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The burden of severe haemophilia A (HA) has been studied extensively owing to the higher bleeding frequency and associated treatment requirements, leaving a clear unmet need for research focused on the burden of mild and moderate HA.

BACKGROUND Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2,3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.) [ABSTRACT FROM AUTHOR]

BACKGROUND Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. [ABSTRACT FROM AUTHOR]

Three major directions for the global progress of adeno-associated virus (AAV) vectors for gene therapies (GT) are analyzed: 1) engineering vectors to increase transgene expression; 2) aligning interests of the health system with costs and challenges for the pharmaceutical industry; and 3) refining patient eligibility criteria and endpoint definition. Currently employed AAV vectors may cause toxicity and adverse events. Furthermore, studies in animals do not fully predict risks and clinical benefits of AAV-based GT, and animal models reflecting the heterogeneity of certain clinical settings (e.g., congestive heart failure) are not widely available for improving AAV-based GT. Finally, antisense and gene editing approaches will soon complement gene augmentation strategies for the stable solution of unsolved issues of AAV-based GT. While minimizing toxicity, next-generation AAV vectors should decrease the viral load needed to achieve therapeutic efficacy, be functional in a restricted cellular subset, avoid transgene expression in unwanted cells (e.g., hepatocytes), and escape immune oversight in AAV-based GT. The role of stress-induced apoptosis in the loss of transgene expression in GT should also be explored. Aligning the interests and obligations of the pharmaceutical industry with those of the health system is critical for the success of AAV-based GT. Costs and challenges for the pharmaceutical industry include: a) removing impurities from AAV; b) validating tests to measure treatment efficacy; c) promoting training programs to standardize vector genome delivery; d) collecting long-term follow-up data; and e) maintaining sustainability and cost-effectiveness of AAV-based GT. In rare disorders with small patient numbers (e.g., hemophilia), clear-cut outcomes are mandatory as endpoints of unequivocal efficacy data.

Children with hemophilia have a significantly higher risk of intracranial hemorrhage (ICH) compared to the normal population. Prophylaxis reduces the risk of ICH and earlier initiation of prophylaxis may now be feasible, especially in hemophilia A (HA). The aim of the study is to explore the potential for preventing ICH by earlier start of prophylaxis by assessing the natural course of ICH before the initiation of prophylaxis and describe timing and incidence. In total, 2727 children (2275 with HA; 452 with HB) were included from the PedNet Registry, followed from 28 days until 36 months of life. ICH was observed in 61 children (incidence 2.2%; 10 per 1000 patient years), with 75% of cases occurring before one year of age. Cumulative incidence was significantly lower in HB (0.9%) compared to HA (2.5%) and in non-severe HA (0.7%) compared to severe HA (3.5%). ICH occurred early, with a rise at 3 months, and a median age of 7.0 months in severe HA and 5.4 months in severe HB. In 40% of children, ICH occurred before the diagnosis of hemophilia was established, underscoring the importance of early diagnosis. Assuming that prophylaxis would have been started at the time of diagnosis and preventing all ICH in children with severe HA, the number needed to treat with prophylaxis would be 44 patients to prevent one ICH. Hopefully, prophylaxis options allowing initiation early in life, ideally before 3 months of age for children with severe HA, will reduce the incidence of ICH in the future.

Abstract: Adeno-associated virus-based gene therapy (valoctocogene roxaparvovec) is an attractive treatment for hemophilia A. Careful clinical management is required to minimize the risk of hepatotoxicity, including assessment of baseline liver condition to determine treatment eligibility and monitoring liver function after gene therapy. This article describes recommendations (developed by a group of hemophilia experts) on hepatic function monitoring before and after gene therapy. To prevent harmful liver-related effects, gene therapy is contraindicated in patients with uncontrolled liver infections, autoimmune hepatitis, liver stiffness ≥8 kPa, or cirrhosis. Before using gene therapy in patients with liver steatosis or other liver disorders, the risk of liver damage should be considered using a highly individualized approach. Treatment is not recommended in patients with abnormal liver enzymes, including alanine aminotransferase (ALT) at any level above the upper limit of normal (ULN). Therefore, pretreatment assessment of liver health should include laboratory tests, abdominal ultrasound, and liver stiffness measurements by transient elastography (TE). In the first year after therapy, ALT levels should be monitored 1 to 2 times per week to detect elevations ≥1.5× ULN, which may require immunosuppressant therapy. Patients with ALT elevation should receive prednisone 60 mg/d for 2 weeks, followed by stepwise tapering when ALT returns to baseline. ALT monitoring should continue long term (every 3-6 months), along with abdominal ultrasound (every 6 months) and TE (yearly) evaluations. When patients with good liver health are selected for treatment and closely monitored thereafter, ALT elevations can be promptly treated and are expected to resolve without long-term hepatic sequelae., (© 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.)

Background/Objective: Lysosomal storage diseases (LSDs) are a group of rare, inborn, metabolic errors characterized by deficiencies in normal lysosomal function and by the intralysosomal accumulation of undegraded substrates, resulting in the damage of multiple organ systems. The spectrum of clinical manifestations is extremely heterogeneous. LSD diagnosis and management still present many issues. Methods: A group of Italian experts and patients' representatives met to discuss some critical aspects, and among the most impactful are early diagnosis, the transition of the patient from pediatric to adult age, territorial management, and the multidisciplinary approach. Results: Possible solutions to diagnostic delays may be a widespread newborn screening and screening programs on selected populations. The lack of a structured transition process could be helped by the drafting of shared diagnostic and therapeutic care pathways beyond the availability of databases accessible to the different levels that manage a patient. Territorial management could benefit from telemedicine, but a homogeneous diffusion of home therapy, not yet everywhere possible, is essential. A fundamental role is played by the patient associations, which should be increasingly involved in the political choices. It is also crucial to create structured multidisciplinary teams of experts for disease management and comorbidities. A transversal need appears to be greater training on LSDs. In Italy, the "Statement of Udine" was developed to guide further steps towards improvements in inherited metabolic medicine in adults, referencing the experience from the United Kingdom. Conclusions: Much can be done for the early diagnosis and management of LSDs with an effective treatment, but many aspects need improvement for the overall management of the patient. An investment in dedicated resources, formal recognition, and training is needed to address these unmet needs.

Background: Gene therapy is designed to provide people with hemophilia B with a steady and elevated factor (F)IX activity, thereby strengthening protection and relieving the burden of frequent replacement therapy infusions. The European Medicines Agency has approved gene therapy for the severe and moderately severe forms of hemophilia B that uses the FIX-Padua variant (etranacogene dezaparvovec)., Objectives: The aim was to provide a document dedicated to hemophilia B gene therapy and give a comprehensive overview of the topic., Methods: An Italian group of experts in hemophilia carried out a narrative review of the literature and discussed during a virtual meeting several key aspects of the delivery of this treatment in Italy. The discussion covered the organizational model, the role of the multidisciplinary team, the laboratory surveillance, and the patient's journey, from the follow-up to the identification of safety issues and outcome measures., Results: This article highlights the need to follow the Hub and Spoke organizational model and sheds light on the role of each professional figure within the multidisciplinary teams to favor patient engagement, management, and retention. Moreover, this article stresses the need to perform laboratory tests for patient screening and follow-up and proposes a checklist to help patient identification. Finally, the needs of Italian hemophilia centers have been considered to ensure an efficient implementation of the care delivery model., Conclusion: It is crucial to ensure that centers are appropriately organized, equipped, and trained to adequately select patients, deliver the gene therapy, and perform follow-up., Competing Interests: Declaration of competing interests G.C. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, BIOVIIIx, CSL Behring, BioMarin, Sanofi, Novo Nordisk, Takeda, Kedrion, LFB, Grifols, Roche, Sobi, and uniQure and reports participation on data safety monitoring board or advisory board for Bayer, CSL Behring, BioMarin, Sanofi, Novo Nordisk, Takeda, Kedrion, LFB, Grifols, Pfizer, Roche, and uniQure. G.D.M. reports being a speaker or a member of a speaker bureau for BioMarin, Bayer, CSL Behring, Roche, Takeda, and Viatris Pharmaceuticals and consultant or ad hoc speaker/consultant for BioMarin, Bayer, Pfizer, Takeda, and Viatris Pharmaceuticals. P.S. reports being a speaker for Bayer, CSL Behring, Stago, uniQure, Werfen, and Pfizer. S.S. has acted as a consultant for CSL Behring, Amgen, Novartis, Novo Nordisk, Sobi, and Bayer. E.B. participated in advisory boards for Amgen, Novartis, CSL Behring, Bayer, Roche, and Sobi. V.L.M. is a member of the advisory board of Pfizer, CSL Behring, and BioMarin; is a speaker for Gore and Alfasigma; and received research grants from Gilead and travel grants from Sobi, Sanofi, and Takeda. A.L. has participated in speaker bureaus for BioMarin and CSL Behring. F.P. reports consulting for and being a member of advisory boards of CSL Behring, BioMarin, Roche, Sanofi, and Sobi and is a member of the speaker’s bureau or educational programs/symposia for Takeda/Spark. E.F.G. has participated in speaker bureaus and advisory boards for BioMarin, Sobi, and Roche e Novo Nordisk. A.C.M. declares that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inhibitor eradication to restore factor (F)VIII efficacy is the treatment goal for persons with severe hemophilia A (HA) and inhibitors. Immune tolerance induction (ITI) is demanding and successful in about 70% of people. Until now, it has remained difficult to quantify the probability of ITI success or failure, complicating the decision to initiate or not initiate ITI. Estimating the individual chance of ITI success allows clinicians, patients, and their families to support shared decision-making., Objectives: We aimed to identify clinical predictors of ITI success and to develop a clinical prediction model to estimate the chance of successful ITI in persons with severe HA., Methods: This multicenter study included persons with severe HA who received ITI. Clinical data were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. A multivariable logistic regression model was developed. Model performance and internal validation were performed., Results: Of 206 participants with a median age of 19.8 months (IQR, 12.1-38.8) at ITI start, 148 (71.8%) achieved ITI success. Our clinical prediction model included 4 predictors of ITI success: cumulative number of FVIII exposure days at inhibitor development, peak inhibitor titer, ethnicity, and F8 mutation type. The C statistic was 0.801 (95% CI, 0.70-0.87)., Conclusion: In our study, including 206 people with severe HA and inhibitors, we developed a clinical prediction model to estimate the chance of successful ITI. After future external validation, this clinical prediction model may be useful for informing clinicians and families., (© 2024 The Author(s).)

Competing Interests: Declaration of competing interests There are no competing interests to disclose.

Background: Little information regarding the management of invasive procedures in people with hemophilia B (HB) after undergoing gene therapy is available. Here, we report the management of invasive procedures in people with severe or moderately severe HB who had previously been treated with etranacogene dezaparvovec in the phase 2b and phase 3 Health Outcomes with Padua Gene; Evaluation in Hemophilia B clinical trials (NCT03489291 and NCT03569891)., Objectives: The objective of this study was to describe the use of exogenous FIX, endogenous FIX activity prior to invasive procedures, and peri- and postoperative bleeds in participants who underwent invasive procedures after receiving etranacogene dezaparvovec gene therapy., Methods: This retrospective analysis included invasive procedures performed within 3 and 2 years following a single infusion of 2 × 10 13 gc/kg of etranacogene dezaparvovec in participants in the phase 2b and Health Outcomes with Padua Gene; Evaluation in Hemophilia B trials, respectively. Data for factor (F)IX dosing, duration of postoperative FIX use, FIX activity prior to invasive procedures, and postoperative bleeds were collected and analyzed., Results: The analysis included 64 procedures in 29 participants: 9 major surgeries, 24 minor surgeries, 11 endoscopies, 3 endoscopies with biopsy/polypectomy, and 17 dental procedures. Uncontaminated endogenous FIX activity corresponded to mild hemophilia or normal levels prior to 98% of all procedures, with a median endogenous FIX activity of 43.8 IU/dL (range, 3.1-113 IU/dL). All major surgeries were managed with exogenous FIX, 67% with ≤4 days of FIX infusion. Most minor surgeries (88%), endoscopies (82%), and dental procedures (94%) were managed with no or a single FIX infusion. Postoperative bleeds occurred after 1 minor surgery and 4 dental procedures. There were no symptomatic thrombotic events or FIX inhibitor developments., Conclusion: Etranacogene dezaparvovec has the potential to facilitate perioperative management in people with HB by reducing the need for perioperative exogenous FIX and its associated risks., Competing Interests: Declaration of competing interests N.O. has received financial support for research from Sobi; received consultancy fees from F. Hoffmann-La Roche Ltd, uniQure, Sobi, and CSL Behring; and is a member of Speakers Bureaus for F. Hoffmann-La Roche Ltd, Sobi, CSL Behring, Takeda, Bayer, and Novo Nordisk. All fees are donated to an institutional charitable body that supports education in hemostasis and thrombosis. P.v.d.V. has received consultancy fees from Bayer. E.G. is a member of the Global Blood Therapeutics Speaker Bureau and has received consultant fees from CSL Behring. P.E.M. is an employee of CSL Behring. S.L.Q. is an employee of CSL Behring. S.E.C. has received consultancy fees from Novartis for service on a data safety monitoring board and has received payment for service on advisory boards from Pfizer, Sanofi, and Medexus. M.C. has received financial support for research from Anthos, Bayer, CSL Behring, Novo Nordisk, and Hoffmann-La Roche and honoraria for lecturing or consultancy from Alexion, CSL Behring, Daiichi Sankyo, Sanofi, Spark Therapeutics, Octapharma, Pfizer, Sobi, and Viatris. All funds were received by his institution. Nonfinancial conflicts of interest include being a member of the gene therapy working group of the European Association for Haemophilia and Allied Disorders (EAHAD) and a member of the European Reference Network (ERN) EuroBloodNet. R.L. has received fees for consulting, advisory boards, and speakers’ bureaus from CSL Behring, Pfizer, and Novo Nordisk. G.C. has received financial support for research from CSL Behring, Pfizer, and Sobi; has consulted for and received honoraria from Bayer, Roche, Sobi, Grifols, Novo Nordisk, Werfen, and Kedrion; and was a member of the Board of Directors or advisory committees for Ablynx, Alexion, Bayer, LFB, Takeda, CSL Behring, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, and uniQure. R.K. has received honoraria from and/or been a member of advisory committees for Bayer, BioMarin, Biotest, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, and Takeda. E.S. has received support for attending conferences from CSL Behring, Roche, and Novo Nordisk. D.V.Q. has received fees for consulting/advisory boards/speakers bureaus from Bayer, BioMarin, CSL Behring, Genentech/Roche, Novo Nordisk, Pfizer, Sanofi, and Takeda. P.K. has received consultancy fees from BioMarin, CSL Behring, Novo Nordisk, Takeda, and uniQure., (Copyright © 2024. Published by Elsevier Inc.)

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).)

Background/Objectives: A compartmental pharmacokinetics (PK) analysis of new extended half-life FVIII concentrates has never been performed in a large cohort of hemophilia patients. An improved PK analysis of individual outcomes may help to tailor hemophilia replacement treatment. Methods: PK outcomes after the infusion of a standard single dose of Efmoroctocog alfa were collected from 173 patients with severe/moderately severe hemophilia A in 11 Italian hemophilia centers. Factor VIII clotting activity (FVIII:C) was measured by one-stage clotting assay (OSA) in all patients, and chromogenic substrate assay (CSA) in a subgroup ( n = 52). Fifty patients underwent a comparative PK assessment with standard half-life (SHL) recombinant FVIII (rFVIII) products. Non-compartmental analysis (NCA), one compartment model (OCM), and TCM were used to analyze the decay curves of all patients, and one-way paired ANOVA to compare the PK outcomes. Results: All 173 PKs conformed to the NCA and OCM, but only 106 (61%) conformed to the TCM based on the biphasic features of their decay curves. According to the TCM, the Beta HL and MRT of rFVIIIFc were 20.42 ± 7.73 and 25.64 ± 7.61 h, respectively. ANOVA analysis of the outcomes from the three PK models showed significant differences in clearance, half-life (HL), and mean residence time (MRT) ( p < 0.001 for all parameters). As anticipated, the HL and MRT of rFVIIIFc were longer than those of SHL rFVIII. Comparing OSA with CSA outcomes, Cmax resulted higher when measured by CSA ( p = 0.05) and, according to TCM, Beta HL resulted longer when measured by OSA ( p = 0.03). FVIII:C trough levels obtained with SHL concentrates were significantly lower than those obtained with rFVIIIFc at each post-infusion time point. Conclusions: In a large group of hemophilia A (HA) patients, three different PK models confirmed the improved pharmacokinetic (PK) characteristics of rFVIIIFc, compared with standard half-life rFVIII concentrates. The TCM only fits two-thirds of the PKs, highlighting their biphasic decay and a long Beta half-life. In these patients, the TCM would be preferable to properly evaluate individual PK features.

Introduction: Hemophilia can detrimentally affect patients' quality of life and likelihood of survival. In the evolving landscape of therapies, the therapeutic gain of each treatment must be understood to accurately position it in the therapeutic armamentarium. Accordingly, appropriate outcomes must be measured with appropriate tools., Areas Covered: Our narrative review (PubMed search for 'hemophilia AND outcome' until June 2023), provides a compendium of outcome measures used in hemophilia clinical research. To define each outcome measure's relative value and applicability, several characteristics are critically discussed., Expert Opinion: Bleeding assessment, first annual/annualized bleeding rate, remains central in evaluating the efficacy and safety of hemophilia treatments. As modern therapies improve clinical outcomes toward zero bleeding events, this endpoint may become less sensitive to detect differences between therapeutic approaches. Technological advancements necessitate the adaptation of outcome measures to address infrequent bleeding events, age-related comorbidities, and laboratory parameters with limited comparability after different treatments. Considerable effort has been dedicated to the development of tools that comprehensively assess coagulation, such as thrombin generation assays. Patient-reported outcome measures are gaining importance although limited by their subjectivity. A definitive set of research outcome measures remains elusive. Outcomes may need to be tailored to different therapeutic interventions.

Background  Recombinant von Willebrand factor (rVWF, vonicog alfa, Takeda Pharmaceuticals USA) is indicated in adults diagnosed with von Willebrand disease (VWD). In this study, the exposure-response (ER) relationship between VWF activity (VWF:RCo) or factor VIII activity (FVIII:C) and spontaneous bleeding events (BEs) was evaluated in adults with severe VWD receiving rVWF prophylaxis for up to 1 year. Methods  This secondary analysis included 23 patients receiving rVWF prophylaxis in the open-label, phase 3 prophylaxis trial (NCT02973087). Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were used to characterize VWF activity and endogenous FVIII:C, and PK/PD simulations were linked to spontaneous BEs to develop an ER model. Results  None of the five patients with VWD types 1 or 2A/B experienced spontaneous BEs. Five of 18 patients with VWD type 3 experienced ≥1 spontaneous BEs. An ER relationship was observed whereby higher VWF:RCo levels were associated with a numerically lower spontaneous BE risk ( p  < 0.10). This relationship was independent of patients' pretrial VWF treatment. A statistically significant ER relationship was observed after accounting for relevant data (average ± standard error exposure estimate for VWF:RCo over 24 hours prior to the spontaneous BE: -0.043 ± 0.021, p  = 0.041). The model-generated hazard ratio for a 10 IU/dL increment in the average exposure of VWF:RCo 24 hours before a spontaneous BE was 0.651 (95% confidence interval: 0.431-0.982). Conclusions  This ER analysis suggests a causal association between VWF:RCo and spontaneous BEs, with an increase of VWF:RCo exposure leading to a decrease in spontaneous BE risk., Competing Interests: Conflict of Interest [disclosures] • Frank W.G. Leebeek has received grants/research funding from CSL Behring, Sobi, Takeda, and uniQure; consultancy fees from BioMarin, CSL Behring, Takeda, and uniQure (all fees to university), and has been a data safety monitoring board member for Roche. • Giancarlo Castaman has served on advisory boards or been a consultant for Bayer, BioMarin, CSL Behring, Grifols, Kedrion, LFB, Novo Nordisk, Roche, Sanofi, Sobi, Takeda, and uniQure. • Jean François Marier is an employee of Certara Strategic Consulting and has received research funding to perform this analysis from Takeda Development Center Americas, Inc. • Indranil Bhattacharya, Yi Wang, Jingmei Zhang, and Scarlett Wang are employees of Takeda Development Center Americas, Inc. and Takeda stockholders. • Gülden Özen was an employee of Takeda Development Center Americas, Inc. at the time of the study., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Patient-reported outcomes (PROs) reflect patient perceptions of disease and treatment and are important for evaluating new therapies., Objectives: Evaluate the effects of once-daily concizumab prophylaxis on health-related quality of life (HRQoL), treatment burden, and treatment preference in males aged ≥12 years with hemophilia A/B with inhibitors., Methods: Patients enrolled in the multicenter, open-label explorer7 phase 3 study (ClinicalTrials.gov identifier: NCT04083781) were randomized to receive no prophylaxis (arm 1) or concizumab prophylaxis (arm 2) or were nonrandomly allocated to concizumab prophylaxis (arms 3 and 4). The study included questionnaires to assess patients' perception of HRQoL (Haemophilia Quality of Life Questionnaire for Adults), treatment burden (Hemophilia Treatment Experience Measure), and treatment preference (Haemophilia Patient Preference Questionnaire)., Results: The estimated treatment difference between patients receiving concizumab prophylaxis vs no prophylaxis at week 24 for Haemophilia Quality of Life Questionnaire for Adults "total score" was -22.6 points (95% CI, -42.5; -2.7), directionally favoring patients receiving concizumab prophylaxis. For Hemophilia Treatment Experience Measure "total score," the estimated treatment difference was -19.9 points (95% CI, -34.3, -5.6) in favor of concizumab vs no prophylaxis. The majority of patients receiving concizumab expressed a preference for concizumab over their previous treatment, the main reasons being "fewer bleeds," "require less time," and "less painful to inject." Across all PROs, there were less responses collected than anticipated, limiting interpretations., Conclusion: PROs collected during the explorer7 study showed improvements in some domains of HRQoL, treatment burden, and patient treatment preference in persons with hemophilia A or B with inhibitors receiving concizumab prophylaxis compared with no prophylaxis., (© 2024 The Authors.)

Hemophilia B is the first bleeding disorder for which gene therapy clinical programs began. Presently, adenovirus-associated vectors represent the best means to deliver the transgene, and their administration by intravenous route has been used in recent clinical trials. The natural occurring factor IX (FIX) Padua variant, which allows for a 5- to 8-fold higher activity of FIX, while maintaining a normal protein concentration, was subsequently used to enhance the level of transgene expression. All the recent trials using this variant showed good results, and accumulating data suggest that long-term expression durability could be maintained at a significant hemostatic level. However, the risk of loss of transgene expression associated to immune response with liver enzymes elevation remains a concern, especially as to the efficacy and duration of immunosuppressive treatment. Notwithstanding this limitation, the results of clinical trials suggest that gene therapy in hemophilia B has the potential to provide long-term benefits with sustained factor activity levels predicted to last several years in many patients., Competing Interests: G.C. has received honoraria as a speaker/participant on advisory boards for Alexion, Bayer, Biomarin, Bioviiix, Shire/Takeda, CSL Behring, Novo Nordisk, Sobi, Roche, uniQure, Sanofi, Werfen, Kedrion, LFB, and Grifols. W.M. has received honoraria as a speaker/participant on advisory boards for Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, Takeda/Shire, uniQure., (Thieme. All rights reserved.)

Background: This study aimed to gather data on physical activity (PA), bleeding, health-related quality of life, and health status, using a wearable device and an electronic patient-reported outcome (ePRO) app, in individuals with moderate or severe hemophilia A (HA) without inhibitors receiving treatment according to the clinical practice. Methods: This is a 12-month multicenter cohort study conducted in Italy. The primary outcomes included the description of PA by type and intensity, adherence to World Health Organization guidelines, bleeding, and health-related quality of life by EQ-5D questionnaire. PA data were collected continuously through a fitness tracker worn by the patient; all the other variables were collected through ePRO questionnaires. Results: Only 54 of the 103 enrolled subjects (52.4%) used their fitness tracker for the defined valid period; adolescents were the least compliant age group. PA was performed at low rates and intensity. Approximately 52% of the subjects had sedentary behavior. The mean EQ-5D values did not change over time. At least one bleeding was reported in 43.7% of the subjects, mostly with sedentary behavior. The PA in the 2 days preceding the bleeding was comparable to the one observed in the overall observational period. Conclusions: The systematic recording of data through a fitness tracker and ePRO app shows that subjects with HA without inhibitors have lower-than-expected PA and that they still experience issues related to bleeding.

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.)