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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

Hemophilia A (HA) and hemophilia B (HB) are rare inherited bleeding disorders. Although causative genetic variants are clinically relevant, in 2012 only 20% of US patients had been genotyped.My Life, Our Future (MLOF) was a multisector cross-sectional US initiative to improve our understanding of hemophilia through widespread genotyping.Subjects and potential genetic carriers were enrolled at US hemophilia treatment centers (HTCs). Bloodworks performed genotyping and returned results to providers. Clinical data were abstracted from the American Thrombosis and Hemostasis Network dataset. Community education was provided by the National Hemophilia Foundation.From 2013 to 2017, 107 HTCs enrolled 11 341 subjects (68.8% male, 31.2% female) for testing for HA (n = 8976), HB (n = 2358), HA/HB (n = 3), and hemophilia not otherwise specified (n = 4). Variants were detected in most male patients (98.2%% HA, 98.1% HB). 1914 unique variants were found (1482 F8, 431 F9); 744 were novel (610 F8, 134 F9). Inhibitor data were available for 6986 subjects (5583 HA; 1403 HB). In severe HA, genotypes with the highest inhibitor rates were large deletions (77/80), complex intron 22 inversions (9/17), and no variant found (7/14). In severe HB, the highest rates were large deletions (24/42). Inhibitors were reported in 27.3% of Black versus 16.2% of White patients.The findings of MLOF are reported, the largest hemophilia genotyping project performed to date. The results support the need for comprehensive genetic approaches in hemophilia. This effort has contributed significantly towards better understanding variation in the F8 and F9 genes in hemophilia and risks of inhibitor formation.

Introduction: dental extractions (DEs) in persons with hemophilia A or B (PWH-A or PWH-B) are often associated with bleeding and needing hemostatic therapies (HTs). Aim: to analyze the American Thrombosis and Hemostasis Network (ATHN) dataset (ATHNdataset) to assess trends, uses and impacts of HT on bleeding outcomes following DEs. Methods: PWH seen at ATHN affiliates who underwent DEs and opted to share their data with the ATHNdataset between 2013–2019 were identified. The type of DEs, use of HT and bleeding outcomes were assessed. Results: Among 19,048 PWH ≥2 years of age, 1157 underwent 1301 episodes of DE. Those on prophylaxis experienced a nonsignificant reduction in dental bleeding episodes. Standard half-life factor concentrates were used more often than extended half-life products. PWHA were more likely to undergo DE in the first 30 years of life. Those with severe hemophilia were less likely to undergo DE than those with a mild disease (OR: 0.83; 95% CI: 0.72–0.95). PWH with inhibitors had statistically significantly increased odds of dental bleeding (OR: 2.09, 95% CI; 1.21–3.63). Conclusion: our study showed that persons with mild hemophilia and younger age were more likely to undergo DE; the presence of inhibitors increased the likelihood of bleeding, while those with prophylaxis and receiving HT experienced a non-statistically significant reduction in bleeding.

BackgroundBefore the official US Food and Drug Administration approval in 2021, pediatric hematologists across the United States have used direct oral anticoagulants (DOACs) "off-label" and based on extrapolation from labeling for adults with venous thromboembolism (VTE) and interim results of pediatric-specific DOAC clinical studies.ObjectivesThe American Thrombosis and Hemostasis Network 15 (ATHN 15) study aimed to characterize the use of DOACs from 2015 to 2021 at 15 specialized pediatric hemostasis centers in the United States, with emphasis on safety and effectiveness.MethodsEligible participants were those aged 0 to 21 years who had a DOAC included as part of their anticoagulation regimen for the treatment of acute VTE or secondary prevention of VTE. Data were collected for up to 6 months after initiation of the DOAC.ResultsA total of 233 participants were enrolled, with a mean age of 16.5 years. Rivaroxaban was the most commonly prescribed DOAC (59.1%) followed by apixaban (38.8%). Thirty-one (13.8%) participants reported bleeding complications while on a DOAC. Major or clinically relevant nonmajor bleeding events occurred in 1 (0.4%) and 5 (2.2%) participants, respectively. Worsening menstrual bleeding was reported in 35.7% of females aged >12 years and occurred more frequently in those using rivaroxaban (45.6%) compared with apixaban (18.9%). The recurrent thrombosis rate was 4%.ConclusionPediatric hematologists at specialized hemostasis centers in the United States have been using DOACs for the treatment and prevention of VTEs, primarily in adolescents and young adults. Reported DOAC use showed adequate safety and effectiveness rates.

Gene therapy for hemophilia is designed to produce health gains for patients over many years. Rewarding that value creation on the basis of a one-time treatment implies a large upfront cost. This cost can only be justified by long-term health benefits and being cost-effective compared with conventional treatments. Yet, uncertainties about the long-term benefits make it challenging to assess clinical and economic value of gene therapies at launch. We identify and discuss key methodological challenges in assessing the value of gene therapy for hemophilia, including the immaturity of evidence on the durability of benefits, lack of definition and valuation of cure for chronic diseases, absence of randomized controlled trials, limitations of traditional quality of life measures in hemophilia, approach for qualifying cost-savings compared with current treatments, and choice of perspective. The Institute for Clinical and Economic Review has developed a framework for assessing single or short-term therapies (ICER-SST) and has applied it in hemophilia. After reviewing this framework and its application, we recommend the following when assessing the value of hemophilia gene therapies: (1) leveraging expert clinical opinion to justify assumptions on the durability of benefits; (2) using external synthetic controls and lead-in, self-controlled trials to assess comparative effectiveness; (3) addressing limitations of traditional quality of life measures through the use of modified utility collection approaches; (4) adjusting cost offsets from gene therapies with caution; (5) considering outcome-based contracting to address uncertainties about prices and long-term outcomes; and (6) presenting societal and healthcare system perspectives in parallel.

Etranacogene dezaparvovec (AMT-061) is a recombinant adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) transgene with a liver-specific promoter. Here we report 3-year outcomes from a Phase 2b, open-label, single-dose, single-arm, multi-center trial (NCT03489291) conducted in adults with severe or moderately severe hemophilia B (FIX ≤2%). All participants (n=3) received a single intravenous dose (2×1013 gene copies/kg) and will be followed for 5 years. The primary endpoint of FIX activity ≥5% at 6 weeks was met (mean 30.6% [min-max, 23.9%-37.8%]). Secondary endpoints included bleed frequency, FIX concentrate use, joint health, and adverse events (AEs). All participants required routine FIX prophylaxis and had neutralizing antibodies to AAV5 (mean titer at screening=39) prior to etranacogene dezaparvovec treatment. Post administration, FIX activity rose to a mean of 40.8% (min-max, 31.3%-50.2%) at year 1, sustained at year 3 (mean 36.9% [min-max, 32.3%-41.5%]). All participants discontinued FIX prophylaxis. Complete elimination of bleeds occurred in 2/3 participants. One participant required on-demand FIX replacement therapy post treatment per protocol due to elective surgeries, for 2 reported bleeding episodes, and twice for a single self-administered infusion due to an unreported reason. One participant experienced 2 mild, self-limiting AEs shortly after dosing. During the 3-year study period, there were no clinically significant elevations in liver enzymes, no requirement for steroids, no FIX inhibitor development, and no late emergent safety events in any participant. Etranacogene dezaparvovec was safe and effective in adults with hemophilia B through 3 years post-administration. ClinicalTrials.gov Identifier: NCT03489291.

Introduction Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. Aim To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. Methods Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. Results Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. Conclusion Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.

Sreenivas P Veeranki,1 Priti Pednekar,1 Marlon Graf,1 Rifat Tuly,1 Michael Recht,2,3 Katharine Batt1 1PRECISIONheor, Los Angeles, CA, USA; 2American Thrombosis and Hemostasis Network, Rochester, NY, USA; 3The Hemophilia Center, Oregon Health & Science University, Portland, OR, USACorrespondence: Priti PednekarPRECISIONheor, 11100 Santa Monica Blvd, Ste 500, Los Angeles, CA, 90025, USATel +1 267 438 3588Email Priti.Pednekar@precisionvh.comIntroduction: Over the past decade, there has been an increase in novel therapeutic options to treat hemophilia A. It is still unclear how these novel treatments are used in the management of patients with hemophilia A, particularly those with challenging clinical scenarios who are typically excluded in clinical trials.Purpose: This study aimed to understand the areas of consensus and disagreement among hematologists regarding the preferences toward therapeutic approaches for difficult-to-treat patients with severe hemophilia A without inhibitors.Patients and Methods: During February–June 2020, a three-round modified Delphi study was conducted to generate consensus among 13 US experts in the field of hemophilia. Experts were asked about their preferences toward therapeutic options for patients with challenging clinical situations, including age-related morbidities (eg, myocardial infarction, joint arthropathy), increasing demand for high-impact physical activities, early onset osteoporosis, and newborns with hemophilia A. Consensus was defined as ≥ 75% agreement between the panelists.Results: Consensus was reached on many, but not all cases, leaving uncertainty about appropriateness of therapeutic approaches for some patients where clinical evidence is not available or driven by physicians’ or patients’ preferences toward therapeutic options. A majority of panelists preferred FVIII replacement therapy rather than emicizumab prophylaxis for the challenging cases presented due to established evidence on safety, efficacy, and level of bleed protection for FVIII treatment.Conclusion: Recommendations emerging from this study may help guide practicing hematologists in the management of challenging hemophilia A cases. Future studies are needed to address treatment options in the clinical cases where no consensus was reached.Keywords: emicizumab, expert elicitation, FVIII, treatment, management

Introduction High collision-risk physical activity can increase bleeding risk in people with hemophilia A, as can increasing the time between factor VIII (FVIII) administration and physical activity. FVIII prophylaxis may be tailored to planned activities to prevent activity-related bleeding. Aim To explore the relationship between physical activity levels, FVIII infusion timing, and occurrence of bleeding in patients with severe/moderately severe hemophilia A without FVIII inhibitors receiving antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA). Methods SPACE was a 6-month, prospective, multicenter, observational outcomes study (NCT02190149). Enrolled patients received an eDiary application and a wearable activity tracker, which recorded physical activity, rAHF infusion, and occurrence of bleeding. Physical activity risks were ranked using National Hemophilia Foundation criteria. Results Fifty-four patients aged 11–58 years (n = 47 prophylaxis, n = 7 on-demand) were included in the analysis. Patients had a mean (SD) 8.14 (10.94) annualized bleeding rate, and recorded 4980 intervals between an rAHF infusion and physical activity; 1759 (35.3%) of these intervals were ≤24 hours. Analysis of recorded eDiary data showed that the risk of activity-related bleeding did not significantly increase with time between last infusion and activity, but did increase with higher-risk physical activities. Analysis of activity tracker recorded data showed that the risk of bleeding reported by patients as spontaneous increased with prolonging time (≤24 to >24 hours) from last infusion to physical activity start (odds ratio 2.65, p < 0.05). Joint health data collected at baseline were not included in the regression analysis because of small sample size; therefore the study could not assess whether patients with more joint disease at baseline were at higher risk of injury-related and reported spontaneous occurrence of bleeding. Conclusion These results show that activities with a high risk of collision lead to an increased risk of bleeding. Further investigation is warranted to explore potential benefits of FVIII infusion timing to reduce the risks of activity-related occurrence of bleeding.

Rare, chronic diseases such as hemophilia and other congenital coagulation disorders require coordinated delivery of services for optimal outcomes. Hemophilia Treatment Centers (HTCs) are specialized, multidisciplinary health-care centers providing team-based care to meet the physical, psychosocial, and emotional needs of people with hemophilia (PWH) and may serve as a model for other rare coagulation disorders. Health-care purchasers, as well as the general medical community, may not appreciate the breadth and quality of services provided by HTCs. They exemplify the acculturalization and actualization of integrated care by providing comprehensive diagnostic and treatment services that reduce morbidity, mortality, avoidable emergency room visits, hospitalizations, and overall costs, while promoting a longer lifespan and improved patient functioning and outcomes. This is accomplished by a team-based approach relying upon a shared decision-making model to effectively prevent complications and manage symptoms in PWH, who are dependent on high-cost treatments. This article provides a concise yet comprehensive description of the core components of an HTC and the regional and national networks in the United States, which together achieve their incomparable value for all stakeholders., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/_Nx_76pDKLw

PUPs B-LONG evaluated the safety and efficacy of recombinant factor IX Fc fusion protein (rFIXFc) in previously untreated patients (PUPs) with hemophilia B. In this open-label, phase 3 study, male PUPs (age 85%) bleeding episodes required only 1 infusion for bleed resolution. In this first study reporting results with rFIXFc in pediatric PUPs with hemophilia B, rFIXFc was well tolerated, with the adverse event profile as expected in a pediatric hemophilia population. rFIXFc was effective, both as prophylaxis and in the treatment of bleeding episodes. This trial was registered at www.clinicaltrials.gov as #NCT02234310.

GOAL-Hēm is a novel, haemophilia-specific, patient-centred outcome measure (PCOM) based on goal attainment scaling, allowing people with haemophilia (PwH) to set and monitor the attainment of individualized goals for treatment.To provide a thorough overview of the creation, validation, and development of GOAL-Hēm.Clinician workshops were held to develop a haemophilia-specific goal menu. Qualitative data from semistructured interviews with PwH and their caregivers guided further revisions to the goal menu (i.e., goal domains and descriptors). A feasibility study was performed including a 12-week, prospective, noninterventional evaluation involving clinicians and PwH at four US haemophilia treatment centres. Finally, the Patient Voice Study gathered feedback from PwH and their caregivers via an online survey, interviews, and a focus group.The feasibility study validated GOAL-Hēm with successful outcomes in construct/content validity and responsiveness, including a large effect in patient- and clinician-rated goal attainments. The Patient Voice Study led to significant refinement of GOAL-Hēm goals and descriptors, resulting in a more straightforward and relatable menu for PwH and their caregivers. Overall, GOAL-Hēm captured qualitative data in areas important to PwH and employed quantitative methods to evaluate meaningful changes in those areas. The individualized tool was well equipped to handle the complex and chronic nature of haemophilia and was endorsed by PwH, their caregivers, and clinicians.The GOAL-Hēm development journey may serve as a roadmap for other PCOMs in a variety of settings, including clinical studies, haemophilia treatment centres for care planning, and as a tool to gather real-world evidence.

Hemophilia B (HB) is a rare congenital disorder characterized by bleeding-related complications which are managed by prophylactic or post-bleeding event ("on-demand") replacement of clotting factor IX (FIX). The standard of care for severe HB is life-long prophylaxis with standard half-life (SHL) or extended half-life (EHL) products given every 2-3 or 7-14 days, respectively. FIX treatment costs in the US have been investigated, but the lifetime costs of HB treatment have not been well characterized, particularly related to the impact of joint health deterioration and associated health resource utilization. We developed a decision-analytic model to explore outcomes, costs and underlying cost drivers associated with FIX treatment options over the lifetime of an adult with severe or moderately severe HB.With participation from clinicians, health technology assessment specialists and patient advocates, a Markov model was constructed to estimate bleeding events and costs associated with health states including "bleed into joint", "bleed not into joint", "no bleed" and "death". Sub-models of joint health were based on 0, 1, or ≥2 areas of chronic joint damage. US third-party payer and societal perspectives were considered with a lifetime horizon; sensitivity analyses tested the robustness of primary findings.Total adult lifetime costs per patient with severe and moderately severe HB were $21,086,607 for SHL FIX prophylaxis, $22,987,483 for EHL FIX prophylaxis, and $20,971,826 for on-demand FIX treatment. For FIX prophylaxis, the cost of FIX treatment accounts for90% of the total HB treatment costs.This decision analytic model demonstrated significant economic burden associated with the current HB treatment paradigm.

Introduction Epidemiologic studies suggest that joint bleeding occurs in patients with mild-to-moderate haemophilia, including women and girls. However, most previous studies on the impacts of haemophilia focus on men with severe disease. Aim To identify unmet needs in men and women with mild-to-moderate haemophilia. Methods The Pain, Functional Impairment, and Quality of Life (P-FiQ) study assessed the impact of pain on functional impairment and health-related quality of life in men with haemophilia A or B of any severity. The Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B-HERO-S) study evaluated the psychosocial needs of adults and children with haemophilia B of any severity, including women and girls. Both studies employed patient-reported outcome measures. Results In the P-FiQ study, 16% (62/381) of participants had mild and 13% (50/381) had moderate haemophilia. In the B-HERO-S study, 29% (86/299) of adult participants were female, 25% (74/299) had mild haemophilia, and 63% (189/299) had moderate haemophilia. In addition, 63% (46/74) of patients with mild and 86% (162/189) of patients with moderate haemophilia routinely infused factor products to prevent bleeding. Patients reported difficulty gaining access to factor products (54%; 142/263) and a haemophilia treatment centre (17%; 44/263). During the P-FiQ study, 78% (48/62) of patients with mild and 87% (44/50) with moderate haemophilia described problems with pain on the Brief Pain Inventory. Patients also reported issues with anxiety, depression and relationships. Conclusions Mild-to-moderate haemophilia has physical and psychosocial impacts on patients. We offer some solutions to help alleviate these impacts and resolve unmet needs.

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products (“true PUPs”) and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

Decades of inherited bleeding disorders (BD) research transformed severe haemophilia from a childhood killer to a disorder managed across a full lifespan for many in economically developed countries. Health equity, a life unimpaired by disease complications, however, remains unimaginable for most people with an inherited BD (PWIBD).The National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network (ATHN) undertook the development of a community-driven United States (US) National Blueprint for Inherited Bleeding Disorders Research to transform the experience of all PWIBD and those who care for them.Extensive community consultations were conducted to identify the issues most important to PWIBD and those who love and care for them. Expert multidisciplinary teams distilled these key areas of need into prioritised research questions, and identified the resources and infrastructure required to pursue them. A summit was held to gather feedback and inform the detailed blueprint.Community-prioritised research areas fell into three broad categories: issues common across inherited BDs, those specific to individual disorders, and issues of infrastructure and capacity. NHF State of the Science Research Summit discussions of the research questions derived from the community priorities by six working groups provided important input for the drafting of the research blueprint for the coming decades.The inherited BD community came together to develop the US National Blueprint for Inherited Bleeding Disorders Research dedicated to transforming the lives of all PWIBD including innovating solutions for the rarest disorders and under-represented populations.

INTRODUCTION: Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children

Gene therapy trials aim to provide a functional cure for patients with haemophilia B (HB), and treatment impact is analyzed by factor IX expression levels (FELs). We investigated the relationship of FELs with health-related quality of life (HRQoL) and costs.This was a retrospective cross-sectional analysis of the European (CHESS I-II) and US (CHESS-US) CHESS population studies. Physicians recruited consecutive patients and extracted information from the medical records; patients completed questionnaires between 2014 and 2015 (CHESS-I), 2018-2019 (CHESS-II) and 2019 (CHESS US). Patients with inhibitors were excluded. HRQoL was assessed using the EQ-5D-5L. Twelve-month haemophilia-related direct medical costs included office visits and hospitalizations based on country-level unit costs. A Tobit model was used to analyze FELs and HRQoL and generalized linear models for direct medical costs.A total of 191 men with HB completed the EQ-5D questionnaire; the mean age was 36.8 years, with a mean FEL of 10.1 IU/dL (median, 4.0). Mean EQ-5D was 0.77 (SD, 0.23). The Tobit model adjusting for age, body mass index and blood-borne viruses showed every 1% increase in FEL was associated with +0.006 points in the mean EQ-5D score (Direct medical costs were based on physician extraction of encounters from medical records, potentially underestimating costs of care. The voluntary nature of participation may have introduced selection biases.We observed a significant association of increases in FEL with increased HRQoL and decreased costs in Europe and the United States among men with HB and no inhibitors.

Although persons with nonsevere hemophilia A (NSHA) account for about one-half of the hemophilia A population, epidemiological data in this subset of individuals are scarce. We set out to describe the clinical characteristics of persons with NSHA with inhibitors, and to determine mortality rates, predictors of mortality, and primary causes of death in persons with NSHA in the United States over a 9-year period (2010-2018). We queried the American Thrombosis and Hemostasis Network dataset (ATHNdataset) for information on demographics, inhibitor status, and date and cause of death. A total of 6624 persons with NSHA (86.0% men; 14.0% women) were observed for an average of 8.5 years; total 56 119 person-years . The prevalence of inhibitors was 2.6% (n = 171), occurring at a median age of 13 years. At the end of follow-up, 136 persons died at a median age of 63 years; an age-adjusted mortality rate of 3.3 deaths per 1000 person-years. Three deaths occurred in inhibitor participants. Presence of inhibitors was not associated with increased mortality risk (hazard ratio [HR], 0.7, 95% confidence interval [CI], 0.2-2.3). Factors independently associated with increased risk of death (HR, 95% CI) were the following: age (10-year increase) (2.1, 2.0-2.4); male (2.6, 1.0-6.4); hepatitis C (2.2, 1.5-3.1); and HIV (3.6, 2.2-6.0). The most common primary cause of death was malignancy (n = 27, 20.0%). In persons with NSHA, the development of inhibitors occurred at an early age and was not associated with increased mortality.

Persons with haemophilia (PwH) have abnormally low bone density and increased risk of fractures. We previously demonstrated decreased skeletal health in factor VIII (FVIII)-deficient mice. Thus, we hypothesized factor deficiency is an independent risk factor for decreased skeletal health.We seek to identify differences in bone-related cytokine expression among PwH and healthy controls.We evaluated plasma samples from 79 participants with severe FVIII deficiency and 51 age-matched healthy controls. Plasma samples were assessed for RANKL and OPG, cytokines that regulate bone metabolism, and CTX-1, a biomarker for bone resorption, as well as 10 bone-related cytokines.CTX-1 is higher among samples from FVIII-deficient participants compared to controls (P .01) but not among participants with recent factor use (within 24 hours of sample collection) (P = .21). Among PwH greater than 16 years of age (PwH ≥ 16), OPG is increased with recent factor use (P .01) but not without (P = .34). Lower levels of TNF-α (P .01), interleukin (IL)-12 (P .01) and IL-10 (P .001) were found among samples from PwH. Controlling for subject age, IL-12 and IL-10 levels are lower in PwH ≥ 16 (P .01, P .001) but not PwH under 16 (PwH 16) (P .05). Levels of TNF-α were lower among PwH 16 only (P .05). These differences are not observed in participants with recent factor use.In PwH, markers of bone metabolism and circulating cytokine levels are abnormal. Recent factor use reverses many of these differences suggesting FVIII replacement ameliorates this pathology. This study suggests bone disease present in PwH is intrinsic to FVIII deficiency.

Introduction The goal of gene therapy for haemophilia is to alter the clinical phenotype to a milder form or even cure, by increasing endogenous coagulation factor levels through transfer of a functional gene encoding the respective deficient coagulation factor and subsequent transgene expression. Over the past decade, there has been tremendous progress in gene therapy, particularly in use of liver-directed adeno-associated viral vectors, such that several programmes for both haemophilia A and B are in phase 3 trials. With regulatory approval of the first gene therapy product expected as early as mid-2020, there is an urgent need for a mechanism to collect long-term data on safety and variability and durability of efficacy. There will be elements required by regulators for postmarketing surveillance and additional data needed to enhance our understanding of gene therapy outcomes and their impact on the lives of people with haemophilia. Aim The aim of this manuscript was to describe efforts underway by the American Thrombosis and Hemostasis Network and the World Federation of Hemophilia to collect long-term harmonized data and considerations of the European and US regulatory agencies, which will inform ongoing data collection. Methods The status of data collection around gene therapy in haemophilia and important outcome measures were obtained by literature review. Each author described elements relevant to the activities of their organization. Conclusion Support of all stakeholders in gene therapy, providers, patients, industry and regulators, augers successful capture of uniform long-term safety and efficacy data to ensure optimal treatment of people with haemophilia.

The Joint Outcome Study (JOS), a randomized controlled trial, demonstrated that children with severe hemophilia A (HA) initiating prophylactic factor VIII (FVIII) prior to age 2.5 years had reduced joint damage at age 6 years compared with those treated with episodic FVIII for bleeding. The Joint Outcome Continuation Study (JOS-C) evaluated early vs delayed prophylaxis effects on long-term joint health, following JOS participants to age 18 years in an observational, partially retrospective study. Index joint magnetic resonance imaging (MRI) scores of osteochondral (OC) damage (primary outcome), joint physical examination scores, and annualized rates of joint/other bleeding episodes (secondary outcomes) were collected. Thirty-seven of 65 JOS participants enrolled in JOS-C, including 15 randomized to prophylaxis at mean age 1.3 years (“early prophylaxis”); 18 initially randomized to episodic treatment, starting “delayed prophylaxis” at mean age 7.5 years; and 4 with high-titer inhibitors. At JOS-C exit, MRI OC damage was found in 77% of those on delayed and 35% of those on early prophylaxis for an odds ratio of OC damage, in the delayed vs early prophylaxis group, of 6.3 (95% confidence interval, 1.3, 29.9; P = .02). Annualized bleeding rates were higher with delayed prophylaxis (mean plus or minus standard deviation, 10.6 ± 6.6 vs 3.5 ± 2.1; P < .001), including when only comparing time periods on prophylaxis (6.2 ± 5.3 vs 3.3 ± 1.9; P < .05). In severe HA, early initiation of prophylaxis provided continued protection against joint damage throughout childhood compared with delayed initiation, but early prophylaxis was not sufficient to fully prevent damage. This trial was registered at www.clinicaltrials.gov as #NCT01000844.

Background The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. Methods In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. Results The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration). Conclusions Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).

BACKGROUND: Hemophilia A (HA) is marked by substantial economic burden, including costs of ongoing treatment, increased monitoring, bleed events, and other health care utilization associated with m...

INTRODUCTION Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments. AIM We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes. METHODS We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Participants indicated preferences for gene therapy attributes including dosing frequency/durability, effect on annual bleeding, uncertainty related to side effects, impact on daily activities, impact on mental health, and post-treatment requirements. The relative importance of each attribute was analysed overall and for subgroups based on haemophilia type and severity. RESULTS A total of 183 males with haemophilia A (n = 120) or B (n = 63) were included. Half (47%) had severe haemophilia; most (75%) were White. Overall, participants gave effect on bleeding rate the greatest relative importance (31%), followed by dose frequency/durability (26%), uncertainty regarding safety issues (17%), and impact on daily activities (11%). Dose frequency/durability had the greatest importance for those with haemophilia B (35%). CONCLUSION People with haemophilia prioritised reduced bleeding and treatment burden; the former was more important in haemophilia A and the latter in haemophilia B, followed by safety and impact on daily life in this DCE of gene therapy attributes. These findings and differences can inform clinical and health policy decisions to improve health equity for people with haemophilia.