Search

Abstract: Coagulation factor IX plays a central role in hemostasis through interaction with factor VIIIa to form a factor X-activating complex at the site of injury. The absence of factor IX activity results in the bleeding disorder hemophilia B. This absence of activity can arise either from a lack of circulating factor IX protein or mutations that decrease the activity of factor IX. This review focuses on analyzing the structure of factor IX with respect to molecular mechanisms that are at the basis of factor IX function. The proteolytic activation of factor IX to form activated factor IX(a) and subsequent structural rearrangements are insufficient to generate the fully active factor IXa. Multiple specific interactions between factor IXa, the cofactor VIIIa, and the physiological substrate factor X further alter the factor IXa structure to achieve the full enzymatic activity of factor IXa. Factor IXa also interacts with inhibitors, extravascular proteins, and cellular receptors that clear factor IX(a) from the circulation. Hemophilia B is treated by replacement of the missing factor IX by plasma-derived protein, a recombinant bioequivalent, or via gene therapy. An understanding of how the function of factor IX is tied to structure leads to modified forms of factor IX that have increased residence time in circulation, higher functional activity, protection from inhibition, and even activity in the absence of factor VIIIa. These modified forms of factor IX have the potential to significantly improve therapy for patients with hemophilia B., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Aim: Hemophilic pseudotumor (HP) is a very rare complication of hemophilia seen in only 1-2% of the cases. Although it is much more common in long bones, pelvis and small bones of hands and feet and very rarely involving jaw bones., Method and Result: In the present case, the presence of a rare hemophilic pseudotumor of the mandible with the positive history of Hemophilia B justifies that the history, clinical and radiological examinations were sufficient to arrive at conclusive diagnosis precluding invasive diagnostic procedures such as biopsy hence avoiding the risk of hemorrhage, infection, or fistula. This case also highlights that patient was conservatively managed with Factor IX replacement alone with a very good clinical outcome., Conclusion: HP should be considered as a differential diagnosis of any progressive swelling of hard and soft tissues occurring in a patient with severe haemophilia., (© 2024 Special Care Dentistry Association and Wiley Periodicals LLC.)

Objectives: Haemophilia B (HB), characterised by deficient factor IX (FIX), leads to spontaneous bleeds. Severe cases require prophylactic FIX replacement. This post hoc analysis assessed the first spontaneous bleeds among previously untreated patients (PUPs) with HB treated with recombinant FIX Fc fusion protein (rFIXFc) (NCT02234310) to identify factors influencing bleeds., Methods: Subjects included paediatric PUPs with HB (≤2 IU/dL endogenous FIX). Analyses described treatment patterns (on demand [OD] vs. prophylaxis) and prophylaxis type (started on vs. switched to prophylaxis). Kaplan-Meier analyses assessed the time to first spontaneous bleed, including median time to event and fitting models with predictors for treatment regimen and/or baseline age., Results: PUPs B-LONG enrolled 33 subjects. Baseline age did not influence the time to first spontaneous bleed for any rFIXFc regimen. Those who started on prophylaxis with rFIXFc (n = 11), compared with those treated OD (n = 22), had an extended time to first spontaneous bleed. Starting prophylaxis afforded a 93% reduced risk of first spontaneous bleed versus starting OD (hazard ratio [95% confidence interval]: 0.071 [0.009-0.592]) (p = .015)., Conclusion: rFIXFc prophylaxis, particularly starting early, reduced the risk of bleeding and delayed time to first spontaneous bleed compared with rFIXFc OD. Hence, initial treatment regimens impact bleed patterns in paediatric PUPs., (© 2024 Sanofi and The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Hemophilia B is characterized by a deficiency of clotting factor IX (FIX), leading to excessive bleeding. Hemophilia B is commonly treated using replacement FIX therapy, which may be administered prophylactically or on-demand following a bleeding episode. Previous research has found high health care resource use (HCRU) and costs among Medicare and commercially insured people with hemophilia B (PwHB), with FIX therapy being a primary driver of health care costs., Objective: To assess HCRU, outcomes, and costs among US Medicaid beneficiaries receiving FIX prophylaxis for hemophilia B., Methods: This study employed a retrospective comparative cohort design to assess HCRU, outcomes, and costs among adult male Medicaid beneficiaries receiving FIX prophylaxis for hemophilia B, relative to a matched comparator population of beneficiaries without bleeding disorders. Nationwide Medicaid claims and enrollment data from 2015 to 2020 were used for this analysis. Adult male PwHB who received FIX prophylaxis, defined as not having identified gaps in FIX therapy exceeding 60-days during a 1-year measurement period, and were continuously enrolled in Medicaid for at least 2 years, were matched 1:4 to comparator beneficiaries without bleeding disorders based on baseline demographic and clinical characteristics. Key measures of HCRU and outcomes included inpatient hospital admissions, outpatient hematologist visits, and bleeding events. Measures of health care costs were assessed among a subset of beneficiaries enrolled in fee-for-service Medicaid., Results: PwHB receiving FIX prophylaxis were significantly more likely to have multiple inpatient hospital admissions and had a longer cumulative length of stay per person relative to comparator beneficiaries (30.2 vs 14.8 days, respectively; P = 0.0473). PwHB receiving FIX prophylaxis also had significantly higher rates of bleeding events relative to comparator beneficiaries (0.54 vs 0.02 per person, respectively; P < 0.0001) and outpatient hematologist visits (1.58 vs 0.20 per person, respectively; P < 0.0001). Annual costs among PwHB receiving FIX prophylaxis were significantly higher than costs among comparator beneficiaries ($928,370 vs $34,553 per person, respectively; P < 0.0001) and were overwhelmingly driven by costs associated with FIX therapy., Conclusions: This analysis found higher rates of HCRU and costs among Medicaid beneficiaries receiving FIX prophylaxis for hemophilia B relative to a matched comparator population of beneficiaries without bleeding disorders. Future research should examine hemophilia B costs and outcomes within the context of new treatments with innovative mechanisms of action, such as gene therapies, RNA interference therapies, and antitissue factor pathway inhibitor therapies.

Background:  Fidanacogene elaparvovec, an adeno-associated virus-based gene therapy vector expressing the high-activity factor IX (FIX) variant FIX-R338L, is in development for hemophilia B. One-stage clotting (OS) assays and chromogenic substrate (CS) assays are commonly used to measure FIX-R338L variant activity. Data from ongoing trials suggest FIX activity varies between different OS and CS assays., Material and Methods:  To better understand FIX-R338L activity in clinical samples, an international multisite field study was conducted across a central laboratory and 18 local laboratories, using standard protocols, reagents, and instrumentation, with individual participant samples from a phase 1/2a study of fidanacogene elaparvovec., Results:  Unlike the wild-type FIX control, FIX-R338L activity was higher with the OS silica-based assay versus OS ellagic acid-based and CS assays. Variation in FIX activity was greater at the lowest activity levels. Activated FIX (FIXa) in plasma could result in higher OS assay activity or increased thrombin generation, which could overestimate FIX activity. However, FIXa was not detected in the participant samples, indicating that it was not contributing to the OS assay differences. Since individuals on gene therapy may receive exogenous replacement FIX products, replacement products were spiked into patient plasma samples to target a therapeutic concentration. Exogenous FIX was additive to endogenous FIX-R338L, with no interference from FIX-R338L., Conclusion:  These results demonstrate FIX-R338L activity can be measured with OS and CS assays in clinical laboratories and provide insight into assay variability when measuring FIX with endogenously produced FIX-R338L. The findings may help establish best practices for measuring FIX-R338L activity (Clinicaltrials.gov identifier: NCT02484092)., Competing Interests: C.C., J.M., C.Y.T., J.Z.L., P.G., and J.R. are employees of Pfizer and may own stock/options in the company. D.D.P., H.S., S.R., J.-C.M., and J.E.M. were employees of Pfizer at the time of the study conduct and may own stock/options in the company., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product's optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences., (© 2024. The Author(s).)

Objective: To review efficacy and safety data of valoctocogene roxaparvovec (Roctavian) and etranacogene dezaparavovec (Hemgenix), novel gene therapies for the treatment of the life-threatening bleeding disorders hemophilia A and B, respectively., Data Sources: A PubMed/Google Scholar search from inception through August 11, 2023 was conducted using the following keywords: gene therapy , hemophilia A , hemophilia B , etranacogene dezaparavovec , valoctocogene roxaparvovec , and bleeding., Study Selection and Data Extraction: Data, including phase 1 to 3 clinical trials (non-comparator), were obtained from primary literature and package inserts. These reports evaluated clinical pharmacology, efficacy, safety, adverse events, warnings, and precautions., Data Synthesis: Valoctocogene phase 3 study in males (n = 134): 87% had factor VIII (FVIII) levels that at least met criteria for mild hemophilia. Etranacogene phase 3 study in males (n = 54): within 3 weeks of infusion, mean factor IX (FIX) levels had reached 26.8 IU/dL. Both therapies provided clinically and statistically significant decreases in bleeding events and prophylactic factor infusions. Most common adverse event was elevations in liver function tests that were treated with glucocorticoids., Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs: The endogenous production of clotting factors mimics physiological production while decreasing morbidity and mortality related to bleeding events similar to the effects of existing replacement strategies. Gene therapy was also shown to increase patient quality of life., Conclusion: Valoctocogene and etranacogene provide another treatment for selected patients with hemophilia. Treatment for the patient with hemophilia (gene therapy vs replacement strategy) must be personalized as new clinical data are published being cognizant of drug affordability., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This viewpoint discusses cost-effectiveness estimates for EtranaDez, a gene therapy for hemophilia B, using the Institute for Clinical and Economic Review's (ICER) framework for single and short-term therapies (SSTs). EtranaDez offers long-term benefits from a single administration, in contrast to the high costs and frequent dosing required by current factor IX prophylaxis. However, the projected gains in health from EtranaDez are small relative to the cost implications of the therapy, and consequently, how the cost offsets associated with EtranaDez are counted has a substantial impact on assessing its cost-effectiveness. Strategies for assessing cost offsets used in the ICER SST framework include a 50/50 cost-sharing model between the health care system and the manufacturer and a cap of $150,000 annually on health care cost offsets. Results from the standard full cost-offset analysis as reported by ICER depicted EtranaDez as a dominant therapy with substantial cost savings compared with factor IX prophylaxis. However, while considering the ICER SST framework, particularly the $150,000 annual cap scenario, the cost-effectiveness was significantly reduced. The incremental cost-effectiveness ratio varied notably between these scenarios, challenging the conventional perception of value of gene therapy in health care. These cost-sharing scenarios highlight the potential of the ICER SST framework to help curtail inefficient health care spending. In cases in which the cost of existing treatment is exceedingly high, the application of such frameworks would improve efficiency in resource allocation, fostering a balance between incentives for innovation and economic sustainability in managed care systems.

Background: Etranacogene dezaparvovec is a recently approved gene therapy for people with hemophilia B (PwHB). Current standard of care is prophylaxis with factor IX (FIX) to prevent bleeding. Etranacogene dezaparvovec increases blood FIX levels such that FIX prophylaxis could be eliminated., Objective: To estimate the budgetary impact of etranacogene dezaparvovec adoption and utilization in a commercial health plan of the United States., Methods: A budget impact model was developed to evaluate the introduction of etranacogene dezaparvovec to treat severe or moderately severe hemophilia B. The model considered a hypothetical 1-million-member plan over a 5-year horizon. FIX therapy prophylaxis use was estimated based on a weighted average of relevant brands using US market share data. A scenario of etranacogene dezaparvovec adoption/utilization was compared with one without etranacogene dezaparvovec utilization. Two etranacogene dezaparvovec uptake (market share growth) analyses were performed: one with gradual uptake and alternatively assuming all eligible PwHB received etranacogene dezaparvovec in year 1. The one-time cost of etranacogene dezaparvovec was assumed to be $3.5 million. Other costs (FIX prophylaxis, disease monitoring, bleed management, and adverse events) were estimated from published literature. All costs were in 2022 US dollars. Bleed and adverse event rates were sourced from the HOPE-B trial comparing etranacogene dezaparvovec to previous FIX therapy prophylaxis. The model estimated annual and per-member per-month costs over 5 years. Secondary analyses were performed considering a 10-year horizon., Results: In the 1-million-member health plan, an estimated 1.8 PwHB were eligible for treatment with etranacogene dezaparvovec. Gradual uptake of etranacogene dezaparvovec resulted in cumulative 5-year budget impact of $848,509 compared with a scenario without etranacogene dezaparvovec. In years 1-5, the incremental annual and per-member per-month costs ranged from $79,824 to $271,435 and from $0.007 to $0.023, respectively. In the alternative uptake analysis, etranacogene dezaparvovec became cost saving annually beginning in year 2 and cumulatively beginning in year 5, for a 5-year savings of $754,844. Secondary analyses over 10 years found both uptake analyses cost saving. Other scenarios considered did not affect results substantially., Conclusions: Introducing etranacogene dezaparvovec as treatment for PwHB would have a modest budget increase within 5 years after treatment but may become cost saving if all eligible PwHB were treated in year 1. Initiating PwHB on etranacogene dezaparvovec sooner may produce greater overall savings and earlier annual savings. Etranacogene dezaparvovec is a treatment option that may provide overall cost savings for US commercial health plans, which would increase as the plan size increases.

Case: A 29-year-old man with hemophilia B presented with advanced arthropathy of the right knee, resulting in poor knee functional scores and difficulties in his livelihood. The patient underwent total knee replacement while receiving nonacog beta pegol factor IX by a multidisciplinary approach., Conclusion: Hemophilias commonly result in end-stage hemophilic arthropathy of the joints at a young age that may warrant joint replacement surgeries. This case report illustrates the surgical protocol of total knee arthroplasty in a patient who received a long-acting factor IX preparation., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C405)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Congenital hemophilia B is a rare X-linked recessive bleeding disorder caused by factor IX deficiency. Acquired hemophilia A is a rare, acquired bleeding disorder that presents with new-onset bleeding, especially in older adults, due to the development of auto-antibodies against factor VIII (FVIII). This case report presents the medical management of a patient with congenital hemophilia B and acquired hemophilia A. We highlight the limitations of maintaining factor levels with factor replacement therapy alone, particularly in hemophilia patients who have developed factor inhibitors. In addition, we draw attention to the need for dose escalation, the cost, and the need for immune-tolerance induction therapy. This case illustrates that when the current diagnosis does not explain the full clinical picture and laboratory data are inadequate, it is important to continue to seek alternative diagnoses and cost-effective treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Hemophilia A/B are caused by deficiency or lack of coagulation factors VIII (FVIII) or factor IX (FIX), respectively, in plasma. A person with hemophilia develops bleeding in the joints and muscles at an early age, which, if left untreated, leads to early arthropathy. Preventive treatment can be achieved by regular (prophylactic) administration of FVIII/FIX. In 1958, this was implemented on a small scale in Sweden with FVIII in patients with severe hemophilia A, and in those with hemophilia B in 1972 when FIX became available. However, there were problems with human immunodeficiency virus and hepatitis infection from contaminated blood products. In the 1990s, recombinant FVIII and FIX concentrates were introduced. The major remaining problems then were the development of inhibitors, and the need for a venous route for the injections in very young children. High-titer inhibitors were treated by immune tolerance induction according to a modified model of the original Bonn high-dose protocol. A central venous line, i.e., Port-A-Cath, has enabled early prophylaxis in many children with poor venous access and has enabled the early start of home treatment with adequate injection frequency. Scoring systems for X-rays, magnetic resonance imaging, and function of joints were developed early in Sweden and have been widely disseminated worldwide, partly with modifications. Extended half-life products with half-life increased three to five times have been developed, which can provide superior bleed protection when dosed once-weekly and can maintain therapeutic trough levels when administered less frequently. The ultimate prophylaxis therapy in the future may be gene therapy., Competing Interests: R.L. has during the past 3 years received consultancy or speaker's fee from Idogen AB, Sobi, NovoNordisk, Takeda, Sanofi, and Bayer; none of these are related to the present work., (Thieme. All rights reserved.)

Introduction: Recombinant factor IX (rFIX) and recombinant FIX Fc fusion protein (rFIXFc) are standard half-life and extended half-life FIX replacement therapies, respectively, and represent established treatment options indicated for adults and children with haemophilia B. These FIX replacement therapies can be administered as prophylaxis (to prevent bleeding) or 'on-demand' (to stop bleeding). This analysis aimed to estimate the cost-effectiveness of once-weekly prophylaxis with rFIXFc versus on-demand treatment with rFIX in patients with haemophilia B without inhibitors in the Italian healthcare setting., Methods: A Markov model was developed to assess a hypothetical cohort of adolescent or adult male patients (≥ 12 years) with haemophilia B (FIX level of ≤ 2 IU/dL) without inhibitors. Model inputs were derived from the pivotal phase 3 clinical studies for rFIXFc and rFIX, published literature and assumptions when published data were unavailable. The model employed a lifelong time horizon with 6-monthly transitions between health states, and it estimated total costs, total quality-adjusted life years (QALYs), number of bleeds, number of surgeries and incremental cost-effectiveness ratio., Results: rFIXFc prophylaxis was associated with lower total costs per patient (€5,308,625 versus €6,564,510) and greater total QALYs per patient (15.936 versus 11.943) compared with rFIX on-demand; rFIXFc prophylaxis was therefore the dominant treatment strategy. The model also demonstrated that rFIXFc prophylaxis was associated with fewer incremental bleeds (- 682.29) and surgeries (- 0.39) compared with rFIX on-demand., Conclusions: rFIXFc prophylaxis provides improved health outcomes and lower costs, and represents a cost-effective treatment option compared with rFIX on-demand for adolescent and adult male patients with haemophilia B. This comparative assessment of cost-effectiveness should help to inform both clinicians and healthcare policy makers when making treatment decisions for patients with haemophilia B., (© 2024. The Author(s).)

Introduction: For people with haemophilia B (PwHB), bleeding may occur despite prophylaxis, negatively affecting health-related quality of life (HRQoL). The pivotal phase 3 HOPE-B trial investigating the adeno-associated virus gene transfer product, etranacogene dezaparvovec (EDZ), demonstrated sustained factor IX (FIX) activity and bleed protection in PwHB with baseline FIX levels ≤2%., Aim: Assess how EDZ affects HRQoL in HOPE-B trial participants., Methods: HRQoL was evaluated using generic and disease-specific patient reported outcomes (PROs) including the EQ-5D-5L and the Hem-A-QoL questionnaires. Mean domain and total scores were compared 6 months pre- and the first 2 years post-EDZ administration using repeated measures linear mixed models. The percentage of participants with minimal clinically important improvements in HRQoL was also evaluated., Results: Two years post-EDZ, there were nominally significant increases in the least squares (LS) mean score for the EQ-5D-5L Index Value (.04; p = .0129), reflecting better HRQoL. Nominally significant decreases in the LS mean scores, reflecting better HRQoL, were also found for the Hem-A-QoL total score (-6.0; p < .0001) and the Treatment (-13.94; p < .0001), Feelings (-9.01; p < .0001), Future (-6.45; p = .0004) and Work/School (-5.21; p = .0098) domains. The percentage of participants with ≥15-point improvement ranged from 45.83% (95% CI: 31.37%, 60.83%) for Treatment to 13.89% (95% CI: 4.67%, 29.50%) for Family Planning. Results were similar for Year 1., Conclusion: In conclusion, gene therapy with EDZ improved HRQoL in the first and second years in several Hem-A-QoL domains, including Treatment, Feelings, Work/School and Future domains, whereas improvement in other aspects of HRQoL were not demonstrated., (© 2024 CSL Behring and The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Objectives: to assess the variability in expenditure compared to 2022 assuming different rates of shifting of therapy days from current active ingredients used for the treatment of haemophilia B to nonacog beta pegolDesign: descriptive cross-sectional study., Setting and Participants: consumption in the year 2022 (data source: Medicines Utilisation Monitoring Centre, Italian Medicines Agency) of all medicinal products available in Italy containing coagulation factor IX., Main Outcomes Measures: for each active ingredient, the total number of therapy days and the variability in expenditure compared to 2022 were estimated on the basis of a switch of therapy days, between 5% and 20%, to nonacog beta pegol., Results: on the basis of considered scenarios, the analysis shows that the total annual expenditure for clotting factors used in the treatment of haemophilia B could remain at most unchanged or reduced. Particularly, the extent of the reduction in spending could vary from 0.11% to 2.26%. This trend would be in contrast to the stable increase seen in recent years, particularly in 2022., Conclusions: this predictive spending assessment may be useful in evaluating the economic impact from new treatment options, such as etranacogene dezaparvovec gene therapy already approved by the European Medicines Agency and the Food and Drug Administration, and to improve pharmaceutical governance.

Objectives: To describe people with hemophilia B (PWHB) in the US who experience bleeds despite factor replacement therapy and to quantify the associated burden from the third-party payer perspective., Study Design: Observational study of adult male PWHB treated with factor IX replacement therapy identified from the PharMetrics Plus claims data from 2010 to 2019., Methods: Patients with medically recorded bleeds (MRBs) were identified using diagnostic codes. Rates and rate ratios of inpatient admissions, emergency department (ED) visits, and outpatient visits among PWHB with and without MRBs were estimated. The presence of comorbidities was identified using diagnostic codes, and the analysis was stratified by age group., Results: There were 345 PWHB with MRBs and 252 without MRBs. More than half of PWHB with MRBs (56.8%) had 1 or more comorbidity vs 39.3% of PWHB without MRBs. The prevalence of anxiety and depression was high in PWHB, regardless of bleed status and age group, whereas the prevalence of other comorbidities increased with age group. The rate of all-cause inpatient admissions for PWHB with MRBs was 14.8 per 100 person-years (95% CI, 12.8-17.1), 2.5 times higher than for PWHB without MRBs. The rate of all-cause ED visits for PWHB with MRBs was 67.6 per 100 person-years (95% CI, 63.2-72.3), 2.7 times higher than for those without MRBs., Conclusions: This study reports significant resource use and clinical burden among PWHB who seek medical care. PWHB with MRBs had considerable all-cause resource use compared with PWHB without MRBs. The prevalence of mental illness was consistently high across all age groups.

Objectives: To evaluate pattern of use and clinical outcomes in pediatric/adolescent patients enrolled in the IDEAL study., Methods: This post-hoc analysis of IDEAL retrospective-prospective observational study focused on patients <18 years, 100% on prophylaxis during the entire observation period., Results: Thirteen subjects (median age 10.0 years; 61.5% ≤ 11 years) were analyzed. The infusion frequency changed from 2/week in 84.6% (N = 11) of patients with previous rFIX, to less than 1/weekly in 76.9% (N = 9) with rIX-FP and the annualized number of infusions reduced of 57% (p = .002), from a mean ± SD of 95.1 ± 22.77 to 40.4 ± 6.79, respectively. Annualized mean consumption decreased of about 56% (p = .001), from 3748.4 ± 1155.40 IU/kg with previous rFIX, to 1656.8 ± 456.63 IU/kg of rIX-FP. Mean FIX trough level changed from 3.0% ± 1.98% to 10.92% ± 3.6%. Low mean Annualized Bleeding Rate was maintained across all prophylaxis regimens (0.8 ± 1.69 vs. 0.3 ± 0.89) and zero bleeding patients moved from 69.2% (N = 9) with previous rFIX to 84.6% (N = 11) with rIX-FP (p = .63). Two adverse events, none related to rIX-FP, occurred in two patients. No inhibitors development was reported., Conclusions: The results in this pediatric/adolescent subgroup support rIX-FP prophylaxis may reduce infusion frequency, while providing high FIX trough levels, stable annualized bleeding rate and a good safety profile., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Abstract: The US Food and Drug Administration (FDA)'s authorization of etranacogene dezaparvovec (Hemgenix) is a significant milestone, constituting not only the first FDA approval of a gene therapy for hemophilia but also the first approval of a liver-targeted adeno-associated virus vector gene therapy. This review summarizes the nonclinical studies and clinical development that supported regulatory clearance. Similar to other gene therapies for single gene disorders, both the short-term safety and the phenotypic improvement were unequivocal, justifying the modest-sized safety and efficacy database, which included 57 participants across the phase 2b (3 participants) and phase 3 (54 participants) studies. The most common adverse reactions included liver enzyme elevation, headache, flu-like symptoms, infusion-related reactions, creatine kinase elevation, malaise, and fatigue; these were mostly transient. One participant had hepatocellular carcinoma on a study-mandated liver ultrasound conducted 1 year after vector infusion; molecular analysis of the resected tumor showed no evidence of vector-related insertional mutagenesis as the etiology. A remarkable 96% of participants in the phase 3 trial were able to stop factor IX (FIX) prophylaxis, with the study demonstrating noninferiority to FIX prophylaxis in terms of the primary end point, annualized bleeding rate. Key secondary end points such as the annualized infusion rate, which declined by 97%, and the plasma FIX activity level at 18 months after infusion, with least squares mean increase of 34.3 percentage points compared with baseline, were both clinically and statistically significant. The FDA's landmark approval of Hemgenix as a pioneering treatment for hemophilia stands on the shoulders of >20 years of gene therapy clinical research and heralds a promising future for genomic medicines., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Inferior vena cava thrombosis (IVCT) is rare. Thrombophilia is one of the important risk factors. It is also uncommon for gene mutations in F9 gene to cause thrombosis but not hemorrhage. A 35-year-old male patient was admitted to our department with left lower limb swelling without an obvious cause for 1 day. Through contrast-enhanced computed tomography and color Doppler ultrasound, he was found to have lower extremity deep vein thrombosis, IVCT and pulmonary embolism. Through whole-exome sequencing analysis, he was found to carry a 925.7 kb duplication (chrX:137939698-138865419, hg19) encompassing ATP11C , SRD5A1P1 , MCF2 , FGF13 and F9 genes. This duplication of F9 gene was not detected in his parents. Other thrombophilic genes defects were not found. The factor IX activities of this patient, his father and mother were 194, 70 and 148, respectively. He was treated with catheter-directed thrombolysis, AngioJet-assisted pharmaco-mechanical thromboectomy and manual aspiration thromboectomy. Complete recanalization of left femoral, iliac veins and inferior vena cava was achieved. F9 gene duplication is a rare mutation, which can induce multiple venous thrombosis through increasing the activity level of factor IX in plasma. IVCT is a serious type of venous thrombosis. Personalized intervention treatment plans should be developed based on the different clinical characteristics of each case to achieve a higher benefit-risk ratio., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The advent of therapeutic recombinant factor VIII (FVIII) and factor IX (FIX) protein infusions revolutionized the care of persons with haemophilia in the 1990s. It kicked off an era with the increasing use of prophylactic factor infusions for patients and transformed conversations around the ideal trough activity levels as well as the ultimate goals in tailored, individualized care. Our knowledge surrounding the immunologic basis of inhibitor development and treatment derives from a time when patients were receiving frequent factor infusions and focused on immune tolerance induction following inhibitor development., Discussion: More recently, care was revolutionized again in haemophilia A with the approval of emicizumab, a bispecific antibody mimicking activated FVIII function, to prevent bleeding. The use of emicizumab prophylaxis has resulted in a significantly slower accumulation of factor exposure days and continued effective prophylaxis in the case of inhibitor development. While emicizumab is effective at reducing the frequency of bleeding events in patients with haemophilia A, management of breakthrough bleeds, trauma, and surgeries still requires additional treatment. Ensuring that FVIII is a therapeutic option, particularly for life-threatening bleeding events and major surgeries is critical to optimizing the care of persons with haemophilia A. Other novel non-factor concentrate therapies, including rebalancing agents, will dramatically change the landscape for persons with haemophilia B with inhibitors., Conclusion: This review discusses the changing landscape regarding the timing of inhibitor development and management strategies after inhibitor development, stressing the importance of education across the community to continue to vigilantly monitor for inhibitors and be prepared to treat persons with inhibitors., (© 2024 John Wiley & Sons Ltd.)

Early gene therapy clinical trials for the treatment of Haemophilia B have been instrumental to our global understanding of gene therapy and have significantly contributed to the rapid expansion of the field. The use of adeno-associated viruses (AAVs) as vectors for gene transfer has successfully led to therapeutic expression of coagulation factor IX (FIX) in severe haemophilia B patients. Expression of FIX has remained stable following a single administration of vector for up to 8 years at levels that are clinically relevant to reduce the incidence of spontaneous bleeds and have permitted a significant change in the disease management with reduction or elimination of the need for coagulation factor concentrates. These trials have also shed light on several concerns around AAV-mediated gene transfer such as the high prevalence of pre-existing immunity against the vector capsid as well as the elevation of liver transaminases that is associated with a loss of FIX transgene expression in some patients. However, this field is advancing very rapidly with the development of increasingly more efficient strategies to overcome some of these obstacles and importantly raise the possibility of a functional cure, which has been long sought after. This review overviews the evolution of gene therapy for haemophilia B over the last two decades., Competing Interests: Declaration of competing interest VM has no conflict of interest. ACN is a founder of, owns equity in and acts as a consultant for Freeline Therapeutics. In addition he holds a sponsored research agreement from Freeline Therapeutics and is an inventor on patents licenced to the company. ACN also holds Revenue Sharing Agreement with St Jude's hospital., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: Andexanet alfa is a targeted reversal agent for life threatening hemorrhage associated with direct acting oral anticoagulants (DOACs), but there is uncertainty regarding the benefit when compared to 4-factor prothrombin complex concentrate (4F-PCC) for this indication. We investigated the clinical outcomes and cost associated with reversal of DOACs in the setting of life-threatening intracranial hemorrhage (ICH)., Methods: A retrospective evaluation was conducted to evaluate patients with ICH in the setting of anticoagulation with DOAC from 9/1/2013 to 4/30/2020. Patients were included in the study if they received reversal with either andexanet alfa or 4F-PCC., Results: Eighty-nine patients were included in the study. There was no statistically significant difference in 30-day mortality between patients who received andexanet alfa or 4F-PCC (52% vs. 35%, P  = 0.14). Radiographic stability of bleed was identified in 57% of patients receiving andexanet alfa vs. 58% of patients receiving 4F-PCC ( P  = 0.93). Median length of stay was not different between the andexanet alfa and 4F-PCC populations (7 days [IQR 6 - 12] vs. 6 days [IQR 3-12], P  = 0.66). Median cost of reversal agent was higher in patients receiving andexanet alfa compared to 4F-PCC ($15 000 [IQR 15 000-$27 000] vs. $11 650 [IQR $8567-$14 149])., Conclusion: Among patients with life-threatening intracranial hemorrhage in the setting of DOAC therapy, no clinical differences were observed with respect to selection of reversal agent. Prothrombin complex concentrates remain a viable alternative to reversal of DOAC therapy though multicenter, randomized, prospective studies are needed to further evaluate the role of 4F-PCC in the reversal of DOAC therapy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Hemophilia B (HB) is a rare, hereditary disease caused by a defect in the gene encoding factor IX (FIX) and leads to varying degrees of coagulation deficiency. The prevailing treatment for people with HB (PWHB) is FIX replacement product. The advent of recombinant coagulation products ushered in a new era of safety, efficacy, and improved availability compared with plasma-derived products. For people with severe HB, lifelong prophylaxis with a FIX replacement product is standard of care. Development of extended half-life FIX replacement products has allowed for advancements in the care of these PWHB. Nonetheless, lifelong need for periodic dosing and complex surveillance protocols pose substantive challenges in terms of access, adherence, and healthcare resource utilization. Further, some PWHB on prophylactic regimens continue to experience breakthrough bleeds and joint damage, and subpopulations of PWHB, including women, those with mild-to-moderate HB, and those with inhibitors to FIX, experience additional unique difficulties. This review summarizes the current challenges faced by PWHB, including the unique subpopulations; identifying the need for improved awareness, personalized care strategies, and new therapeutic options for severe HB, which may provide future solutions for some of the remaining unmet needs of PWHB., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Introduction: Prophylactic treatment of hemophilia B with recombinant factor IX (rFIX) molecules with enhanced pharmacokinetics including rIX-FP (albutrepenonacog alfa; Idelvion © ) and rFIXFc (eftrenonacog alfa; Alprolix © ) have commonly been used in the clinic. In the absence of head-to-head comparative trials, the aim of this study was to estimate the efficacy of rIX-FP versus rFIXFc using matching-adjusted indirect comparisons (MAICs)., Methods: MAIC analyses leveraged individual patient data from the PROLONG-9FP trial and published summary-level data from the B-LONG trial for subjects who received weekly prophylaxis regimens. Individual patient data were used to assign weights and balance subjects from PROLONG-9FP with subjects from B-LONG on baseline disease severity, age, prior FIX regimen, and body mass index (BMI). Six efficacy outcomes were analyzed including annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR), annualized joint bleeding rate (AjBR), and the proportion of subjects without bleeding events (for total, spontaneous, and joint bleeding events)., Results: After adjustment for baseline disease severity, age, prior FIX regimen, and BMI, rIX-FP was associated with a statistically significant decrease in AsBR (rate ratio [RR] 0.42; 95% confidence interval [CI] 0.22, 0.82; P = 0.0107), and the proportion of patients without bleeding events (odds ratio [OR] 3.24; 95% CI 1.41, 7.45; P = 0.0057), spontaneous bleeding events (OR 3.47; 95% CI 1.56, 7.73; P = 0.0023), and joint bleeding events (OR 2.41; 95% CI 1.10, 5.26; P = 0.0274) compared with rFIXFc. Prophylactic treatment with rIX-FP was also associated with a numerically lower ABR (RR 0.75; 95% CI 0.32, 1.75; P = 0.5095) and AjBR (RR 0.82; 95% CI 0.37, 1.82; P = 0.6178)., Conclusion: The MAICs demonstrated that weekly prophylaxis treatment of severe hemophilia B with rIX-FP resulted in favorable efficacy outcomes as compared to rFIXFc. These findings suggest rIX-FP may offer improved clinical benefits over rFIXFc., (© 2024. The Author(s).)

Introduction: Haemophilia B (HB) is an X-linked hereditary bleeding disorder characterized by coagulation factor IX (FIX) deficiency. To improve the quality of life of patients and adherence to treatment, recombinant factor concentrates modified to extend their half-life have been developed, called extended half-life factors (EHL: extended half-life). Nonacog beta pegol (N9-GP) is a glycopegylated recombinant human FIX molecule that has a half-life of 93 h with a single dose and has shown a higher recovery percentage than other molecules. To diagnose and monitor the treatment of haemophiliac patients, FIX activity is determined with the one-stage clotting assay (OSA) and/or the chromogenic assay. The objective of this work, carried out in three centres, was to measure the recovery of N9-PG with 10 different activated partial thromboplastin time (APTT) reagents on three platforms, in samples spiked in vitro with N9-GP, at four different concentration levels., Methods: It was measured the recovery of N9-GP with 10 different APTT reagents (polyphenol, ellagic acid, silice dioxide, colloidal silica as APTT activator on three platforms, in sample spiked in vitro with N9-GP., Results: The results show heterogeneity in the activity of N9-GP measured by OSA with the different APTT reagents when the calibrations were performed with the specific calibrator of each coagulometer. A recovery percentage between 87% and 108% was obtained only with polyphenol and ellagic acid as activator in the three platforms evaluated. The other reagents studied overestimate or underestimate, with no clear profile. When a calibration curve was performed with a calibrator prepared from the N9-GP vial, all APTT reagents met the established recovery requirement., Conclusion: APTT reagents with polyphenol or ellagic acid as activator would be the only ones appropriate when using the commercially available OSA with specific calibrator to monitor patients treated with N9-GP., (© 2023 John Wiley & Sons Ltd.)

Abstract: Hemophilia B (HB) is caused by an inherited deficiency of plasma coagulation factor IX (FIX). Approximately 60% of pediatric patients with HB possess a severe form of FIX deficiency (<1% FIX activity). Treatment typically requires replacement therapy through the administration of FIX. However, exogenous FIX has a limited functional half-life, and the natural anticoagulant protein S (PS) inhibits activated FIX (FIXa). PS ultimately limits thrombin formation, which limits plasma coagulation. This regulation of FIXa activity by PS led us to test whether inhibiting PS would extend the functional half-life of FIX and thereby prolong FIX-based HB therapy. We assayed clotting times and thrombin generation to measure the efficacy of a PS antibody for increasing FIX activity in commercially obtained plasma and plasma from pediatric patients with HB. We included 11 pediatric patients who lacked additional comorbidities and coagulopathies. In vivo, we assessed thrombus formation in HB mice in the presence of the FIXa ± PS antibody. We found an accelerated rate of clotting in the presence of PS antibody. Similarly, the peak thrombin formed was significantly greater in the presence of the PS antibody, even in plasma from patients with severe HB. Furthermore, HB mice injected with PS antibody and FIX had a 4.5-fold higher accumulation of fibrin at the thrombus induction site compared with mice injected with FIX alone. Our findings imply that a PS antibody would be a valuable adjunct to increase the effectiveness of FIX replacement therapy in pediatric patients who have mild, moderate, and severe HB., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Etranacogene dezaparvovec (EDZ), Hemgenix, is a gene therapy recently approved for people with hemophilia B (PwHB)., Objective: To estimate long-term clinical impact and cost of EDZ in the United States (US)., Methods: A decision-analytic model was developed to evaluate the long-term impact of introducing EDZ for PwHB over a 20-year time horizon. Factor IX (FIX) prophylaxis comparator was a weighted average of different FIX prophylaxis regimens based on US market share data. We compared a scenario in which EDZ is introduced in the US versus a scenario without EDZ. Clinical inputs (annualized FIX-treated bleed rate; adverse event rates) were obtained from HOPE-B phase 3 trial. EDZ durability input was sourced from an analysis predicting long-term FIX activity with EDZ. EDZ one-time price was assumed at $3.5 million. Other medical costs, including FIX prophylaxis, disease monitoring, bleed management, and adverse events were from literature. The model estimated annual and cumulative costs, treated bleeds, and joint procedures over 20 years from EDZ introduction., Results: Approximately 596 PwHB were eligible for EDZ. EDZ uptake was estimated to avert 11,282 bleeds and 64 joint procedures over 20 years. Although adopting EDZ resulted in an annual excess cost over years 1-5 (mean: $53 million annually, total $265 million), annual cost savings were achieved beginning in year 6 (mean: $172 million annually; total $2.58 billion in years 6-20). The total cumulative 20-year cost savings was $2.32 billion, with cumulative cost savings beginning in year 8., Conclusion: Introducing EDZ to treat PwHB is expected to result in cost savings and patient benefit over 20 years. Initiating PwHB on EDZ sooner can produce greater and earlier savings and additional bleeds avoided. These results may be a conservative estimate of the full value of EDZ, as PwHB would continue to accrue savings beyond 20 years.

Aims: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data., Methods: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling., Results: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01)., Conclusions: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Etranacogene dezaparvovec gene therapy for haemophilia B demonstrated superior efficacy at 24 months in reducing bleeds versus a ≥6-month lead-in period of prophylaxis with FIX products in the phase 3 trial, HOPE-B. In the absence of head-to-head comparisons of etranacogene dezaparvovec versus FIX products, indirect treatment comparisons (ITC) can be used., Aim: To compare the efficacy of etranacogene dezaparvovec versus rIX-FP, rFIXFc and N9-GP using ITC, and support HOPE-B results., Methods: Data were leveraged from Phase 3 pivotal trials: HOPE-B, PROLONG-9FP, B-LONG and Paradigm 2. Annualised bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds, and FIX consumption were assessed using inverse probability of treatment weighting and matching adjusted indirect comparisons., Results: Etranacogene dezaparvovec demonstrated statistically significantly lower bleeding rates versus all comparators. Rate ratios for ABR, AsBR and AjBR versus rIX-FP were 0.19 (p < .0001), 0.08 (p < .0001) and 0.09 (p < .0001), respectively. Rate ratios for ABR, AsBR and AjBR versus rFIXFc were 0.14 (p < .0001), 0.13 (p = .0083) and 0.15 (p = .0111), respectively. Rate ratios for ABR and AsBR, versus N9-GP were 0.24 (p = .0231) and 0.13 (p = .0071), respectively. Etranacogene dezaparvovec demonstrated significantly higher percentage of patients with no bleeds versus rIX-FP and rFIXFc; odds ratios: 17.60 (p < .0001) and 5.65 (p = .0037), respectively. Etranacogene dezaparvovec resulted in significantly lower FIX consumption than all comparators., Conclusions: ITC suggests that etranacogene dezaparvovec offers patients with haemophilia B (≤2% of normal FIX expression) a single dose treatment that can significantly reduce bleeding rates and eliminate routine infusions associated with FIX therapies., (© 2023 CSL Behring and The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: The impact of moderate haemophilia on health-related quality of life (HRQoL) and physical activity (PA) is not well known. In previous studies, persons with factor VIII/factor IX activity (FVIII/FIX:C) below 3 IU/dL were associated with a more severe bleeding phenotype than predicted., Aim: To explore HRQoL and PA in patients with moderate haemophilia A (MHA) and B (MHB)., Methods: A cross-sectional, multicentre study covering patients with MHA and MHB in Sweden, Finland, and Norway. HRQoL was assessed with the EuroQoL 5-Dimensions (EQ-5D) form and PA with the International Physical Activity Questionnaire among participants aged ≥15 years., Results: We report on 104 patients aged 15-84 years from the MoHem study. Overall, EQ-5D utility was .85 (median) (Q1-Q3 0.73-1.0) with corresponding visual analogue scale (VAS) 80 (70-90), which were similar regardless of treatment modality, FVIII/FIX:C, and MHA or MHB. Pain and mobility were most frequently affected dimensions. Utility (r = -.54), VAS (r = -.42), and PA (r = -.32) correlated negatively with arthropathy (HJHS). Only patients aged 41-50 years displayed lower utility (p = .02) and VAS (p < .01) than the Norwegian population norm. Patients on prophylaxis aged 35-54 years reported higher PA than those treated on-demand (p = .01)., Conclusion: Haemophilic arthropathy had negative impact on HRQoL and PA in Nordic patients with moderate haemophilia. Middle-aged patients captured lower utility and VAS than observed in the general population. Tailored prophylaxis and improved joint health may influence positively on HRQoL and PA also in moderate haemophilia., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Competing Interests: Declaration of competing interests M.H.A.B. is listed as inventor on intellectual property and has received consultancy fees from VarmX B.V. (all fees to the institution) unrelated to this work. V.J.F.S. and J.V. have no competing interests to disclose.

Background: Hemophilia B (HB) is a bleeding disorder characterized by coagulation factor (F) IX (FIX) deficiency. The current standard-of-care for severe HB is prophylaxis with long-term repetitive intravenous (i.v.) infusions of recombinant FIX (rFIX) with standard half-life or extended half-life. Unmet needs remain regarding the development of non-invasive administration routes for coagulation factors. The aim of this study was to evaluate the effectiveness of intranasal delivery (IND) of rFIX and rFIX fused to Fc fragment (rFIX-Fc) in mice., Methods: Drops of rFIX and rFIX-Fc were deposited in the nostrils of wild-type, FcRn knock-out, FcRn humanized, and FIX knock-out mice. rFIX mucosal uptake was evaluated by measuring plasma FIX antigen and FIX activity (FIX:C) levels, and by performing histologic analysis of the nasal mucosa following IND., Results: After IND, both rFIX and rFIX-Fc were equally delivered to the blood compartment, irrespective of the mouse strain studied, mostly through a passive mechanism of transportation across the mucosal barrier, independent of FcRn receptor. Both plasma FIX antigen and FIX:C activity levels increased following IND in FIX knock-out mice., Conclusion: This proof-of-concept study describes evidence supporting the nasal route as an alternative to FIX i.v. infusion for the treatment of HB., Competing Interests: Funding This work was partly supported by a grant from “Fond de dotation France,” CSL Behring, the non-profit organization EURECa, University Claude Bernard Lyon I, the Société Française d’Oto-rhino-laryngologie et de chirurgie cervico-faciale (SFORL) and Amplifon. Relationship Disclosures S.L.Q. has received grant/research support from CSL Behring, honoraria from SOBI, Roche, LFB Biomedicaments, Octapharma, NovoNordisk, and is currently a full-time employee at CSL Behring. All other authors have no competing interests in relation to this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction and Aim: Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3-5 IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half-life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII-B (FXIIIB) subunit prolonged the half-life of the rFIX-LXa-FXIIIB fusion molecule in mice and rats 3.9- and 2.2-fold, respectively, compared with rFIX-WT. However, the mechanism behind the extended half-life was not known., Materials and Methods: Mass spectrometry and ITC were used to study interactions of rFIX-LXa-FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen-KO and FcRn-KO mice were performed to evaluate the effect of albumin and fibrinogen on in-vivo half-life of rFIX-LXa-FXIIIB. Finally saphenous vein bleeding model was used to assess in-vivo haemostatic activity of rFIX-LXa-FXIIIB., Results and Conclusion: We report here the key interactions that rFIX-LXa-FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half-life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX-FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX-WT., (© 2023 John Wiley & Sons Ltd.)

Gene therapy for hemophilia has been investigated for decades but no breakthroughs were made until Nathwani et al. achieved a significant and sustainable factor IX increase in hemophilia B patients in 2011. About eleven years later, in August 2022, the first hemophilia A gene therapy product was approved by the European Commission and hemophilia treatment entered a new era. This review does not focus on the newest advances but rather the practical aspects of gene therapy aiming to provide an overview for physicians who treat hemophiliacs who did not participate in the clinical trials. The current status of gene therapy, focusing particularly on products likely to be clinically available soon, are reviewed and summarized. Currently, possible limitations of gene therapy are pre-existing neutralizing antibodies toward the vector, liver health, age, and inhibitor status. Possible safety concerns include infusion reactions, liver damage, and adverse effects from immune suppressants or steroids. In summary, generally speaking, gene therapy is effective, at least for several years, but the exact effect may be unpredictable and intensive monitoring for several months is needed. It can also be considered safe with careful practice on selected patients. In its current form, gene therapy will not replace all hemophilia treatments. Advances in non-factor therapy will also improve hemophilia care greatly in the future. We envisage that gene therapy may be included in multiple novel therapies for hemophilia and benefit some hemophilia patients while novel non-factor therapies may benefit others, together fulfilling the unmet needs of all hemophilia patients., Competing Interests: Declaration of competing interest All authors have no relevant competing interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Four-factor prothrombin complex concentrate (4F-PCC) may be an option for patients with bleeding unrelated to therapeutic anticoagulation to help with bleeding cessation and reduce blood component requirements., Materials and Methods: Retrospective, observational study of adult patients who received 4F-PCC for bleeding not associated with therapeutic anticoagulation between June 2019 and July 2021. Primary outcome was to describe off-label 4F-PCC use in patients not on therapeutic anticoagulation for bleeding management in surgical and non-surgical patients. Additional outcomes evaluated were blood product use, chest tube and drainage output, and coagulation studies before and after 4F-PCC administration as well as other hemostatic agent use and thromboembolic events., Results: Seventy-six patients were included; median age 64 years (IQR 50-69), 66% of bleeding events were associated with surgery, and the majority of 4F-PCC doses ordered by cardiac surgery (68.4%). A total of 110 4F-PCC doses were administered; median 1 dose/patient (IQR 1-2), median total dose 1000 units (IQR 500-1484). Other hemostatic agents commonly administered were protamine (59%), desmopressin (43%), and tranexamic acid (42%). Packed red blood cells, fresh frozen plasma, platelet, and cell saver blood administration and prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (aPTT) were significantly reduced following 4F-PCC administration. Eight patients (11%) experienced thromboembolic complications., Conclusion: Relatively low doses of 4F-PCC (median total dose 1000 units) were associated with decreased blood component requirements and improved PT, INR, and aPTT values in patients with bleeding unrelated to therapeutic anticoagulation. Other hemostatic agent use was common and thromboembolic complications occurred., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Extended half-life recombinant FIX (rFIX) molecules have been generated to reduce the dosing burden and increase the protection of patients with hemophilia B. Clinical pharmacology studies with recombinant factor IX Fc fusion protein (rFIXFc) report a similar initial peak plasma recovery to that of rFIX, but with a larger volume of distribution. Although the pegylation of N9-GP results in a larger plasma recovery, there is a smaller volume of distribution, suggesting less extravasation of the latter drug. In this study, we set out to compare the biodistribution and tissue localization of rFIX, rFIXFc, and glycoPEGylated rFIX in a hemophilia B mouse model. Radiolabeled rFIX, rFIXFc, and rFIX-GP were employed in in vivo single-photon emission computed tomography imaging (SPECT/CT), microautoradiography (MARG), and histology to assess the distribution of FIX reagents over time. Immediately following injection, vascularized tissues demonstrated intense signal irrespective of FIX reagent. rFIX and rFIXFc were retained in joint and muscle areas through 5 half-lives, unlike rFIX-GP (assessed by SPECT). MARG and immunohistochemistry showed FIX agents localized at blood vessels among tissues, including liver, spleen, and kidney. Microautoradiographs, as well as fluorescent-labeled images of knee joint areas, demonstrated retention over time of FIX signal at the trabecular area of bone. Data indicate that rFIXFc is similar to rFIX in that it distributes outside the plasma compartment and is retained in certain tissues over time, while also retained at higher plasma levels. Overall, data suggest that Fc fusion does not impede the extravascular distribution of FIX., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Haemophilia B is a debilitating hereditary coagulation disorder characterized by prolonged or spontaneous episodes of bleeding caused by a deficiency of endogenous factor IX. In Algeria, even though many studies are being carried out to evaluate the prevalence and management of haemophilia B, there is a paucity of locally published literature that can be used to understand the most recent information on the disease's epidemiology, diagnostic techniques and treatment options., Aims: The aim of this manuscript is to raise awareness among patients and family clinicians about current practices, recent developments and unmet needs related to haemophilia B in Algeria., Methods: A comprehensive literature search was conducted through online scientific databases to review publications regarding haemophilia B in Algeria. Exclusions of the review include case studies, interregional comparisons, abstract-only papers and studies outside the range of 2012-2022., Results: The findings discussed relate to the epidemiology of haemophilia B in Algeria, the clinical diagnostic process, disease symptoms, the benefits of molecular and genetic testing, advancements in prophylactic care, as well as unmet needs hindering the progression of optimal haemophilia B management., Conclusion: These findings are crucial to encourage the maintenance of national registries with updated epidemiological data, facilitate early and timely detection of disease symptoms, improve the provision of diagnostic facilities and enhance the overall treatment landscape for better patient outcomes., (© 2023 John Wiley & Sons Ltd.)

Purpose of Review: We present a case of a boy diagnosed in 2007 with severe haemophilia B [factor IX (FIX) concentration < 1%] at age of 9 months. He was initially treated with recombinant FIX concentrates, but changes in regimens were frequent due to spontaneous hemarthros. In 2013, he entered a phase III trial (NCT01662531) and received rIX-FP, IDELVION at 50 IU/kg once a week. Although the boy was safely maintained with this regimen (2015-2017), the number of hemarthros increased after he started to play football. Thus, rIX-FP regimen was modified (40 IU/kg twice/week) to optimize therapy. This modification was efficient on maintaining patient's thought levels (33%), helped during his fully incorporation at school and social life, and significantly improved synovial hypertrophy. In the last year, the boy has not suffered any bleeding episode and his joint situation improved significantly, which allowed reducing doses to weekly recommended doses., Recent Findings: FIX replacement therapies with intravenous plasma-derived FIX (pdFIX) or standard half-life recombinant FIX (rFIX) concentrates are hampered by the relatively short terminal elimination half-life (t1/2) of these substances (around 17-34 h), resulting in the need for frequent infusions (e.g. once every 3 or 4 days) to maintain protective FIX levels. In the past years, the first genetically recombinant fusion of rFIX with another protein - a recombinant human albumin - was developed (albutrepenonacog-alfa or rIX-FP; IDELVION) as a strategy to extend the t1/2 of rFIX-FP (around 95 h)., Summary: We provide information about the difficult management of a patient with a major bleeding haemorrhagic phenotype, which caused serious limitations in the patient's daily life, impacting his quality of life at his young age, and how the switch to IDELVION allowed the situation to improve considerably., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Accurate measurement of clotting factors VIII (FVIII) or IX (FIX) is vital for comprehensive diagnosis and management of patients with hemophilia A or B. The one-stage activated partial thromboplastin time (aPTT)-based clotting assay is the most commonly used method worldwide for testing FVIII or FIX activities. Alternatively, FVIII and FIX chromogenic substrate assays, which assess the activation of factor X, are available in some specialized laboratories. The choice of reagent or methodology can strongly influence the resulting activity. Variation between one-stage FVIII or FIX activities has been reported in the measurement of some standard and extended half-life factor replacement therapies and gene therapy for hemophilia B using different aPTT reagents. Discrepancy between one-stage and chromogenic reagents has been demonstrated in some patients with mild hemophilia A or B, the measurement of some standard and extended half-life factor replacement therapies, and the transgene expression of hemophilia A and B patients who have received gene therapy. Finally, the measurement of bispecific antibody therapy in patients with hemophilia A has highlighted differences between chromogenic assays. It is imperative that hemostasis laboratories evaluate how suitable their routine assays are for the accurate measurement of the various hemophilia treatment therapies., Competing Interests: A.E.B. reports grants and personal fees from Novo Nordisk, personal fees from Stago, personal fees from Takeda, grants and personal fees from Roche, personal fees from Sobi, and personal fees from Pfizer, outside the submitted work.R.C.G. reports personal fees from Sysmex America Incorporated and from Diagnostica Grifols, and honoraria from Diagnostica Stago, outside the submitted work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: Dalcinonacog alfa (DalcA), a novel subcutaneously administered recombinant human factor IX (FIX) variant is being developed for adult and paediatric patients with hemophilia B (HB). DalcA has been shown to raise FIX to clinically meaningful levels in adults with HB. This work aimed to support dosing regimen selection in adults and perform first-in-paediatric dose extrapolations using a model-based pharmacokinetic (PK) approach., Methods: A population PK model was built using adult data from two clinical trials (NCT03186677, NCT03995784). With allometry in the model, clinical trial simulations were performed to study alternative dosing regimens in adults and children. Steady-state trough levels and the time-to-reach target were derived to inform dose selection., Results: Almost 90% of the adults were predicted to achieve desirable FIX levels, i.e. 10% FIX activity, following daily 100 IU/kg dosing, with 90% of the subjects reaching target within 1.6-7.1 days. No every-other-day regimen met the target. A dose of 125 IU/kg resulted in adequate FIX levels down to 6 years, whereas a 150 IU/kg dose was needed below 6 down to 2 years of age. For subjects down to 6 years that did not reach target with 125 IU/kg, a dose escalation to 150 IU/kg was appropriate. The children below 6 to 2 years were shown to need a dose escalation to 200 IU/kg if 150 IU/kg given daily was insufficient., Conclusion: This study supported the adult dose selection for DalcA in the presence of sparse data and enabled first-in-paediatric dose selection to achieve FIX levels that reduce risk of spontaneous bleeds., (© 2023. The Author(s).)

Objective: To assess the impact of prophylaxis with rIX-FP, a fusion protein linking recombinant factor IX (FIX) with human albumin, on joint outcomes., Methods: Joint outcomes were assessed in pediatric (<12 years) and adult/adolescent (≥12 years) patients receiving rIX-FP prophylaxis every 7, 10, or 14 days; patients (>18 years) well-controlled on a 14-day regimen could switch to a 21-day regimen. Target joints were defined as ≥3 spontaneous bleeds into a single joint within a 6-month period., Results: For adult/adolescent (n = 63) and pediatric (n = 27) patients, median (Q1, Q3) annualized joint bleeding rate was 0.39 (0.00, 2.31), 0.80 (0.00, 2.85), 0.20 (0.00, 2.58), and 0.00 (0.00, 1.78) when treated with 7-, 10-, 14-, or 21-day prophylaxis. 50.0%, 38.9%, 45.5%, and 63.6% of adult/adolescent patients had no joint bleeds when treated with 7-, 10-, 14-, or 21-day prophylaxis, respectively, and 40.7%, 37.5%, and 37.5% of pediatric patients had no joint bleeds when treated with 7-, 10-, or 14-day prophylaxis. Ten adult and two pediatric patients developed target joints; all resolved by the end of the study., Conclusion: Prophylaxis with rIX-FP produced low joint bleeding rates and provided excellent hemostatic efficacy in the treatment of joint bleeds. All target joints reported resolved with rIX-FP prophylaxis., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Oral factor Xa (FXa) inhibitors significantly reduce incidence of stroke and thromboembolic events in patients with atrial fibrillation or venous thromboembolism. Due to various factors and the lack of a randomized controlled trial comparing andexanet alfa to usual care, non-specific replacement agents including 4 F-PCC are still used off-label for FXa inhibitor bleed management. Clinical and mortality data were extracted from the inpatient medical data and Veteran Affairs (VA) vital status files over the time of March 2014 through December 2020. Propensity score-weighted models were used for this retrospective cohort study using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). The study included 255 patients (85-andexanet alfa and 170-4 F-PCC) exposed to an oral factor Xa inhibitor and hospitalized with an acute major, gastrointestinal (GI), intracranial (ICH) or other bleed. In-hospital mortality was significantly lower in the andexanet alfa cohort compared to the 4 F-PCC cohort (10.6% vs. 25.3%, p = 0.01). Propensity score-weighted Cox models reveal a 69% lower hazard of in-hospital mortality for those treated with andexanet alfa (HR 0.31, 95% CI 0.14-0.71) compared to those treated with 4 F-PCC. Additionally, those treated with andexanet alfa had a lower 30-day mortality rate and lower 30-day hazard of mortality in the weighted Cox model (20.0% vs. 32.4%, p = 0.039; HR 0.54, 95% CI 0.30-0.98) compared to those treated with 4 F-PCC. Among 255 US veterans with major bleeding in the presence of an oral factor Xa inhibitor, treatment with andexanet alfa was associated with lower in-hospital and 30-day mortality than treatment with 4 F-PCC., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Etranacogene dezaparvovec is the first gene therapy approved for treatment of adults with severe and moderately severe hemophilia B., Areas Covered: This review describes the results of the clinical trial program of AMT-060 and etranacogene dezaparvovec, outlining the pharmacokinetic, clinical efficacy and safety data. With the entry of etranacogene dezaparvovec into the market, this review summarizes the treatment landscape in hemophilia B and discusses the current unknowns in the field., Expert Opinion: Gene therapy appears to be a feasible option for adults with severe and moderately severe hemophilia B. Etranacogene dezaparvovec enables most patients to reach stable factor IX (FIX) levels after a single intravenous infusion, eliminating the need for regular prophylaxis; thus, drastically reducing treatment burden and avoiding variable bleeding risk owing to fluctuating FIX activity levels. Efficacy of etranacogene dezaparvovec has been demonstrated even in the presence of preexisting neutralizing antibodies (up to a titer of 1:678), with a relative low risk of transaminitis and its associated potential loss of transgene expression. However, long-term data are required to ascertain the durability of FIX levels achieved and safety. The cost-effectiveness and adoption of innovative payment models for reimbursement are key in choosing gene therapy over existing treatments.

Introduction: Congenital hemophilia B (HB) is an X-linked bleeding disorder resulting in Factor IX (FIX) deficiency and bleeding of variable severity. There is no cure for HB. Typical management consists of prophylactic intravenous (IV) recombinant or plasma-derived FIX infusions. Etranacogene dezaparvovec-drlb (Hemgenix, AMT-061) is an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant of the human F9 gene with a liver-specific promoter. Etranacogene dezaparvovec-drlb received FDA approval on 22 November 2022 for the treatment of HB in adult patients who use FIX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have experienced repeated, serious spontaneous bleeding episodes., Areas Covered: This drug profile discusses the safety and efficacy of etranacogene dezaparvovec-drlb in patients with HB., Expert Opinion: Etranacogene dezaparvovec-drlb therapy results in stable and sustained expression of near-normal to normal FIX levels in patients with HB regardless of neutralizing antibodies to AAV5 up to a titer of 678. Its use has led to significant reduction in bleeding and FIX prophylaxis. Etranacogene dezaparvovec-drlb was well tolerated; however, 17% of patients required corticosteroid therapy for alanine aminotransferase (ALT) elevation. Etranacogene dezaparvovec-drlb therapy marks the beginning of an exciting era in HB treatment and opens questions regarding treatment longevity and long-term safety.

In contrast to the standard enzyme-replacement therapy, administered from once per 7-14 days to 2-3 times a week in patients with severe hemophilia B, as a result of a single injection, gene therapy can restore F9 gene expression and maintain it for a prolonged time. In clinical research, the approach of delivering a functional copy of a gene using adeno-associated viral (AAV) vectors is widely used. The scientific community is actively researching possible modifications to improve delivery efficiency and expression. In preclinical studies, the possibility of genome editing using CRISPR/Cas9 technology for the treatment of hemophilia B is also being actively studied.

Hemophilia, a congenital coagulopathy characterized by a deficiency in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B), results in a tendency of bleeding proportional to the lacking factor. Most bleeds in patients with hemophilia occur in their joints and muscles, and because of these bleeding episodes, patients may end up developing musculoskeletal alterations resulting from hemophilic arthropathy, even receiving hemostatic treatment. The third edition of the World Federation of Hemophilia's Guidelines for the Management of Hemophilia defines 12 principles that encompass all the different types of multidisciplinary care required by people with hemophilia, one of these being clinical and epidemiological research. The expected number of patients with hemophilia across the world has been estimated at 1125 000, most of them undiagnosed, and the total number of patients with severe hemophilia at 418 000 males. Data available from medium and high-income countries show that the prevalence at birth (incidence) and the prevalence of hemophilia differ, which means that patients with hemophilia are at a disadvantage in terms of life expectancy as compared with the general population. In medium-to-high-income countries, the life expectancy disadvantage of patients with hemophilia A and B as compared with the rest of the population is 30% and 24%, respectively. This life expectancy disadvantage is much greater in countries with more limited access to treatments for hemophilia., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)