Long-term outcomes with emicizumab in hemophilia A without inhibitors: results from the HAVEN 3 and 4 studies.

Background: Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX and FX, mimicking the function of missing or deficient activated FVIII in people with hemophilia A (HA). Objectives: To evaluate the long-term efficacy and safety of emicizumab prophylaxis in people with HA without FVIII inhibitors in the HAVEN 3 and 4 studies. Methods: HAVEN 3 and 4 were phase 3 open-label studies. Participants received emicizumab maintenance doses of 1.5 mg/kg every week or 3 mg/kg every 2 weeks (HAVEN 3), or 6 mg/kg every 4 weeks (HAVEN 4). Long-term efficacy and safety were assessed. Results: A total of 151 and 40 individuals without FVIII inhibitors received emicizumab in HAVEN 3 and 4, respectively. At the last patient, last visit dates (May 12, 2022 [HAVEN 3] and June 29, 2022 [HAVEN 4]), the median (range) duration of emicizumab exposure across the 2 studies was 248.1 (6.1-287.1) weeks. The mean (95% CI) annualized bleed rate for treated bleeds was 2.0 (0.23-7.15) for weeks 1 to 24, decreasing to 0.9 (0.01-5.28) by weeks 217 to 240. Overall, 188 (98.4%) participants experienced ≥1 adverse event (AE), with 185 treatment-related AEs in 71 (37.2%) participants. Forty-four (23.0%) participants reported a serious AE. Two thromboembolic events were reported, which were deemed unrelated to emicizumab by the investigator. No thrombotic microangiopathies were reported. Conclusion: With nearly 5 years of emicizumab exposure across the HAVEN 3 and 4 studies in people with HA without inhibitors, these data indicate continued bleed control with no new safety signals observed during long-term follow-up.

Women and girls with inherited bleeding disorders: Focus on haemophilia carriers and heavy menstrual bleeding.

Raising awareness and improving recognition, accurate classification, and enhanced access to new treatments represent current key challenges for carriers of haemophilia. Women and girls carrying genes for haemophilia often experience significant bleeding and/or low factor levels. The bleeding associated with female haemophilia is frequently overlooked, has a weak correlation with factor levels, and manifests differently than in males, with heavy menstrual bleeding being a predominant symptom. Recent changes in terminology now allow the diagnosis of haemophilia in females with low factor levels and differentiate between symptomatic and asymptomatic carriers of the gene. Observations from real-world experiences and limited clinical trial data have highlighted the positive impact of various new haemophilia treatments for women and girls with clotting factor deficiencies. There is an urgent need for initiatives that increase their access to these treatments and encourage well-designed clinical trials focusing on female-specific outcomes. In women with inherited bleeding disorders, early recognition and optimal management of heavy menstrual bleeding are crucial. However, treatment options and guidance from high-quality clinical trials are currently insufficient. Menstrual health assessment should be a regular part of monitoring women and girls with inherited bleeding disorders throughout their lives, emphasizing the importance of gathering data to improve future management.

Cost-Effectiveness Analysis of Etranacogene Dezaparvovec Versus Extended Half-Life Prophylaxis for Moderate-to-Severe Haemophilia B in Germany.

BACKGROUND AND OBJECTIVE: Haemophilia B is a rare genetic disease that is caused by a deficiency of coagulation factor IX (FIX) in the blood and leads to internal and external bleeding. Under the current standard of care, haemophilia is treated either prophylactically or on-demand via intravenous infusions of FIX. These treatment strategies impose a high burden on patients and health care systems as haemophilia B requires lifelong treatment, and FIX is costly. Etranacogene dezaparvovec (ED) is a gene therapy for haemophilia B that has been recently approved by the United States Food and Drug Administration and has received a recommendation for conditional marketing authorization by the European Medicines Agency. We aimed to examine the cost-effectiveness of ED versus extended half-life FIX (EHL-FIX) prophylaxis for moderate-to-severe haemophilia B from a German health care payer perspective. METHODS: A microsimulation model was implemented in R. The model used data from the ED phase 3 clinical trial publication and further secondary data sources to simulate and compare patients receiving ED or EHL-FIX prophylaxis over a lifetime horizon, with the potential for ED patients to switch treatment to EHL-FIX prophylaxis when the effectiveness of ED waned. Primary outcomes of this analysis included discounted total costs, discounted quality-adjusted life years (QALYs), incremental cost-effectiveness, and the incremental net monetary benefit. The annual discount rate for costs and effects was 3%. Uncertainty was examined via probabilistic analysis and additional univariate sensitivity analyses. RESULTS: Probabilistic analysis indicated that patients treated with ED instead of EHL-FIX prophylaxis gained 0.50 QALYs and experienced cost savings of EUR 1,179,829 at a price of EUR 1,500,000 per ED treatment. ED was the dominant treatment strategy. At a willingness to pay of EUR 50,000/QALY, the incremental net monetary benefit amounted to EUR 1,204,840. DISCUSSION: Depending on the price, ED can save costs and improve health outcomes of haemophilia patients compared with EHL-FIX prophylaxis, making it a potentially cost-effective alternative. These results are uncertain due to a lack of evidence regarding the long-term effectiveness of ED.

The effectiveness and safety of octocog alfa in patients with hemophilia A: up to 7-year follow-up of the real-world AHEAD international study.

Background: Real-world data assessing treatment outcomes in patients with hemophilia A in routine clinical practice are limited. Objective: To evaluate the effectiveness and safety of octocog alfa in patients with moderate/severe hemophilia A receiving treatment in clinical practice. Design: The international Antihemophilic Factor Hemophilia A Outcome Database study is an observational, noninterventional, prospective, multicenter study. Methods: This planned interim data read-out was conducted following 7 years of observation of patients receiving octocog alfa (cut-off, 30 June 2020). The primary endpoint was joint health status, assessed by the Gilbert Score. Secondary endpoints included annualized bleeding rates (ABRs), Hemophilia Joint Health Score (HJHS), health-related quality of life, consumption, and safety. This post hoc analysis stratified data by hemophilia severity at baseline [moderate, factor VIII (FVIII) 1-5%; severe, FVIII <1%]. Results: Of the 711 patients in this analysis, 582 (82%) were receiving prophylaxis with octocog alfa at enrollment, and 498 (70%) had severe disease. Median Gilbert Scores were higher with on-demand therapy versus prophylaxis and scores were comparable in moderate and severe disease. In patients receiving prophylaxis, there was an improvement in HJHS Global Gait Score over 7 years of follow-up overall and in patients with severe disease. ABRs and annualized joint bleeding rates were low across all 7 years. An ABR of zero was reported in 34-56% of prophylaxis patients versus 20-40% in the on-demand group. ABRs were similar in severe and moderate disease. In total, 13/702 (1.9%) patients experienced 18 treatment-related adverse events. Conclusion: These data demonstrate the long-term effectiveness and safety of octocog alfa in patients with moderate and severe hemophilia A, especially in those receiving prophylaxis. The high number of patients receiving on-demand treatment experiencing zero bleeds could be due to selection bias within the study, with patients with less severe disease more likely to be receiving on-demand treatment. Trial registration: ClinicalTrials.gov: NCT02078427.

Acquired von Willebrand syndrome associated with a smoldering multiple myeloma, successfully treated by daratumumab, lenalidomide and dexamethasone.

INTRODUCTION: Acquired von Willebrand syndrome (AvWS) is a rare entity with approximately 700 cases described in the literature. A number of etiologies are responsible for this condition, mainly lymphoproliferative, myeloproliferative syndromes and cardiac diseases. Management is aimed at preventing and treating bleeds, as well as treating the underlying pathology. In the case of a monoclonal gammopathy, there is limited evidence and high heterogeneity only based on old case reports, resulting in poor quality recommendations. It seems essential in 2023 to take into account and offer the new anti-myeloma treatments available. CASE PRESENTATION: We describe the case of a patient with an AvWS secondary to an IgG smoldering multiple myeloma, experiencing multiple bleeding, treated successfully with daratumumab, lenalidomide and dexamethasone, after multiples treatment failure. CONCLUSION: Daratumumab, lenalidomide, and dexamethasone demonstrated as a rapid and effective treatment for a patient with severe AvWS and multiple bleeding complications.

Reliability and construct validity of the ACTIVLIM-Hemo and Haemophilia Activities List (HAL) questionnaires in individuals with haemophilia.

OBJECTIVE: The objective of this study is to assess the reliability and construct validity of ACTIVLIM-Hemo, a newly developed Rasch-built questionnaire designed to evaluate activity limitations in people with haemophilia (PwH), in comparison with the Haemophilia Activities List (HAL), which was developed using Classical Test Theory. METHODS: A total of 130 participants with haemophilia A or B were included. They underwent various assessments, including joint health scoring (HJHS), functional tests (TUG and 2MWT) and completed questionnaires such as the BPI, IPAQ, HAL and ACTIVLIM-Hemo. Reliability indices and the minimum detectable change (MDC95) were determined for ACTIVLIM-Hemo and for HAL. Construct validity was evaluated through correlations and multiple linear regression, considering demographic and clinical factors. RESULTS: Both ACTIVLIM-Hemo (Person Separation Index = 0.92) and HAL (Cronbach's α = 0.98) demonstrated high reliability. The MDC95 for ACTIVLIM-Hemo represented 11.6% of its measurement range, while for HAL, it amounted to 18/100 score points. Activity limitations measured by both instruments were significantly correlated with demographic and clinical factors. Joint health (HJHS), pain severity (BPI) and walking performance (2MWT) emerged as the main predictors of activity limitations, explaining 75% of the variance in ACTIVLIM-Hemo and 60% in HAL. CONCLUSION: ACTIVLIM-Hemo stands as a reliable and valid instrument for assessing activity limitations in PwH. Both instruments exhibited significant correlations with demographic and clinical factors, but ACTIVLIM-Hemo displayed a more homogeneous construct. Given its linear scale and lower MDC95 and better targeting, ACTIVLIM-Hemo shows promise as a patient-centric instrument for assessing responsiveness to treatment during individual follow-up.

The value-based healthcare approach to haemophilia: Development of outcome measures for the evaluation of care of people with haemophilia.

INTRODUCTION: Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations. AIM: The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process. METHODS: A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia. RESULTS: A final list of three COIs and five PROIs was created and validated. The identified COIs focus on two domains: musculoskeletal health and function, and safety. The identified PROIs cover five domains: bleeding frequency, pain, mobility and physical activities, Health-Related Quality of Life and satisfaction. Finally, two composite outcomes, one based on COIs, and one based on PROIs, were proposed as synthetic outcome indicators of quality of care. CONCLUSION: The presented standard set of health outcome indicators provides the basis for harmonised longitudinal and cross-sectional monitoring and comparison. The implementation of this value-based approach would enable a more robust assessment of quality of care in haemophilia, within a framework of continuous treatment improvements with potential added value for patients. Moreover, proposed COIs and PROIs should be reviewed and updated routinely.

Eptacog beta for the management of patients with haemophilia A and B with inhibitors: A European perspective.

Eptacog beta (activated), a recombinant human factor VIIa (rFVIIa), was approved by the US Food and Drug Administration (FDA) in 2020 (SEVENFACT®, LFB & HEMA Biologics) and the European Medicines Agency (EMA) in 2022 (CEVENFACTA®, LFB). In Europe, eptacog beta is indicated for the treatment of bleeds and the prevention of bleeds during surgery or invasive procedures in adults and adolescents (≥12 years old) with congenital haemophilia A or B with high-titre inhibitors (≥5 BU) or with low-titre inhibitors who are expected to have a high anamnestic response to factor VIII or factor IX, or to be refractory to increased dosing of these factors. The efficacy and safety of eptacog beta were evaluated in three Phase III clinical studies, PERSEPT 1, 2 and 3. For the EMA filing dossier, the analysis of data from PERSEPT 1 and 2 differed from the analysis used to support the filing in the US. In this review, we summarise current data regarding the mode of action, clinical efficacy and safety of eptacog beta for the management of haemophilia A and B in patients with inhibitors from a European perspective. In addition to providing a valuable summary of the analyses of the clinical data for eptacog beta conducted for the EMA, our review summarises the potential differentiators for eptacog beta compared with other current bypassing agents.

The underevaluated impacts of the therapeutic revolution of hemophilia on women and girls.

The advent of new treatment options over the last decades has markedly improved the lives of male persons with hemophilia (PwH). However, this therapeutic revolution has not benefited women and girls with hemophilia (WGH) and symptomatic carriers of the disease to the same extent as their male counterparts. This inequity is primarily due to the exclusion of WGH from clinical trials and a failure to fully recognize their specific treatment needs. Additionally, the indirect impact of innovative therapies, when used for male PwH, on the lives of mothers, other relatives, and partners of these individuals has been largely overlooked until now. In addition to improving access of WGH and carriers to new hemostatic treatments and comprehensive hemophilia care, it is imperative to strive for alleviating the mental burden imposed on them by this chronic disease. The recently proposed concept of a "hemophilia-free mind," primarily focused on male PwH, should therefore also be applied to WGH, symptomatic carriers, and the predominantly female support network of PwH.

Joint status, pain and quality of life in elderly people with haemophilia: A case-control study.

INTRODUCTION: Elderly people with haemophilia (PwH) develop haemophilic arthropathy, pain, and reduced health-related quality of life (HR-QoL). The condition of elderly mild haemophilia patients have rarely been evaluated. This study aimed to compare joint status, pain, and HR-QoL between elderly with mild, moderate/severe haemophilia and healthy elderlies. METHODS: Knee/ankle abnormalities were assessed by ultrasound (HEAD-US) and physical examination (HJHS 2.1). Pain severity and pain interference were investigated using the Brief Pain Inventory. Pressure pain thresholds (PPTs) were obtained at knees/ankles and forehead. Functional limitations were evaluated using the 2-Minute-Walking-Test, Timed-Up-and-Go and HAL. The EQ-5D-5L questionnaire evaluated HR-QoL. Healthy controls (HCs) and elderly individuals with moderate/severe and mild haemophilia were compared using Kruskal-Wallis and Mann-Whitney U tests. RESULTS: From the 46 elderly PwH approached, 40 individuals (≥60 years) with haemophilia A/B (17 moderate/severe; 23 mild) and 20 age-matched HCs were recruited. Moderate/severe PwH displayed worse joint status, lower PPTs, and poorer HR-QoL than mild PwH and HCs (p-value = .010-<.001). HEAD-US abnormalities were observed in 100% of knees and 94% of ankles in moderate/severe PwH, versus 50% of knees and 61% of ankles in mild PwH. Pain was reported by 80% and 57% of moderate/severe and mild PwH, respectively. Low PPTs, functional limitations, and poor HR-QoL scores were likewise observed in some mild PwH, yet without significantly differing from HCs. CONCLUSION: This study highlights poor joint/functional status, pain, and HR-QoL outcomes in elderly with moderate/severe haemophilia. A few mild haemophilia subjects presented joint abnormalities, pain, functional limitations, and poor HR-QoL, without significantly differing from HCs. HIGHLIGHTS: Elderly individuals with mild haemophilia have not yet been extensively studied, whereas moderate/severe haemophilia individuals have proven to suffer from haemophilic arthropathy, pain, and poor health-related quality of life (HR-QoL). Using a case-control design, joint status, pain, and HR-QoL outcomes were examined in elderly haemophilia individuals and compared with those of healthy controls (HCs). Elderly moderate/severe haemophilia individuals exhibited worse joint status, increased joint pain sensitivity, and reduced HR-QoL compared with both mild haemophilia subjects and HCs. A subset of mild haemophilia subjects exhibited poor joint status, pain, and HR-QoL outcomes, without any differences noted when compared with HCs.

Direct Oral Anticoagulants for Inferior Vena Cava Agenesis.

Deep vein thrombosis (DVT) is common in the general population, with an annual incidence of 1 to 2 per 1000 people. Inferior vena cava agenesis (IVCA) increased the risk of developing DVT and is found in approximately 5% of young adults (20-40-year-olds) diagnosed with unprovoked proximal DVT. IVCA can be caused by a defective embryological process, or be a result of intrauterine or perinatal thrombosis. Its estimated incidence in the general population ranges from 0.0005% to 1%, usually involving a partial absence of one of the four segments of the inferior vena cava (IVC). The management during the extended phase of patients with DVT associated with IVCA is not yet harmonized, as it is poorly described in the literature. Patients with IVCA are considered to be at high risk of DVT occurrence, prompting physicians to continue extended anticoagulation, often using vitamin K antagonists. In this retrospective study, we present a cohort of 11 patients diagnosed with IVCA following a DVT, who subsequently received extended treatment with a direct oral anticoagulants. These findings offer reassuring insights into the extended utilization of direct oral anticoagulants, demonstrating both antithrombotic efficacy and a favorable safety profile.

The Classification of Suspected Predominant Nociplastic Pain in People with Moderate and Severe Haemophilia: A Secondary Exploratory Study.

In people with haemophilia (PwH), joint pain is a major comorbidity that is often overlooked and under-treated. It is believed that, to ensure the most successful outcome, pain management should be tailored to the predominant pain phenotype (i.e., nociceptive, neuropathic and nociplastic). The 2021 clinical criteria and grading system for nociplastic pain, established by the International Association for the Study of Pain (IASP), emphasize the necessity of early-stage identification and predominant pain type classification. Consistent with findings in other chronic musculoskeletal pain conditions, studies suggest that a subgroup of PwH suffers from nociplastic pain, i.e., pain arising from altered nociception rather than structural damage, but this has not yet been explored in PwH. This study aimed to identify PwH with "unlikely", "possible" and "probable" nociplastic pain and investigate differences in anthropometric, demographic and clinical characteristics and psychological factors between subgroups of PwH and healthy individuals.: The IASP clinical criteria and grading system were used to classify pain types in adult men with moderate or severe haemophilia recruited from two Belgian haemophilia treatment centres. Statistical analyses were applied to study between-subgroup differences. Of 94 PwH, 80 PwH (85%) were classified with "unlikely" and 14 (15%) with "at least possible" nociplastic pain (including 5 PwH (5%) with "possible" and 9 PwH (10%) with "probable" nociplastic pain). PwH in both the "unlikely" and "at least possible" nociplastic pain groups showed significantly higher levels of unhelpful psychological factors compared to healthy individuals. Additionally, age may partially account for the observed differences in body height and psychological factors. Larger sample sizes may be needed to detect more subtle between-group differences. study confirmed the presence of nociplastic pain in haemophilia, categorising a notable subgroup as individuals who experience at least possible nociplastic pain. These exploratory insights may provide a starting point for future studies and the development of more effective and tailored pain management.

Bispecific antibodies mimicking factor VIII in hemophilia A: converting innovation to an essential medicine.

Preventive subcutaneous treatment of severe hemophilia A with bispecific antibodies that mimic the action of coagulation factor VIII (FVIII) is emerging as an effective alternative to replacement therapy with intravenous administration of FVIII concentrates, either derived from plasma or produced by biotechnology. Access to this innovative therapeutic approach for a growing number of patients worldwide increasingly appears to be a priority public health strategy. Inclusion of FVIII mimetic bispecific antibodies on the World Health Organization essential medicines list would contribute to health equity in lower-income countries.

MariClus: Your One-Stop Platform for Information on Marine Natural Products, Their Gene Clusters and Producing Organisms.

BACKGROUND: The marine environment hosts the vast majority of living species and marine microbes that produce natural products with great potential in providing lead compounds for drug development. With over 70% of Earth's surface covered in water and the high interaction rate associated with liquid environments, this has resulted in many marine natural product discoveries. Our improved understanding of the biosynthesis of these molecules, encoded by gene clusters, along with increased genomic information will aid us in uncovering even more novel compounds. RESULTS: We introduce MariClus (https://www.mariclus.com), an online user-friendly platform for mining and visualizing marine gene clusters. The first version contains information on clusters and the predicted molecules for over 500 marine-related prokaryotes. The user-friendly interface allows scientists to easily search by species, cluster type or molecule and visualize the information in table format or graphical representation. CONCLUSIONS: This new online portal simplifies the exploration and comparison of gene clusters in marine species for scientists and assists in characterizing the bioactive molecules they produce. MariClus integrates data from public sources, like GenBank, MIBiG and PubChem, with genome mining results from antiSMASH. This allows users to access and analyze various aspects of marine natural product biosynthesis and diversity.

Building a haemophilia-specific navigator in Epic® Electronic Health Records: Single-centre preliminary experience.

INTRODUCTION: With the increasing complexity of haemophilia care and the advent of numerous therapeutic innovations, there is an unmet need for documentation and data collection tools tailored to people with haemophilia (PwH). To date, no fully integrated haemophilia-specific electronic health record (EHR) has been described in the literature. AIM: To evaluate the feasibility of integrating a haemophilia-specific navigator into the Epic EHR. METHODS: Based on clinical experience and registry datasets, we identified key variables describing both PwH and carriers of haemophilia. These were then incorporated into a REDCap database, which served as a starting point for the development of a comprehensive haemophilia flowsheet. We built a dedicated haemophilia navigator within Epic that includes a flowsheet featuring up to 212 variables, as well as customised note templates and patient lists integrating data from the haemophilia flowsheet. RESULTS: It was feasible to develop a haemophilia navigator within Epic over the course of 12 months. The navigator's flowsheet enables systematic and comprehensive clinical assessment of PwH and carriers, while customised patient lists provide a quick summary of each patient's profile to the haemophilia treatment centre staff and highlight issues that require an intervention. In our clinical practice, patients actively participated in the new documentation process and responded positively to the navigator. CONCLUSION: Adapting EHRs to the needs of PwH and carriers promotes holistic care for this population and provides an opportunity for patient empowerment. Such haemophilia-specific EHRs are expected to promote standardisation of care and facilitate the collection of registry data on a national and international level.