Standard Half-life Research Articles

Intercambio guiado por farmacocinética de factores VIII de vida media estándar a factores VIII de vida media extendida pegilados en la terapia de la hemofilia A en práctica clínica

ObjectiveTo analyze the differences in pharmacokinetic and clinical parameters (bleeding rates and joint health) before and after switching from standard half-life factor VIII (FVIII) to extended half-life pegylated FVIII in patients with severe/moderate hemophilia A on prophylaxis, one year before and after the switch in real-life. MethodThis is a single-center, comparative, observational, sequential, retrospective, and multidisciplinary study. Population pharmacokinetic models from the WAPPS-Hemo® application were used to calculate pharmacokinetic parameters and individualize prophylaxis. The annual rate of total and joint bleeds, joint health (Hemophilia Joint Health Score), plasma half-life and area under the curve ratios, FVIII consumption, administration frequency, and cost were analyzed. ResultsThirty-eight adult patients with hemophilia A who switched from standard half-life FVIII to extended half-life pegylated FVIII were analyzed. Significant improvements (p < 0.05) were observed in all pharmacokinetic parameters, with plasma half-life and area under the curve improvement ratios of 1.5 and 1.9, respectively, as well as reductions in annual total and joint bleeding rates were registered. A higher number of patients with zero total (16.0 vs. 29.0) and joint bleeds (23.0 vs. 33.0) was also observed. The median reductions in administration frequency and dose/kg/week were 30.0% and 19.7%, respectively, avoiding 44.3 infusions/patient/year, resulting in savings of 20,843 €/patient/year. Furthermore, joint health improved (23.0 vs. 21.0; p = 0.017), and target joints resolved after the switch. ConclusionsThe pharmacokinetically guided switch from standard half-life FVIII to pegylated FVIII demonstrated significant clinical benefits with reduced bleeding rates and improvements in joint health. Additionally, improvements in pharmacokinetic parameters were observed, allowing for reduced treatment burden by decreasing administration frequency, as well as lower consumption and costs.

Superior Prophylactic Effectiveness of a Recombinant FVIIIFc Over Standard Half-Life FVIII in Hemophilia A: A-SURE Study.

The 24-month, prospective, non-interventional, European multicenter A-SURE study evaluated the real-world effectiveness of prophylaxis using an extended half-life recombinant factor VIII (FVIII) Fc fusion protein, efmoroctocog alfa (hereinafter rFVIIIFc), compared with prophylaxis using standard half-life (SHL) FVIII products in patients with hemophilia A. Primary endpoints were annualized bleeding rate (ABR), annualized injection frequency, and annualized factor consumption. A comparative study design unique for an observational hemophilia study was implemented to reduce potential confounding in effectiveness estimates, wherein each patient prescribed rFVIIIFc was matched with one receiving SHL FVIII. Propensity scores were used for adjustment in statistical analyses. Outcomes for all primary endpoints were significantly better in the rFVIIIFc group (n = 184) compared with the SHL FVIII group (n = 170): mean ABR 1.5 versus 2.3 (difference of -0.8; p = 0.0147); mean annualized injection frequency 114.4 versus 169.2 (difference of -54.8; p < 0.0001); and mean annualized factor consumption 243 024.2 versus 288 718.6 International Units (difference of 45 694.5; p = 0.0003). rFVIIIFc was well tolerated, with no inhibitor development. rFVIIIFc has superior prophylactic effectiveness versus SHL FVIII, providing higher bleed protection with fewer injections and lower factor consumption.

Real-world insights into the management of hemophilia A in Italy: treatment patterns and healthcare resource utilization

PurposeThis real-world analysis described the Hemophilia A (HA) population in Italy, evaluating drug utilization and consumption of factor VIII (FVIII) products of patients under prophylaxis and on-demand therapy.MethodsFrom Jan-2017 to Jun-2022, male patients with HA were identified through prescriptions of FVIII products [extended half-life FVIII, standard half-life recombinant FVIII, and plasma-derived FVIII (EHL FVIII, SHL rFVIII, and pdFVIII, respectively)], or emicizumab or FVIII plus von Willebrand factor or HA-related hospitalization using administrative flows of Italian healthcare entities. Patients on treatment with FVIII products during 2021–2022 were stratified by treatment regimen (prophylaxis/on-demand). The mean annual consumption expressed in International Units (IU) of EHL FVIII and SHL FVIII in patients treated during 2021–2022 having at least 12-month follow-up were assessed.ResultsAmong included HA patients, 145 (39.5%) received EHL FVIII and 222 (60.5%) SHL FVIII. Of 165 patients on prophylaxis, 105 (64%) received an EHL FVIII and 60 (36%) an SHL FVIII. The mean annual consumption of FVIII was 336,700 IU (median 319,000 IU) for EHL FVIII and 440,267 IU (median 360,500 IU) for SHL FVIII. Specifically, for patients on EHL FVIII, the most common drugs were efmoroctocog alfa (N = 51) and damoctocog alfa pegol (N = 50), followed by turoctocog alfa pegol (N = 25) and rurioctocog alfa pegol (N = 19). Of 702 HA patients initially treated with FVIII products, 74 (10.5%) switched to emicizumab during follow-up.ConclusionThese findings revealed an extensive use of EHL FVIII products, suggesting growing efforts from clinicians to optimize prophylactic strategies and achieve better bleeding protection.

Changes in clinical and laboratory parameters in adolescents and young adults with hemophilia A after switching from standard half-life factor VIII to efmoroctocog alfa.

Changes in clinical and laboratory parameters in adolescents and young adults with hemophilia A after switching from standard half-life factor VIII to efmoroctocog alfa.

PBPK modeling of recombinant factor IX Fc fusion protein (rFIXFc) and rFIX to characterize the binding to type 4 collagen in the extravascular space.

Patients with severe and sometimes moderate hemophilia B are prophylactically treated with factor IX concentrates to prevent bleeding. For some time now, various extended terminal half-life (EHL) recombinant factor IX concentrates are available allowing less frequent administration during prophylaxis in comparison to standard half-life recombinant FIX (rFIX). Especially, recombinant FIX-Fc fusion protein (rFIXFc; Alprolix®) exhibits a rapid distribution phase, potentially due to binding to type IV collagen (Col4) in the extravascular space. Studies suggest that the presence of extravascular rFIXFc is protective against bleeding as without measurable FIX activity in plasma, and no extra bleeding seems to occur. The physiologically based pharmacokinetic (PBPK) model for rFIXFc which we describe in this study, is able to accurately predict the observed concentration-time profiles of rFIXFc in plasma and is able to quantify the binding of rFIXFc to Col4 in the extravascular space after an intravenous dose of 50 IU/kg rFIXFc in a male population. Our model predicts that the total AUC of rFIXFc bound to Col4 in the extravascular space is approximately 19 times higher compared to the AUC of rFIXFc in plasma. This suggests that rFIXFc present in the extravascular compartment may play an important role in achieving hemostasis after rFIXFc administration. Further studies on extravascular distribution of rFIXFc and the distribution profile of other EHL-FIX concentrates are needed to evaluate the predictions of our PBPK model and to investigate its clinical relevance.

Pharmacokinetics of Efmoroctocog alfa by Two-Compartment Model Highlights Hemophilia A Patients with Biphasic Decay, Long Mean Residence Time, and Beta Half-Life.

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

Real-World Amount of Clotting Factor Products and Non-Factor Products Dispensed and Annual Medical Expenditures for Japanese Patients with Haemophilia A.

Treatment for haemophilia A has expanded from plasma-derived factor VIII (pdFVIII) and standard half-life (SHL) recombinant FVIII (rFVIII) to extended half-life (EHL) rFVIII and non-factor products that mimic FVIII activity. To determine amounts of clotting factor concentrates (CFCs) and emicizumab dispensed and associated healthcare expenditures in Japanese patients with haemophilia A. This retrospective, non-interventional, observational study analysed data from 2016 to 2020 from a large-scale, hospital-based administrative database. Patients had haemophilia A without inhibitors and ≥ 2 prescriptions of the same CFC or emicizumab. In total, 974 patients with haemophilia A (median age, 30.0 years; median follow-up, 3.7 years) were included. Outpatient use of EHL rFVIII and emicizumab increased, although pdFVIII/SHL rFVIII were still used over the study. Median annual total healthcare expenditures/patient increased from ¥9,200,230 in 2016 to ¥19,748,221 in 2020. Overall, the median annual drug expenditure/patient increased from ¥8,723,120 in 2016 to ¥18,051,689 in 2020. Drug expenditure was highest with emicizumab, with an increase in median annual expenditure/patient from 2018 (n = 4, ¥26,030,206) to 2020 (n = 107, ¥45,430,408). Overall, 233 patients (23.9%) switched from an SHL to an EHL product. Although amounts of FVIII prescribed increased in the 3 months after switching, overall, there was no noticeable difference before and after switching. Median total healthcare and FVIII product expenditures increased following switching. Prescribing of EHL products increased over the study and healthcare expenditures increased for patients who switched from SHL to EHL rFVIII products.

Mixed effect estimation in deep compartment models: Variational methods outperform first-order approximations.

This work focusses on extending the deep compartment model (DCM) framework to the estimation of mixed-effects. By introducing random effects, model predictions can be personalized based on drug measurements, enabling the testing of different treatment schedules on an individual basis. The performance of classical first-order (FO and FOCE) and machine learning based variational inference (VI) algorithms were compared in a simulation study. In VI, posterior distributions of the random variables are approximated using variational distributions whose parameters can be directly optimized. We found that variational approximations estimated using the path derivative gradient estimator version of VI were highly accurate. Models fit on the simulated data set using the FO and VI objective functions gave similar results, with accurate predictions of both the population parameters and covariate effects. Contrastingly, models fit using FOCE depicted erratic behaviour during optimization, and resulting parameter estimates were inaccurate. Finally, we compared the performance of the methods on two real-world data sets of haemophilia A patients who received standard half-life factor VIII concentrates during prophylactic and perioperative settings. Again, models fit using FO and VI depicted similar results, although some models fit using FO presented divergent results. Again, models fit using FOCE were unstable. In conclusion, we show that mixed-effects estimation using the DCM is feasible. VI performs conditional estimation, which might lead to more accurate results in more complex models compared to the FO method.

Inhibitor development according to concentrate after 50 exposure days in severe hemophilia: data from the European HAemophilia Safety Surveillance (EUHASS)

BackgroundPatients with hemophilia have a life-long risk of developing neutralizing antibodies (inhibitors) against clotting factor concentrates. After the first 50 exposure days (EDs), ie, in previously treated patients (PTPs), data on inhibitor development are limited. ObjectivesTo report inhibitor development according to factor (F)VIII or FIX concentrate use in PTPs with severe hemophilia A and B. MethodsInhibitor development in PTPs was collected since 2008 from 97 centers participating in European HAemophilia Safety Surveillance. Per concentrate, inhibitors were reported quarterly and the number of PTPs treated annually. Incidence rates (IRs)/1000 treatment years with 95% CIs were compared between concentrate types (plasma derived FVIII/FIX, standard half-life recombinant FVIII/FIX, and extended half-life recombinant (EHL-rFVIII/IX) concentrates using IR ratios with CI. Medians and IQRs were calculated for inhibitor characteristics. ResultsFor severe haemophilia A, inhibitor rate was 66/65,200 treatment years, IR 1.00/1000 years (CI 0.80-1.30), occurring at median 13.5 years (2.7-31.5) and 150 EDs (80-773). IR on plasma-derived pdFVIII (IR, 1.13) and standard half-life recombinant FVIII (IR, 1.12) were similar, whereas IR on EHL-rFVIII was lower at 0.13 (incidence rate ratio, 0.12; 95% CI, <0.01-0.70; P < .01).For severe hemophilia B, inhibitor rate was 5/11,160 treatment years and IR was 0.45/1000 years (95% CI, 0.15-1.04), at median 3.7 years (95% CI, 2.1-42.4) and 260 EDs (95% CI, 130 to >1000). Data were insufficient to compare by type of FIX concentrates. ConclusionLow inhibitor rates were observed for PTPs with severe hemophilia A and B. Data suggested reduced inhibitor development on EHL-rFVIII, but no significant difference between plasma-derived FVIII and standard half-life recombinant FVIII. FIX inhibitor rates were too low for robust statistical analysis.

Cost-Effectiveness of Recombinant FactorIX Fc Prophylaxis and Recombinant FactorIX On-Demand Treatment in Patients with HaemophiliaB Without Inhibitors.

Recombinant factor IX (rFIX) and recombinant FIX Fc fusion protein (rFIXFc) are standard half-life and extended half-life FIX replacement therapies, respectively, and represent established treatment options indicated for adults and children with haemophiliaB. These FIX replacement therapies can be administered as prophylaxis (to prevent bleeding) or 'on-demand' (to stop bleeding). This analysis aimed to estimate the cost-effectiveness of once-weekly prophylaxis with rFIXFc versus on-demand treatment with rFIX in patients with haemophiliaB without inhibitors in the Italian healthcare setting. A Markov model was developed to assess a hypothetical cohort of adolescent or adult male patients (≥ 12years) with haemophiliaB (FIX level of ≤ 2IU/dL) without inhibitors. Model inputs were derived from the pivotal phase3 clinical studies for rFIXFc and rFIX, published literature and assumptions when published data were unavailable. The model employed a lifelong time horizon with 6-monthly transitions between health states, and it estimated total costs, total quality-adjusted life years (QALYs), number of bleeds, number of surgeries and incremental cost-effectiveness ratio. rFIXFc prophylaxis was associated with lower total costs per patient (€5,308,625 versus €6,564,510) and greater total QALYs per patient (15.936 versus 11.943) compared with rFIX on-demand; rFIXFc prophylaxis was therefore the dominant treatment strategy. The model also demonstrated that rFIXFc prophylaxis was associated with fewer incremental bleeds (- 682.29) and surgeries (- 0.39) compared with rFIX on-demand. rFIXFc prophylaxis provides improved health outcomes and lower costs, and represents a cost-effective treatment option compared with rFIX on-demand for adolescent and adult male patients with haemophiliaB. This comparative assessment of cost-effectiveness should help to inform both clinicians and healthcare policy makers when making treatment decisions for patients with haemophiliaB.

Classification of recombinant factor VIII products and implications for clinical practice: A systematic literature review.

Consensus over the definition of recombinant factor VIII (rFVIII) product classification in haemophilia A is lacking. rFVIII products are often classified as standard half-life (SHL) or extended half-life (EHL); despite this, no universally accepted definition currently exists. One proposed definition includes half-life, area under the curve, and technology designed to extend half-life; however, the International Society on Thrombosis and Haemostasis defines activity over time as the most intuitive information for building treatment regimens and the World Federation of Hemophilia describes rFVIII product classification in terms of infusion frequency. To summarise published data on the clinical and pharmacokinetic criteria used to define rFVIII product classification. PubMed and EMBASE database searches of English-language articles (2002-2022) were conducted using search strings to identify the relevant population, intervention, and outcomes (e.g., clinical and pharmacokinetic parameters). Articles then underwent title/abstract and full-text screens. Among 1147 identified articles, 62 were included. Half-life was the most widely reported outcome with no clear trends or product groupings observed. No clear groupings emerged among other outcomes, including infusion frequency, consumption, and efficacy. As activity over time was reported in few articles, further investigation of its relevance to rFVIII product classification is warranted. The findings of this systematic literature review suggest that parameters other than half-life might be important for the development of a comprehensive and clinically relevant rFVIII product classification definition. There seems to be an opportunity to consider parameters that are clinically meaningful and useful for shared decision-making in haemophilia A treatment.

Six-Year, Real-World Use of Prophylaxis with Recombinant Factor IX-Albumin Fusion Protein (rIX-FP) in Persons with Hemophilia B: A Single-Center Retrospective-Prospective Study.

Background: Extended half-life (EHL) factor IX (FIX) concentrates allow for prophylaxis with prolonged dosing intervals and high bleeding protection in persons with hemophilia B. Long-term real-world studies are lacking. Methods: In a retrospective-prospective study, the six-year use of prophylaxis with the EHL recombinant FIX-albumin fusion protein (rIX-FP) was analyzed, comparing outcomes with previous standard half-life (SHL) FIX in patients already on prophylaxis. Results: Prophylaxis with rIX-FP was prescribed in 15 patients (10 severe, 5 moderate; follow-up: 57 ± 17 months). Based on a pharmacokinetic assessment and clinical needs, the first regimen was 47 ± 7 IU/Kg every 9 ± 2 days. All but one patient remained on rIX-FP prophylaxis, adjusting infusion frequency and/or dose; the last prescribed frequency was ≥10 days in 10/13 patients, being reduced in seven and increased in four vs. the first regimen. The weekly FIX dose was unchanged; FIX trough levels were >5% in all patients. The annual infusion number and FIX IU/Kg significantly decreased (~60%) in eight patients previously on SHL FIX prophylaxis, with similar concentrate costs. Very low bleeding rates (most traumatic bleeds and the last quartile of the infusion interval), improved orthopedic and pain scores, unchanged HEAD-US scores and problem joints, and high treatment adherence (>90%) and satisfaction were registered. Conclusions: Personalized, carefully adjusted rIX-FP regimens contribute to the diffusion and optimization of prophylaxis in persons with severe and moderate hemophilia B, with long-term favorable bleeding, joint, and patient-reported outcomes.

An observational study of haemophilia A patients without inhibitors using the French national claims (SNDS) database

ABSTRACT Objectives: To describe clinical characteristics, factor consumption, and events of interest in patients with haemophilia A without inhibitors receiving prophylaxis in France, and the clinical impact of switching to Elocta® in this population. Methods: This retrospective, observational study using the Système National des Données de Santé database, analysed data from patients with haemophilia A without inhibitors using prophylactic factor VIII (FVIII) replacement therapy during 2016–2019. Clinical characteristics, treatment patterns and switches, factor consumption, and rate of events of interest were determined. In a sub-cohort of patients treated with Elocta®, clinical characteristics, factor consumption, and rate of events of interest before and after switching to Elocta® were compared. Results: For 545 patients, with mean age (standard deviation [SD]) 25.4 (17.8) years, Elocta® was the most used treatment. Bleeding events and articular non-bleeding events leading to hospitalization occurred in 15.4% and 13.9% of patients, respectively, and 9.9% of patients had surgeries or procedures related to haemophilic arthropathy. The mean (SD) FVIII product consumption was 344 (93) IU/kg/month for extended half-life treatment, and 331 (98) IU/kg/month for standard half-life products. For the sub-cohort of 146 patients, bleeding events (SD) decreased from 0.32 (2.2) to 0.09 (0.42) events/patient/year (p = 0.227) after switching to Elocta®. There was no statistically significant difference in rates of factor consumption or articular non-bleeding events before and after initiation of Elocta®. Conclusion: This study provides real-world insights that advance the understanding of treatment patterns and events of interest in patients with haemophilia A on prophylactic regimens in France.

Intraindividual bleeding outcomes in patients with hemophilia A on emicizumab prophylaxis in Australia

AbstractEmicizumab became routinely available in Australia in November 2020 as regular prophylaxis for certain patients with hemophilia A (HA). We performed an intraindividual comparison of bleeding outcomes in Australian patients with HA before and after commencement of emicizumab. Data regarding demographics, severity, treatment, inhibitors, and number and type of intraindividual treated bleeds before and after starting emicizumab in patients with HA were extracted from the Australian Bleeding Disorders Registry. As of April 2022, there were 459 eligible patients with HA on emicizumab in Australia, 397 of 459 (86%) of whom had severe disease. Overall, 59 of 459 (13%) had a current inhibitor. Adults (aged ≥18 years) composed 49% (223/459) of the population. The proportion of patients with zero bleeds increased from 54% to 63% after commencement of emicizumab (relative risk [RR], 1.24; 95% confidence interval [CI], 1.09-1.41; P < .01). RR for zero treated bleeds after commencement was significant in subgroups including pediatric patients (RR, 1.34; 95% CI, 1.13-1.59; P < .01) and those not on regular prophylaxis prior (RR, 1.75; 95% CI, 1.22-2.52; P < .01). There was no significant difference in zero-bleed prevalence in the adult, standard half-life, and extended half-life subgroups. Spontaneous bleeding was reduced (RR, 1.69; 95% CI, 1.34-2.13; P < .01), whereas provoked bleeding was not (P = .15). Real-world data from Australia shows a reduction in bleeding events with emicizumab prophylaxis for the overall population of patients with HA, although not in all subgroups. This reduction appears to be most pronounced in spontaneous bleeds within the pediatric population, and in those on on-demand therapy before switching.

Canadian clinical experience on switching from standard half-life recombinant factor VIII (rFVIII), octocog alfa, to extended half-life rFVIII, damoctocog alfa pegol, in persons with haemophilia A ≥ 12 years followed in a Comprehensive Hemophilia Care Program in Canada.

Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an extended half-life recombinant factor (F)VIII replacement, indicated for the treatment of haemophilia A in patients aged ≥12 years. Following introduction of damoctocog alfa pegol in Canada in 2020, there have been no reports on routine clinical effectiveness and satisfaction, when switching from a previous FVIII product in Canada. To report changes in pharmacokinetics, effectiveness, utilization and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973, Kovaltry®) treatment. A single-centre, intra-patient comparison of pharmacokinetics and clinical outcomes was performed. Blood samples drawn once pre-dose and ≥2 times post-dose were measured by a one-stage assay to assess pharmacokinetic parameters including area under the curve (AUC, primary endpoint). Patient-reported outcomes data were collected using the Patient-Reported Outcomes, Burdens and Experiences questionnaire (PROBE). Clinical outcomes included annualized bleeding rate (ABR) and factor utilization. Dose-normalized AUC was significantly increased after switch to damoctocog alfa pegol from octocog alfa. Median (quartile [Q]1; Q3) annualized bleeding rates were 0.67 (0.00; 1.33) with damoctocog alfa pegol and 1.33 (0.00; 2.67) with octocog alfa. Half of the patients receiving damoctocog alfa pegol prophylaxis experienced zero bleeds (n=9, 50.0%) versus 38.9% (n=7) of patients treated with octocog alfa. Patients' good quality of life was maintained. This study provides routine clinical evidence supporting the benefits of switching from octocog alfa to damoctocog alfa pegol for patients with severe haemophilia A.

Barriers to gene therapy, understanding the concerns people with haemophilia have: an exigency sub-study

BackgroundGene therapy has the potential to offer people with haemophilia (PwH) a life free from bleeding and the burden posed by current treatment regimens. To date, gene therapy has only been available in clinical trial settings, to PwH without pre-existing or historical factor inhibitors, significant concomitant liver damage or pre-existing neutralising antibodies to the adeno-associated viruses used to deliver the therapy. Thus, most PwH treated at centres not currently involved in gene therapy trials, either as a referral/follow-up centre or as a dosing centre, have been unable to access the therapy. This Exigency sub-study aims to gain a greater understanding of the opinions of PwH in the United Kingdom who have not had access to gene therapy: asking what they understand, what concerns they have, and whether they perceive any barriers preventing their access to gene therapy.ResultsTwenty-three PwH were approached; 14 consented, and one withdrew prior to interview. The mean age of the participants was 35.7 years (range 25–74 years). Eleven had haemophilia A and two haemophilia B. Two were treated with standard half-life factor products, five with extended half-life products, five with a FVIII mimetic and one with a clinical trial product. One family member (a participant's partner) was also interviewed. The participants identified four barriers to gene therapy: concerns about the process of gene therapy (Expectations), uncertainty about the results (outcomes), (Access) to treatment, and a lack of understanding about gene therapy (education).ConclusionsThis Exigency study subgroup sees gene therapy as a positive treatment development that promises an improved quality of life. For this participant group, four issues impact their decision to undergo gene therapy. If the promise of gene therapy is to be realised, these barriers need to be acknowledged and addressed by healthcare professionals, patient organisations, and gene therapy providers.

Real-World Amount of Clotting Factor Concentrates Dispensed and Annual Medical Expenditures for Japanese Patients with Hemophilia B.

Until extended half-life (EHL) factor IX (FIX) concentrates became available in Japan in 2010, patients with hemophilia B received intravenous FIX replacement therapy with standard half-life (SHL) FIX concentrates. To investigate the amount of factor dispensed and the associated medical expenditures for the treatment of hemophilia B in the real-world clinical setting in Japan. This retrospective study comprised patients with hemophilia B (N=197) who had filled prescriptions for FIX concentrates reported in Japan's Medical Data Vision database from 2015 to 2019. Patients were included if they had 2 or more prescriptions for the same FIX concentrates within the first 6 months of the study period and the interval between prescriptions was at least 2 weeks. Since 2015, there was a decrease in the proportion of patients using SHL FIX concentrates and a corresponding increase in international units of dispensed EHL FIX concentrates. Median annualized dispensed dosages (IU/kg body weight) of EHL FIX concentrates were lower than for SHL concentrates for outpatient use only. Annual total health care expenditures per patient and annual expenditures for prescribed FIX concentrates increased each year during the study period. Following a switch from an SHL to an EHL concentrate, the median amount of prescribed FIX concentrate decreased slightly, although median total health care expenditures and FIX concentrate expenditures increased. In the real-world setting in Japan, medical expenditures and the proportion of patients prescribed EHL FIX concentrates for the treatment of hemophilia B have increased.

Bleeding Outcomes and Treatment Adherence in Patients with Hemophilia Receiving Standard and Extended Half-Life Factor Replacement Therapy: A Real-World Multinational Survey

Introduction Hemophilia A (HA) and B (HB) are heritable X-linked disorders characterized by recurrent and extended bleeding episodes resulting from a deficiency of factor VIII and IX, respectively. Management of hemophilia often relies on standard half-life (SHL) and extended half-life (EHL) factor replacement therapy. Effectiveness of these regimens can be affected by level of patient adherence. There are limited data describing the bleeding outcomes and treatment adherence of HA and HB patients receiving SHL or EHL therapy. Here, we aim to describe clinical outcomes, such as bleeding rates and types of bleeds, in a real-world setting among patients receiving either EHL or SHL prophylactic therapy, while also considering perceived treatment adherence. Methods Data were drawn from the Adelphi Hemophilia Disease Specific Programme™, a real-world cross-sectional survey of male HA and HB patients conducted in France, Germany, Italy, Spain, the United Kingdom, and the United States of America from February 2020 - May 2021. Hematologists and hematologist-oncologists reported data on consecutively consulting male HA and HB patients, including demographics, treatment history, perceived treatment adherence and bleed history. Patients received treatment prophylactically and had been receiving current treatment for ≥12 months prior to data collection. Patients were grouped by treatment type (SHL or EHL therapy). Analyses were descriptive. Results Overall, physicians provided data for 367 patients. Mean (standard deviation; SD) age was 26.9 (14.8) years, 286 patients had HA (66% were receiving SHL and 34% were receiving EHL) and 81 patients had HB (42% were receiving SHL and 58% were receiving EHL). Of the patients with baseline clotting factor data, 58% (n=209) had a baseline activity level of &amp;lt;1%. Table 1 shows treatment data split by hemophilia severity. Mean (SD) annualized bleed rates (ABR) for HA patients receiving SHL or EHL were 1.2 (1.8) and 1.6 (3.6), respectively. Mean (SD) treatment duration was 7.5 (6.7) years for SHL and 3.0 (2.3) years for EHL. In the 12 months prior to data collection the most common bleed types for SHL (n=96) and EHL (n=49) were joint bleeds (59% and 51%), nosebleeds (26% and 33%) and small cuts (25% and 31%), respectively. Physicians reported the most recent bleed as ‘spontaneous cause’ in 42% and 43% of patients receiving SHL (n=96) and EHL (n=49) treatment, respectively. Physicians perceived that 42% of SHL and 29% of EHL patients were 100% adherent to their prophylaxis regimen and took their treatment on time. Mean (SD) ABR for those with 100% adherence vs &amp;lt;100% adherence in SHL patients was 1.0 (1.3) and 1.3 (2.1), respectively. This was 0.3 (0.7) and 2.1 (4.1) in EHL patients. Mean (SD) ABR for HB patients receiving SHL or EHL were 1.4 (1.3) and 0.9 (1.1), respectively. Mean (SD) treatment duration was 9.7 (7.7) years for SHL and 3.4 (4.5) years for EHL. In the 12 months prior to data collection the most common bleed types for SHL (n=25) and EHL (n=23) were joint bleeds (52% and 65%) and bruising/skin bleeds (28% and 26%), respectively, and nosebleeds (36% SHL) or microbleeds (22% EHL). Physicians reported the most recent bleed as ‘spontaneous cause’ in 36% and 43% of patients receiving SHL (n=25) and EHL (n=23) treatment, respectively. Physicians perceived that 12% of SHL and 51% of EHL patients were 100% adherent to their prophylaxis regimen and took their treatment on time. Mean (SD) ABR for those with 100% adherence vs &amp;lt;100% adherence in SHL patients was 0.5 (1.0) and 1.5 (1.3), respectively. This was 0.9 (1.1) and 1.0 (1.2) in EHL patients. Conclusion We described the bleeding rates of HA and HB patients receiving prophylactic SHL and EHL therapy. Most patients were reported to have more than one bleed a year, and spontaneous bleeds were prevalent despite the use of EHL treatment in HA and HB patients. Physicians perceived that a high proportion of HA and HB patients were not 100% adherent to either SHL or EHL treatment. Patients who were &amp;lt;100% adherent had numerically higher mean ABRs than those who were 100% adherent. This indicates a need for treatments that maximize adherence and improve upon the current standard of care.

Cost-Effectiveness of Emicizumab Vs Efanesoctocog Alfa, Standard Half Life (SHL) and Other Extended Half Life (EHL) FVIII Products for Prophylaxis in People with Severe Hemophilia a without Inhibitors

Background: Hemophilia A is a bleeding disorder characterized by a deficiency in factor VIII (FVIII). Routine prophylaxis with FVIII products or emicizumab is the recommended approach to management for people with hemophilia A (PwHA). The burden of lifelong prophylaxis treatments to prevent bleeding events for PwHA is substantial, impacting both the patients and the healthcare system. The objective of this study is to estimate the relative cost-effectiveness of these prophylactic therapies for PwHA, including the newly approved efanesoctocog alfa. Methods: A Markov model was developed with four FVIII-based health states (normal clotting function, mild hemophilia, moderate hemophilia, severe hemophilia) and death to compare emicizumab, efanesoctocog alfa, standard half-life (SHL) and other extended half-life (EHL) FVIII products as prophylaxis for PwHA in the United States (US). Advate and Eloctate data were used to represent SHL and EHL, respectively. The model considered a cohort of 38 years old hemophilia A patients with average weight of 94.4 kg treated with prophylaxis. Probability of experiencing each health state was based on each product's pharmacokinetic data, where FVIII activity levels were used to determine disease severity. Other clinical inputs, including annualized bleed rates and adverse event risks, were estimated from clinical trial data. Wholesale acquisition cost (WAC) of drugs and healthcare costs of bleed management and adverse events were included and were estimated from published literature. Utilities by disease severity were derived from published real-world health-related quality of life studies for hemophilia patients. Disutility of infusion was obtained from the published literature. Costs (in 2023 US dollars), quality-adjusted life-year (QALY), and total bleeds were estimated over a lifetime horizon. Cost-effectiveness was estimated as incremental cost per QALY gained. One-way and probabilistic sensitivity analyses were conducted. Results: Over a lifetime, emicizumab was estimated to be less costly (total cost at $17.0 million for emicizumab vs $24.0 million, $19.3 million, and $18.2 million for efanesoctocog alfa, SHL, and EHL) and more effective (18.61 vs 18.58, 16.91, and 17.33 QALY) compared with efanesoctocog alfa, SHL, and EHL FVIII, respectively. Although efanesoctocog led to fewer bleeds (26.58 vs 59.91 bleeds over a lifetime), PwHA on emicizumab were expected to incur fewer bleeds (59.91 vs 198.45, and 108.58 bleeds) compared with EHL and SHL. Results were robust to one-way and probabilistic sensitivity analyses. Conclusions: Findings in this cost-effectiveness analysis suggest that emicizumab is less costly and more effective (i.e., dominant) over a lifetime compared with available FVIII prophylaxis in pediatrics and adult PwHA in the US.

Real-World Data on Hemophilia a Patients Transitioning from Bay 81-8973 to Bay 94-9027 and from Bay 14-2222 to Bay 81-8973 and then to Bay 94-9027 in the Athndataset

Background: The ATHNdataset is sponsored by the American Thrombosis and Hemostasis Network, including 17,109 hemophilia A people as of the cutoff date, 4/30/22. Patients with Hemophilia A are transitioning more and more from standard half-life (SHL) products to extended half-life (EHL) recombinant factor VIII (rFVIII) products Objective: To evaluate the effect of Hemophilia A patients transitioning from BAY 81-8973 (Kovaltry ®) to BAY 94-9027 (Jivi ®) and from BAY 14-2222 (Kogenate FS ®) to BAY 81-8973 and then to BAY 94-9027 in a real-world setting. Methods: The ATHNdataset was queried for patients treated with BAY 94-9027 that had BAY 81-8973 as a prior medication as well as for the latter that had BAY 14-2222 as a prior medication. Data included demographic data, treatment history, and bleed rates. Query dates were between January 1, 2010 and April 30, 2022. Summary: A total of 205 patients were treating with BAY 94-9027 and 354 with BAY 81-8973 at data cut-off. Thirty patients that treated with BAY 94-9027 had BAY 81-8973 listed as one of their prior medications. Of these, 90% had severe Hemophilia A, while 7% had moderate and 3% had mild disease. All were male, with an average age of 37 years at data cut-off; 80% being White and 90% not Hispanic, Latino or of Spanish origin. Overall, 24/30 patients were consistently treated prophylactically with BAY 81-8973 and with BAY 94-9027. The mean annualized total bleed rate (Total ABR) on BAY 81-8973 was 0.47 and 0.42 on BAY 94-9027, while the annualized joint bleed rate (Joint ABR) was 0.28 on both products and the annualized spontaneous bleed rate (Spontaneous ABR) was 0.17 and 0.30, respectively. The most frequent dosing regimen on BAY 81-8973 was 3x/week or more often, while on BAY 94-9027 more than 80% of patients were using a less frequent regimen than 3x/week, with 2x/week being the most common. (Figure 1) In addition, a sub-analysis was performed on the same patients that transitioned from BAY 81-8973 to BAY 94-9027, to include those patients that also used BAY 14-2222 as a prior medication to BAY 81-8973. A total of 12 patients transitioned from BAY 14-2222 to BAY 81-8973 and then to BAY 94-9027. Of these, all (100%) had severe Hemophilia A and were male. The average age was 33 years at data cut-off; 83% being White and 92% not Hispanic, Latino or of Spanish origin. Overall, 8/12 patients were treating consistently prophylactically with BAY 14-2222, BAY 81-8973 and BAY 94-9027. For these patients, the mean Total ABR on BAY 14-2222 was 3.59, on BAY 81-8973 it was 1.10 and 0.72 on BAY 94-9027, while the Joint ABR was 0.30 on BAY 14-2222, 0.64 on BAY 81-8973 and 0.34 on BAY 94-9027. The Spontaneous ABR was 0.14, 0.35 and 0.67, respectively. (Figure 2) The most frequent dosing regimen on BAY 14-2222 and BAY 81-8973 was 3x/week, while on BAY 94-9027 nearly 90% of patients were using a less frequent regimen than 3x/week, with 2x/week being the most common. Conclusions: The data show that hemophilia A patients who transitioned to BAY 94-9027 from BAY 81-8973, or those that transitioned from BAY 14-2222 to BAY 81-8973 and then to BAY 94-9027 did experience similar or decreased total annual bleed rates with a decrease in their prophylaxis regimen frequency when transitioning to BAY 94-9027 in the real world. The therapeutic burden of frequent infusions can be reduced when patients transition between rFVIII product classes (SHL to EHL), without change in their annual bleed rate. These data should be interpreted with caution owing to limitations of real-world studies and further studies are needed to confirm the impact of switching to BAY 94-9027 and BAY 81-8973 in real-world settings. Additional studies are needed to expand on these results.