proteins

2026-08-27 | Physiologically Based Pharmacokinetic (PBPK) Modeling of FIX in Pediatric Hemophilia B: Extravascular Distribution and Dosing Optimization.

Background: Prophylaxis in children with hemophilia B (HB) lacks quantitative approaches that integrate both plasma exposure and tissue distribution. This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model of factor IX (FIX) for pediatric HB. The model incorporated the binding of FIX to type IV collagen (Col4) to characterize its distribution in both plasma and extravascular tissues. Methods: A total of 20 children with severe HB were included, contributing 219 plasma samples. The base PBPK model was first established and verified using adult and plasma-derived FIX (pdFIX) data. It was subsequently extrapolated to children by integrating FIX-CTBB parameters and pediatric observations for model calibration. The validated model was used to characterize plasma pharmacokinetics, predict tissue distribution and target attainment, and simulate alternative prophylactic dosing regimens. Results: The model adequately described the plasma pharmacokinetics of FIX in children and predicted substantial extravascular distribution. Total extravascular exposure was approximately sixfold higher than plasma exposure. Marked heterogeneity in target attainment was identified across tissues. Lower target attainment was observed in the colon, pancreas, and brain, whereas delayed attainment occurred in bone and muscle. Simulations of prophylactic dosing regimens suggested that 75 IU/kg twice weekly may provide a favorable balance among sustained FIX exposure, tissue-level target attainment, and treatment burden. Conclusions: This PBPK model provides a mechanistic and quantitative framework for characterizing plasma and tissue exposure to FIX in children with HB and may support individualized optimization of FIX prophylactic dosing.

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2026-07-23 | Haemodialysis in haemophilia B: a case report. Challenges and strategies from a nephrology perspective.

Haemophilia B, the result of factor IX deficiency, is a complex clinical condition that is particularly challenging when associated with kidney failure. This is primarily due to the high bleeding risk associated with kidney replacement therapies. The increase in life expectancy in haemophilia patients has resulted in a greater prevalence of age-related comorbidities, including chronic kidney disease. Nevertheless, a consensus has yet to be reached regarding the most suitable dialysis modality for this population. In this report, we present a case study of a 68-year-old male patient suffering from severe haemophilia B, who was administered prophylactic Idelvion® (albutrepenonacog alfa) and subsequently underwent arteriovenous fistula creation and haemodialysis initiation without encountering any bleeding complications. This narrative review, from the perspective of a nephrologist, addresses the epidemiology and main clinical considerations regarding dialysis in haemophilia B. These considerations include the choice between haemodialysis and peritoneal dialysis, vascular access planning, haemostasis management with factor IX replacement, and anticoagulation strategies aimed at minimising bleeding risk. A review of the extant literature and clinical reports published between 2020 and 2025 was conducted, integrating documented experiences and available guideline recommendations. In addition, we put forward a series of pragmatic recommendations that are -underpinned by a systematic decision-making framework. Through meticulous multidisciplinary planning incorporating the utilisation of factor IX concentrates, meticulous surgical techniques, and tailored anticoagulation protocols, patients with haemophilia B can be deemed eligible for chronic haemodialysis with a reasonable degree of safety.

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2026-07-07 | Real-World Outcomes of Prophylaxis With rIX-FP in Germany: A Prospective, Non-Interventional Study in Haemophilia B.

Efficacy and safety of albutrepenonacog alfa (rIX-FP) in people with haemophilia B (PwHB) has been previously demonstrated in clinical trials. However, real-world data insights are required. To describe real-world effectiveness and tolerability of rIX-FP in PwHB in Germany. Prospective, non-interventional study conducted across 19 sites in Germany. Patients of any age treated with rIX-FP were enrolled between March 2018 and February 2024. Patients were monitored every 3-12 months and followed-up for 3 years or until ≥100 exposure days. To our knowledge, this is the largest study of factor replacement therapy in PwHB in Germany to date. Of the patients who completed the study (63/73), most (80.8%) had moderate or severe haemophilia B. The mean (standard deviation) duration of observation was 30.5 (8.32) months. For any prophylaxis regimen, the median (range) annualised bleeding rate (ABR) was 0.89 (0.0-9.6) and annualised spontaneous bleeding rate (AsBR) was 0.08 (0.0-5.2). The median ABR was 1.12, 0.68 and 0.13, and the median AsBR was 0.17, 0.00 and 0.06 for those treated with a 7-, 10- or 14-day regimen, respectively. Investigators rated the overall haemostatic effectiveness as 'good' or 'excellent' in 94% of cases (based on the worst assessment). Overall, 82 adverse events in 34 patients were reported, none were considered related to rIX-FP. This multicentre, non-interventional study in Germany demonstrates that rIX-FP prophylaxis is effective and well tolerated in PwHB of all ages in routine clinical practice and reinforces the results of the clinical trials.

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2026-06-23 | Nonacog Beta Pegol (N9-Gp) Prophylaxis in Pediatric Patients with Severe Hemophilia B: A Single Center Real World Experience.

Hemophilia B (Christmas disease) is a rare genetic bleeding disorder. Frequent FIX prophylaxis is challenging in pediatric patients because of difficult venous access and pain during factor administration. Nonacog beta pegol (N9-GP) is an extended half-life (EHL) recombinant FIX. The study assessed the efficacy of Nonacog beta pegol (N9-GP) in reducing bleeding episodes and its safety as prophylaxis in pediatric patients. The primary end-point was reduction in Annual bleeding rates (ABR) and Annual Joint bleeding rates (AJBR). The secondary objectives were to assess the days of school absenteeism, number of emergency visits, measurement of Hemophilia Joint Health Score (HJHS) 2.1 score, pediatric Hemophilia Activities List (pedHAL) score, development of inhibitor against FIX during treatment, and safety & adverse effects (AEs) profile. Ten pediatric patients managed with on-demand SHL FIX were included in the study. Their median age at study entry was 3 years (range, 1-13 years). The median duration of follow-up was 12 months (range, 6-60 months). They were subsequently started on N9-GP prophylaxis, and the mean duration of follow-up was 24 months (range, 11-30 months). There was a significant reduction in ABR (p-value, 0.002), AJBR (p-value, 0.022), and improvement in HJHS, pedHAL score, and reduction in school absenteeism in these children. Four patients experienced bleeding, which required treatment. Two patients developed an inhibitor to N9-GP. Mild adverse effects were noted in 20% of the patients. N9-GP prophylaxis compared to PD/r FIX replacement is a safe and effective strategy in prevention of bleeds, improving QOL and reducing joint related disability in pediatric patients with Hemophilia B.

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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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small molecules

2026-09-07 | Catheter salvage with antibiotic lock therapy for central venous port infection due to Pseudoxanthomonas sp. in a child with hemophilia B.

Catheter-related bloodstream infections (CRBSIs) generally necessitate prompt catheter removal, which poses significant hemorrhagic risks in patients with hemophilia. Consequently, catheter salvage utilizing antibiotic lock therapy (ALT) serves as a critical adjunctive strategy. We describe an exceptionally rare case of CRBSI caused by Pseudoxanthomonas sp., an environmental Gram-negative bacillus, and its successful management. A 4-year-old boy with severe hemophilia B developed persistent bacteremia originating from an implanted central venous access port. The pathogen was identified as Pseudoxanthomonas sp. utilizing matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA gene sequencing. Catheter removal was deemed high-risk due to the patient's underlying hemophilia B and associated risk of major bleeding. Therefore, a catheter salvage strategy was pursued through a combination of systemic antimicrobial therapy and ALT. The patient received systemic antibiotics, adapting through piperacillin/tazobactam, ceftazidime, and trimethoprim-sulfamethoxazole. ALT was administered concurrently, initially using a ceftazidime-heparin lock solution, and later transitioning to a ciprofloxacin-heparin lock following an episode of suspected drug fever. Despite initial persistent bacteremia, this dual approach effectively eradicated the intraluminal infection. The central venous port was successfully retained with no recurrence observed over four months post-therapy. Systemic antimicrobial therapy combined with ALT can be an effective catheter-preserving strategy for high-risk patients with device-related infections caused by rare environmental non-fermenting Gram-negative organisms such as Pseudoxanthomonas sp.

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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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2026-01-31 | Evidence-based dental management strategies for individuals with congenital hemophilia: a systematic review.

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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2026-01-20 | Screening chemical libraries for the development of oral treatments in bleeding disorders

• A high-throughput screening of 2300 chemical compounds allowed to identify adapalene as a procoagulant on severe hemophilia A plasma. • The mechanism of action of adapalene involves Factor XII activation. Hemophilia is a rare bleeding disorder due to Factor VIII (FVIII) or Factor IX (FIX) deficiency respectively involved in hemophilia A (HA) or B (HB). Treatment has long relied on invasive intravenous infusions of the missing factor for prophylaxis or bleeding treatments. Despite significant progress in patient care, there is still no oral procoagulant drug available for hemophiliacs. Such an oral procoagulant could benefit to other inherited and acquired bleeding disorders, as well as anticoagulants-induced bleedings. To find chemical compounds that could become potential future orally-administered procoagulants, we designed a hierarchical high-throughput screening protocol combining two successive screening filters: a miniaturized fibrin formation assay, followed by a thrombin generation assay, both on severe HA plasma. We screened three chemical collections totalizing more than 2300 chemical compounds; we identified adapalene, a commercialized anti-acneic compound (Differin®) which is strongly hydrophobic. In order to design a drug that could be orally administered, we developed a series of chemical analogs of adapalene, and three of them, with similar procoagulant activities in FVIII deficient plasma, showed improved solubilities. The mechanism of action was thoroughly investigated by a series of thrombin generation and enzymatic assays. These studies allow to conclude that the procoagulant activity of the chemical compounds in FVIII-deficient plasma is due to the activation of Factor XII.

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2026-01-13 | Ischemic stroke in severe hemophilia B: a rare presentation

Hemophilia B, a rare X-linked bleeding disorder caused by factor IX deficiency, predisposes patients to hemorrhages. Thromboembolic events like ischemic stroke are uncommon due to impaired coagulation, but cardiovascular risk factors may increase thrombotic risk, challenging the expected clinical profile. Case report: A 42-year-old male with severe hemophilia B, diabetes mellitus, obesity, and hypertension, previously independent (mRS 1), presented to the emergency department with sudden dysarthria, left hemiparesis, and moderate left hypoesthesia 2 h post-factor IX infusion. His history included a remote ischemic stroke (1 year prior, fully recovered) and traumatic subarachnoid hemorrhage with subdural hematoma. On admission, NIHSS was 10. Angio-computed tomography (CT) revealed right M1 middle cerebral artery occlusion with distal reperfusion and an ASPECTS of 8. Thrombolysis was contraindicated due to prior intracranial bleeding. Mechanical thrombectomy achieved complete recanalization (TICI 3), with no bleeding on control CT. Etiological workup showed carotid and basilar atherosclerosis on angio-CT, sinus rhythm on ECG, and a normal echocardiogram, suggesting atherothrombotic etiology. At discharge, NIHSS was 12, reflecting persistent hemiparesis, dysarthria, and new-onset aphasia. Clopidogrel, statin, and factor IX were prescribed after hematology consultation, balancing thrombotic and bleeding risks. Conclusion: This case highlights ischemic stroke as a rare complication in hemophilia B, likely driven by atherosclerosis and cardiovascular comorbidities rather than cardioembolism. It underscores the need for tailored risk assessment and management in hemophiliacs, with further studies needed to optimize antithrombotic strategies.

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antibodies

2026-08-01 | Bridging The Gap Between Traditional Factor Replacement Therapy and Novel Non-Factor Replacement Therapy in Hemophilia

Hemophilia, which means “love” (philia) of blood (hem), is the most common severe hereditary hemorrhagic disease. Hemophilia A and B are congenital bleeding disorders caused by an absence or complete lack of coagulation factor VIII (FVIII) or factor IX (FIX), respectively.[1] It can be recognized by the prolonged and heavy bleeding that occurs after minor trauma and occasionally on its own. Hemophilia is more common in men than in women (1 in 10,000 for men and 1 in 100,000,000 for women) [3]. Hemophilia was once called as “the royal disease” [4]. Arthropathy is a frequent result of hemophilia, mainly arising from ongoing bleeding in the elbows, knees, and ankles caused by the lack of coagulation factors [6].When a joint experiences repeated episode of bleeding (known as a target joint), it undergoes chronic alterations [7]. The 1964 finding by Judith Pool that the cryoprecipitate obtained from plasma had high concentrations of FVIII marked a significant advancement in the treatment of hemophilia[4]. The most significant and challenging problem with managing hemophilia is the development of inhibitors, which makes it hard to implement safe and efficient standards of care, especially in prophylaxis [2]. innovative methods of action that aimed to imitate coagulation factor VIII or restore thrombin production. New non-replacement therapies are being tested in clinical trials to reduce the treatment burden for patients with hemophilia A or B, regardless of the presence of inhibitors, in addition to the bispecific monoclonal antibody emicizumab, which is already approved for patients with severe hemophilia A both with and without inhibitors. These treatments have the potential to provide effective bleeding prevention, improve patient adherence, and improve the general health-related quality of life for hemophiliacs due to their distinct mechanisms and subcutaneous delivery [46].

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2026-08-01 | Subcutaneous MG1113 in severe hemophilia A&B: Phase 1b study for safety, pharmacokinetics, and pharmacodynamics

Background MG1113 is an IgG4 monoclonal antibody targeting the Kunitz-2 domain of tissue factor pathway inhibitor (TFPI), developed as a hemostatic rebalancing agent for hemophilia A or B. Objectives We aimed to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary hemostatic effects of MG1113. Methods This phase 1b clinical trial was constructed in a multicenter, prospective, stepwise dose-escalating (2.0, 3.0, and 3.3 mg/kg) design. MG1113 was administered subcutaneously once weekly for 8 weeks. Results Fifteen male patients (n=5/cohort) diagnosed with severe hemophilia A (n=14) or B (n=1) without inhibitors were enrolled. MG1113 was well tolerated, with an adverse event rate of 40.0% (6/15). No serious adverse events, early withdrawals, or dose interruptions occurred. PK analysis demonstrated a non-linear profile, with the peak plasma concentration at 33-48 hours post-dose. Free TFPI and diluted prothrombin time decreased from baseline, while thrombin generation markers increased. Exploratory analysis showed a notable numerical reduction in annualized total bleeding rates at higher doses: 91.7% at 3.0 mg/kg and 76.2% at 3.3 mg/kg. Zero bleeding rate was 20.0%, 60.0%, and 40.0% at doses of 2.0, 3.0, and 3.3 mg/kg, respectively. Conclusion MG1113, administered subcutaneously as a prophylaxis in severe hemophilia A or B without inhibitors for 8 weeks, demonstrated an acceptable safety profile with a PK profile suitable for once-a-week dosing. The PD marker changes were consistent with TFPI inhibition, which was associated with reductions in bleeding events.

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2026-07-30 | Concizumab prophylaxis in a 2-year-old patient with severe hemophilia B and inhibitor: a case report.

Hemophilia B is a rare X-linked congenital bleeding disorder characterized by a deficiency in coagulation factor IX (FIX). Standard management relies on exogenous factor replacement; however, the development of neutralizing alloantibodies (inhibitors) against infused clotting factor can significantly reduce therapeutic efficacy and complicate long-term management. Consequently, patients turn to bypassing agents or non-factor therapies to help achieve adequate hemostatic control. Concizumab is a novel subcutaneous non-factor therapy for hemophilia A and B that targets the tissue factor pathway inhibitor (TFPI). While it is approved for patients >12 years old, data remains sparse in younger children. Prophylactic treatment with concizumab reduces several limitations associated with inhibitor development and variability in treatment response with conventional therapies, especially in pediatric populations. We report a toddler with hemophilia B who developed a low-titer inhibitor following treatment with recombinant coagulation factor IX agents, resulting in recurrent bleeding complications and consistent subtherapeutic hemostatic control on standard bypassing agents. The patient was transitioned to concizumab for long-term prophylaxis, with dose adjustments based on clinical response and concizumab drug levels. Following the initiation of concizumab, the patient demonstrated a marked reduction in bleeding episodes. We highlight an individualized early drug-level-guided dose escalation approach in a very young child, demonstrating that pharmacokinetic monitoring can be utilized proactively to optimize therapeutic response in this age group, leading to effective drug levels and excellent clinical response. This case supports the role of concizumab in potentially reducing treatment burden and improving hemostatic outcomes in young patients with severe hemophilia B and inhibitors.

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2026-07-14 | CLINICAL AND LABORATORY CHARACTERISTICS, INHIBITOR FORMATION, AND THE EFFICACY OF MONOCLONAL ANTIBODY THERAPY IN CHILDREN WITH HEMOPHILIA A AND B

Hemophilia A (HA) and B (HB) are severe hereditary coagulopathies, the main complication of replacement therapy for which is the formation of inhibitors to coagulation factors. The aim of the study was to conduct a comparative analysis of the clinical and laboratory features of the onset, to evaluate the dynamics of therapy and the frequency of inhibitor formation in children with GA and GV, using monoclonal antibodies – emicizumab (MtAB) in pediatric practice. A retrospective cohort study of 68 patients with congenital coagulopathies (GA – 58, GV – 10) observed in the State Autonomous Healthcare Institution of the Sverdlovsk Region "Regional Clinical Hospital" (Yekaterinburg) by a hematologist in 2015-2025. The onset of inhibitory GA (Me = 4.5 months) was significantly earlier than non-inhibitory (Me = 9 months, p = 0.032), and hemorrhagic syndrome at the debut was more common in GV (100% versus 63.8% in GA, p = 0.029). Ferritin levels in GA were significantly lower (Me=23 μg/L) than in BG (Me=73 μg/L, p=0.003), indicating chronic blood loss. By 2025, inhibitors had developed in 21 patients with GA (36.2%). Switching 12 patients from GA to MtAT resulted in a reduction in the annual bleeding rate (ABR) from 8.5 to 1.0 (p<0.001), and in patients with an inhibitor form, a significant reduction in the inhibitor titer from 3.0 to 0.2 BU (p<0.05). Early onset predicts a high risk of inhibitor formation, and the high cumulative inhibitor rate (36.2%) necessitates regular screening, as MtAT therapy demonstrates high clinical efficacy and a favorable safety profile in children with GA, including patients with inhibitors.

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2026-06-30 | Anti-TFPI Single-Domain Antibodies: Novel Rebalancing Therapies for Hemophilia and Other Rare Bleeding Disorders

Tissue factor pathway inhibitor (TFPI) is an important determinant of thrombin generation in patients with deficiency in factor (F)VIII, FIX, and FXI. As such, anti-TFPI monoclonal antibodies such as concizumab have been developed to treat hemophilia A (HA) and B (HB).The objective of this study is to generate single-domain antibodies (sdAbs) as a novel class of pharmacological agents blocking TFPI and increasing thrombin generation in the plasma of patients with severe HA, HB, and FXI deficiency.A large synthetic library of sdAbs was generated and selected by phage-display on recombinant human TFPIα (rhTFPIα). Anti-TFPI sdAbs were screened on their ability to promote thrombin generation. Their binding to the Kunitz (K1, K2, K3) domains of TFPIα were measured by enzyme-linked immunosorbent assay. Their effects on the inhibitory activity of rhTFPIα toward FXa and TF/FVIIa complex were tested in purified systems. Thrombin generation was measured on plasmas from patients with severe HA, HB, or FXI-deficiency spiked with the anti-TFPI sdAbs.A total of 14 out of 188 screened sdAbs specifically bound to rhTFPIα, and two of them (26E5 and 26E8) targeted the K1 domain of TFPI and increased thrombin generation in the plasma of patients with HA. Both sdAbs impaired the ability of rhTFPIα to inhibit FXa and TF/FVIIa, in the absence and presence of their physiological modulators (protein S and FXa, respectively). These sdAbs efficiently increased thrombin generation in HB and FXI-deficient plasmas.Our large synthetic library could be used for readily generating diverse and functionally relevant anti-TFPI sdAbs that may be therapeutically attractive.

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gene therapies

2026-09-17 | Factor IX Padua AAV gene therapy in adolescents with hemophilia B: a phase 1 trial.

Adeno-associated virus (AAV)-mediated factor IX Padua gene therapy has demonstrated good safety and efficacy in adult patients with hemophilia B, but its safety and efficacy in adolescent patients with hemophilia B remain unknown. Here we report a multicenter, single-arm, phase 1 study involving 11 adolescent participants (aged 12-18 years) with severe or moderately severe hemophilia B (factor IX coagulant activity (FIX:C) ≤2 IU dl-1) in China. All of them received the AAV gene therapy BBM-H901 at a dose of 5 × 1012 vector genomes per kilogram of body weight and were then enrolled in a 52-week follow-up. The primary endpoint was safety. No dose-limiting toxicity was observed throughout the study. The most common adverse events included elevation of white blood cell count, elevation of neutrophil count and rash associated with corticosteroid use. One serious adverse event and two grade 3 adverse events occurred. Abnormal liver function was observed in one participant, with elevated alanine aminotransferase (197.0 U l-1) and aspartate aminotransferase (75.0 U l-1) levels, which returned to normal 4 weeks after immunosuppression therapy. The key secondary endpoints included the mean (s.d.) FIX:C at week 52 following infusion, which was 41.8 (30.1) IU dl-1 (one-stage SynthASil method), and the mean annualized bleeding rate, which decreased from 13.9 to 0.5. In this study, we show that the gene therapy drug BBM-H901 for hemophilia B is safe in adolescent patients, providing initial insights into its efficacy. ClinicalTrials.gov identifier: NCT05709288 .

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2026-08-28 | Unraveling Hemophilia in the Modern Era: From Pathogenesis to Emerging Therapies

Introduction: Hemophilia is a rare X-linked inherited bleeding disorder caused by a deficiency of coagulation factor VIII (hemophilia A) / factor IX (hemophilia B), resulting in impaired clot formation and recurrent bleeding episodes. This review aims to provide a comprehensive overview of the epidemiology, pathophysiology, diagnostic approaches, and evolving therapeutic strategies for hemophilia. It focuses on current treatments, inhibitor complications, and emerging therapies to improve outcomes. Methods: A comprehensive literature review was conducted using established databases, including PubMed, Scopus, Web of Science, and Google Scholar. Particular emphasis was placed on literature covering gene therapy, extended half-life factor concentrates, non-factor therapies, and inhibitor management. Results: The study found that hemophilia primarily affects males and presents with varying degrees of severity. Prophylactic therapy significantly reduces bleeding rates (by ~70-90%) and prevents joint damage. However, inhibitor development (seen in ~20-30% of severe cases) remains a key challenge. Emerging therapies, including non-factor treatments and gene therapy, show substantial improvement in bleeding control and patient quality of life. Discussion: The findings show that effective management of Hemophilia A and B relies on early prophylactic therapy, including extended half-life factor VIII and IX with pharmacokinetic-guided dosing. Inhibitor development remains a major challenge. Emerging therapies, such as Emicizumab, Fitusiran, Concizumab, and gene therapy using AAV vectors and CRISPR approaches, improve outcomes and reduce treatment burden. Conclusion: Hemophilia is a lifelong disorder requiring individualized and evolving treatment strategies. Integration of conventional factor replacement with emerging therapies has significantly improved outcomes and reduced morbidity. This review highlights key challenges, recent advances, and future directions, providing an updated and concise resource for clinical and research applications.

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2026-08-01 | Post-Vaccination Symptom: Local Reaction or a Bleeding Disorder?

Introduction: Hemophilia is a genetic bleeding disorder inherited in an X-linked recessive pattern. In this case report, the diagnostic process leading to severe hemophilia B in a 7-month-old infant who developed refusal to move the leg following vaccination is presented. Case presentation: A seven-month-old male patient was brought by his mother to the family medicine outpatient clinic of a tertiary care hospital with the complaint of avoiding movement of his right leg. No remarkable findings were noted in his personal or family history. It was learned that his 6-month-old vaccinations had been administered 10 days earlier in accordance with the national immunization schedule. On physical examination induration and tenderness on palpation were observed in the distal part of the right thigh accompanied by irritability. There was no limitation in the movements of the left lower extremity. Further evaluation was planned as the findings were disproportionate to the expected response following injection and were sufficient to limit extremity movement. Laboratory investigations revealed that Hb, PLT, and PT values were within normal limits, while aPTT was prolonged at 67.2 seconds. Ultrasonography of the right thigh was reported as diffuse intramuscular hematoma in the deep muscle planes. Based on these findings, the patient was referred to the pediatrics department for evaluation of a bleeding diathesis. Following clinical evaluation, the presence of intramuscular hematoma on magnetic resonance imaging and decreased Factor IX activity (0.5%; reference: 70-120%) led to the consideration of Factor IX deficiency (severe hemophilia B), and the diagnosis was confirmed by genetic analysis. The patient is currently being followed through collaboration between the hematology and family medicine physicians, and vaccination practices and timing are being determined according to treatment schedules. Conclusion: Musculoskeletal complaints that arise following injection procedures such as vaccination may not always represent simple local reactions. Careful and holistic evaluation of clinical findings in primary care, along with timely referral, is of critical importance for early diagnosis, initiation of treatment, and the implementation of preventive measures.

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2026-06-12 | Nonviral delivery of a base editor enables personalized correction of hemophilia B nonsense variants in a mouse model.

Hemophilia B is caused by loss-of-function variants in the F9 gene encoding factor IX (FIX). Although adeno-associated virus (AAV) vector-based gene therapy can restore FIX expression for over a decade, it does not restore the pathogenic variants and faces limitations related to immunogenicity and re-dosing. To develop a variant-specific, nonviral base editing strategy using lipid nanoparticles (LNPs) for the precise personalized correction of pathogenic nonsense variations in F9. Editing efficiency was evaluated in HEK293 cells harboring F9 variants treatable by A•T to G•C base editing. Functional and molecular restoration in vivo was assessed in hemophilia B model mice created with AAV8 vectors expressing F9 variants. LNPs harboring adenine base editor (Cas9 nickase conjugated with ABE8e) mRNA and the corresponding guide RNA were intravenously injected into the mice. We created HEK293 stably expressing 6 correctable nonsense variants: c.1067G>A, c.1068G>A, c.1222C>T, c.1292G>A, c.1358G>A, and c.1359G>A. Transfection of the cells with a base editor consisting of SpRY, an engineered SpCas9 with broader protospacer adjacent motif compatibility, and ABE8e, together with the guide RNA sequence, successfully induced A>G conversion at all target sites. The administration of LNPs harboring the base editor mRNA and guide RNA to the hemophilia B model restored the pathological variants (62.8% ± 14.4% for c.1068G>A, 35.9% ± 3.8% for c.1222C>T, and 70.6% ± 2.7% for c.1292G>A) and increased plasma FIX activity. This variant-specific, nonviral base editing platform represents a truly curative intervention for severe hemophilia B caused by single-nucleotide variants.

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2026-05-12 | Gene therapy for liver diseases: methods, challenges and opportunities.

Gene therapy has emerged as a promising and pivotal strategy for addressing numerous genetic disorders that currently lack effective therapeutic options. For many other presently incurable conditions, including the majority of inherited metabolic liver diseases, gene therapy offers a realistic and transformative treatment modality. This review highlights recent advancements in gene delivery vectors targeting the liver-specifically hepatocytes-with a focus on strategies involving gene supplementation and gene editing, as well as notable progress achieved through RNA-based therapeutic agents. Several early trials utilizing lipid nanoparticle (LNP)-based and recombinant adeno-associated virus (rAAV)-mediated approaches for gene supplementation and editing in liver diseases have yielded encouraging results. For example, rAAV-mediated FIX supplementation (2 × 1013 genome copies/kg) achieves sustained therapeutic activity in a subset of HOPE-B trial participants with hemophilia B, and LNP-CRISPR editing of ANGPTL3 (0.5 mg/kg mRNA) produces marked reductions in LDL-C and triglycerides. However, several translational challenges have been identified, including unintended activation of the innate immune system and severe hepatotoxicity following high-dose vector administration. These concerns necessitate rigorous and ongoing safety monitoring. In this review, we summarize major advancements, current challenges, and future perspectives in the field of liver-directed gene therapy. Additionally, we highlight key limitations inherent to existing approaches and discuss potential strategies to overcome these barriers and improve therapeutic outcomes.

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2026-04-18 | Pseudoexon inclusion induced by three deep intronic variants in hemophilia B and correction achieved through an antisense oligonucleotide-based strategy.

Although studies have identified deep intronic variants associated with hemophilia B in patients undiagnosed by conventional genetic testing, knowledge in this field remains limited. Long range-PCR of entire F9 gene was used to screen variants of three unrelated genetically unresolved severe hemophilia B patients. In silico analysis and minigene assay with two minigene plasmid construction methods were conducted to explore the effects of candidate deep intronic variants on splicing. Three novel putative pathogenic deep intronic variants (c.278-765_278-764ins6.1kb, c.392-903A>G and c.724-751T>G) and one variant of uncertain significance (c.723+2708del) in F9 were identified in three patients. All the three putative pathogenic variants created de novo donor splice site and utilized cryptic acceptor splice site to generate pseudoexon. We successfully developed antisense oligonucleotide-mediated exon-skipping correction strategies for the three identified putative pathogenic variants and the previously reported c.392-864T>G. However, the results obtained from minigene assay revealed certain discrepancies with the clinical phenotype. It is still challenging to accurately characterize the pathogenicity of deep intronic variants in vitro. Overall, our results highlight the complementary role of whole-gene sequencing of F9 to conventional genetic diagnosis. Furthermore, we provide insight into a potential therapeutic approach based on antisense oligonucleotide technology-mediated exon-skipping.

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2025-12-03 | Selective embolization for recurrent gingiva bleeding associated with aneurysmal bone cyst and hemophilia: A case report.

Spontaneous and massive gingival bleeding is a rare clinical symptom that can lead to severe morbidity, particularly when associated with systemic diseases such as hemophilia. Aneurysmal bone cyst (ABC) is a vascular lesion capable of causing massive gingival bleeding. A 2-year-old male presented with a gradually enlarging lump on the left cheek over 5 months, accompanied by recurrent bleeding. The patient had a history of hemophilia B and prior treatment. Massive recurrent gingival bleeding associated with ABC and hemophilia represents a clinical challenge. Management must focus on preventing complications from severe blood loss. Selective embolization provides an effective therapeutic option in such cases. Selective embolization is a minimally invasive and effective treatment for preventing severe complications in patients with ABC and hemophilia, offering a valuable alternative to invasive surgical intervention.

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2024-11-05 | Become-9: A Phase 1/2 Dose Escalation and Expansion Study of be-101 for the Treatment of Adults with Moderately Severe or Severe Hemophilia B

Background: Despite advances in treatment options for people with hemophilia B, significant unmet needs remain, notably disease and treatment burden. To overcome the limitations of available therapies, we developed BE-101, a first-in-class B cell medicine (BCM) comprised of expanded and differentiated B lymphocyte lineage cells that have been genetically engineered to express and secrete Factor IX (FIX). Participants' B lymphocyte lineage cells are collected through leukapheresis, edited ex vivo using CRISPR/Cas9 in combination with AAV-mediated homology-directed repair to precisely insert a human F9 gene encoding full length FIX protein (activity-enhanced Padua variant) into the CCR5 safe harbor gene locus. The terminally-differentiated human plasma cell BCMs derived from these precision gene engineered cells potentially offer natural longevity (persisting for decades), the capacity to secrete high levels of protein, the ability to engraft without host preconditioning, and re-dosability, thus making them an attractive platform for durable and tunable therapeutic effects in adolescents and children as well as adults. A robust nonclinical data package including genome safety assessments as well as short and long-term in vivo studies was submitted as an Investigational New Drug (IND) application to the US FDA. The FDA cleared this application as well as later granted orphan drug designation for BE-101. The initial clinical trial is planned to initiate later this year. Study Design and Methods: The BeCoMe-9 Study (Study BE-101-01) is a Phase 1/2, first in human, multi-center, open-label, dose-escalation study to evaluate the safety and clinical activity of a single intravenous (IV) dose of BE-101 in adults with moderately severe or severe Hemophilia B (&lt;2 IU/dL FIX). Once infused, BE-101 is designed to engraft and continuously secrete FIX into the circulation to restore clinically meaningful levels of functionally active FIX. The study includes 2 distinct parts: part 1 and part 2. In part 1, an ascending-dose design will be utilized to enable evaluation of increasing doses in a stepwise manner with the first dose level planned to target FIX activity above 1%. The objective for this dose escalation is to identify the dose of BE-101 required to achieve FIX activity at or above 15% of normal activity 28 days after infusion while also minimizing the number of participants who are potentially exposed to subtherapeutic or unsafe doses. Upon identification of a safe and efficacious dose in part 1 an expansion phase (part 2) will initiate. The initial cohort in the Part 2 expansion (Part 2a) phase will include up to 6 adult participants to further characterize the safety and activity of BE-101 at the selected dose. Further cohorts to evaluate BE-101 both in adolescents and in a multiple dose setting are also planned Up to 24 participants will be enrolled across Part 1 (up to 18) and Part 2a (up to 6). Consented participants will complete a screening period to assess eligibility and upon enrollment will undergo leukapheresis collection to support BE-101 manufacturing. Following administration, participants are monitored for safety and clinical activity. The total duration of study participation is approximately 52 weeks (1 year) post IV administration of BE-101. The study is expected to initiate enrollment in the first dose escalation cohort in the second half of 2024 (NCT: Pending).

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2024-03-25 | Pleiotropic effects of different exonic nucleotide changes at the same position contribute to hemophilia B phenotypic variation.

The disease-causing effects of genetic variations often depend on their location within a gene. Exonic changes generally lead to alterations in protein production, secretion, activity, or clearance. However, owing to the overlap between proteins and splicing codes, missense variants can also affect messenger RNA splicing, thus adding a layer of complexity and influencing disease phenotypes. To extensively characterize a panel of 13 exonic variants in the F9 gene occurring at 6 different factor IX positions and associated with varying severities of hemophilia B (HB). Computational predictions, splicing analysis, and recombinant factor IX assays were exploited to characterize F9 variants. We demonstrated that 5 (38%) of 13 selected F9 exonic variants have pleiotropic effects. Although bioinformatic approaches accurately classified effects, extensive experimental assays were required to elucidate and deepen the molecular mechanisms underlying the pleiotropic effects. Importantly, their characterization was instrumental in developing tailored RNA therapeutics based on engineered U7 small nuclear RNA to mask cryptic splice sites and compensatory U1 small nuclear RNA to enhance exon definition. Overall, albeit a multitool bioinformatic approach suggested the molecular effects of multiple HB variants, the deep investigation of molecular mechanisms revealed insights into the HB phenotype-genotype relationship, enabling accurate classification of HB variants. Importantly, knowledge of molecular mechanisms allowed the development of tailored RNA therapeutics, which can also be translated to other genetic diseases.

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2023-05-08 | Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.

Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors. This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete. Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported. In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia. Sanofi.

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