proteins

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.

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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.

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2026-08-14 | Current State of Moderate Congenital Haemophilia A and the Need for Preventive Treatment.

The severity of haemophilia A is classified by the degree of factor VIII (FVIII) deficiency, rather than by clinical manifestations. However, FVIII activity alone does not necessarily accurately reflect clinical severity such as bleeding tendency, and patients with mild-to-moderate haemophilia A can experience significant disease burden. This narrative review explores the clinical relevance of non-severe haemophilia A (focusing on moderate disease), and examines the profile of patients with, and the evidence supporting the use of prophylaxis to manage, this disease form. A PubMed search was conducted (no language/date limits), using terms including 'hemophilia' or 'haemophilia', and 'moderate', 'nonsevere' or 'non-severe', with the names of prophylactic agents. Some patients with moderate haemophilia A experience significant disease burden (in terms of bleeding frequency and joint damage), diminished health-related quality of life and marked economic impact. In addition, variation in bleeding phenotype across disease severity levels has been recognised, such that patients with moderate disease may have a severe phenotype and experience more frequent spontaneous bleeds than those with a mild phenotype. Few studies have specifically assessed outcomes associated with prophylaxis in patients with moderate haemophilia A. However, available data suggest that prophylaxis with FVIII concentrates and non-factor treatments (i.e. emicizumab) provides beneficial effects in terms of bleeding frequency and joint health. Severity classification alone is insufficient to predict bleeding tendency, and joint bleeding and joint injury are observed in patients with moderate disease. As such, routine prophylaxis may be recommended for some patients with moderate haemophilia A.

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2026-07-22 | A case report of the coagulation management of an adult with moderate haemophilia A undergoing transcatheter aortic valve implantation.

Haemophilia A is an X-linked bleeding disorder resulting from factor VIII deficiency. While surgical management requires the correction of factor VIII levels by the administration of factor VIII concentrate, antiplatelet therapy after lower-risk cardiac surgery/procedures (such as transcatheter aortic valve implantation-TAVI) is not yet standardized. This report describes the management of a patient with moderate haemophilia A undergoing TAVI for severe aortic stenosis. A 76-year-old man with untreated haemophilia A was admitted with traumatic bleeding. After initial stabilization, he developed acute heart failure due to newly discovered severe aortic stenosis. TAVI procedure was performed by transfemoral access according to multidisciplinary team-discussion; a bio-prosthetic valve was successfully implanted. We outline the peri-procedural haemostatic management, which included factor VIII replacement therapy to achieve guideline-recommended activity levels, followed by progressive dose reduction. In view of the high bleeding risk and absence of significant coronary artery disease, antiplatelet therapy was limited to a short course. The procedure was successful, with no bleeding complications. In our patient, replacement therapy with rFVIII was initiated with a target FVIII activity between 80 and 100 IU/dL. During the procedure, unfractionated heparin was administered to achieve an ACT target 29 of 200 s. Post-operatively, FVIII replacement therapy was maintained above 60 IU/dL for the first 30-72 h, followed by 40-50 IU/dL from day 4 to day 7. Subsequently, it was decided to continue low-dose FVIII replacement for 32 additional 7 days. This strategy led to a successful management of both cardiological and hematological aspects. Although evidence is limited to case reports, TAVI appears to be feasible and safe in patients with haemophilia A. Maintaining high factor VIII activity levels and minimizing antithrombotic exposure through multidisciplinary evaluation can effectively reduce haemorrhagic risk. Our case, in line with previous reports, resulted in no bleeding complications.

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2026-06-26 | Enhancing Hemophilia Care: Real-World Outcomes Following Switching to Extended Half-Life Factor VIII in Greece-The TOOL Study.

Introduction: Extended half-life (EHL) factor VIII (FVIII) products aim to reduce treatment burden and improve bleeding control in hemophilia A. Real-world evidence remains essential to complement clinical trials. Aim: To evaluate clinical outcomes following switching from standard half-life (SHL) rFVIII to efmoroctocog alfa in routine clinical practice in Greece. Methods: Multicenter observational pre-poststudy including patients with moderate to severe hemophilia A. Outcomes were assessed during the 12 months before and after switching. The primary endpoint was change in annualized bleeding rate (ABR). Secondary endpoints included annualized joint bleeding rate (AjBR), infusion frequency, joint health, pain, and FVIII consumption. Results: Sixty patients were included. Following switching, ABR decreased from 6.8 to 3.2 (53%), and AjBR from 6.4 to 2.9 (55%), p < 0.001. Reductions were more pronounced in patients switching from on-demand treatment, while more modest improvements were observed among patients already on prophylaxis. HJHS significantly decreased from 17.9 to 11.5 (p < 0.007), accompanied by a decrease in pain scores (p < 0.001), in available paired subsets. Weekly infusion frequency decreased (3.2 to 2.2; p < 0.001), while mean dose per infusion increased, resulting in no consistent reduction in total annual FVIII consumption. No inhibitor or treatment-related adverse events have been observed. Conclusions: Switching to efmoroctocog alfa in routine practice was associated with improved bleeding outcomes, reduced infusion frequency, and better joint-related parameters. These findings support the real world feasibility and clinical utility οf EHL FVIII therapy, while further controlled studies are needed to better define the independent effect of product switching from changes in treatment regimen and other potential confounders.

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small molecules

2026-09-19 | The outcome of chemical synovectomy with Rifampicin in chronic hemophilic synovitis: The Syrian experience.

Chronic arthropathy is the most common complication of moderate to severe hemophilia. Chemical synovectomy with Rifampicin offers a cost-effective alternative to radioactive synovectomy, especially in resource-limited settings like Syria. A retrospective study was conducted at the Syrian Hemophilia Society (2020-2024), involving 50 patients (69 target joints) with hemophilic synovitis. Outcomes were assessed using the Hemophilia Joint Health Score visual analogue scale (VAS) for pain, range of motion (ROM), Arnold-Hilgartner classification, and annual bleeding rate,pre- and post-intervention. Participants were predominantly young (mean age 18.99 ± 6.51 years), with hemophilia A (80%). A significant delay was noted between target joint onset and intervention (mean 40.30 months). The knees were most affected (72%), with moderate joint involvement (Arnold-Hilgartner Class II-III). Regional disparities emerged: Damascus patients showed better outcomes (HJHS: 2.33 vs 7.04; VAS: 1.11 vs 3.27, P < .001). Most patients improved significantly (P < .05), except those with mild phenotypes (no HJHS/VAS improvement), ankle involvement (no ROM improvement), and Arnold score 0 (no ROM improvement). Findings underscored inequities in care access across regions. Rifampicin-based chemical synovectomy is a viable, accessible treatment for hemophilic synovitis in low-resource settings. It led to significant improvements in pain, bleeding episodes, joint health, and mobility. However, regional healthcare disparities and delayed interventions remain key challenges affecting outcomes.

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2026-02-01 | Hepatocyte-Targeted Immunosuppression With Budesonide Supports Long-Term Transgene Expression After AAV Gene Therapy in Hemophilia

Introduction Hemophilia is an inherited bleeding disorder caused by deficiency of clotting factor VIII (FVIII) or IX (FIX). Gene therapy using adeno-associated viral (AAV) vectors enables sustained endogenous production of these factors but may trigger immune-mediated liver inflammation, leading to elevated ALT levels and reduced transgene expression [ 1 ]. Systemic corticosteroids such as prednisone are commonly used for management but pose risks of metabolic and skeletal side effects. Budesonide offers a liver-targeted alternative, effectively controlling hepatic immune reactions while minimizing systemic toxicity, potentially stabilizing transgene expression and improving long-term safety and efficacy [ 2 ]. Method Patient 1, a 44-year-old male with severe hemophilia A, received a single infusion of valoctocogene roxaparvovec at a dose of 6×10¹³ vector genomes/kg. Patient 2, a 40-year-old male with severe hemophilia B, was administered a single intravenous dose of fidanacogene elaparvovec at 5×10¹¹ vector genomes/kg. Follow-up evaluations included monitoring of FVIII/FIX activity levels, liver function parameters, and management of immunosuppressive therapy. Results Both infusions were completed without complications, and no immediate adverse reactions were observed. Patient 1 developed elevated ALT levels five weeks post-treatment, accompanied by reduced FVIII expression. Oral prednisone was initiated, but ALT levels further increased. Intravenous methylprednisolone induced a rapid ALT decline, after which corticosteroid therapy continued with oral prednisone. To mitigate side effects, budesonide was introduced during prednisone tapering and continued for six months. Chromogenic FVIII activity peaked at 202 IU/dL at month 6 and stabilized at 50–70 IU/dL at year 6. Patient 2 exhibited a moderate increase in ALT levels five weeks after infusion, while FIX expression remained stable at 30 IU/dL. Following initiation of prednisone, ALT levels normalized, and tapering was completed by week 20. Between weeks 20 and 24, FIX activity declined despite stable ALT levels. Corticosteroid therapy with budesonide was then initiated, resulting in stabilization of FIX activity between 10 and 20 IU/dL. During long-term follow-up—6 years for Patient 1 and 4 years for Patient 2—both patients maintained stable clotting factor activity without bleeding episodes or the need for FVIII/FIX replacement therapy. Conclusion Gene therapy for hemophilia A and B enables durable and clinically significant clotting factor activity. These cases offer valuable insights into personalized immunosuppressive management strategies that support long-term efficacy and safety. Moreover, budesonide proved to be an effective hepatocyte-targeted alternative to systemic corticosteroids, promoting sustained gene expression and enhancing the overall safety profile. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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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.

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2025-11-03 | Joint injury induces a robust proinflammatory cytokine response in hemophilia A mice: Implications for immune-mediated arthropathy

Abstract Background: Hemophilic arthropathy, driven by repeated joint bleeds and unresolved inflammation, remains a major complication in patients with hemophilia A. Although the mechanical and hemostatic contributors are well recognized, the immunological responses following joint injury in the context of FVIII deficiency are poorly characterized. Objective: To define the systemic inflammatory cytokine profile triggered by joint injury in a murine model of hemophilia A. Methods: Plasma samples were collected from FVIII-deficient (F8-/-) mice 72 hours after needle-induced knee joint injury (n = 4) and from uninjured naïve F8-/- controls (n = 6). Cytokine profiling was performed using a 32-plex mouse cytokine array, and statistical analysis was carried out with unpaired t-tests or the Mann-Whitney U-test if the data did not pass the normality test. Results: Joint injury triggered a complex proinflammatory response, with several cytokines showing highly significant increases compared to naïve controls. The elevated cytokines were categorized into three groups: 1) The strongest upregulation (P &lt; 0.001) was observed in IL-9 (65.96 ± 10.65 pg/mL vs. 16.29 ± 10.15 pg/mL) and IL-17 (4.61 ± 1.63 pg/mL vs. 0.35 ± 0.23 pg/mL), key mediators of Th2 and Th17 inflammation, respectively, indicating robust T-cell–mediated immune activation. 2) Moderate increases (P &lt; 0.01) included TNF-α (75.57 ± 18.07 pg/mL vs. 3.01 ± 2.09 pg/mL), a central driver of synovial inflammation and joint destruction; LIF (0.72 ± 0.21 pg/mL vs. 0.19 ± 0.18 pg/mL), a cytokine involved in tissue remodeling and chronic inflammation; and MIP-1β (CCL4) (270.9 ± 187.4 pg/mL vs. 13.73 ± 16.92 pg/mL), which recruits monocytes and macrophages to inflammation sites. 3) Mild yet significant increases (P &lt; 0.05) were seen in IL-10 (32.74 ± 20.44 pg/mL vs. 8.08 ± 6.31 pg/mL), an anti-inflammatory cytokine potentially reflecting a compensatory regulatory response; IL-12p70 (41.52 ± 20.15 pg/mL vs. 4.88 ± 5.24 pg/mL), a cytokine that promotes Th1 responses; IP-10 (CXCL10) (234.2 ± 213.4 pg/mL vs. 48.66 ± 33.72 pg/mL), and MIG (CXCL9) (24.91 ± 4.02 pg/mL vs. 17.00 ± 4.73 pg/mL), both involved in T-cell trafficking; and MIP-2 (CXCL2) (236.3 ± 166.5 pg/mL vs. 22.31 ± 34.71 pg/mL), a neutrophil chemoattractant involved in acute joint inflammation. Conversely, IL-13—a Th2 cytokine with anti-inflammatory and tissue repair roles—was significantly decreased (10.59 ± 3.12 pg/mL vs. 31.68 ± 20.43 pg/mL), indicating a shift away from regulatory Th2 responses. No significant differences were observed in the remaining cytokines assessed. Conclusion: These results reveal that joint injury in hemophilia A mice induces a hierarchically structured proinflammatory cytokine cascade, with marked Th17, Th1, and chemokine responses, and suppression of regulatory Th2 signals. The prominence of IL-17, TNF-α, and MIP-1β suggests key mediators driving hemophilic joint inflammation and provides rationale for targeting these pathways in efforts to mitigate arthropathy. Moreover, the suppression of IL-13 may contribute to the persistence of inflammation and impaired resolution. Together, these findings highlight potential biomarkers and therapeutic targets in hemophilia-related joint disease.

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2025-04-30 | Cell-Based Small-Molecule Screening Identifying Proteostasis Regulators Enhancing Factor VIII Missense Mutant Secretion.

Missense mutations are the most prevalent alterations in genetic disorders such as hemophilia A (HA), which results from coagulation factor VIII (FVIII) deficiencies. These mutations disrupt protein biosynthesis, folding, secretion, and function. Current treatments for HA are extremely expensive and inconvenient for patients. Small molecule drugs offer a promising alternative or adjunctive strategy due to their lower cost and ease of administration, enhancing accessibility and patient compliance. By screening drug/chemical libraries with cells stably expressing FVIII-Gaussia luciferase fusion proteins, we identified compounds that enhance FVIII secretion and activity. Among these, suberoylanilide hydroxamic acid (SAHA) improved the secretion and activity of wild-type FVIII and common HA-associated missense mutants, especially mild and moderate ones. SAHA increased FVIII interaction with the endoplasmic reticulum chaperone BiP/GRP78 but not with calreticulin. Lowering cellular BiP levels decreased SAHA-induced FVIII secretion and enhancing BiP expression increased FVIII secretion. SAHA also enhanced secretion and BiP interactions with individual domains of FVIII. In vivo, treating mice with SAHA or a BiP activator boosted endogenous FVIII activity. These findings suggest that SAHA serves as a proteostasis regulator, providing a novel therapeutic approach to improve the secretion and functionality of FVIII missense mutants prone to misfolding.

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gene therapies

2026-03-24 | Estimating the Impact of Hemophilia A Treatment Administration on Patient Health Utility: Combining a Discrete Choice Experiment with Time Trade-Off Method.

Preferences between treatment characteristics can be understood and quantified by combining discrete choice experiment (DCE) and time trade-off (TTO) (DCETTO) methods. The goal is to elicit preferences for people with hemophilia A (PWHA) and quantify impacts of treatment attribute changes on patient health utility with DCETTO. A total of 119 PWHA from a hemophilia treatment center and the National Bleeding Disorders Foundation Community Voices in Research were recruited. Their sociodemographics, clinical characteristics, and EQ-5D-5L scores were gathered. Treatment attributes for the DCE survey were based on the core outcome set for hemophilia gene therapy (coreHEM). For DCETTO, 10-, 15-, and 20-year life durations were used. In total 115 PWHA completed 12 DCE and DCETTO tasks, which were analyzed using conditional logistic models. Moderately burdensome treatment (24% treat > once/week) was reported by 67%. Mean EQ-5D-5L visual analogue score was 75; mean utility score was 0.684. All DCE attributes were significant; treatment administration was most important (2-3 intravenous [IV] infusions/week vs. a single IV infusion with 10-year durability, regression coefficient [RC], - 1.99), followed by mental health (always vs. no concern, RC, - 1.37), annual bleeding frequency (≥ 5 vs. none, RC, - 0.73), and chronic pain (yes vs. no, RC, - 0.36). For DCETTO, multiple IV infusions weekly and multiple monthly subcutaneous (SQ) injections were associated with annualized utility decrements (0.046 vs. 10-year durability, 0.044 vs. 5-year; 0.037 vs. 10-year, 0.030 vs. 5-year, respectively). All coreHEM outcomes are important for treatment choices of PWHA. One-time IV infusion with 5- to 10-year durability can provide important patient utility gains over lifelong repeated SQ injections or IV infusions.

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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).

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2025-11-01 | HTRS2025.O8C.4 Efficacy and Safety of Giroctocogene Fitelparvovec in Adults With Moderately Severe to Severe Hemophilia A: Results From the Phase 3 AFFINE Gene Therapy Trial

Background: The effectiveness of damoctocog alfa pegol for the prevention and treatment of bleeding in previously treated children with severe hemophilia A was demonstrated in the PROTECT VIII Kids trial (NCT01775618).Children aged < 12 years were excluded from damoctocog alfa pegol's initial marketing authorization application because of observed loss of efficacy and/or hypersensitivity reactions occurring within the first 4 exposure days (EDs) in some children aged < 6 years due to an immune response to PEG.These responses were not seen in children aged 7 years.Objectives: To evaluate the risk of hypersensitivity and loss of efficacy associated with anti-PEG antibodies during the first 4 EDs with damoctocog alfa pegol in children aged 7 to < 12 years.Methods: The phase 3, multicenter, open-label, single-arm Alfa-PROTECT study (NCT05147662) comprised a 6-month main study (completed) with 50 EDs, and an 18 month extension (ongoing).In the main study, patients received 40 IU/kg (up to 60 IU/kg at the investigator's discretion) of damoctocog alfa pegol prophylaxis, twice weekly.The primary endpoint (estimated by a Bayesian model including prior information from PRO-TECT VIII Kids) was the incidence of adverse events of special interest (AESI) -hypersensitivity or loss of efficacy -leading to discontinuation during the first 4 EDs.Secondary endpoints included adverse reactions, development of anti-drug antibodies, annualized bleeding rate, and utilization.Results: In total, 35 patients (safety analysis set [SAF]) received at least 1 dose of study drug.The median (range) treatment duration was 182 (7-198) days with a median of 53 (1-59) EDs.Median age at baseline was 8 years (Table 1).Of the SAF, 32 had documented bleed and utilization data for 3 months (Table 2) and 31 had 50 damoctocog alfa pegol EDs.In the SAF, 21/35 patients (60%) experienced 1 adverse event (AE), all mild or moderate, and 3/35 patients (9%) had AEs related to the study drug.Study-drug-related AEs of injection site pain or injection site itch of moderate intensity occurred in 2 patients, not leading to treatment disruption.Loss of efficacy at Day 12, due to high-titer anti-PEG antibodies (after 2nd ED), leading to treatment interruption occurred in one patient; this was considered a study-drug-related AESI.Antibodies disappeared and patient resumed treatment 2 months later.Mean and median of the posterior distribution of the true incidence of AESI were 2.1% and 1.59%, respectively (90% CI [0.18; 5.76%]).No AEs resulted in study drug discontinuation, no deaths were reported.Mean (SD) number of bleeds in the 12 months before screening was 3.25 (5.6), and during the study the mean (SD) annualized number of treated bleeds was 1.3 (2.7).Conclusions: These data confirm the safety profile of damoctocog alfa pegol in children aged 7 to < 12 years with severe hemophilia A, and secondary endpoints indicate effectiveness of treatment in this population.

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2025-08-04 | CRISPR-Cas9 Mediated Gene Editing in Inherited Hematologic Disorders

The CRISPR-Cas9 system has proved to be one of the most powerful gene-editing tools that have massive therapeutic potentials on inherited hematologic disorders. Such disorders as the β-thalassemia, sickle cell disease, hemophilia A and B, and Fanconi anemia are majorly monogenic, and therefore, the best targets of genetic correction per se. This paper only has concentrations on pre-clinical testing on animals in order to analyse the usage, effectiveness, and safety of CRISPR-Cas9 therapies. Data translated in mice, dog, and non-human primate models showed great edit efficiencies (between 42% and 65%) that were associated with improvements of hematologic functions, development of haemoglobin and replenishment of clotting factors. Requiring minimal to moderate off-target effects were both found to be dependent upon delivery systems and genetic targets. The research demonstrates the feasibility of the CRISPR-Cas9 to treat disease-causing mutations in vivo and the need of animal studies with long-term follow-ups to go further towards clinic applications. Results emphasize the worth of animal model in filling the gap between laboratory study and human gene therapy on blood conditions.

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2025-05-19 | Prevalence and Clinical Correlation of Intron 22 Inversion in Hemophilia A in Northeast India.

Hemophilia A is an X-linked bleeding disorder caused by mutations in the F8 gene, with intron 22 inversion being the most common genetic alteration in severe cases. This study aimed to determine the prevalence of intron 22 inversion in hemophilia A patients in Assam, Northeast India, and evaluate its correlation with disease severity. This hospital-based observational study included 80 hemophilia A patients at Assam Medical College from March 2023 to February 2024. Clinical history, coagulation tests (activated partial thromboplastin time (APTT), prothrombin time (PT), and factor VIII assay), and nested long-distance polymerase chain reaction (NLD-PCR) for intron 22 inversion detection were performed. Statistical analysis was conducted using SPSS v25 (IBM Corp., Armonk, New York, USA). Among the 80 patients, 41 (51.25%) had severe hemophilia A, 22 (27.5%) moderate, and 17 (21.25%) mild. Intron 22 inversion was detected in 24 patients (30%), with a significantly higher prevalence in severe cases 22/41 (53.65%) compared to moderate 2/22 (9.09%) and mild cases (0%) (p < 0.001). APTT was significantly prolonged in severe cases (109.35 ± 15.62 sec) compared to moderate (86.92 ± 9.87 sec) and mild cases (61.71 ± 8.94 sec) (p < 0.001), reinforcing the genetic basis of disease severity. This study confirms a strong correlation between intron 22 inversion and severe hemophilia A, consistent with global and Indian studies. It emphasizes the need for routine genetic screening for early diagnosis and personalized treatment strategies, including genetic counseling. Future research should explore other F8 mutations, gene therapy, and the role of intron 22 inversion in inhibitor development.

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antibodies

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.

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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.

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2026-05-20 | When and How to Start Prophylaxis in Children with Hemophilia.

Hemophilia A and B are X-linked inherited bleeding disorders resulting from factor VIII or IX deficiency and are associated with substantial morbidity beginning in early childhood. Recurrent musculoskeletal bleeding can lead to hemophilic arthropathy and long-term disability. Intracranial hemorrhage, especially in early infancy, remains a life-threatening complication with high risks of mortality and neurological sequelae. As treatment decisions in early life decisively influence lifetime outcomes, the optimal timing and mode of prophylaxis are central aspects of pediatric hemophilia care. This review summarizes the current evidence and expert opinions regarding the initiation of prophylaxis in children with hemophilia, focusing on early diagnosis, perinatal management, the timing of and indications for prophylaxis, therapeutic options, inhibitor development, and psychosocial aspects. Prophylaxis is recommended as early as possible in children with severe hemophilia and in those with moderate disease and a severe bleeding phenotype, ideally before the first joint bleed, to prevent future bleeds and microbleeds and to therefore preserve joint health. The choice of therapy (nonfactor replacement therapy, factor concentrate) should be individualized on the basis of the type and severity of hemophilia, patient age, venous access, risk of inhibitor development, clinical presentation, and family circumstances. For hemophilia A, the early use of nonfactor therapy (emicizumab) in newborns and toddlers represents an efficacious and safe therapeutic option. Data on FVIII inhibitor development in children on nonfactor prophylaxis with infrequent exposure to FVIII are still lacking. In the course of life with improved venous access, switching to FVIII prophylaxis may be beneficial in cases of bleeding despite prophylaxis with nonfactor therapy in daily life or based on parental choice. The psychosocial impact on patients and their families, especially related to treatment burden and venous access, highlights the need for shared decision-making and multidisciplinary care. Early individualized prophylaxis is the cornerstone of modern pediatric hemophilia management. For children with hemophilia, prompt initiation after diagnosis, tailored therapeutic approaches, and close interdisciplinary support are essential for preventing life-threatening bleeding, preserving musculoskeletal and neurodevelopmental health, and ensuring a normal quality of life and participation in daily activities.

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2026-05-11 | Management of breakthrough bleeds and surgical procedures in participants with hemophilia A or B without inhibitors receiving marstacimab prophylaxis in the phase 3 BASIS study.

Marstacimab, a subcutaneous antitissue factor pathway inhibitor monoclonal antibody, has demonstrated efficacy in reducing treated bleeds in severe hemophilia A or moderately severe to severe hemophilia B without inhibitors in the phase 3 BASIS study. Evidence guiding management of breakthrough bleeds and perioperative hemostasis during marstacimab prophylaxis remains limited. Describe the frequency, treatment, and outcomes of breakthrough bleeds and surgical/medical procedures in participants without inhibitors receiving marstacimab prophylaxis. After the 6-month observation phase, participants received a 300 mg marstacimab loading dose followed by 150 mg once-weekly in a 12-month active treatment phase (ATP). Bleed incidence, factor replacement therapy (FRT) use, and perioperative management were analyzed descriptively due to the small sample size and event distribution RESULTS: Of 116 participants in the ATP, 75 (64.7%) experienced 453 acute breakthrough bleeds and were treated with FRT; 83% were controlled with a single infusion, most often standard half-life recombinant or plasma-derived factor VIII/IX. Thirteen participants underwent 15 procedures (8 dental and 7 other), with marstacimab continued in 86.7% and FRT used in 13 of 15 (86.7%). No thromboembolic events occurred during ATP. Breakthrough bleeds were generally controlled with standard FRT, with most requiring only 1 infusion. Perioperative management of minor procedures was feasible without interruption of marstacimab, with FRT use comparable with other nonfactor prophylactic agents. Data on major surgery are lacking due to study exclusions, and conclusions should be restricted to minor and dental procedures. Further studies are needed to define perioperative protocols for higher-risk interventions.

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2026-05-08 | Marstacimab for People with Severe Hemophilia A or Moderate to Severe Hemophilia B Without Inhibitors: A Plain Language Summary of Publication of the BASIS Study.

What is this summary about? This is a summary of the results from a clinical study of treatment for people with severe hemophilia A or moderately severe to severe hemophilia B without inhibitors. Because severe hemophilia A and B predominantly affect men and boys, this study only included men and boys aged 12 to 74 years. The study was published in Blood. People with hemophilia either have low amounts of clotting factors or are missing certain clotting factors in their blood. There are medicines that people with hemophilia can take to replace the missing clotting factor. These medicines must be injected into a vein and are usually given more than once a week. Marstacimab is an antibody that works by attaching to a protein in the blood called tissue factor pathway inhibitor (or TFPI). TFPI works separately from clotting factors. Marstacimab helps the balance between blood flowing freely and clotting. Marstacimab is given by a simple injection under the skin (not in a vein or muscle) and can be taken less often than clotting factors. Marstacimab may offer a new way to help people with hemophilia. What were the results of the study? The study showed that men with hemophilia had fewer treated bleed events during 1 year with marstacimab treatment compared to previous factor replacement therapy. The researchers reported that marstacimab was safe and most side effects were mild to moderate. What do the results mean? These studies showed that marstacimab could help prevent bleeding in men with hemophilia A or B, without inhibitors.

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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.

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2024-07-12 | Kinetic Modeling for BT200 to Predict the Level of Plasma-Derived Coagulation Factor VIII in Humans.

Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.

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2023-10-01 | PB0635 A Usability Study Assessing Handling and Preference of the Concizumab Pen-Injector in Patients with Haemophilia and Caregivers

screening period of approximately 60 days, a 6-month standard of care period in which participants continue their prior CFC/BPA regimen, and a 36-month treatment period where participants receive fitusiran prophylaxis, beginning with a dose of 50 mg once every two months (Q2M; Figure).To target AT activity levels of 15-35%, possible fitusiran dose adjustments include 20 mg Q2M or QM; 50 mg Q2M or QM and 80 mg QM.The primary objective is to characterize the frequency of treated bleeding episodes with fitusiran prophylaxis.Key secondary objectives evaluate the efficacy of fitusiran prophylaxis versus prophylaxis or on-demand SoC.The primary endpoint is ABR during the 12-month primary efficacy period from Month 6 to Month 18; secondary endpoints are listed in the Table.

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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.

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2021-11-25 | Generation of induced pluripotent stem cell, BCHSCTi001-A, derived from a Hemophilia A patient with F8 (p. R391C) mutation.

F8 is the defective gene of Hemophilia A (HA). The F8 genotype correlates well with the clinical phenotype in most cases. However, phenotypic variation has been found in some rare cases with patients who have the same genotype. In this study, we generatedinduced pluripotent stem cells (iPSCs) from a Hemophilia A patient with F8 (p. R391C) mutation. The clinical phenotype of this patient is moderate, compared to the more severe phenotypes found in other patients. This iPSCs line could be used as a valuable diseased cell model for gene therapy and will facilitate future mechanism research.

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