVshort-PS, which we call protein S complex (PSC). PSC has been proposed to strongly inhibit thrombin production by enhancing the ability of TFPI$α$ to inhibit clotting factor Xa up to 100-fold and by localizing to platelet membranes, limiting fXa activity shortly after coagulation starts. Yet, exactly how PS functions with TFPI$α$ as an anticoagulant remains poorly understood. To investigate, we extend an experimentally validated mathematical model of blood coagulation to include PSC and free PS (not part of PSC) in the plasma, as well as free PS and TFPI$α$ in platelets. We find that shortly after coagulation initiation, PSC strongly inhibits thrombin production. We find that the (unknown) magnitude of the enhanced affinity of PSC binding to inhibit fXa critically regulates PSC's impact on thrombin production. We find that under flow, PSC can unexpectedly accumulate on platelets to concentrations ~50 times higher than in the plasma. We also find that PSC limits thrombin production by occupying fV-specific binding sites on platelets. Our results show that changes in PSC can dramatically impact severity of pathological bleeding disorders. For the east Texas bleeding disorder, elevated PSC concentrations eliminate thrombin bursts, leading to bleeding. With fV deficiency, reducing PSC rescues thrombin production in severe fV deficiency and returns thrombin production due to mild fV deficiency to normal. Finally, thrombin production in severe hemophilia A can be substantially improved by blocking PSC's anticoagulant function.
antibodies
2026-09-05 | Clinical Pharmacokinetics and Pharmacodynamics of Marstacimab, an Anti-tissue Factor Pathway Inhibitor Monoclonal Antibody, in Adolescent and Adult Participants with Hemophilia.
Marstacimab, a monoclonal antibody that targets tissue factor pathway inhibitor (TFPI), was developed for prophylactic treatment of hemophilia, with or without inhibitors. A nonlinear mixed-effects modeling approach was used to characterize plasma marstacimab and TFPI concentrations and identify covariates impacting marstacimab concentration. Population modeling using nonlinear mixed-effects modeling (NONMEM) 7.5.0 software was performed with marstacimab and total TFPI concentration data pooled from 213 participants across 6 clinical trials including healthy volunteers (n = 63) and participants with hemophilia (n = 150). Participants received subcutaneous marstacimab at doses ranging from 30 mg to 450 mg. Plasma samples to determine marstacimab and total TFPI were analyzed using validated assays. An Emax pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to link model-predicted free TFPI concentrations to peak thrombin. Marstacimab and total TFPI concentrations were adequately described with a target mediated drug disposition (TMDD) model with nonlinear clearance. Body weight was the key structural covariate. After adjusting for body weight, no clinically relevant effect of age (adolescent vs adult), race (Asian vs non-Asian), participant status (healthy vs hemophilia) or mild hepatic impairment was seen. There was good agreement between observed and model-predicted peak thrombin levels in adults and adolescents, with no clinically relevant differences between the populations. A TMDD model with first-order absorption and quasi-steady-state approximation adequately characterized marstacimab PK and total TFPI concentrations. An Emax model adequately described the relationship between model-predicted free TFPI and peak thrombin. The PK/PD simulation indicated that no changes in dosing regimen based on age or body weight were warranted. ClinicalTrials.gov: NCT02531815, NCT02974855, NCT03363321, NCT03938792, NCT04832139, NCT04878731.
2026-09-01 | Concizumab for the Management of Heavy Menstrual Bleeding in a Woman with Mild Hemophilia A
Background Heavy menstrual bleeding (HMB) is a common bleeding manifestation in women with hemophilia A and may impair quality of life. Key Clinical Question Can concizumab control refractory HMB in a woman with mild hemophilia A who cannot tolerate conventional therapies? Clinical Approach An 18-year-old woman with mild hemophilia A had prolonged menstruation. Combined oral contraceptives improved bleeding but were discontinued because of mood-related adverse effects. Extended half-life factor VIII (FVIII) concentrates shortened menstruation but caused significant burden due to repeated venipuncture. Following shared decision-making, subcutaneous concizumab was initiated. During concizumab treatment, menstrual duration was generally maintained at 7–11 days per cycle. Menstrual control deteriorated after temporary concizumab dose reduction and remained inadequate despite the addition of tranexamic acid (TXA), prompting restoration of the previous concizumab dose. Subsequent concizumab concentration and D-dimer levels were within their respective target or reference ranges. Conclusions Concizumab provided menstrual bleeding control broadly comparable to intravenous FVIII replacement while reducing treatment burden. This single case does not establish concizumab as a treatment for HMB in women with mild hemophilia A, but its potential role in carefully selected patients warrants further investigation.
2026-04-16 | Expanding the Toolbox With Non-Factor Therapies.
Prophylaxis is the standard of care for people living with haemophilia (PwH) as it is able to prevent majority of bleeding episodes, including joint bleeds and life-threatening bleeds (i.e., intracranial haemorrhage). However, despite undeniable advantages, prophylaxis has limitations including need for frequent intravenous infusions and cost. Adherence to long-term treatment regimens based on multiple weekly intravenous injections of standard half-life products is challenging, and it is highly likely that injections are skipped or delayed with great impact on efficacy due to the rather rapid clearance of the drug from the body. The advent of extended half-life products allowed for greater flexibility and easier treatment personalization with the possibility to improve protection as well as to reduce number of intravenous injections. For people living with haemophilia A and inhibitors the advent of the first non-replacement therapy, emicizumab, made a turning point offering for the first time an effective prophylaxis with the additional advantage of a consistent steady state of haemostatic effect across different ages and body weights and of subcutaneous route of administration. However, during emicizumab prophylaxis breakthrough bleeds might occur due to the limited haemostatic potential which stays in the mild haemophilia range with some interindividual variability and not clearly definable FVIII equivalence. More recently the toolbox for haemophilia care has further expanded with several non-factor therapies that will offer the opportunity of effective prophylaxis to people with haemophilia B with inhibitors, subcutaneous prophylaxis for all PwH and the promise of protection in the non-haemophilia range.
2026-02-05 | NXTAGE: a phase 1/2 study of NXT007 to assess safety, pharmacokinetics, and efficacy in hemophilia A without inhibitors.
NXT007 is a next-generation, activated factor VIII (FVIIIa)-mimetic bispecific antibody under investigation in the phase 1/2 NXTAGE trial. Here, we report the primary analysis of the multiple-ascending-dose Part B study in people with hemophilia A (PwHA). Eligible participants were men with severe HA without FVIII inhibitors. Four dose cohorts (B1-B4) were planned, with NXT007 administered subcutaneously at maintenance doses of 0.072 mg/kg, 0.28 mg/kg, 0.70 mg/kg, and 1.08 mg/kg, respectively, every 4 weeks. Primary end points were safety (adverse events [AEs] and serious AEs [SAEs]), tolerability, pharmacokinetics, pharmacodynamics, and efficacy; secondary end points included incidence of anti-drug antibodies (ADAs). Participants in cohorts B1 (n = 10), B2 (n = 6), B3 (n = 6), and B4 (n = 8) had received NXT007 for a median (minimum to maximum) of 114.1 (29-140), 96.4 (88-112), 58.1 (52-72), and 22.2 (4-28) weeks, respectively. Two participants discontinued treatment: NXT007-unrelated AE (n = 1) and complete loss of NXT007 exposure due to ADAs (n = 1). Participants' plasma NXT007 concentration showed a dose-dependent increase, and predicted FVIII-equivalent activity reached a nonhemophilic level (≥40 IU/dL) in B2 onward. NXT007 had a favorable safety profile at all doses. Most AEs were mild/moderate and all 3 SAEs were considered unrelated to NXT007. Mean annualized treated bleed rates were 1.48 (B1), 0.28 (B2), 0.00 (B3), and 0.00 (B4). Two participants had pharmacokinetics-affecting NXT007 ADAs, including the B1 participant who discontinued treatment. NXTAGE Part B demonstrates that NXT007 could provide nonhemophilic coagulation activity in PwHA, with a less burdensome dose regimen than currently available therapies. This trial was registered at Japan Registry of Clinical Trials as jRCT2080224835.
2026-01-19 | Anti-emicizumab antibodies and their relevance in clinical practice.
Emicizumab is licensed for treatment of people with hemophilia A (HA) of all ages, with and without factor (F)VIII inhibitors. It is well tolerated, and most of the treatment-related adverse events are of mild intensity and transient. As for other therapeutic proteins, the potential of emicizumab to induce anti-drug antibodies (ADAs) should be considered when a decrease in treatment efficacy is observed. Data from 7 phase 3/3b pivotal studies showed that 5.1% of treated patients developed ADAs, <1% being activity neutralizing. Among them, 1 case required discontinuation of emicizumab due to loss of treatment efficacy. To date, among several thousands of patients treated with emicizumab, 5 cases of ADAs requiring treatment discontinuation have been reported. Monitoring anti-emicizumab antibodies in 67 subjects with congenital HA who switched to emicizumab prophylaxis from FVIII products or bypassing agents. The anti-emicizumab antibodies were tested, depending on patient availability, at baseline and longitudinally at 5, 10, 20, and 50 weeks after the first dose, as well as when clinically required. ADAs were detected in 4 of 67 cases (5.9%) on at least 2 occasions and were not necessarily associated to significant decreased emicizumab concentration, activated partial thromboplastin time prolongation or bleeding episodes. Only 1 of 4 ADA-positive patients required emicizumab discontinuation due to treatment failure. The present findings confirm that the development of anti-emicizumab antibodies is a rare event, particularly those with neutralizing activity. Routine monitoring should be reserved only for patients with clinical manifestations of bleeding when therapy failure is suspected.
gene therapies
2026-02-19 | Gene therapy in the treatment of hemophilia A: a systematic review and meta-analysis.
Gene therapy (GT) is an emerging one-time treatment for people with hemophilia A (PwHA). We conducted a systematic review and meta-analysis to evaluate the efficacy, effectiveness, and safety of GT versus factor VIII (FVIII) or emicizumab prophylaxis. Searches of MEDLINE/PubMed, Embase, Cochrane Library, LILACS and trial registries were run to Aug/02/2025. Eligible studies enrolled adults with severe/moderately hemophilia A treated with GT. Outcomes involved annualized bleeding rate (ABR), FVIII activity, FVIII/emicizumab consumption, annualized infusion rate, health-related quality of life (HRQoL), and adverse events. Risk of bias was assessed with MINORS. (CRD42024562798). Fourteen publications from five studies evaluated valoctocogene roxaparvovec, giroctocogene fitelparvovec, and dirloctocogene samoparvovec. GT reduced ABR [SMD -0.72 (95% CI: -0.96 to -0.48); p < 0.00001] versus FVIII prophylaxis. Mean FVIII activity rose to 8.3-67.5 IU/dL in year 1, then declined over follow-up. FVIII prophylaxis use decreased by >96% in year 4, with marked improvements HRQoL. Return to prophylaxis after GT ranged from 0%-33%. Adverse events were common but mostly mild to moderate, particularly transient liver enzyme elevations managed with corticosteroids. Risk of bias was moderate. GT offered meaningful reductions in bleeding and treatment burden in PwHA. Durability of FVIII expression and long-term safety require further investigation. This study was prospectively registered at PROSPERO (CRD42024562798).
2025-12-26 | Overview of gene therapy for hemophilia: questions and answers to navigate the innovation.
Hemophilia is a rare inherited bleeding disorder affecting approximately 1.1 million individuals worldwide, characterized by deficiency in clotting factor (F)VIII (hemophilia A) or FIX (hemophilia B). Despite advances in prophylactic factor replacement therapy and nonfactor treatments, persons with hemophilia continue to experience breakthrough bleeding, joint deterioration, and treatment burden, highlighting the need for transformative therapeutic approaches. This educational review provides a comprehensive overview of gene therapy developments for hemophilia, focusing on adenoassociated virus (AAV)-based approaches, their clinical implementation, and multidisciplinary care requirements. Gene therapy represents a paradigm shift in hemophilia treatment by addressing the underlying genetic cause through a potentially 1-time intervention. AAV-based gene therapies have demonstrated sustained factor expression in clinical trials, with persons with hemophilia, achieving factor levels in the normal or mild hemophilia range and significant reductions in bleeding rates. Recent phase III trials of valoctocogene roxaparvovec (hemophilia A) and etranacogene dezaparvovec (hemophilia B) have shown durable factor expression for up to 5 years, with the FIX-Padua variant enhancing treatment efficacy 5- to 8-fold. However, approximately 20% to 90% of persons with hemophilia experience transaminase elevation postinfusion, requiring immunosuppressive management and hepatologic monitoring. Gene therapy for hemophilia has evolved from experimental concept to clinical reality, offering sustained hemostatic protection with reduced treatment burden. While challenges remain regarding long-term durability, immune responses, and standardized care pathways, current AAV-based therapies represent a transformative advance. Future developments including alternative vectors, enhanced factor variants, and gene editing technologies promise to further improve treatment outcomes and expand patient access.
2025-08-05 | CS06 | Patient specific iPSCs-derived sinusoidal endothelial cells for phenotypic correction of haemophilia A
Background and Aims: Hemophilia A (HA) is a rare X-linked recessive bleeding disorder caused by variants in the F8 gene, which encodes coagulation factor VIII (FVIII). It affects approximately one in 6,000 males. The severity of HA is determined by the level of plasma FVIII activity and is classified as severe (<1%), moderate (1%–5%), or mild (5%–40%). In patients with HA, increasing FVIII activity to above 2–5% can significantly improve quality of life. The aim of this study was to restore FVIII levels to prevent spontaneous bleeding by correcting FVIII variants using CRISPR-Cas9 base editing in liver sinusoidal endothelial cells (LSECs), which are recognized as a key FVIII producers’ cells. Methods: Peripheral blood mononuclear cells (PBMC) from 3 HA patient and 2 healthy subjects were isolated and reprogrammed into induced pluripotent stem cells (iPSC) after transduction in a feeder-free culture with a non-integrative system with Sendai virus. The clones obtained were stabilized using an enzymatic method with EDTA and characterised for their pluripotency markers expression. Gene correction of the HA-iPSCs will be carried out using CRISPR-Cas9 DNA base editing technologies with specially target of FVIII variations. The following gene variants NM_000132.4:c.6593G>T, NM_000132.4:c.4285C>T and NM_000132.4:c.5373+ 1G>A were considered. Subsequently, HA-iPSCs will be differentiated into liver sinusoidal endothelial cells (LSECs) and hepatocyte-like cells (HLCs) using an optimized differentiation protocol involving BMP4 and VEGF and others growth factors. Specific cells markers were analysed and the expression of FVIII, LSEC and HLCS markers, were evaluated using immunofluorescence (IF) and real-time PCR (RT-qPCR). Results: Obtained iPSCs was positive for alkaline phosphatase staining and immunofluorescence showed the expression of stem cells markers (Oct4, SeV, Sox2, Klf4, KOS and cMyc). The LSECs and HLCs differentiated obtained cells were stained positive for the expression of CD31, STAB2 and LYVE1 and cytokeratin 18 respectively. Following RT-qPCR and flow cytometry analysis expression of the above markers confirmed the obtained cells phenotype. Furthermore, the expression of FVIII were assessed by IF and flow cytometry in the HA-patients obtained cells before and after gene editing and the correction was confirmed. Conclusions: In this study, we generated specific iPSCs from HA-patients carrying different F8 gene variants, derived from PBMCs. These iPSCs were then differentiated in vitro into LSECs and HLCs using optimized protocols. CRISPR-Cas9 mediated gene correction enabled us to demonstrate that specific disease-causing variants can be effectively repaired, resulting in the restoration of FVIII expression. The LSECs and HLCs obtained through these protocols represent a useful in vitro model for evaluating FVIII restoration in HA-patients with different F8 gene variants. Given the limitations of current treatments, new strategies for a definitive cure are urgently needed. Gene and cell therapies offer promising avenues and could provide a powerful, personalized therapeutic approach to optimize treatment for each individual HA-patient.
2025-07-07 | Plain language summary of 4-year results of the GENEr8-1 clinical trial of valoctocogene roxaparvovec gene therapy for hemophilia A
Plain Language SummaryWhat is this summary about?Factor VIII (‘FVIII’) is a protein important for blood clotting. Hemophilia A occurs when F8–the gene that is required to produce FVIII–is not functional, leading to excessive bleeding. Typically, people with hemophilia A use FVIII concentrate or emicizumab to prevent bleeding. Valoctocogene roxaparvovec (ROCTAVIAN) is the first approved gene therapy for hemophilia A that delivers functional copies of F8 to the liver to enable the body to produce its own FVIII and prevent excessive bleeding.What was the objective of this study?To determine whether valoctocogene roxaparvovec continues to provide people with severe hemophilia A better protection against bleeding than FVIII concentrate 4 years after treatment.What were the results?A total of 134 men with severe hemophilia A enrolled in the GENEr8-1 study and received a single infusion of valoctocogene roxaparvovec. After ending regular FVIII prophylaxis, the average number of bleeds that required treatment dropped 83%, from ∼5 bleeds per year to ∼1 bleed per year. Furthermore, 74% of participants had no bleeds requiring treatment during year 4. The average FVIII level was 16% at the end of year 4. Overall, 110 of 134 participants remain off prophylaxis. Elevated levels of the liver enzyme alanine aminotransferase (a sign of liver inflammation) occurred in 43% of participants in year 4; however, no participants required steroids to treat the elevations during year 4.What do the results mean?A single infusion of valoctocogene roxaparvovec continued to provide better protection against bleeds on average than prophylaxis with regular infusions of FVIII concentrate, and most participants remained off prophylaxis and had mild or non-hemophilia FVIII levels. The risk-benefit balance for valoctocogene roxaparvovec did not change and remains favorable.How to say (download PDF and double click sound icon to play sound)…Valoctocogene roxaparvovec: Val-octo-CO-jeen roxa-PARVO-vekProphylaxis: Pro-fi-lax-isHemophilia: Hee-muh-FIL-ee-uhAdeno-associated virus (AAV): ADD-en-o associated virus (A-A-V)Alanine aminotransferase (ALT): Al-ah-neen ah-mean-oh-trans-fear-aze (A-L-T)Emicizumab: Eh-mih-SIZ-oo-mabGene: A template made of DNA that the body uses to produce proteins.Emicizumab: An antibody that is designed to mimic the ability of FVIII to clot blood; emicizumab is an approved therapy for hemophilia A that is used for prophylaxis against bleeding.Prophylaxis: A treatment aimed at preventing an event from occurring.Participant: A person who meets the criteria to be included in a study and chooses to take part.Alanine aminotransferase (ALT): An enzyme (a type of protein) that is commonly monitored by doctors as a sign of liver inflammation.This is an abstract of the Plain Language Summary of Publication article.View the full Plain Language Summary PDF of this article to read the full-textLink to original article hereClinicalTrials.gov identifier: NCT03370913.
2024-12-24 | A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials.
Haemophilia A is an X-linked bleeding disorder resulting from a deficiency of factor VIII (FVIII). To date, multiple gene therapies have entered clinical trials with the goal of providing durable haemostatic protection from a single dose. TAK 754 (BAX 888) is an investigational AAV8-based gene therapy containing a FVIII transgene. Reduction in CpG motifs was performed to reduce immunogenicity based on prior observations. Here, we describe the results of the first two cohorts treated with TAK 754. To report clinical and translational results of the TAK-754 phase 1/2 AAV gene therapy study for the treatment of haemophilia A. A phase 1/2 single arm open-label dose escalation study of TAK-754 was performed in participants with severe haemophilia A (NCT03370172). Participants were monitored for safety events, endogenous FVIII activity and bleeding rates. Glucocorticoids were implemented to preserve transgene expression. A transcriptomics analysis was performed to evaluate immunogenicity along with additional post-hoc analyses. Four participants were dosed in two cohorts. Infusion of TAK 754 was well-tolerated. All participants developed mild transient transaminase elevation and subsequent loss of FVIII expression within the first 12 months of treatment despite use of glucocorticoids. Transcriptomic analysis did not demonstrate significant changes in immunogenicity signals in peripheral blood. One serious adverse event of hypophosphatemia occurred in the second cohort without obvious risk factors. Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow-up periods.
other
2025-08-06 | Cartilage degeneration in hemophilic arthropathy: to focus on prevention or regeneration?
One of the problems that remain unsolved in people with hemophilia (PwH) is how to regenerate articular cartilage. In this article, we have reviewed the existing information on articular cartilage regeneration in the general population and in PwH. In the general population, it has been reported that the clinical results of different types of commercial products are better than those of microfractures and that the results of products that combined microfractures and allograft products are better than those of autologous chondrocyte products. In PwH iron chelators, anti-inflammatory drugs, and anti-fibrinolytics drugs have shown beneficial effects, predominantly in preclinical studies. Hemarthrosis models have shown that mesenchymal stem cells (MSCs) intraarticular injections have some beneficial effects on cartilage structure and function. An in vitro preliminary study has highlighted the opportunity of using hemophilic chondrocytes for autologous cartilage implants in PwH. In a clinical study, bone marrow-derived cells transplantation (BMDCT) seemed to be a promising regenerative treatment for osteochondral lesions in mild ankle hemophilic arthropathy in PwH. Today it is not possible to regenerate articular cartilage. It is essential to perform primary hematologic prophylaxis throughout the life of PwH to prevent the articular cartilage from degeneration.
2025-08-05 | CO32 | Major surgery in patients with severe hemophilia A without inhibitors receiving prophylaxis with fitusiran
Background and Aims: Fitusiran is an RNA interference therapy that lowers antithrombin (AT) levels, thereby restoring hemostatic balance in patients with hemophilia A or B, regardless of inhibitor status. However, clinical experience with perioperative management of major surgery in patients receiving fitusiran is still limited. We report three major surgical procedures performed in two patients with severe hemophilia A without inhibitors, treated with fitusiran, focusing on coagulation parameters and clinical outcomes. Methods: Two adult patients with severe hemophilia A without inhibitors, enrolled in the ATLAS-OLE trial and receiving monthly prophylaxis with subcutaneous fitusiran dat a dosage of 80 mg or 20 mg every 2 months as part of an investigational therapy, underwent the following major surgical procedures: (1) Patient 1 underwent a robot-assisted sigmoidectomy with colorectal anastomosis using the Knight-Griffen technique for the treatment of sigmoid adenocarcinoma; (2) Patient 2 underwent total right knee arthroplasty, followed by (3) joint revision, arthrolysis, and patellar resurfacing. We decided not to discontinue Fitusiran treatment prior to surgery, and also chose not to administer antithrombin to normalize antithrombin levels. Perioperative prophylaxis was conducted using low-dose FVIII, 10 IU/kg/day. Perioperative monitoring included antithrombin (AT, %), hemoglobin (Hb), prothrombin time (PT), activated partial thromboplastin time (aPTT), and factor VIII (FVIII) levels. Results: The three major surgeries (two orthopedic and one abdominal) in patients with hemophilia A without inhibitors, with a mean age of 50.7 years (±17.7 years), receiving prophylaxis with fitusiran, were completed without perioperative complications. The last administration of fitusiran occurred 15, 56, and 77 days before the surgery and the antithrombin (AT) activity level on the day of surgery were 14%, 23.1%, and 21.5%, respectively. A total dose of FVIII (Beriate) ranging from 65 to 90 IU/kg was administered throughout the hospitalization. The median FVIII levels during hospitalization were 27.4%, 13.6%, and 13.4%. Hemoglobin (Hb) values showed a mild/moderate decrease at discharge, with reductions of 0.6 g/L, 0.7 g/L, and 2.1 g/L in the three cases, without signs of active bleeding (Tab 1). Excellent hemostatic control was achieved in all surgeries, with minimal blood loss, and no patient required transfusions or showed signs of significant anemia. No antithrombotic prophylaxis was administered, and no clinical signs of thrombosis were observed during the entire course of treatment. The administration times of fitusiran were maintained according to protocol in the postoperative period. Conclusions: In patients with severe hemophilia A without inhibitors undergoing fitusiran prophylaxis, major surgeries can be safely and effectively performed using low daily doses of FVIII. The use of fitusiran in this context has demonstrated its ability to provide adequate hemostasis throughout the perioperative period. It is important to emphasize that the absence of bleeding complications, the lack of significant anemia, and the absence of thrombotic events during the perioperative course further highlight the safety of this therapeutic strategy.
2023-04-01 | RNAi for the Treatment of People with Hemophilia: Current Evidence and Patient Selection
Severe hemophilia is associated with spontaneous, prolonged and recurrent bleeding.Inadequate prevention and treatment of bleeding can lead to serious morbidity and mortality.Due to the limitations of intravenous clotting factor replacement, including the risk of inhibitory antibodies, innovative novel therapies have been developed that have dramatically changed the landscape of hemophilia therapy.Ribonucleic acid interference (RNAi) has brought the opportunity for multiple strategies to manipulate the hemostatic system and ameliorate the bleeding phenotype in severe bleeding disorders.Fitusiran is a RNAi therapeutic that inhibits the expression of the natural anticoagulant serpin antithrombin.Reduction in antithrombin is known to cause thrombosis if coagulation parameters are otherwise normal and can rebalance hemostasis in severe hemophilia.Reports from late stage clinical trials of fitusiran in hemophilia A and B participants, with and without inhibitory antibodies to exogenous clotting factor, have demonstrated efficacy in preventing bleeding events showing promise for a future "universal" prophylactic treatment of individuals with moderate-severe hemophilia.
2020-09-07 | Clinical manifestation of hemophilia A in the absence of mutations in the F8 gene that encodes FVIII: role of microRNAs.
Hemophilia A (HA) is associated with mutations in the F8 gene that expresses factor VIII (FVIII). Unexpectedly, HA also manifests in a small subset of individuals with no mutations (exonic or intronic) in their F8 gene. MicroRNAs (miRNAs) cause translational interference, affecting protein quality and stoichiometry. Here, by analyzing miRNAs of two patients from this subset, we evaluated miRNA-based FVIII suppression as a testable hypothesis to explain FVIII deficiency in patients with HA with no F8 gene mutations. To test the hypothesis, miRNA sequencing from two patients with mild and moderate HA with no mutations in their F8 gene, followed by experimental verification, was used to identify a group of upregulated miRNAs in patients with HA compared to normal controls; with binding sites in the 3' untranslated region (UTR) of F8 messenger RNA (mRNA), a prerequisite for miRNA-based gene regulation. From this pool, miR-374b-5p and miR-30c-5p, known to be expressed in human liver, where FVIII is expressed, were subjected to extensive characterization. In two cell lines that constitutively express FVIII, we demonstrated that overexpression of miR-374b or miR-30c decreased FVIII expression, while an miR-30c inhibitor partially restored FVIII expression. These data support a role for microRNAs in fine-tuning F8 gene regulation. Based on our findings, our current model suggests that in HA cases where the F8 gene is normal and is predicted to express normal levels of FVIII, F8 mRNA 3' UTR targeting miRNAs may be responsible for a FVIII-deficiency phenotype clinically manifesting as HA.
2020-05-06 | Maternal microchimerism protects hemophilia A patients from inhibitor development
Key Points Deleterious F8 mutations do not necessarily lead to the incidence of inhibitors in hemophilia A patients receiving replacement therapy. Maternal chimeric cells migrated into a fetus with hemophilia A during pregnancy could induce tolerance toward FVIII.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.