Prophylaxis In Haemophilia Research Articles

Evaluating the benefits of emicizumab prophylaxis for haemophilia A with inhibitors: A cost-effectiveness and budget impact analysis in Thailand's upper-middle income setting.

In Thailand, an upper-middle-income country, managing haemophilia A (HA) with inhibitors poses significant challenges, often necessitating bypassing agents (BPAs) for bleeding control. This study evaluates the cost-effectiveness and budget impact of emicizumab, a novel prophylactic agent, as an alternative to both episodic and prophylactic BPA treatments from a societal perspective. A Markov model was employed to estimate the lifetime societal costs and outcomes of emicizumab prophylaxis for HA patients with inhibitors. Treatment efficacy, cost, and epidemiological data were obtained through a comprehensive literature review and incorporated into the model. A 5-year budget impact analysis complemented the cost-utility analysis, with a 3% annual discount rate applied to future costs and outcomes. In the base-case scenario, emicizumab prophylaxis in HA patients aged 2 years and above demonstrated superior cost-effectiveness, yielding 18.1 quality-adjusted life years (QALYs) per patient over a lifetime and resulting in cost savings of 138 million Thai Baht (THB) compared to BPA prophylaxis. Compared to episodic BPA treatment, emicizumab yielded 30.5 QALYs and saved 25 million THB per patient. The 5-year budget impact was projected at 1775 million THB. Emicizumab offers a cost-saving approach for HA treatment with inhibitors in Thailand, promising significant health benefits and budgetary savings. This supports its potential inclusion in Thailand's National List of Essential Medicines to enhance haemophilia care access. Managing haemophilia A (HA) with inhibitors in Thailand, an upper-middle-income country, faces challenges due to limited access to effective treatments or newer drugs for bleeding management. Emicizumab prophylaxis found to as a cost-effective and viable alternative to traditional treatments, effectively preventing bleeding in Thai HA patients over 2 years old with inhibitors. Demonstrating improved clinical outcomes and reduced costs, emicizumab prophylaxis outperforms episodic BPA treatments, positioning it as a superior treatment option for HA patients with inhibitors in Thailand.

Emicizumab in Children with Severe Hemophilia A.

To assess the effectiveness and tolerability of emicizumab prophylaxis in hemophilia A (HA). Emicizumab is a novel therapeutic drug which is the first and only non-factor replacement agent licensed for use in people with HA. Pediatric patients aged 1 mo to 12 y with severe HA and frequent / life threatening bleeding events, with or without coagulation protein factor VIII inhibitors were enrolled (n = 18) in this observational pre-post study. Patients were switched from therapy involving on-demand or prophylactic factor VIII/bypassing agents/immune tolerance induction to emicizumab prophylaxis and followed up for 52 wk. One year before initiating emicizumab, a total of 229 bleeding events occurred among the enrolled children. After emicizumab prophylaxis, 5 patients had one episode of bleeding event each with a mean bleeding duration of 1.2 d in one year. The mean annualized bleeding rate significantly reduced from 12.7 ± 8.61 events pre-emicizumab prophylaxis to 0.28 ± 0.46 events post-emicizumab prophylaxis (p < 0.001). Out of the total cohort (n = 18), 72.2% of patients (n = 13) had no bleeding events (95% Confidence interval: 46.4-89.3) while on emicizumab. The mean annualized joint bleeding rate reduced from 9.72 ± 7.44 to 0.17 ± 0.38 (p < 0.001). The target joint resolution was 100% and no adverse events were noted. Emicizumab was found to be effective and safe as a prophylactic agent for the treatment of severe HA with and without factor VIII inhibitors. Emicizumab prophylaxis can optimize treatment outcomes and promote a better quality of life in children with severe HA.

Assessment of joint health in patients receiving prophylaxis for haemophilia A: a cross-sectional survey in five European countries

ObjectivesTo evaluate joint health, pain and health-related quality of life (HRQoL) in patients with moderate/severe haemophilia A in Europe.DesignMultinational, cross-sectional survey, with retrospective data collection. Data were taken from the...

Assessing health care resource use, outcomes, and costs among Medicaid beneficiaries receiving factor IX prophylaxis for hemophilia B.

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

Cost-effectiveness of emicizumab prophylaxis for haemophilia A with inhibitors: an adaptive health technology assessment for the Indian setting

ObjectiveTo assess the cost-effectiveness of emicizumab prophylaxis for patients having haemophilia A with inhibitors in the Indian context using an adaptive health technology assessment (aHTA) methodology.DesignEconomic evaluation using multiple approaches...

How much prophylaxis is enough in haemophilia?

Prophylaxis has become standard of care for all persons with haemophilia (PWH) with a severe phenotype. However, 'standard prophylaxis' with either factor or non-factor therapies (currently only emicizumab available) is prohibitively expensive for much of the world. We sought to address the question of 'How much prophylaxis is enough?' and 'Can it be individualized?' and specifically 'Can emicizumab be individualized?'. We reviewed the literature on prophylaxis in haemophilia since its inception in the 1950s to the present, the development of more and less intense factor prophylaxis regimens and their outcomes and additionally the published outcomes of prophylaxis with low dose emicizumab. What these experiences collectively show is that low dose emicizumab does result in significant benefits to patients whilst being much less expensive than a "one size fits all" emicizumab prophylaxis approach. We also took note that some non-factor therapies still in development are individualized given that high doses of these can potentially put patients at risk. Prophylaxis is now clearly accepted as standard of care for PWH with a severe phenotype but now in a very short time a large assortment of different treatment options for prophylaxis have become/are becoming available and the haemophilia community will need to determine how to best use these recognizing that no 'one treatment fits all'.

Improved outcomes and cost savings for patients with bleeding disorders: a quality improvement project

BackgroundProviding optimal care for patients with bleeding disorders according to national standards remains a challenge at designated Hemophilia Treatment Centers (HTCs). Improved care may reduce bleeds and costs. ObjectivesTo improve care and demonstrate cost savings by 1) reducing preventable hospitalizations and emergency room visits (PHER) for bleeding, 2) increasing use of prophylaxis in severe hemophilia, and 3) improving patient-HTC communication and primary care engagement. MethodsProspective quality improvement project using the Define, Measure, Analyze, Improve, and Control methodology to implement uniform guideline-based bleeding disorder care at a rural HTC (N = 88). Intervention used a standardized physician checklist, improved communication, and reserved physician time for urgent management. Outcomes were determined by retrospective chart review; urgent management was tracked prospectively. ResultsIntervention significantly reduced PHER by 85.4%. Use of prophylaxis in persons with severe hemophilia increased from 58.8% to 100%; attainment of a primary care physician and electronic portal enrollment met outcomes for intervention success. HTC clinic visit attendance was low at 55.2%. The majority of patients (71.6%) had at least 1 outpatient urgent episode (mean, 0.72 episode per year), and 93% had nonurgent management (mean, 9.3 episodes per year) occurring outside of a clinic visit. Hospital PHER factor cost in the group was reduced by 94.5%, from $11,800 to $640 per patient per year—a cost savings of $982,088 yearly. ConclusionThis collaborative study shows that implementation of a carefully designed quality improvement project, such as uniform guidelines with focus on strengthening ambulatory management, led to improved outcomes and cost savings.

Economic analysis of the use of drugs for the treatment of hemophilia A, B and Willebrand's disease

Relevance. Therapy of hemophilia A, B and Willebrand's disease is carried out under the program of 14 VZN due to the use of federal budget funds. The use of funding is increasing in line with the growth of the total number of patients. In 2022,85.99 billion rubles were allocated, which corresponds to a 1.5‑fold increase in funding compared to 2018. The aim of the study was to conduct an economic analysis of the use of drugs for the therapy of hemophilia A, B and Willebrand's disease. Methods. The materials for the analysis were the dosing regimen of LPs selected on the basis of clinical recommendations, the availability of LPs in the 14 VZN program, and the prices for LPs from the State Register of maximum selling prices for VED drugs. Costs of on demand prophylaxis and treatment regimens for hemophilia A, B and Willebrand's disease according to clinical recommendations for each INN for all trade names (TN) were assessed. Results. For hemophilia A the number of submitted drugs by INN is 7;IN — 14; of them domestic drugs were submitted — 1. The minimum cost of LPs for prophylaxis is 2 584 764,00 rubles. Coit-DVI (Grifols Therapeutics LLC, USA), and the maximum cost is RUR 9,955,517.21. Advait (Takeda Manufacturing AG, Austria). Forhemophilia B, the number of represented PL — 2 INN; INN — 6; domestic drugs — 2. The minimum cost is RUR 1,559,376.00. Innonafactor (AO Generium, Russia), maximum — 3 079 319,88 rubles for a year course of prophylaxis LP Immunin (TakedaManufacturing, Austria). To stop bleeding in patients with inhibitor form use anti-inhibitor coagulant complex (Feiba, Austria), which is necessary on average 9100 units per 1 patient, and the average cost of application — 430 863,52 rubles or eptacog alpha(activated) (Coagil-VII, Russia) at multiple administration to the patient 6 times a day — maximum cost — 2 739 803,64 rubles or once a day — 293 550,35 rubles. Conclusion. In the structure of drug supply for patients with hemophilia, domestic drugs are represented by 5 names: Octofactor (JSC "Generium", Russia); Agemfil B (FGBU "NMIC Hematology" of the Ministry of Health of Russia, Russia) and Innonafactor (JSC "Generium", Russia); ArioSaven (LLC "PSK Pharma", Russia) and Coagil-VII (JSC "SG Biotech", Russia). There are no domestic drugs available for the therapy of Willebrand's disease.

The role of emicizumab in acquired hemophilia A.

Acquired hemophilia is a rare bleeding disorder that predominantly affects older people with potential underlying comorbidities, including cardiovascular and thrombotic risk factors. The current standard therapies with hemostatic agents for acute bleeding and immunosuppression often require inpatient management, are not approved for routine bleeding prophylaxis, and contribute to the high mortality in this population. Emicizumab is a factor VIII (FVIII) mimetic approved for bleeding prophylaxis in congenital hemophilia A with and without FVIII inhibitors. Given subcutaneously, it may allow easier outpatient bleeding prophylaxis and reduce intensity of immunosuppression. This article summarizes the currently available data on the efficacy and safety of emicizumab in acquired hemophilia A.

Design of an Observational Study (PROVE) to Assess the Long-Term Effects of Prophylaxis with Simoctocog Alfa or Emicizumab on Joint and Bone Health in Hemophilia a Patients

Background: Arthropathy caused by repeated joint bleeding is a major complication in patients with severe hemophilia A and is associated with long-term morbidity. Factor VIII (FVIII) prophylaxis has proven benefits for prevention of bleeding, including joint bleeding, in these patients. Alongside preservation of joint health, FVIII prophylaxis may preserve bone mineral density (BMD) and reduce the risk of fractures. Emicizumab is a bi-specific monoclonal antibody with no structural homology to FVIII and is approved for prophylaxis in hemophilia A patients. However, data on the long-term impact of emicizumab on joint and bone health are limited. Aims: To assess the impact of long-term prophylaxis with simoctocog alfa (Nuwiq ®; a fourth generation recombinant FVIII) versus emicizumab on joint and bone health in people with hemophilia A. Methods: PROVE is a multinational, prospective, two-arm, low-interventional study that will collect clinical data on joint and bone health in patients receiving prophylaxis with simoctocog alfa or emicizumab in routine clinical practice. Approximately 200 male participants (100 in each treatment arm) at least 12 years of age with severe hemophilia A (FVIII activity [FVIII:C] &amp;lt;1%) will be enrolled. Written, informed consent will be obtained from each patient or their legal representative. The primary objective of the study is to evaluate the long-term effect of simoctocog alfa versus emicizumab on joint health as measured by magnetic resonance imaging (MRI). The primary endpoint will be a between-group comparison of the change in total score on the extended MRI (eMRI) scale (Table 1). Secondary and exploratory endpoints include the impact of simoctocog alfa vs emicizumab on bleeding rates, joint and bone health, physical activity, quality of life and safety (Table 1). Study treatments will be defined by the treating physician prior to inclusion of a patient into the study. Patients will not be randomized to the treatment groups but will continue with their current prophylactic regimen (simoctocog alfa or emicizumab). Patients will be provided with an electronic diary (eDiary) in which to record study related data, including treatment-related data, bleeding event details, fracture details, concomitant medications and adverse drug reactions. Each patient will be followed for up to 4 years. An interim analysis is planned after 2 years. Conclusion: ThePROVE study aims to generate real-world data on the long-term effects of prophylaxis with simoctocog alfa or emicizumab on joint and bone health in hemophilia A.

Pharmacokinetics, Safety and Preliminary Efficacy of Multiple Doses of Pegylated Recombinant Human Coagulation Factor VIII-Fc Fusion Protein (FRSW117) in Previously Treated Adult and Adolescent Subjects with Severe Hemophilia a: Results from an Open-Label, Multicenter, Phase 2 Study

Introduction ：Prophylaxis of severe hemophilia A (HA) with standard half-life Factor VIII (FVIII) products necessitates frequent administration, and low trough FVIII activity levels lead to higher risk of bleeds. FRSW117 is a PEGylated recombinant human coagulation factor VIII Fc fusion protein (PEGylated rhFVIII-Fc), in a phase 1 study, single-dose FRSW117 was well tolerated and provided a prominently longer t1/2 with FVIII activity maintaining at ≥ 1% for more than 7 days. This open-label, multicenter phase 2 study (NCT05265286) aimed to evaluate the PK, safety, and preliminary efficacy of multiple 4 doses of FRSW117 in previously treated subjects with severe HA. Methods ：Severe HA (FVIII:C &amp;lt;1%) patients aged 12 (inclusive) to 65 years, previously treated with FVIII products ≥ 150 exposure days (EDs) were enrolled in two cohorts (M1, 40IU/kg; M2, 50IU/kg), to receive 4 once-weekly doses of FRSW117 on day 1, 8, 15, and 22 (ED1 to ED4), respectively. The PK characteristics, safety, and immunogenicity of FRSW117 were evaluated. PK samples were collected pre-dose on day 1, 8, 15, 22, and at multiple times after infusion on day 1 and day 22. The primary endpoints were the PK parameters, the occurs of AEs, inhibitor development, and other immunogenicity profiles; the secondary endpoints were the bleeding episodes during multiple dosing. FVIII activity was determined using one-stage clotting assay. FVIII inhibitor was tested using the Nijmegen-modified Bethesda assay. PK analyses were performed using noncompartmental analysis (Phoenix WinNonlin 8.3). Results ：Between April 2022 and August 2022, a total of 15 male subjects were enrolled in cohort M1 (N=8) and M2 (N=7). 13/15 (86.7%) of the subjects were adults, 2 of them were adolescent, both in M1. The mean age was 28.1 (range: 13, 44) in M1 and 30.6 (range: 23, 36) in M2. 14 subjects completed the study, with 1 subject in M2 withdrew early after the PK sampling of ED1 due to personal reasons. Baseline-corrected PK parameters were summarized in Table 1. Geometric mean elimination half-life (t 1/2) of M1 and M2 were 29.536h and 31.545 h, respectively, consisting with the first-in-human single dose study. Area under the activity-time curve (AUC 0-t), and steady-state maximum concentration (C max) after 4 weekly doses for M1 and M2 were 4557.1 and 4937.9 h*IU/dL, 101.26 and 122.76 IU/dL, respectively. The mean FVIII activity at 168h after dose for M1 and M2 were summarized in Table 2, and it were 3.25 and 2.88 IU/dL on 168 h (7 day) after the dose on D22. Baseline-corrected FVIII activity over time of 2 cohorts are shown in Figure 1. The accumulation index based on AUC tau were 1.008 and 1.098, respectively, indicating there was minimal accumulation after 4 once-weekly doses. A total of 10 (66.7%,10/15) subjects reported 20 treatment emergent adverse events (TEAE) during the study. No ≥ grade 3 adverse events, serious adverse events (SAE), adverse event leading to treatment discontinuation, or AESI were reported. No positive FVIII inhibitor was detected during the study. Pre-existing Anti-PEG-rhFVIII-Fc antibodies (ADA) were observed in 4/15 (26.7%) subjects.Pre-existing anti-PEG antibodies were observed in 3/15 (20.0%) subjects. No treatment emergent ADA and anti-PEG antibodies were observed, no treatment-boost ADA and anti-PEG antibodies were observed in subjects with pre-existing ADA and anti-PEG antibodies. No significant impact of pre-existing ADA and/or anti-PEG antibodies on PK variable, safety profile and preliminary efficacy was observed. 12/15 (80.0%) patients experienced zero bleeding episodes during the 4-week FRSW117 treatment period (from day 1 through day 28, 7 days after D22 dosing). Three of 15 (20.0%) subjects experienced 6 bleeding events among which only 1 spontaneous bleeding episode in cohort M1. 2 bleeds episodes were treated with FRSW117 of mean dose of 30.01 IU/kg and both were controlled after one infusion, with a hemostatic response rate of 100%. Conclusion: The therapy of 4 once-weekly doses of FRSW117 displayed favorable safety profile and provided about 3% mean FVIII activity on day 7 postdose with minimal accumulation. These results suggest that FRSW117 may offer extended bleeding protection with weekly dose interval and support further assessment of FRSW117 in phase 3 study.

Reducing Preventable Bleeding Visits and Institutional Factor Costs for Patients with Bleeding Disorders with a Prospective Quality Improvement Project

Providing optimal care to patients with bleeding disorders requires specialized physician, laboratory, pharmacy, nursing, and institutional resources best achieved at Hemophilia Treatment Centers (HTCs). Current systems for managing the care of a resource intensive patient population may be suboptimal. We observed frequent bleeding related hospitalizations and emergency room (ER) visits in patients with bleeding disorders treated at our HTC that could have been potentially prevented by changes in outpatient care delivery. We initiated a prospective quality improvement (QI) project to improve care delivery and to reduce preventable bleeding related hospitalizations and ER visits for adult patients treated at our HTC. The interventions targeted patient-level and systems-level factors contributing to preventable visits, and barriers to care in our patient population. We compared preventable bleeding related hospitalizations and ER visits, institutional factor cost, use of prophylaxis in severe hemophilia, primary care physician attainment, and patient electronic portal enrollment before and after the QI intervention. In our population of adult patients with bleeding disorders (N=88), the intervention significantly reduced the primary outcome of preventable bleeding hospitalization or ER visit (P=0.0082, Figure), and reduced such visits by 85.4%, meeting the pre-specified criteria for success. Institutional factor acquisition costs to treat preventable bleeding were reduced by 94.5%, from $11,800 to $640 per patient per year; a projected savings of $982,088 yearly. Use of factor prophylaxis in patients with severe hemophilia increased from 58.8% to 100%, attainment of a primary care physician increased from 69.4% to 86.4%, and use of the electronic patient portal increased from 53.2% to 83%; all secondary outcomes met pre-specified criteria of success and were statistically significant. HTC clinic visit attendance was low at 55.2%. The majority of patients (71.6%) had at least one outpatient urgent episode (mean 0.72 episode per year), and 93% had non-urgent management (mean 9.3 episodes per year) occurring outside of a clinic visit. These data demonstrate that concerted outpatient management of patients with bleeding disorders with a quality improvement framework can reduce preventable hospitalization and ER visits. Decreased inpatient utilization resulted in substantial reductions in factor costs at the health system level. The clinical effort required to achieve these results was substantial, and required frequent provider engagement outside of regular clinic visits. The HTC can improve patient outcomes and reduce institutional costs from preventable bleeding episodes by supporting a collaborative quality improvement process led by physician, nursing, and laboratory coagulation experts.

Emicizumab Efficacy in Severe Hemophilia (A): Experience in Ecuador

Introduction: In Ecuador, there are 1708 cases of hemophilia in a population of 17,643,060 habitants; according to the World Federation of Hemophilia (WFH) Annual Global Survey Report 2020 released in October 2021. Eleven patients use emicizumab in Ecuador (ten patients under ministerial authorization, and one patient through private insurance); being the first administered in June 2021. Objectives: To describe the demographic characteristics of patients receiving emicizumab in Ecuador. To determine efficacy and response with emicizumab: based on annual bleeding rate (ABR), performance status assessment, activity, and participation. Methods: Population: Pediatric Severe Hemophilia A (PwHA) patients (&amp;lt;12 years) and adults/adolescents (&amp;gt;12 years), both from the public and private health sector. Study design: Retrospective, multicentric study, with a case-report research design. The sources of information were the medical records of the patients. Efficacy variables: ABR was calculated by: (number of bleeds/number of days times 365.25). Body structure and function was assessed with the Hemophilia Joint Health Score 2.1 (HJHS). Activity and participation were assessed with the Functional Independence Score in Hemophilia (FISH). Statistic analysis: Shapiro-Wilk test to know the distribution of the sample, t-Test paired tests (parametric), Wilcoxon statistic (non-parametric); Descriptive statistics: relative frequencies, measures of central tendency and dispersion, column graphs. Analysis and results: Ten patients with an average (Q1,Q3) age of 11.5 years (7.15) were registered. The youngest patient was one year old and the oldest, fifty years old. 90% (n:9) had hemophilia A with high-response inhibitors. Prior to starting emicizumab: 20% (n:2) presented Central Nervous System bleeding, 30% (n:3) had muscle bleeding, and 10% (n:1) developed catheter-associated infection. The mean ABR was 10 pre-emicizumab events, and 0.3 post-emicizumab events (p=0.002), with follow-ups at 22 months (n: 2), 17 months (n:2), 3 months (n:2 ), 4 months (n: 3), 5 months (n: 1). The mean HJHS (±SD, n) was 20.9 (± 20,096, 10) pre-emicizumab, and 9.7 (± 16.52, 10) (p=0.003) The mean by FISH (±SD, n) was 16.2 (± 8.59, 10) pre-emicizumab, and from 22.6 (± 11.62, 10) with the use of emicizumab. The use of the t-Test for paired samples determined that there are statistically significant differences between the pre-emicizumab and post-emicizumab groups for the variables ABR, HJHS and FISH (95% confidence level). Conclusion: The use of Emicizumab allowed better control of joint bleeding; and it contributed favorably in the evolutionary course of both the functional state and the activity. It is essential to corroborate these results with a longer follow-up and a larger sample size. Bibliography: 1. Alvarez Roman M: Spanish guidelines for the management of hemophilia. 2022, 1-190. 2. Callaghan M, Negrier C, Paz-Priel I, Chang T, Chebon S y col: Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood. 2021;137(16):2231-2242 3. Carcao M, Escurriola C, Santagostina E, Oldenburg J, Liesner R y col: The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab. Haemophilia. 2019;25:676-684. 4. Ellsworth P, Ma A: Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates?. Hematology Am Soc Hematol Educ Program. 2021, Dec 10;2021(1):219-225. 5. Young G: Management of children with hemophilia A: How emicizumab has changed the landscape. Journal of Thrombosis and Haemostasis. 2021 Jul;19(7):1629-1637

Advancing Hemophilia Prophylaxis: Personalized Low-Dose CFC and Emicizumab in Resource-Limited Settings

Introduction: Hemophilia, a congenital bleeding disorder resulting from clotting factor deficiency, significantly impacts the lives of persons due to recurrent bleeding. Prophylaxis, involving clotting factor replacement, has been recognized as a vital approach to reduce complications and to improve the quality of life in people with hemophilia. However, access to this remains limited, in low-income countries like India. This study examines the effectiveness of personalized low-dose clotting factor concentrates (CFC) prophylaxis and Emicizumab in children with hemophilia, aiming to achieve zero annual bleed rates (ABR), thereby enhancing their well-being and reducing healthcare burden. Patients and Methods: This retrospective observational study was conducted at the Hemophilia Treatment Centre (HTC) in Aluva, Kerala, India, spanning from May 31, 2022, to June 1, 2023. Study included children under 18 years with hemophilia A/B, with or without inhibitors, who had commenced prophylaxis with personalized low-dose CFC since 2015 and completed one year of prophylaxis. The total sample size was 31. Data on ABR, Annual Joint Bleed Rate (AJBR), Hemophilia Joint Health Status (HJHS) score, and Functional Independence Score Hemophilia (FISH) were extracted from the HTC registry.Standard half-life CFCs were used for prophylaxis, with a starting frequency of twice a week for Factor VIII and once a week for Factor IX. Patients were regularly followed up in the Hemophilia Clinic, and the frequency/doses of prophylaxis were increased in case of breakthrough bleeds. Additionally, children were advised to organize peak activities to coincide with the days of CFC injections. Personalization of doses was not based on pharmacokinetic software but was determined through close monitoring and individual adjustments.Health education on identifying and managing bleeding episodes followed ISTH guidelines. Prophylaxis outcomes were assessed with changes in ABR and AJBR during the last year of prophylaxis and compared to the bleed rates in the one year prior to prophylaxis. Changes in HJHS and FISH were documented for older children. All analysis were done using SPSS version24. For quantitative variables results were presented as mean with standard deviation and for qualitative variables, results were presented in percentages. Comparison achieved with standard paired t-test, and p value &amp;lt; 0.05 considered as significant. Results: Out of 36 children receiving prophylaxis, 31 met the inclusion criteria. Among them,10 (32%) received Emicizumab prophylaxis, while 21 (68%) were managed with personalized low-dose CFC prophylaxis. Hemophilia A constituted 24(77%) of cases, mostly classified as severe disease-29 (94%). Table :1 summarises the patient characteristics, prophylaxis dose, cost and outcome measures of the study population.The personalized low-dose CFC prophylaxis had significant measurable improvements, reducing the ABR from 14.90 to 2.90( p 0.000) and the AJBR from 4.95 to 1.43( p 0.004). Additionally, HJHS improved from 3.30 to 0.95( p 0.102), and FISH increased from 29.90 to 32.00( p 0.020).Children on Emicizumab achieved exceptional results, with all reporting zero ABR ( p 0.027), and AJBR ( p 0.131) even with lower than recommended doses(1.02mg/kg/week). In contrast, personalized low-dose CFC prophylaxis (Factor VIII: 36.35/kg/week, Factor IX:32/kg/week) showed varied outcomes, with only 4(19%) achieving zero ABR. HJHS and FISH were not evaluated in Emicizumab group as 7(70%) were belonging to the age group of less than 5 years. Conclusion: This study highlights the effectiveness of personalized low-dose CFC prophylaxis and Emicizumab in reducing bleeding rates and improving musculoskeletal health and functional independence in children with hemophilia. Emicizumab prophylaxis demonstrated remarkable outcomes, achieving zero bleeds even with lower doses. However, personalized low-dose CFC prophylaxis struggled to achieve zero bleed rates for most of them. The findings underscore the need for alternative strategies and increased accessibility to Emicizumab and other newer drugs to achieve the goal of zero bleed rates for children with hemophilia in resource-limited settings. The study's results provide hope for achieving zero bleed rates, ultimately enhancing the well-being of children with hemophilia in resource-limited regions.

Matching-Adjusted Indirect Comparison between Personalized Prophylaxis with Simoctocog Alfa Versus Standard Prophylaxis with Emicizumab in Adults with Hemophilia a

Background: Personalized prophylaxis with factor VIII (FVIII) concentrates remains the mainstay therapy for patients with severe hemophilia A. The bispecific monoclonal antibody emicizumab, which mimics FVIII function, is also approved for prophylaxis in hemophilia A patients. Head-to-head comparative studies on the relative efficacy of different therapeutic strategies are not feasible in a rare disease such as hemophilia A. In such situations, the use of indirect comparison methods can help to compare relative efficacies. Matching-adjusted indirect comparison (MAIC) is a well-established statistical method to indirectly compare outcomes from separate clinical studies. It can be used to adjust for differences in patient characteristics between studies, with the goal to reduce bias in the treatment effect estimates which can occur with comparison of efficacy data across clinical trials. Aims: To indirectly compare the efficacy of a pharmacokinetics (PK)-guided personalized prophylaxis regimen with a recombinant, fourth generation, FVIII concentrate, simoctocog alfa (Nuwiq ®), against standard prophylaxis with the bispecific monoclonal antibody emicizumab (Hemlibra ®) in patients with hemophilia A using MAIC methodology. Methods: After matching study populations, accounting for clinically important baseline characteristics,individual patient-level data (IPD) from 65 patients treated with simoctocog alfa from the NuPreviq study were compared against aggregate data for emicizumab administered once weekly (Q1W, N=99), every 2 weeks (Q2W, N=35) or every 4 weeks (Q4W, N=41) from the HAVEN 3 and HAVEN 4 studies. All patients enrolled in all studies were male. Baseline patient variables for matching were chosen based on availability, clinical relevance and distribution overlap. Baseline age and body weight were used to re-weight the simoctocog alfa IPD to match the aggregate data reported for the emicizumab studies. Patients were removed from the NuPreviq study population if they did not meet the eligibility criteria for the comparator studies (but none were excluded from this analysis based on this). Unanchored indirect treatment comparisons were performed for various clinical outcomes using the re-weighted data for simoctocog alfa and the published comparator study data. The endpoints analyzed were total annualized bleeding rates (ABRs) and percentage of patients with zero bleeds. All endpoints considered treated and untreated bleeds. Results: No patients were excluded from the NuPreviq study population due to imposing the body weight or age criteria of the HAVEN 3 and 4 studies. After matching populations, the effective sample size for simoctocog alfa was 33.1, 39.8 and 29.1 participants for the Q1W, Q2W and Q4W comparisons, respectively. The percentage of patients with zero bleeds was significantly higher with simoctocog alfa across all 3 comparisons: simoctocog alfa (74.3%) vs emicizumab Q1W (46.5%); simoctocog alfa (70.3%) vs emicizumab Q2W (40.0%), and simoctocog alfa (81.9%) vs emicizumab Q4W (29.3%; Figure 1, Table 1). The total ABRs were significantly lower with simoctocog alfa versus emicizumab Q1W (1.5 vs 2.9) and emicizumab Q4W (1.4 vs 4.5; Table 1). When comparing simoctocog alfa versus emicizumab Q2W, the difference was not statistically significant (1.3 vs 2.6; Table 1). Conclusion: Indirect comparisons demonstrated that PK-guided, personalized prophylaxis with simoctocog alfa can lead to statistically significantly higher zero bleed rates and decreased ABRs compared with standard emicizumab prophylaxis. This MAIC analysis provides important comparative efficacy and utilization data, which can help guide patients and physicians in making decisions regarding product choice for prophylaxis regimens.

PB0640 Safety and Efficacy of Combined Dual Antiplatelet Therapy and FVIII Prophylaxis in Hemophilia A Patients after the Acute Coronary Syndrome

PB0640 Safety and Efficacy of Combined Dual Antiplatelet Therapy and FVIII Prophylaxis in Hemophilia A Patients after the Acute Coronary Syndrome

The prophylaxis of severe hemophilia A with inhibitors in children in the Republic of Belarus: a 12-year experience

The development of inhibitory antibodies against FVIII is the most serious complication associated with the use of FVIII concentrates in hemophilia A patients. There is a need for more research on measures that could reduce the risk of inhibitor formation in previously untreated patients (PUPs) with severe hemophilia A. The purpose of this study was to determine the effectiveness of the prevention of clotting inhibitor development in PUPs (or minimally treated patients) with severe hemophilia A by administering plasma-derived factor VIII concentrate (pdFVIII) at a dose of 25 IU/kg once a week for a year. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). Between 2010 and 2022, 56 boys were newly diagnosed with severe hemophilia A. Twenty-one of them received pdFVIII as on-demand treatment to stop bleeding (Group 1). Thirty-five boys received pdFVIII at a dose of 25 IU/kg body weight once a week during the first 50 weeks of treatment for the prevention of inhibitor development (Group 2). The administration of pdFVIII at a dose of 25 IU/kg once a week in the PUPs (or minimally treated patients) contributed to a decrease in the cumulative incidence of inhibitors to 15.9 ± 7.7% (4 out of the 35 patients who had been treated prophylactically) compared with 43.7 ± 11.8% (8 out of the 21 patients who had received hemostatic therapy to stop bleeding) (log-rank test, p = 0.041). Thus, the administration of pdFVIII concentrate at a dose of 25 IU/kg once a week for the first 50 weeks of treatment lead to a decrease (p = 0.009) in the cumulative incidence of inhibitors against the administered coagulation factor VIII to 15.9 ± 7.7%.

OC 43.2 Low-Dose Emicizumab Prophylaxis in Severe Hemophilia a Patients – A Pilot Study with a Much Anticipated Promise for a Resource Limited Country

OC 43.2 Low-Dose Emicizumab Prophylaxis in Severe Hemophilia a Patients – A Pilot Study with a Much Anticipated Promise for a Resource Limited Country

Targeting higher factor VIII levels for prophylaxis in haemophilia A: a narrative review.

The standard of care in severe haemophilia A is prophylaxis, which has historically aimed for a factor VIII (FVIII) trough level of ≥1%. However, despite prophylactic treatment, people with haemophilia remain at risk of bleeds that have physical and quality of life implications, and that impact everyday life. The aim of this review was to evaluate evidence supporting the relationship between targeting higher FVIII activity levels with prophylaxis and improved outcomes in people with haemophilia A. We conducted a narrative review that defined the unmet needs and treatment goals in people with haemophilia A, evaluated evidence to support targeting higher FVIII activity levels, and highlighted therapies that may support higher and sustained FVIII activity levels and improved outcomes for people with haemophilia A. Despite recent advances in treatment, unmet needs remain, and people with haemophilia continue to experience joint and functional impairment, acute and chronic pain, and poor mental health. All these negatively impact their health-related quality of life. Evidence suggests that FVIII activity levels of up to 50% may be needed to achieve a near-zero joint bleed rate. However, achieving high FVIII activity levels with current standard and extended half-life (EHL) FVIII replacement therapies is associated with a high treatment burden. Innovative treatment options may provide high sustained FVIII activity levels and improved patient outcomes. Evidence suggests that FVIII activity levels in people with haemophilia A should be sustained at higher levels to improve joint and patient outcomes and enable progression towards health equity.

Depression and anxiety in people with hemophilia A and B.

This study described the prevalence of and correlates of depression and anxiety in adult patients with hemophilia A and B. In this cross-sectional study, we investigated patients with hemophilia who were being seen at an adult hemophilia center. Participants were screened for depression and anxiety during their annual clinic visit, which included administration of the Beck Depression Inventory and State-Trait Anxiety Scale. Of the 90 patients, 22 (24.4%) met criteria for significant depressive symptoms and and 67 (74.4%) met criteria for significant anxiety symptoms. There were no significant associations between depression and any psychosocial or clinical characteristics or adherence to hemophilia prophylaxis, except for educational status. No association was found between state and trait anxiety scores and psychosocial and clinical characteristics other than hemophilia type. After adjusting for confounding factors, multivariable analysis showed that high school education level was associated with depression (OR: 1.872, CI: 1.312-2.356, P = .010) and type B hemophilia was associated with anxiety (OR: 1.319, CI: 1.089-1.745, P = .042). Depression and anxiety are major psychiatric comorbidities in patients with hemophilia in Turkey. Routine evaluation for mood and anxiety disorders are crucial in the care of patients with haemophilia.