RARE DISEASE
Moderate hemophilia B
Moderate hemophilia B
Moderate hemophilia B
Synonyms: Moderate congenital F9 deficiency, Moderate congenital factor IX deficiency
Synonyms: Moderate congenital F9 deficiency, Moderate congenital factor IX deficiency
Synonyms: Moderate congenital F9 deficiency, Moderate congenital factor IX deficiency
Drug discovery
246
papers
On emerging therapies
Overview
Moderate hemophilia B is an X-linked recessive bleeding disorder characterized by factor IX deficiency (1-5% activity), leading to prolonged bleeding after trauma, surgery, or dental procedures, with rare spontaneous hemorrhages. Diagnosis involves factor IX activity assays, with management focused on replacement therapy and coordinated care through hemophilia treatment centers (HTCs) [1][5][6].
Burden
Chronic joint damage in 30-40% of patients due to recurrent hemarthrosis [6][9]
Annual treatment costs exceed $300,000 for prophylactic factor replacement [7][10]
Inhibitors develop in 3-5% of patients, complicating therapeutic efficacy [6][16]
Gene therapies (e.g., etranacogene dezaparvovec) show long-term efficacy in severe cases but remain under investigation for moderate disease [3][4][7].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
246 drug discovery papers about Moderate hemophilia B. Recent publications:
246 drug discovery papers about Moderate hemophilia B. Recent publications:
categories:
Small molecules
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.
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.
2026-04-03 | Cardiac surgery in an infant hemophilia B carrier with moderate hemophilia: a case report.
This is the first reported case of a female infant with moderate hemophilia B undergoing complex cardiac surgery, highlighting challenges in managing bleeding disorders in this rare clinical setting. A 4-month-old girl with Trisomy 21 was found to have moderate hemophilia B and an atrioventricular septal defect requiring surgery. Genetic testing confirmed hemophilia B. Surgery was performed successfully using extended half-life recombinant factor IX (rFIX-FP) to maintain stable coagulation. The patient experienced no excessive bleeding and recovered well. This case demonstrates that extended half-life FIX products enable safe and effective management of moderate hemophilia B during complex cardiac surgery in infants. Individualized perioperative planning and interdisciplinary collaboration are essential for optimal outcomes.
2026-02-01 | Real-World Effectiveness and Usage of Recombinant Factor IX Fc: Final Data from the B-MORE Study
Introduction Extended half-life (EHL) recombinant factor IX Fc fusion protein (rFIXFc) has an established efficacy and safety profile in people with hemophilia B across all ages. Here, we report final data from B-MORE (NCT03901755), a real-world, 24-month prospective study evaluating rFIXFc effectiveness and usage across Europe and the Middle East. Method Eligible patients, including previously untreated patients, were prescribed rFIXFc prophylaxis (PPX) or on-demand prior to/at enrolment. Twelve-month retrospective data on previous FIX (as available), baseline characteristics, and follow-up on rFIXFc (retrospective/prospective periods) are reported. Annualized endpoints only include patients with≥6 months treatment. Results B-MORE enrolled 151 patients from 29 centers (median [range] age: 20.5 [1–81] years; three patients were female). Twelve patients were previously untreated; 119 had severe hemophilia (26 moderate, 6 mild). For the primary endpoints, 137 patients prospectively treated with rFIXFc PPX were analyzed (mean [range] treatment duration: 22.4 [7.3–30.0] months). Median (interquartile range [IQR]) annualized bleeding rate (ABR) was 0.45 (0.0–1.2), annualized injection frequency (IF) was 52.5 (52.2–52.6), and annualized factor consumption (FC) was 2,442.7 (2,021.9–2,969.7) IU/kg/year. An intrapatient comparison was conducted in 92 patients switching from prior standard half-life (SHL) FIX PPX to rFIXFc PPX (mean [range] duration: 11.5 [6.4–12.0] vs 40.6 [9.8–83.3] months, since rFIXFc PPX initiation). In these patients, median (IQR) change in ABR was 0.0 (-1.0–0.4), change in IF was -52.7 (-56.6– -38.4), and change in FC was -1,379.9 (-2,594.4– -264.3; n=91) IU/kg/year. Overall, most physicians (88.5%; 69/78) and patients (90.0%; 90/100) were satisfied/highly satisfied with rFIXFc PPX, at last assessment. No inhibitor development or serious adverse events related to rFIXFc were reported. Conclusion Real-world B-MORE data confirm the effectiveness of rFIXFc and demonstrate that rFIXFc PPX can reduce IF and FC while improving/maintaining bleed protection, compared with SHL PPX. B-MORE is sponsored by Sobi. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-01-14 | Improvements in pharmacokinetics, bleeding control, and cost analysis after PK-guided transition to extended-half-life factor IX in hemophilia B: A multicentric study.
Extended half-life factor IX concentrates (FIX-EHL) have been shown to improve clinical outcomes and reduce treatment burden in patients with hemophilia B (HB). To analyze the differences in pharmacokinetic (PK) and clinical parameters one year before and after the PK-guided switch from standard half-life FIX (FIX-SHL) to FIX-EHL in patients with severe/moderate HB on prophylaxis. A multicenter, comparative, observational, sequential, retrospective, and multidisciplinary study was conducted. PK parameters were calculated with WAPPS-Hemo®, and annualized total (ABR) and joint bleeding rates, the t1/2 ratio and area under the curve (AUC), FIX consumption, infusion frequency, and cost were recorded. A total of 21 patients (9 pediatric and 12 adult) with HB who switched from FIX-SHL to FIX-EHL were analyzed. All PK parameters improved significantly, with median improvement ratios for t1/2 and AUC of 4.1 (IQR: 3.4-4.8) and 4.2 (IQR: 2.6-5.0), respectively. Regarding clinical outcomes, the difference in ABR reached statistical significance and among the 6 patients with target joints, 5 (83.3 %) achieved resolution after switching. Infusion frequency and weekly dose were reduced by 50.0 % and 56.3 %, respectively, avoiding 52.1 (IQR: 26.1-67.8) injections and 130,357.3 (IQR: 5142.9-203,357.3) IU of FIX per patient per year. However, the switch resulted in an additional cost of € 28,254.9 (IQR: 4432.1- 44,060.8) per patient per year. The PK-guided switch from FIX-SHL to FIX-EHL was associated with improvements in all PK parameters, and a significant clinical benefit was also demonstrated with the reduction of the bleeding rates. Following the switch, the weekly dose and administration frequency were reduced; however, this did not result in a cost reduction.
small molecules
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
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.
2024-11-05 | Retrospective Study of Intraarticular Synovectomy in Chronic Synovitis in Person with Hemophilia
Aim To evaluate the safety and efficacy of Radiosynoviorthesis in Chronic Synovitis in Persons with Hemophilia. Materials and Methods : This retrospective observational study reviewed all radiosynoviorthesis conducted in persons with Hemophilia (PWH) from June 2016 to May 2024. Yttrium-90 (68%) was used for knee and shoulder joints. Lutetium-177(32%) was used for elbow, wrist and ankle joints. The inclusion criteria were patients of any sex, ³8 years or older, with stage 2 and 3 haemophilic arthropathy and target joint. Exclusion criteria included patients <8 years, pregnant females, those with acute bleeds, local infections, and stage 4 haemophilic arthropathy. Data were collected on resolution of target joints, functional (FISH and HJHS)and radiological score (Denver) before the procedure and at 1, 3, 6 months and 12 months post-procedure to assess the efficacy of the intervention. Results A total of 115 procedures were performed in 81 PWH. The median age of patients was 22 years (range: 8-62). Of all the cases, Haemophilia A were 85.3% (n=98), Haemophilia B were 10.4% (n=12), Hemophilia A with Inhibitor were 4.3% (n=5). Among all 94.4% were severe haemophiliacs and 5.6% were moderate haemophiliacs. Of 115 procedure, 57% (n=41) were knee, 25%(n=22) were elbow 13.8% (n=16) were Ankle, 3.4%(n=2) were shoulder joints. The majority 69% of patients had a good Caviglia score, while 31% had a poor score. Out of 81 PWH, 37 PWH with 56 (48.6%) procedures followed up regularly at the defined time-points and assessment was done accordingly. Out of 56 joints 50 had resolution of target joints. Median FISH, HJHS and VAS Scoring at pre procedure, 1 month, 3 months and 6 months are (27, 25, 25 and 24), (18,16,15 and 15) and (6, 5, 5 and 5) respectively with statistically significant improvement (P <0.001). The Denver score didn't show any statistical difference post procedure. The procedure was safe, with two episodes of skin burns reported. Conclusion : People who followed regularly has a decrease in the Annual Joint Bleed Rate. Radiosynovectomy is safe and effective intervention for patients with chronic haemophilic arthropathy irrespective of the type of radionuclide used
2021-01-18 | [Diagnosis and management of hemophilia].
Hemophilia A and B are hereditary coagulation disorders caused by functional and quantitative abnormalities of coagulation factor VIII (FVIII) in hemophilia A and coagulation factor IX (FIX) in hemophilia B. A definitive diagnosis is made through the measurement of FVIII or FIX activity and ruling out other pathological conditions or diseases with decreased FVIII or FIX activity. Severity is classified as severe, moderate, and mild according to factor activity level. Moreover, as frequency of hemorrhage and severity are usually correlated, severe patients have a high risk of intracranial hemorrhage during infancy as well as joint damage due to recurrent hemarthrosis. However, there are some non-severe patients who have symptoms like bleeding and joint damage. Therefore, it is necessary to determine the treatment strategy not only based on severity but also on bleeding symptoms. The treatment for hemophilia is mainly replacement therapy using clotting factor concentrates (standard or extended half-life), such as prophylaxis or on-demand therapy for bleeding. However, there are also clinical problems, such as venous access and development of inhibitors. Recently, a non-factor agent has emerged as a new treatment option. Thus, the management of hemophilia is on a turning point.
2019-12-23 | The chaperone-like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation.
Essentials Missense mutations often impair protein folding, and thus intracellular trafficking and secretion. Cellular models of severe type I hemophilia B were challenged with chaperone-like compounds. Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q. The increased coagulant activity levels (∼3%) of p.R294Q would ameliorate the bleeding phenotype. Background Missense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone-like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications. Objectives To rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I hemophilia B (HB) through chaperone-like compounds. Methods Expression studies of recombinant (r)FIX variants and evaluation of secreted levels (ELISA), intracellular trafficking (immunofluorescence) and activity (coagulant assays) before and after treatment of cells with chaperone-like compounds. Results As a model we chose the most frequent HB mutation (p.R294Q, ~100 patients), compared with other recurrent mutations associated with severe/moderate type I HB. Immunofluorescence studies revealed retention of rFIX variants in the endoplasmic reticulum and negligible localization in the Golgi, thus indicating impaired intracellular trafficking. Consistently, and in agreement with coagulation phenotypes in patients, all missense mutations resulted in impaired secretion (< 1% wild-type rFIX). Sodium phenylbutyrate (NaPBA) quantitatively improved trafficking to the Golgi and dose dependently promoted secretion (from 0.3 ± 0.1% to 1.5 ± 0.3%) only of the rFIX-294Q variant. Noticeably, this variant displayed a specific coagulant activity that was higher (~2.0 fold) than that of wild-type rFIX in all treatment conditions. Importantly, coagulant activity was concurrently increased to levels (3.0 ± 0.9%) that, if achieved in patients, would ameliorate the bleeding phenotype. Conclusions Altogether, our data detail molecular mechanisms underlying type I HB and candidate NaPBA as affordable 'personalized' therapeutics for patients affected by the highly frequent p.R294Q mutation, and with reduced access to substitutive therapy.
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 .
2026-05-12 | Perceptions and Recommendations Regarding Haemophilia B Gene Therapy: A Multistakeholder View From Patients, Caregivers and Healthcare Professionals.
Gene therapy for Haemophilia B has received FDA approval, offering patients a transformative therapeutic option. However, effective communication about the benefits, risks, long-term efficacy and follow-up of gene therapy remains essential for informed decision-making. This study aimed to explore the diverse expectations, concerns and perspectives of patients with Haemophilia B, their caregivers and healthcare professionals (HCPs) regarding gene therapy and to identify strategies for improving communication. A prospective qualitative study was conducted using semi-structured interviews with male patients aged ≥12 years with moderate or severe Haemophilia B (factor level ≤ 2%), their caregivers and HCPs (physicians, nurses, social workers, advanced practice providers and pharmacists). Interviews were audio-recorded, transcribed and analysed thematically. Thirty participants were interviewed, including 15 patients (mean age, 21.1 years), caregivers and 15 HCPs across the United States. Patients and caregivers emphasised five themes: (1) current challenges; (2) hope and optimism; (3) concerns and skepticism; (4) the complex emotional challenges of decision-making and (5) preferences for transparent, patient-friendly communication. HCPs identified four complementary themes: (1) variable patient knowledge; (2) the need for transparency in discussing 'curative' language; (3) factors influencing treatment decisions (trust, prior experiences and financial concerns) and (4) strategies to improve communication (clear language, visuals and testimonials). Stakeholders view gene therapy as both promising and uncertain. Targeted educational interventions, transparent communication and patient-centred decision discussions are essential to fill knowledge gaps and support informed consent in this transformative era of treatment for Haemophilia B.
2026-02-27 | Etranacogene dezaparvovec in people with hemophilia B with preexisting adeno-associated virus 5 neutralizing antibodies: 4-year subgroup results from the HOPE-B trial.
Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) is the first phase 3 trial of adeno-associated virus (AAV) serotype 5 vector-based gene therapy for hemophilia B to have enrolled participants with neutralizing antibodies (NAbs) to the viral vector. Evaluate the efficacy and safety of etranacogene dezaparvovec in a post hoc subgroup of participants with preexisting AAV5 NAbs 4 years posttherapy. After a ≥6-month lead-in period on continuous prophylaxis, people with moderately severe/severe hemophilia B (factor [F]IX ≤ 2%) received a single infusion of etranacogene dezaparvovec. AAV5 NAb status prior to infusion was determined. FIX activity, annualized bleeding rates (ABRs), and safety were evaluated in participants with preexisting AAV5 NAbs. A total of 21/54 participants had detectable preexisting AAV5 NAbs (titer: 8.5-678, n = 20; titer: 3212, n = 1). Two participants did not respond to treatment (high titer: 3212, n = 1; received partial dose, n = 1). The mean FIX activity was 36 IU/dL (SD, 18) at 1 year (n = 18) and 34 IU/dL (SD, 16) at 4 years (n = 15) posttreatment. Unadjusted ABRs for all bleeds (treated and untreated) decreased by 74.4% from 4.64 during lead-in to 1.18 during months 7 to 48 (n = 21). ABRs for spontaneous and joint bleeds decreased by 79% and 82%, respectively. The mean FIX consumption decreased from 245,476 IU/y (SD, 144,497) during lead-in to 23,975 IU/y (SD, 48.928) during years 1 to 4 (P < .0001). The most frequent treatment-related adverse events were infusion-related reactions (23.8%) and transient alanine aminotransferase elevations (14.3%). No late hepatotoxicity was observed. Etranacogene dezaparvovec demonstrated long-term efficacy and safety in individuals with preexisting AAV5 NAb titers ≤ 678, expanding eligibility for gene therapy to a broader hemophilia B population.
2026-02-02 | Etranacogene dezaparvovec in people with hemophilia B and without adeno-associated virus serotype 5 neutralizing antibodies: a 4-year subgroup analysis of the Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) trial.
In the phase 3 Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) trial, a single dose of etranacogene dezaparvovec was administered to people with severe or moderately severe hemophilia B following a lead-in period (≥6 months) during which they received factor (F)IX prophylaxis. Participants were enrolled regardless of adeno-associated virus serotype 5 (AAV5)-neutralizing antibody (NAb) status at screening. To determine efficacy, pharmacokinetic, and safety outcomes over 4 years postgene therapy in HOPE-B participants who were NAb-negative (NAb-). Participants provided serum samples for AAV5 NAb determination using an in vitro AAV5 transduction inhibition assay prior to etranacogene dezaparvovec infusion. Participants who were AAV5 NAb- at this time point were examined in the post hoc subgroup analysis. In NAb- participants (N = 33), the mean adjusted annualized bleeding rate was significantly reduced between months 7 and 48 postetranacogene dezaparvovec vs lead-in (0.57 vs 3.80; P < .0001). In years 1 to 4, the annualized bleeding rates were 0.99, 0.72, 0.41, and 0.41, respectively (P < .0001 vs lead-in; N = 33 throughout). The mean (SD) endogenous FIX activity was 40.6 IU/dL (18.6) at month 6 postinfusion (N = 33), remained stable, and was 39.0 IU/dL (16.8) at year 4 (N = 33). Exogenous FIX consumption decreased by 99% during months 7 to 48 vs the lead-in period, and no NAb- participant returned to continuous FIX prophylaxis for 4 years postinfusion. No treatment-related oncogenic events or persistent late hepatotoxicity were observed. Etranacogene dezaparvovec proved to be highly effective, superior to FIX prophylaxis for bleeding protection, and safe for 4 years postinfusion in NAb- persons with severe or moderately severe hemophilia B.
2025-12-12 | Liver dysfunction in AAV-mediated Hemophilia B gene therapy: Mechanisms and management strategies.
Hemophilia B, an X-linked recessive bleeding disorder caused by mutations in the gene encoding coagulation factor IX (FIX). Gene therapy using adeno-associated viral (AAV) vectors targeting hepatocytes has emerged as a promising treatment, enabling sustained FIX expression. However, AAV vectors exhibit strong liver tropism, often triggering immune responses that lead to hepatotoxicity. Clinical trials involving Etranacogene Dezaparvovec, Fidanacogene Elaparvovec, and BBM-H901 (Dalnacogene Ponparvovec) reported transient elevations in liver enzymes, typically occurring 2-6 weeks post-infusion. These elevations are usually mild to moderate and respond well to corticosteroid-based immunosuppression. The hepatic complications, while manageable, pose a risk to therapeutic efficacy and highlight the need for careful monitoring, early detection, and personalized immunosuppressive strategies. This review explores the mechanisms of AAV-induced liver dysfunction in gene therapy for Hemophilia B, with a focus on clinical manifestations, immune-mediated pathogenesis, and emerging approaches for mitigating liver-related adverse effects and providing clinical guidance.
antibodies
2026-06-01 | Effect of marstacimab in young people living with severe hemophilia A or moderate to severe hemophilia B without inhibitors: A plain language summary from the BASIS study.
What is this summary about? This summary describes a study that looked at how well the study treatment (marstacimab) works in people living with hemophilia. The summary describes how well marstacimab reduced bleeding episodes in young people (adolescents) 12 to 17 years old. Hemophilia is a condition that causes people to bleed more easily because their blood is unable to clot properly. Clotting is when blood turns from liquid into gel to stop bleeding. Hemophilia is caused by not having enough blood clotting factors, which are proteins found in the blood that help in forming a clot and stop bleeding. People living with hemophilia either don't make these proteins, have low amounts of these proteins, or their proteins do not work well. There are different types of hemophilia, depending on which clotting factor is affected. For example, people living with hemophilia A lack clotting factor 8, and people living with hemophilia B lack clotting factor 9. Some treatments for hemophilia work by replacing clotting factors. These treatments are called factor replacement therapy, and are given directly into a vein (called intravenous, or IV for short). They are given frequently, sometimes even more than once a week. In some people living with hemophilia, the body develops antibodies called inhibitors that block replacement clotting factors from working properly. Not all people living with hemophilia produce these antibodies - those who don't are classified as having hemophilia without inhibitors. A different way to treat people living with hemophilia is by using treatment called non-factor replacement therapy. One type of non-factor treatment called marstacimab is given as a regular preventive treatment (called prophylaxis). It works without replacing the missing clotting factors but brings blood clotting and bleeding back to a normal balance. Marstacimab is given once a week as a flat-dose (not based on body weight) injection under the skin (called subcutaneous) using an auto-injector device. This injection is sometimes called a shot and can be easier than injecting directly into a vein. In some cases, marstacimab can be taken less often than clotting factors. Marstacimab offers a new way to treat people living with hemophilia A or B without inhibitors. What were the results of the study? In this study, young people treated with marstacimab for 1 year had on average fewer bleeding episodes than on previous clotting factor replacement treatment. Marstacimab was well tolerated in young people (similar to adults), which means that most side effects that people had were mild to moderate and resolved by the end of the study. What do the results mean? This study showed that a once weekly injection of marstacimab could help reduce bleeding episodes in young people living with hemophilia A or B, without inhibitors.
2026-05-11 | 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.
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.
2026-02-01 | Use of concizumab in children with severe hemophilia B and factor IX-inhibitors
Introduction Patients with severe hemophilia B complicated by high-titer inhibitors and allergic reactions to factor IX concentrate have very limited therapeutic options. Concizumab, a subcutaneous anti–TFPI antibody, represents a novel prophylactic approach for these patients. We report our experience with use of concizumab in three pediatric patients with severe hemophilia B, recurrent inhibitors, allergic reactions to factor IX, and frequent bleeds. Method Clinical data were collected retrospectively from medical records of the patients treated from 2023 -to 2025 with concizumab. Parameters analyzed included genetic findings, treatment history, bleeding events, immune tolerance induction, and outcomes after concizumab initiation. The primary endpoint was the annualized bleeding rate, secondary endpoints were on demand factor use and adverse events. Results Patient A was diagnosed with severe hemophilia B (FIX activity<1%) at the age of seven months following an intracranial hemorrhage. Factor IX inhibitors (peak 7.2 BU) were diagnosed after 3 months. Multiple immune tolerance induction attempts (2017, 2018, 2022) failed and anaphylactic reactions towards factor IX occurred. Prior to concizumab, prophylaxis consisted of frequent recombinant activated factor VII infusions, complicated by poor venous access and multiple central line placements. The annualized bleeding rate (ABR) was 2–3, including recurrent joint bleeds, extensive hematomas, and mucosal bleeds. Concizumab prophylaxis was initiated as compassionate use in November 2024 at 0.2 mg/kg/day s.c. After 11 months, no breakthrough bleeding events occurred (ABR 0); no thromboembolic complications were observed. Reported adverse events were mild and transient (limited to bloating and sweating, local redness at the injection site). Laboratory monitoring (D-dimers, platelets) showed moderate D-dimer elevation. Patient B developed low-titer inhibitors (peak 1.3 BU) after 20 days of exposure to F IX. With rFVIIa prophylaxis every two days the ABR was 1. Following initiation of concizumab with 0.2 mg/kg/day on-demand administration of recombinant factor VII has been necessary four times, mainly prophylactically (ABR 0). No adverse events were observed. Patient C with severe hemophilia B, developed an inhibitor hemophilia after 90 exposure days followed by multiple unsuccessful immune tolerance induction therapies and complicated by severe allergic reactions to factor IX. Since starting Concizumab in February 2025 with 0.2 mg/kg/day only one hip joint bleed occurred (ABR 1) Laboratory tests in general showed a slight increase in D-dimer with normal platelet counts. No reported side effects. All 3 patients had concizumab levels within the target range. Conclusion Concizumab was safe and effective in preventing bleeding in a pediatric patient with severe hemophilia B and inhibitors, substantially reducing treatment burden and improving quality of life. These results support further use of concizumab in this challenging patient population. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-02-01 | First Experience with Marstacimab Monitoring
Introduction The inhibition of tissue factor pathway inhibitor (TFPI) is a new approach to normalize coagulation in patients with hemophilia A and B. TFPI inhibitors indirectly improve the generation of factor Xa, and subsequently factor IIa, which leads to sufficient hemostasis. Hence, thrombin generation (TG) is the perfect candidate for therapy monitoring. Here, we want to present our first data in three patients receiving TFPI inhibitor marstacimab (Pfizer). Method Three patients were included (age 54-64), two with severe hemophilia B and one with moderate hemophilia B (residual activity 3%). All patients were treated according to the manufacturer’s guideline. Thrombin generation was assessed immediately before the first application (baseline) of marstacimab and regularly after therapy started. Thrombin generation was assessed with ST Bleedscreen and ST Thromboscreen (ST Genesia, Stago) and Technoclone TGA (RC high) on the Ceveron analyzer. Results Thrombin generation improves significantly under therapy with marstacimab, in all assays by a factor of 4 to 5 compared to the baseline value. The results are similar between all methods. The patient with the lowest baseline TG achieved about 80% of normal TG (thrombin peak), the other patients between 130% and 140%. So far, no clinical event, bleeding or thrombosis, has been reported by the patients. Conclusion Thrombin generation is a suitable tool for the monitoring of TFPI inhibitor marstacimab. To which extent the data reflect clinical outcome is not clear at this moment; more and longer monitoring is required to answer that question. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
other
2026-01-09 | Molecular mechanisms and therapeutic strategies for the recurrent F9 (c.520 + 13 A > G) variant in hemophilia B.
Hemophilia B (HB), an X-linked recessive disorder, results from variants in the coagulation factor IX gene (F9). The F9 c.520 + 13 A > G variant is a recurrent intronic variant in HB patients, accounting for 15.05% of all documented F9 intronic variants. Despite prior predictions of its impact, the molecular mechanism associated with moderate to mild HB remains undissected. In silico predictions and splicing-competent cDNA constructs were used to assess the impact of F9 c.520 + 13 A > G on mRNA splicing. Factor IX (FIX) variant (p.V174delinsGHNLM) expression in HEK293T cells was evaluated using activated partial thromboplastin time, enzyme-linked immunosorbent assay, Western blot analysis, and immunofluorescence analyses. Structural modeling and molecular dynamics simulations were performed to evaluate the structural impact of the variant. Engineered U1 small nuclear RNA (U1snRNA) was challenged with F9 full-length splicing-competent constructs to evaluate splicing correction. The F9 c.520 + 13 A > G variant caused nearly complete aberrant splicing, producing the F9 c.520_521insGTCATAATCTGA insertion and the in-frame FIX p.V174delinsGHNLM variant. A small amount (approximately 10%) of wild-type FIX was also detected. We characterize the p.V174delinsGHNLM variant, which exhibited impaired secretion and increased intracellular accumulation. Interestingly, an engineered U1snRNA partially rescued aberrant splicing, restoring functional FIX levels to approximately 40%. This study elucidates the molecular mechanism of the F9 c.520 + 13 A > G variant, which activates a cryptic 5' splice site in intron 5, leading to an in-frame FIX (p.V174delinsGHNLM) with secretion defects and loss of protein function. And Engineered U1snRNA partially rescued the splicing defect.
2024-10-01 | SURGICAL EXPERIENCE IN PEOPLE WITH HEMOPHILIA A OR B WITH AND WITHOUT INHIBITORS RECEIVING FITUSIRAN
Background: Fitusiran, a subcutaneous, investigational siRNA therapeutic lowers antithrombin to rebalance hemostasis and enhance thrombin generation in People with Hemophilia (PwH) A or B, regardless of inhibitor status. For the management of perioperative hemostasis, Bleed Management Guidelines (BMG) with reduced dose and/or frequency of Clotting Factor Concentrates (CFC), or Bypassing Agents (BPA) were implemented. Aims: To describe hemostatic outcomes of major surgeries conducted while on fitusiran prophylaxis in PwHA/B aged ≥12-years, regardless of inhibitor status. Methods: All major surgeries in the fitusiran clinical development program until June 2023 were evaluated, including participants on the 80 mg QM and revised antithrombin-based dose regimen. Informed consent and ethics committee approval were obtained for all studies. Procedures conducted during fitusiran prophylaxis and AT activity < 60% were included. Major surgeries included: opening into a major body cavity, operation on a joint, removal of an organ, operative alteration of normal anatomy, crossing of a mesenchymal barrier, dental extraction of molar teeth or ≥3 nonmolar teeth, or tooth implantation. Investigators/surgeon assessed peri-operative hemostatic control based on the ISTH 4-point response scale (excellent/good/moderate/poor). Results and discussion: Sixty major surgeries (24 in inhibitor patients) were performed. In 47 (78.3%) major surgeries, BMG were followed, and reduced doses were used as perioperative prophylaxis. Four major surgeries were conducted without additional CFC/BPA. Hemostatic control on the day of the surgery was rated excellent/good in 30/31 (97%) cases following BMG and 9/10 (90%) cases not following BMG. ATIII concentrate was used to reverse the pharmacodynamic effect of fitusiran in 7 surgeries with an excellent/good hemostatic outcome. No major treatmentrelated safety concerns were identified perioperatively. Postoperative thrombosis occurred only when dosing exceeded BMG recommendations in 2 participants. Conclusions: Major surgeries can be safely and effectively conducted during fitusiran prophylaxis when BMG are followed, irrespective of inhibitor status. Reversal of lowered AT is not necessary.
2021-07-08 | Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort.
Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors. In this open-label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once-monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient-reported outcomes (exploratory). The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean [SEM]) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean [standard deviation] 69.4 [16.3] days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (-9.2 [2.9]) and physical health (-12.3 [3.9]) domain scores suggested clinically meaningful improvement. Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.
2020-08-03 | Pathological mechanism and antisense oligonucleotide-mediated rescue of a non-coding variant suppressing factor 9 RNA biogenesis leading to hemophilia B.
Loss-of-function mutations in the human coagulation factor 9 (F9) gene lead to hemophilia B. Here, we dissected the consequences and the pathomechanism of a non-coding mutation (c.2545A>G) in the F9 3' untranslated region. Using wild type and mutant factor IX (FIX) minigenes we revealed that the mutation leads to reduced F9 mRNA and FIX protein levels and to lower coagulation activity of cell culture supernatants. The phenotype could not be compensated by increased transcription. The pathomechanism comprises the de novo creation of a binding site for the spliceosomal component U1snRNP, which is able to suppress the nearby F9 poly(A) site. This second, splicing-independent function of U1snRNP was discovered previously and blockade of U1snRNP restored mutant F9 mRNA expression. In addition, we explored the vice versa approach and masked the mutation by antisense oligonucleotides resulting in significantly increased F9 mRNA expression and coagulation activity. This treatment may transform the moderate/severe hemophilia B into a mild or subclinical form in the patients. This antisense based strategy is applicable to other mutations in untranslated regions creating deleterious binding sites for cellular proteins.
2017-09-12 | Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.
Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).
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.
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.
2026-04-03 | Cardiac surgery in an infant hemophilia B carrier with moderate hemophilia: a case report.
This is the first reported case of a female infant with moderate hemophilia B undergoing complex cardiac surgery, highlighting challenges in managing bleeding disorders in this rare clinical setting. A 4-month-old girl with Trisomy 21 was found to have moderate hemophilia B and an atrioventricular septal defect requiring surgery. Genetic testing confirmed hemophilia B. Surgery was performed successfully using extended half-life recombinant factor IX (rFIX-FP) to maintain stable coagulation. The patient experienced no excessive bleeding and recovered well. This case demonstrates that extended half-life FIX products enable safe and effective management of moderate hemophilia B during complex cardiac surgery in infants. Individualized perioperative planning and interdisciplinary collaboration are essential for optimal outcomes.
2026-02-01 | Real-World Effectiveness and Usage of Recombinant Factor IX Fc: Final Data from the B-MORE Study
Introduction Extended half-life (EHL) recombinant factor IX Fc fusion protein (rFIXFc) has an established efficacy and safety profile in people with hemophilia B across all ages. Here, we report final data from B-MORE (NCT03901755), a real-world, 24-month prospective study evaluating rFIXFc effectiveness and usage across Europe and the Middle East. Method Eligible patients, including previously untreated patients, were prescribed rFIXFc prophylaxis (PPX) or on-demand prior to/at enrolment. Twelve-month retrospective data on previous FIX (as available), baseline characteristics, and follow-up on rFIXFc (retrospective/prospective periods) are reported. Annualized endpoints only include patients with≥6 months treatment. Results B-MORE enrolled 151 patients from 29 centers (median [range] age: 20.5 [1–81] years; three patients were female). Twelve patients were previously untreated; 119 had severe hemophilia (26 moderate, 6 mild). For the primary endpoints, 137 patients prospectively treated with rFIXFc PPX were analyzed (mean [range] treatment duration: 22.4 [7.3–30.0] months). Median (interquartile range [IQR]) annualized bleeding rate (ABR) was 0.45 (0.0–1.2), annualized injection frequency (IF) was 52.5 (52.2–52.6), and annualized factor consumption (FC) was 2,442.7 (2,021.9–2,969.7) IU/kg/year. An intrapatient comparison was conducted in 92 patients switching from prior standard half-life (SHL) FIX PPX to rFIXFc PPX (mean [range] duration: 11.5 [6.4–12.0] vs 40.6 [9.8–83.3] months, since rFIXFc PPX initiation). In these patients, median (IQR) change in ABR was 0.0 (-1.0–0.4), change in IF was -52.7 (-56.6– -38.4), and change in FC was -1,379.9 (-2,594.4– -264.3; n=91) IU/kg/year. Overall, most physicians (88.5%; 69/78) and patients (90.0%; 90/100) were satisfied/highly satisfied with rFIXFc PPX, at last assessment. No inhibitor development or serious adverse events related to rFIXFc were reported. Conclusion Real-world B-MORE data confirm the effectiveness of rFIXFc and demonstrate that rFIXFc PPX can reduce IF and FC while improving/maintaining bleed protection, compared with SHL PPX. B-MORE is sponsored by Sobi. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-01-14 | Improvements in pharmacokinetics, bleeding control, and cost analysis after PK-guided transition to extended-half-life factor IX in hemophilia B: A multicentric study.
Extended half-life factor IX concentrates (FIX-EHL) have been shown to improve clinical outcomes and reduce treatment burden in patients with hemophilia B (HB). To analyze the differences in pharmacokinetic (PK) and clinical parameters one year before and after the PK-guided switch from standard half-life FIX (FIX-SHL) to FIX-EHL in patients with severe/moderate HB on prophylaxis. A multicenter, comparative, observational, sequential, retrospective, and multidisciplinary study was conducted. PK parameters were calculated with WAPPS-Hemo®, and annualized total (ABR) and joint bleeding rates, the t1/2 ratio and area under the curve (AUC), FIX consumption, infusion frequency, and cost were recorded. A total of 21 patients (9 pediatric and 12 adult) with HB who switched from FIX-SHL to FIX-EHL were analyzed. All PK parameters improved significantly, with median improvement ratios for t1/2 and AUC of 4.1 (IQR: 3.4-4.8) and 4.2 (IQR: 2.6-5.0), respectively. Regarding clinical outcomes, the difference in ABR reached statistical significance and among the 6 patients with target joints, 5 (83.3 %) achieved resolution after switching. Infusion frequency and weekly dose were reduced by 50.0 % and 56.3 %, respectively, avoiding 52.1 (IQR: 26.1-67.8) injections and 130,357.3 (IQR: 5142.9-203,357.3) IU of FIX per patient per year. However, the switch resulted in an additional cost of € 28,254.9 (IQR: 4432.1- 44,060.8) per patient per year. The PK-guided switch from FIX-SHL to FIX-EHL was associated with improvements in all PK parameters, and a significant clinical benefit was also demonstrated with the reduction of the bleeding rates. Following the switch, the weekly dose and administration frequency were reduced; however, this did not result in a cost reduction.
small molecules
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
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.
2024-11-05 | Retrospective Study of Intraarticular Synovectomy in Chronic Synovitis in Person with Hemophilia
Aim To evaluate the safety and efficacy of Radiosynoviorthesis in Chronic Synovitis in Persons with Hemophilia. Materials and Methods : This retrospective observational study reviewed all radiosynoviorthesis conducted in persons with Hemophilia (PWH) from June 2016 to May 2024. Yttrium-90 (68%) was used for knee and shoulder joints. Lutetium-177(32%) was used for elbow, wrist and ankle joints. The inclusion criteria were patients of any sex, ³8 years or older, with stage 2 and 3 haemophilic arthropathy and target joint. Exclusion criteria included patients <8 years, pregnant females, those with acute bleeds, local infections, and stage 4 haemophilic arthropathy. Data were collected on resolution of target joints, functional (FISH and HJHS)and radiological score (Denver) before the procedure and at 1, 3, 6 months and 12 months post-procedure to assess the efficacy of the intervention. Results A total of 115 procedures were performed in 81 PWH. The median age of patients was 22 years (range: 8-62). Of all the cases, Haemophilia A were 85.3% (n=98), Haemophilia B were 10.4% (n=12), Hemophilia A with Inhibitor were 4.3% (n=5). Among all 94.4% were severe haemophiliacs and 5.6% were moderate haemophiliacs. Of 115 procedure, 57% (n=41) were knee, 25%(n=22) were elbow 13.8% (n=16) were Ankle, 3.4%(n=2) were shoulder joints. The majority 69% of patients had a good Caviglia score, while 31% had a poor score. Out of 81 PWH, 37 PWH with 56 (48.6%) procedures followed up regularly at the defined time-points and assessment was done accordingly. Out of 56 joints 50 had resolution of target joints. Median FISH, HJHS and VAS Scoring at pre procedure, 1 month, 3 months and 6 months are (27, 25, 25 and 24), (18,16,15 and 15) and (6, 5, 5 and 5) respectively with statistically significant improvement (P <0.001). The Denver score didn't show any statistical difference post procedure. The procedure was safe, with two episodes of skin burns reported. Conclusion : People who followed regularly has a decrease in the Annual Joint Bleed Rate. Radiosynovectomy is safe and effective intervention for patients with chronic haemophilic arthropathy irrespective of the type of radionuclide used
2021-01-18 | [Diagnosis and management of hemophilia].
Hemophilia A and B are hereditary coagulation disorders caused by functional and quantitative abnormalities of coagulation factor VIII (FVIII) in hemophilia A and coagulation factor IX (FIX) in hemophilia B. A definitive diagnosis is made through the measurement of FVIII or FIX activity and ruling out other pathological conditions or diseases with decreased FVIII or FIX activity. Severity is classified as severe, moderate, and mild according to factor activity level. Moreover, as frequency of hemorrhage and severity are usually correlated, severe patients have a high risk of intracranial hemorrhage during infancy as well as joint damage due to recurrent hemarthrosis. However, there are some non-severe patients who have symptoms like bleeding and joint damage. Therefore, it is necessary to determine the treatment strategy not only based on severity but also on bleeding symptoms. The treatment for hemophilia is mainly replacement therapy using clotting factor concentrates (standard or extended half-life), such as prophylaxis or on-demand therapy for bleeding. However, there are also clinical problems, such as venous access and development of inhibitors. Recently, a non-factor agent has emerged as a new treatment option. Thus, the management of hemophilia is on a turning point.
2019-12-23 | The chaperone-like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation.
Essentials Missense mutations often impair protein folding, and thus intracellular trafficking and secretion. Cellular models of severe type I hemophilia B were challenged with chaperone-like compounds. Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q. The increased coagulant activity levels (∼3%) of p.R294Q would ameliorate the bleeding phenotype. Background Missense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone-like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications. Objectives To rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I hemophilia B (HB) through chaperone-like compounds. Methods Expression studies of recombinant (r)FIX variants and evaluation of secreted levels (ELISA), intracellular trafficking (immunofluorescence) and activity (coagulant assays) before and after treatment of cells with chaperone-like compounds. Results As a model we chose the most frequent HB mutation (p.R294Q, ~100 patients), compared with other recurrent mutations associated with severe/moderate type I HB. Immunofluorescence studies revealed retention of rFIX variants in the endoplasmic reticulum and negligible localization in the Golgi, thus indicating impaired intracellular trafficking. Consistently, and in agreement with coagulation phenotypes in patients, all missense mutations resulted in impaired secretion (< 1% wild-type rFIX). Sodium phenylbutyrate (NaPBA) quantitatively improved trafficking to the Golgi and dose dependently promoted secretion (from 0.3 ± 0.1% to 1.5 ± 0.3%) only of the rFIX-294Q variant. Noticeably, this variant displayed a specific coagulant activity that was higher (~2.0 fold) than that of wild-type rFIX in all treatment conditions. Importantly, coagulant activity was concurrently increased to levels (3.0 ± 0.9%) that, if achieved in patients, would ameliorate the bleeding phenotype. Conclusions Altogether, our data detail molecular mechanisms underlying type I HB and candidate NaPBA as affordable 'personalized' therapeutics for patients affected by the highly frequent p.R294Q mutation, and with reduced access to substitutive therapy.
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 .
2026-05-12 | Perceptions and Recommendations Regarding Haemophilia B Gene Therapy: A Multistakeholder View From Patients, Caregivers and Healthcare Professionals.
Gene therapy for Haemophilia B has received FDA approval, offering patients a transformative therapeutic option. However, effective communication about the benefits, risks, long-term efficacy and follow-up of gene therapy remains essential for informed decision-making. This study aimed to explore the diverse expectations, concerns and perspectives of patients with Haemophilia B, their caregivers and healthcare professionals (HCPs) regarding gene therapy and to identify strategies for improving communication. A prospective qualitative study was conducted using semi-structured interviews with male patients aged ≥12 years with moderate or severe Haemophilia B (factor level ≤ 2%), their caregivers and HCPs (physicians, nurses, social workers, advanced practice providers and pharmacists). Interviews were audio-recorded, transcribed and analysed thematically. Thirty participants were interviewed, including 15 patients (mean age, 21.1 years), caregivers and 15 HCPs across the United States. Patients and caregivers emphasised five themes: (1) current challenges; (2) hope and optimism; (3) concerns and skepticism; (4) the complex emotional challenges of decision-making and (5) preferences for transparent, patient-friendly communication. HCPs identified four complementary themes: (1) variable patient knowledge; (2) the need for transparency in discussing 'curative' language; (3) factors influencing treatment decisions (trust, prior experiences and financial concerns) and (4) strategies to improve communication (clear language, visuals and testimonials). Stakeholders view gene therapy as both promising and uncertain. Targeted educational interventions, transparent communication and patient-centred decision discussions are essential to fill knowledge gaps and support informed consent in this transformative era of treatment for Haemophilia B.
2026-02-27 | Etranacogene dezaparvovec in people with hemophilia B with preexisting adeno-associated virus 5 neutralizing antibodies: 4-year subgroup results from the HOPE-B trial.
Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) is the first phase 3 trial of adeno-associated virus (AAV) serotype 5 vector-based gene therapy for hemophilia B to have enrolled participants with neutralizing antibodies (NAbs) to the viral vector. Evaluate the efficacy and safety of etranacogene dezaparvovec in a post hoc subgroup of participants with preexisting AAV5 NAbs 4 years posttherapy. After a ≥6-month lead-in period on continuous prophylaxis, people with moderately severe/severe hemophilia B (factor [F]IX ≤ 2%) received a single infusion of etranacogene dezaparvovec. AAV5 NAb status prior to infusion was determined. FIX activity, annualized bleeding rates (ABRs), and safety were evaluated in participants with preexisting AAV5 NAbs. A total of 21/54 participants had detectable preexisting AAV5 NAbs (titer: 8.5-678, n = 20; titer: 3212, n = 1). Two participants did not respond to treatment (high titer: 3212, n = 1; received partial dose, n = 1). The mean FIX activity was 36 IU/dL (SD, 18) at 1 year (n = 18) and 34 IU/dL (SD, 16) at 4 years (n = 15) posttreatment. Unadjusted ABRs for all bleeds (treated and untreated) decreased by 74.4% from 4.64 during lead-in to 1.18 during months 7 to 48 (n = 21). ABRs for spontaneous and joint bleeds decreased by 79% and 82%, respectively. The mean FIX consumption decreased from 245,476 IU/y (SD, 144,497) during lead-in to 23,975 IU/y (SD, 48.928) during years 1 to 4 (P < .0001). The most frequent treatment-related adverse events were infusion-related reactions (23.8%) and transient alanine aminotransferase elevations (14.3%). No late hepatotoxicity was observed. Etranacogene dezaparvovec demonstrated long-term efficacy and safety in individuals with preexisting AAV5 NAb titers ≤ 678, expanding eligibility for gene therapy to a broader hemophilia B population.
2026-02-02 | Etranacogene dezaparvovec in people with hemophilia B and without adeno-associated virus serotype 5 neutralizing antibodies: a 4-year subgroup analysis of the Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) trial.
In the phase 3 Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) trial, a single dose of etranacogene dezaparvovec was administered to people with severe or moderately severe hemophilia B following a lead-in period (≥6 months) during which they received factor (F)IX prophylaxis. Participants were enrolled regardless of adeno-associated virus serotype 5 (AAV5)-neutralizing antibody (NAb) status at screening. To determine efficacy, pharmacokinetic, and safety outcomes over 4 years postgene therapy in HOPE-B participants who were NAb-negative (NAb-). Participants provided serum samples for AAV5 NAb determination using an in vitro AAV5 transduction inhibition assay prior to etranacogene dezaparvovec infusion. Participants who were AAV5 NAb- at this time point were examined in the post hoc subgroup analysis. In NAb- participants (N = 33), the mean adjusted annualized bleeding rate was significantly reduced between months 7 and 48 postetranacogene dezaparvovec vs lead-in (0.57 vs 3.80; P < .0001). In years 1 to 4, the annualized bleeding rates were 0.99, 0.72, 0.41, and 0.41, respectively (P < .0001 vs lead-in; N = 33 throughout). The mean (SD) endogenous FIX activity was 40.6 IU/dL (18.6) at month 6 postinfusion (N = 33), remained stable, and was 39.0 IU/dL (16.8) at year 4 (N = 33). Exogenous FIX consumption decreased by 99% during months 7 to 48 vs the lead-in period, and no NAb- participant returned to continuous FIX prophylaxis for 4 years postinfusion. No treatment-related oncogenic events or persistent late hepatotoxicity were observed. Etranacogene dezaparvovec proved to be highly effective, superior to FIX prophylaxis for bleeding protection, and safe for 4 years postinfusion in NAb- persons with severe or moderately severe hemophilia B.
2025-12-12 | Liver dysfunction in AAV-mediated Hemophilia B gene therapy: Mechanisms and management strategies.
Hemophilia B, an X-linked recessive bleeding disorder caused by mutations in the gene encoding coagulation factor IX (FIX). Gene therapy using adeno-associated viral (AAV) vectors targeting hepatocytes has emerged as a promising treatment, enabling sustained FIX expression. However, AAV vectors exhibit strong liver tropism, often triggering immune responses that lead to hepatotoxicity. Clinical trials involving Etranacogene Dezaparvovec, Fidanacogene Elaparvovec, and BBM-H901 (Dalnacogene Ponparvovec) reported transient elevations in liver enzymes, typically occurring 2-6 weeks post-infusion. These elevations are usually mild to moderate and respond well to corticosteroid-based immunosuppression. The hepatic complications, while manageable, pose a risk to therapeutic efficacy and highlight the need for careful monitoring, early detection, and personalized immunosuppressive strategies. This review explores the mechanisms of AAV-induced liver dysfunction in gene therapy for Hemophilia B, with a focus on clinical manifestations, immune-mediated pathogenesis, and emerging approaches for mitigating liver-related adverse effects and providing clinical guidance.
antibodies
2026-06-01 | Effect of marstacimab in young people living with severe hemophilia A or moderate to severe hemophilia B without inhibitors: A plain language summary from the BASIS study.
What is this summary about? This summary describes a study that looked at how well the study treatment (marstacimab) works in people living with hemophilia. The summary describes how well marstacimab reduced bleeding episodes in young people (adolescents) 12 to 17 years old. Hemophilia is a condition that causes people to bleed more easily because their blood is unable to clot properly. Clotting is when blood turns from liquid into gel to stop bleeding. Hemophilia is caused by not having enough blood clotting factors, which are proteins found in the blood that help in forming a clot and stop bleeding. People living with hemophilia either don't make these proteins, have low amounts of these proteins, or their proteins do not work well. There are different types of hemophilia, depending on which clotting factor is affected. For example, people living with hemophilia A lack clotting factor 8, and people living with hemophilia B lack clotting factor 9. Some treatments for hemophilia work by replacing clotting factors. These treatments are called factor replacement therapy, and are given directly into a vein (called intravenous, or IV for short). They are given frequently, sometimes even more than once a week. In some people living with hemophilia, the body develops antibodies called inhibitors that block replacement clotting factors from working properly. Not all people living with hemophilia produce these antibodies - those who don't are classified as having hemophilia without inhibitors. A different way to treat people living with hemophilia is by using treatment called non-factor replacement therapy. One type of non-factor treatment called marstacimab is given as a regular preventive treatment (called prophylaxis). It works without replacing the missing clotting factors but brings blood clotting and bleeding back to a normal balance. Marstacimab is given once a week as a flat-dose (not based on body weight) injection under the skin (called subcutaneous) using an auto-injector device. This injection is sometimes called a shot and can be easier than injecting directly into a vein. In some cases, marstacimab can be taken less often than clotting factors. Marstacimab offers a new way to treat people living with hemophilia A or B without inhibitors. What were the results of the study? In this study, young people treated with marstacimab for 1 year had on average fewer bleeding episodes than on previous clotting factor replacement treatment. Marstacimab was well tolerated in young people (similar to adults), which means that most side effects that people had were mild to moderate and resolved by the end of the study. What do the results mean? This study showed that a once weekly injection of marstacimab could help reduce bleeding episodes in young people living with hemophilia A or B, without inhibitors.
2026-05-11 | 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.
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.
2026-02-01 | Use of concizumab in children with severe hemophilia B and factor IX-inhibitors
Introduction Patients with severe hemophilia B complicated by high-titer inhibitors and allergic reactions to factor IX concentrate have very limited therapeutic options. Concizumab, a subcutaneous anti–TFPI antibody, represents a novel prophylactic approach for these patients. We report our experience with use of concizumab in three pediatric patients with severe hemophilia B, recurrent inhibitors, allergic reactions to factor IX, and frequent bleeds. Method Clinical data were collected retrospectively from medical records of the patients treated from 2023 -to 2025 with concizumab. Parameters analyzed included genetic findings, treatment history, bleeding events, immune tolerance induction, and outcomes after concizumab initiation. The primary endpoint was the annualized bleeding rate, secondary endpoints were on demand factor use and adverse events. Results Patient A was diagnosed with severe hemophilia B (FIX activity<1%) at the age of seven months following an intracranial hemorrhage. Factor IX inhibitors (peak 7.2 BU) were diagnosed after 3 months. Multiple immune tolerance induction attempts (2017, 2018, 2022) failed and anaphylactic reactions towards factor IX occurred. Prior to concizumab, prophylaxis consisted of frequent recombinant activated factor VII infusions, complicated by poor venous access and multiple central line placements. The annualized bleeding rate (ABR) was 2–3, including recurrent joint bleeds, extensive hematomas, and mucosal bleeds. Concizumab prophylaxis was initiated as compassionate use in November 2024 at 0.2 mg/kg/day s.c. After 11 months, no breakthrough bleeding events occurred (ABR 0); no thromboembolic complications were observed. Reported adverse events were mild and transient (limited to bloating and sweating, local redness at the injection site). Laboratory monitoring (D-dimers, platelets) showed moderate D-dimer elevation. Patient B developed low-titer inhibitors (peak 1.3 BU) after 20 days of exposure to F IX. With rFVIIa prophylaxis every two days the ABR was 1. Following initiation of concizumab with 0.2 mg/kg/day on-demand administration of recombinant factor VII has been necessary four times, mainly prophylactically (ABR 0). No adverse events were observed. Patient C with severe hemophilia B, developed an inhibitor hemophilia after 90 exposure days followed by multiple unsuccessful immune tolerance induction therapies and complicated by severe allergic reactions to factor IX. Since starting Concizumab in February 2025 with 0.2 mg/kg/day only one hip joint bleed occurred (ABR 1) Laboratory tests in general showed a slight increase in D-dimer with normal platelet counts. No reported side effects. All 3 patients had concizumab levels within the target range. Conclusion Concizumab was safe and effective in preventing bleeding in a pediatric patient with severe hemophilia B and inhibitors, substantially reducing treatment burden and improving quality of life. These results support further use of concizumab in this challenging patient population. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-02-01 | First Experience with Marstacimab Monitoring
Introduction The inhibition of tissue factor pathway inhibitor (TFPI) is a new approach to normalize coagulation in patients with hemophilia A and B. TFPI inhibitors indirectly improve the generation of factor Xa, and subsequently factor IIa, which leads to sufficient hemostasis. Hence, thrombin generation (TG) is the perfect candidate for therapy monitoring. Here, we want to present our first data in three patients receiving TFPI inhibitor marstacimab (Pfizer). Method Three patients were included (age 54-64), two with severe hemophilia B and one with moderate hemophilia B (residual activity 3%). All patients were treated according to the manufacturer’s guideline. Thrombin generation was assessed immediately before the first application (baseline) of marstacimab and regularly after therapy started. Thrombin generation was assessed with ST Bleedscreen and ST Thromboscreen (ST Genesia, Stago) and Technoclone TGA (RC high) on the Ceveron analyzer. Results Thrombin generation improves significantly under therapy with marstacimab, in all assays by a factor of 4 to 5 compared to the baseline value. The results are similar between all methods. The patient with the lowest baseline TG achieved about 80% of normal TG (thrombin peak), the other patients between 130% and 140%. So far, no clinical event, bleeding or thrombosis, has been reported by the patients. Conclusion Thrombin generation is a suitable tool for the monitoring of TFPI inhibitor marstacimab. To which extent the data reflect clinical outcome is not clear at this moment; more and longer monitoring is required to answer that question. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
other
2026-01-09 | Molecular mechanisms and therapeutic strategies for the recurrent F9 (c.520 + 13 A > G) variant in hemophilia B.
Hemophilia B (HB), an X-linked recessive disorder, results from variants in the coagulation factor IX gene (F9). The F9 c.520 + 13 A > G variant is a recurrent intronic variant in HB patients, accounting for 15.05% of all documented F9 intronic variants. Despite prior predictions of its impact, the molecular mechanism associated with moderate to mild HB remains undissected. In silico predictions and splicing-competent cDNA constructs were used to assess the impact of F9 c.520 + 13 A > G on mRNA splicing. Factor IX (FIX) variant (p.V174delinsGHNLM) expression in HEK293T cells was evaluated using activated partial thromboplastin time, enzyme-linked immunosorbent assay, Western blot analysis, and immunofluorescence analyses. Structural modeling and molecular dynamics simulations were performed to evaluate the structural impact of the variant. Engineered U1 small nuclear RNA (U1snRNA) was challenged with F9 full-length splicing-competent constructs to evaluate splicing correction. The F9 c.520 + 13 A > G variant caused nearly complete aberrant splicing, producing the F9 c.520_521insGTCATAATCTGA insertion and the in-frame FIX p.V174delinsGHNLM variant. A small amount (approximately 10%) of wild-type FIX was also detected. We characterize the p.V174delinsGHNLM variant, which exhibited impaired secretion and increased intracellular accumulation. Interestingly, an engineered U1snRNA partially rescued aberrant splicing, restoring functional FIX levels to approximately 40%. This study elucidates the molecular mechanism of the F9 c.520 + 13 A > G variant, which activates a cryptic 5' splice site in intron 5, leading to an in-frame FIX (p.V174delinsGHNLM) with secretion defects and loss of protein function. And Engineered U1snRNA partially rescued the splicing defect.
2024-10-01 | SURGICAL EXPERIENCE IN PEOPLE WITH HEMOPHILIA A OR B WITH AND WITHOUT INHIBITORS RECEIVING FITUSIRAN
Background: Fitusiran, a subcutaneous, investigational siRNA therapeutic lowers antithrombin to rebalance hemostasis and enhance thrombin generation in People with Hemophilia (PwH) A or B, regardless of inhibitor status. For the management of perioperative hemostasis, Bleed Management Guidelines (BMG) with reduced dose and/or frequency of Clotting Factor Concentrates (CFC), or Bypassing Agents (BPA) were implemented. Aims: To describe hemostatic outcomes of major surgeries conducted while on fitusiran prophylaxis in PwHA/B aged ≥12-years, regardless of inhibitor status. Methods: All major surgeries in the fitusiran clinical development program until June 2023 were evaluated, including participants on the 80 mg QM and revised antithrombin-based dose regimen. Informed consent and ethics committee approval were obtained for all studies. Procedures conducted during fitusiran prophylaxis and AT activity < 60% were included. Major surgeries included: opening into a major body cavity, operation on a joint, removal of an organ, operative alteration of normal anatomy, crossing of a mesenchymal barrier, dental extraction of molar teeth or ≥3 nonmolar teeth, or tooth implantation. Investigators/surgeon assessed peri-operative hemostatic control based on the ISTH 4-point response scale (excellent/good/moderate/poor). Results and discussion: Sixty major surgeries (24 in inhibitor patients) were performed. In 47 (78.3%) major surgeries, BMG were followed, and reduced doses were used as perioperative prophylaxis. Four major surgeries were conducted without additional CFC/BPA. Hemostatic control on the day of the surgery was rated excellent/good in 30/31 (97%) cases following BMG and 9/10 (90%) cases not following BMG. ATIII concentrate was used to reverse the pharmacodynamic effect of fitusiran in 7 surgeries with an excellent/good hemostatic outcome. No major treatmentrelated safety concerns were identified perioperatively. Postoperative thrombosis occurred only when dosing exceeded BMG recommendations in 2 participants. Conclusions: Major surgeries can be safely and effectively conducted during fitusiran prophylaxis when BMG are followed, irrespective of inhibitor status. Reversal of lowered AT is not necessary.
2021-07-08 | Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort.
Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors. In this open-label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once-monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient-reported outcomes (exploratory). The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean [SEM]) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean [standard deviation] 69.4 [16.3] days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (-9.2 [2.9]) and physical health (-12.3 [3.9]) domain scores suggested clinically meaningful improvement. Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.
2020-08-03 | Pathological mechanism and antisense oligonucleotide-mediated rescue of a non-coding variant suppressing factor 9 RNA biogenesis leading to hemophilia B.
Loss-of-function mutations in the human coagulation factor 9 (F9) gene lead to hemophilia B. Here, we dissected the consequences and the pathomechanism of a non-coding mutation (c.2545A>G) in the F9 3' untranslated region. Using wild type and mutant factor IX (FIX) minigenes we revealed that the mutation leads to reduced F9 mRNA and FIX protein levels and to lower coagulation activity of cell culture supernatants. The phenotype could not be compensated by increased transcription. The pathomechanism comprises the de novo creation of a binding site for the spliceosomal component U1snRNP, which is able to suppress the nearby F9 poly(A) site. This second, splicing-independent function of U1snRNP was discovered previously and blockade of U1snRNP restored mutant F9 mRNA expression. In addition, we explored the vice versa approach and masked the mutation by antisense oligonucleotides resulting in significantly increased F9 mRNA expression and coagulation activity. This treatment may transform the moderate/severe hemophilia B into a mild or subclinical form in the patients. This antisense based strategy is applicable to other mutations in untranslated regions creating deleterious binding sites for cellular proteins.
2017-09-12 | Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.
Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).
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