Long-term efmoroctocog alfa prophylaxis improves perceived pain, mental, and physical health in patients with hemophilia A: post hoc analysis of phase III trials using patient-reported outcomes.

Background: Hemophilia-associated bleeding and resultant joint pain and mobility restrictions can predispose patients to poor health-related quality of life (HRQoL). Therefore, efficacy of a treatment needs to address more than just annualized bleed rates. Objectives: Describe the evolution of HRQoL, pain, and activity in patients with hemophilia A, treated with efmoroctocog alfa prophylaxis. Design: A post hoc analysis from Kids A-LONG (NCT01458106), A-LONG (NCT01181128), and long-term extension study ASPIRE (NCT01454739) assessed change in pain and activity-related patient-reported outcomes (PROs). Methods: Physical health, pain, and HRQoL were assessed by PROs for a cumulative treatment duration of up to ~6 years. The primary endpoint was change from baseline in EuroQoL (EQ)-5D and Haemophilia Quality of Life Questionnaire (Haem-A-QoL). Results: 118 adult/adolescents and 71 pediatric patients were included. The proportion of adults and adolescents reporting no problem in the EQ-5D analysis of 'pain/discomfort' significantly increased from A-LONG baseline (35.04%; 41/117) to ASPIRE month 30 (44.68%; 21/47; p = 0.024). Mean (standard deviation) Haem-A-QoL subdomain scores for 'feeling' and 'physical health' at A-LONG baseline improved by -3.24 (15.13; p = 0.018) and -3.85 (23.07; p = 0.047), respectively, at study end. Proportion of pediatric patients reporting no problem on the EQ-5D analysis of 'pain/discomfort', significantly increased from A-LONG baseline (75.0%; 42/56) to ASPIRE baseline (95.56%; 43/45; p = 0.046). Satisfaction levels for pediatric patients were high at A-LONG baseline and maintained until study end. Conclusion: Long-term efmoroctocog alfa prophylaxis reduces pain and improves HRQoL in adult and adolescent patients with hemophilia A. In pediatric patients, it reduces perceived pain and maintains satisfaction levels. Trial registration: NCT01458106, NCT01181128, NCT01454739.

Real-world usage and effectiveness of recombinant factor VIII/factor IX Fc in hemophilia A/B: final data from the 24-month, prospective, noninterventional PREVENT study in Germany.

Background: Real-world experience with efmoroctocog alfa (a recombinant factor [F]VIII Fc fusion protein [rFVIIIFc]) and eftrenonacog alfa (a recombinant factor IX Fc fusion protein [rFIXFc]) is needed to bridge evidence gaps. Objectives: To describe rFVIIIFc/rFIXFc usage and effectiveness over a 24-month prospective period. Methods: PREVENT (NCT03055611), a noninterventional study across 25 German hemophilia treatment centers, enrolled previously treated persons with hemophilia A and B (all ages/severities) on individualized rFVIIIFc/rFIXFc prophylaxis before/at enrollment. Primary endpoints included annualized bleeding rate (ABR), injection frequency (IF), and factor consumption (FC). Additionally, up to 12 months of retrospective FVIII/FIX data were collected. Physician and patient satisfaction, and safety outcomes were also assessed. Results: Overall, 150 patients received ≥1 rFVIIIFc dose and 47 patients received ≥1 rFIXFc dose, with median prospective follow-up of 20.6 and 21.0 months, respectively. rFVIIIFc/rFIXFc demonstrated low median ABR (0.5/1.7), annualized IF (121.8/52.2 injections/y), and FC (4611.7/2423.9 IU/kg) in line with product labels. Compared with previous FVIII/FIX, there was a 56.0% reduction in ABR for rFVIIIFc (rate ratio, 0.44; 95% CI, 0.31-0.64), with no change for rFIXFc (rate ratio, 0.93; 95% CI, 0.66-1.31); rFVIIIFc/rFIXFc reduced annualized IF (rFVIIIFc, mean difference, -31.7; 95% CI, -40.3 to -23.1; rFIXFc, mean difference, -37.3; 95% CI, -46.9 to -27.8), while FC remained stable (rFVIIIFc, +374.1; 95% CI, +46.8 to +701.3; rFIXFc, +503.9; 95% CI, +95.4 to +912.4). Most physicians and patients were satisfied or highly satisfied with rFVIIIFc/rFIXFc. rFVIIIFc/rFIXFc were well tolerated, with no inhibitor development or treatment-related serious adverse events. Conclusion: Real-world PREVENT data complement phase 3 trials and show that individualized rFVIIIFc/rFIXFc prophylaxis provided stable bleed protection with low IF and maintained FC. Compared with previous FVIII, ABR was considerably reduced with rFVIIIFc, with stable annualized FC. For rFIXFc, bleed protection was maintained vs previous FIX while reducing annualized IF.

Prophylaxis with a recombinant factor VIII Fc in hemophilia A: long-term follow-up on joint health, efficacy, and safety from phase 3 studies in children and adults.

Background: Recurrent joint bleeds are a major cause of morbidity in severe hemophilia. Prophylaxis with efmoroctocog alfa (a recombinant factor VIII Fc fusion protein, [rFVIIIFc]) has demonstrated benefits beyond bleed control, including joint health maintenance. Objectives: To assess long-term efficacy and safety of rFVIIIFc prophylaxis in severe hemophilia A in phase 3 pivotal (A-LONG/Kids A-LONG) and extension (ASPIRE) studies. Methods: Longitudinal analysis included pooled data from A-LONG/Kids A-LONG and ASPIRE. Subgroup analyses investigated outcomes in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score and target joints in subjects with 4 to 5 years follow-up on individualized prophylaxis (IP), and those with the highest annualized bleeding rate (ABR) quartile during Year 1 of IP. Results: Overall, rFVIIIFc consumption remained stable and low ABRs were maintained, with a median treatment duration of 4.2/3.4 years in subjects from A-LONG/Kids A-LONG, respectively. Median overall ABR also remained low (1.0-2.0) in subjects on IP for 4 to 5 years. Sustained improvements in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score were demonstrated over a median follow-up of 3.7 years. In subjects from A-LONG/Kids A-LONG, 99.6% (n = 234)/100% (n = 9) of evaluable baseline target joints were resolved, with no recurrence in 95%/100% of target joints. In IP subjects within the highest ABR quartile in Year 1, continued improvements were observed over a median follow-up of 4.3 years in ABR and joint health, without increased factor consumption. No inhibitors or treatment-related serious adverse events were reported. Conclusion: Previously treated subjects of all ages receiving long-term prophylaxis with rFVIIIFc had sustained clinical benefits, including improved joint health and low ABR.

No immunological changes after factor VIII product switch: An in depth analysis in haemophilia A patients.

BACKGROUND: A challenging complication in the treatment of haemophilia A is the formation of neutralizing anti-FVIII antibodies (inhibitors). There is ongoing debate on the effect of FVIII product and inhibitor risk, rendering patients and physicians reluctant to switch FVIII-products. AIM: This study aimed to evaluate changes in the immune profile of haemophilia A patients after switching FVIII products and their possible relation to inhibitor development. Secondary, FVIII efficacy after switching were assessed. METHODS: Patients, who switched FVIII-products between 2017-2019, were included in this single centre cohort study. Prospective comparison of immunoregulatory cells and markers by flow-cytometry before and after the switch was performed in a subgroup. For the total cohort clinical data regarding inhibitor development and FVIII efficacy 1 year before and after switching were retrospectively collected. RESULTS: One-hundred patients (including 39 with prospective immunological assessment) were analyzed, of which 31% switched from plasma-derived (pdFVIII) to recombinant standard half-life FVIII (SHL-rFVIII), 47% between different SHL-rFVIII, and 22% from pdFVIII/SHL-rFVIII to rFVIII-Fc. No remarkable changes in immunoregulatory cell functions were observed after switching, regardless the type of switch. None of the patients developed an inhibitor. FVIII efficacy, that is, FVIII usage, half-life and annual bleeding rate (ABR), was similar before and after switch for the SHL products, whereas rFVIII-Fc associated with a longer half-life (13.1 vs. 15.0 h) and lower ABR (3.0 vs. 1.0). CONCLUSIONS: Switching to a different FVIII product was not associated with inhibitor development, nor with differences in the immune profile. Switching to rFVIII-Fc lead to lower ABR.

Real-world evidence on efmoroctocog alfa in patients with haemophilia A: A systematic literature review of treatment experience in Europe.

INTRODUCTION: The real-world effectiveness of the efmoroctocog alfa (recombinant FVIII Fc fusion protein, a rFVIIIFc) has been investigated in numerous studies, however, currently, there exists no comprehensive collection of the existing real-world evidence (RWE) on the performance of prophylactic use of rFVIIIFc. AIM: The aims of this systematic literature study were to identify, review, evaluate and collate the RWE of prophylactic rFVIIIFc for patients with haemophilia A reported in Europe. METHODS: We searched Medline and Embase from 2014 to February 2022 to identify publications reporting the effectiveness of rFVIIIFc in patients with haemophilia A. The outcomes of interest were annualised bleeding rates (ABR, AjBR, AsBR), injection frequency, factor consumption, adherence, development of inhibitors and quality-of-life measures. RESULTS: 46 eligible publications (eight full-text articles) were included. rFVIIIFc showed a low ABR in patients with haemophilia A. Studies assessing treatment switching from a standard half-life (SHL) treatment to rFVIIIFc found that the ABR and consumption were reduced in most patients. Studies assessing rFVIIIFc effectiveness reported a median ABR between 0.0 and 2.0 with median injections per week ranging between 1.8 and 2.4 and median doses between 60 and 105 IU/kg/week. Of the studies assessing inhibitor development, only one study reported an incidence of a low titre inhibitor, and no patients developed clinically significant inhibitors. CONCLUSION: rFVIIIFc prophylaxis treatment results in a low ABR across studies in patients with haemophilia A in a European real-world setting, which correlates with findings from clinical trials assessing the efficacy of rFVIIIFc in patients with haemophilia A.

Clinical Predictors and Prediction Models for rFVIII-Fc Half Life in Real-World People with Severe Hemophilia A.

The half life of recombinant factor VIII-Fc (rFVIII-Fc) for people with hemophilia A (PwHA) varies greatly. Understanding the factors influencing the variation and assessment of rFVIII-Fc half life is important for personalized treatment. Eighty-five severe-type PwHA with rFVIII-Fc treatment receiving an evaluation of half life by the Web-Accessible Population Pharmacokinetic (PK) Service-Hemophilia during 2019-2021 were retrospectively enrolled. The 50-patient PK profiles before 2021 were used for analysis and developing prediction models of half life, and the 35-patient PK profiles in 2021 were used for external validation. The patients in the development cohort were aged 8-64, with a median rFVIII-Fc half life of 20.75 h (range, 8.25-41.5 h). By multivariate linear regression analysis, we found two, four, and five predictors of rFVIII-Fc half life for the blood groups non-O, O patients, and overall patients, respectively, including baseline VWF:Ag, BMI, VWF:activity/VWF:Ag ratio, body weight, O blood group, inhibitor history, HCV infection, and hematocrit. The three prediction equations of rFVIII-Fc half life (T) were respectively developed as T for non-O group patients = -0.81 + 0.63 × (BMI, kg/m2) + 6.07 × (baseline VWF:Ag, IU/mL), T for O group patients = -0.68 + 13.30 × (baseline VWF:Ag, IU/mL) + 0.27 × (BW, kg) - 1.17 × (BMI, kg/m2) + 16.02 × (VWF:activity/VWF:Ag ratio), and T for overall patients = -1.76 + 7.24 × (baseline VWF:Ag, IU/mL) - 3.84 × (Inhibitor history) + 2.99 × (HCV infection) - 2.83 × (O blood group) + 0.30 × (Hct, %), which explained 51.97%, 75.17%, and 66.38% of the half life variability, respectively. For external validation, there was a significant correlation between the predicted and observed half lives in the validation cohort. The median half life deviation was +1.53 h, +1.28 h, and +1.79 h for the equations of non-O group, O group, and overall group patients, respectively. In total, eight predictors influencing rFVIII-Fc half life were identified. Prediction equations of rFVIII-Fc half life were developed for the non-O and O blood groups and overall PwHA with a good degree of external validation. The equations could be applied to patients aged 8-64 without the need for PK blood sampling and clinically valuable for personalized therapy.

Real-world bleeding outcomes and product utilization in people with severe-type hemophilia A before and after switching to extended half-life rFVIIIFc prophylaxis therapy.

BACKGROUND: Recombinant factor VIII-Fc (rFVIIIFc) became available in Taiwan in 2018. Before this date, no people with hemophilia A (PwHA) were enrolled in a clinical trial of rFVIIIFc. We investigated changes in bleeding outcomes and product utilization in PwHA switching from rFVIII to rFVIIIFc. METHODS: Data were collected for Taiwanese PwHA (severe-type) who switched from rFVIII to rFVIIIFc, including annualized bleeding rate (ABR) and weekly dose consumption 12 months pre-switch and > 6 months post-switch. RESULTS: The 51 patients were divided into 3 groups according to their pre-switch treatment: on-demand treatment, intermittent periodic prophylaxis, and regular prophylaxis. In every group, the post-switch median ABR was significantly reduced, with no significant differences between groups. Meanwhile, the post-switch median weekly dose of each group was significantly increased. In 32 patients on pre-switch prophylaxis, switching brought a further reduction in median ABR, associated with a significant increase in median weekly dose. No adverse effects or novel inhibitor development were seen. CONCLUSION: This is the first report from Asia on real-world experience of rFVIIIFc, showing that switching to rFVIIIFc prophylaxis led to further reduction in ABR and increase in weekly dose for all patient groups, even those on pre-switch rFVIII prophylaxis.

Expert opinion on current and future prophylaxis therapies aimed at improving protection for people with hemophilia A.

The next frontier in hemophilia A management has arrived. However, questions remain regarding the broader applicability of new and emerging hemophilia A therapies, such as the long-term safety and efficacy of non-factor therapies and optimal regimens for individual patients. With an ever-evolving clinical landscape, it is imperative for physicians to understand how available and future hemophilia A therapies could potentially be integrated into real-life clinical practice to improve patient outcomes. Against this background, nine hemophilia experts from Central European countries participated in a pre-advisory board meeting survey. The survey comprised 11 multiple-choice questions about current treatment practices and future factor and non-factor replacement therapies. The survey questions were developed to reflect current unmet needs in hemophilia management reflected in the literature. The experts also took part in a follow-up advisory board meeting to discuss the most important unmet needs for hemophilia management as well as the pre-meeting survey results. All experts highlighted the challenge of maintaining optimal trough levels with prophylaxis as their most pressing concern. Targeting trough levels of ≥30-50 IU/L or even higher to achieve less bleeding was highlighted as their preferred strategy. However, the experts had an equal opinion on how this could be achieved (i.e., more efficacious non-factor therapies or factor therapy offering broader personalization possibilities such as targeting trough levels to individual pharmacokinetic data). In summary, our study favors personalized prophylaxis to individual pharmacokinetic data rather than a "one-size-fits-all" approach to hemophilia A management to maintain optimal trough levels for individual patients.

Case report: successful perioperative management of patients with haemophilia A using an extended half-life factor VIII (Efmoroctocog alfa) during neurosurgical procedures.

Patients with haemophilia A (HA) undergoing neurosurgical procedures have a high risk of haemorrhage with potential fatal outcome. Here, we present a successful perioperative haemostatic concept applying an extended half-life factor VIII (EHL FVIII), Efmoroctocog alfa, in two patients with HA undergoing neurosurgery for paramedian right-sided disc herniation (case 1) and astrocytoma (case 2). After adequate EHL FVIII treatment the surgical procedures were performed without any bleeding complications despite the high-risk interventions. Laboratory measurements confirmed stable FVIII levels throughout the hospital stay. We suggest close interdisciplinary collaboration between involved clinicians as mandatory prerequisite for an optimized perioperative management in patients with HA. The presented cases indicate, that the increased stability, safety and fewer injections provide a rationale to use EHL FVIII products in HA patients undergoing surgical interventions with a very high bleeding risk.

Population Pharmacokinetic Analysis of Recombinant Factor VIII Fc Fusion Protein in Subjects With Severe Hemophilia A: Expanded to Include Pediatric Subjects.

Recombinant factor VIII Fc fusion protein (rFVIIIFc) has been indicated for adults and children with hemophilia A. The objective of this article was to build a population pharmacokinetic (PK) model using adult and pediatric data sets and explore relevant dosing scenarios across all ages. The activity-time profiles of rFVIIIFc from 3 clinical studies (all trials registered at https://www.clinicaltrials.gov: NCT01027377, NCT01181128, and NCT01458106) were characterized, and covariates that determine variability of rFVIIIFc PK in children and adults were identified and implemented. Data sets were pooled to estimate population PK parameters. Simulations were conducted to generate activity-time profiles at steady state (SS). The proportion of subjects maintaining SS trough >1 and >3 IU/dL and time >10 IU/dL were estimated. The rFVIIIFc model was a two-compartment model that identified weight and von Willebrand factor as significant covariates. Model-predicted SS peaks and troughs of rFVIIIFc activity-time profiles confirmed the necessity of modifying dosing in pediatric subjects. The model also predicted that the average subject in the adult and adolescent group dosed with 40 IU/kg every 2 days maintained factor VIII activity >10 IU/dL for the entire duration. Children aged <6 years and aged 6 to <12 years receiving this dose maintained factor VIII activity of >10 IU/dL for nearly two-thirds and three-quarters of their time, respectively. In conclusion, these population PK analyses characterize activity-time profiles for rFVIIIFc among pediatric and adult subjects. The model was used for simulation of clinically relevant dosing scenarios, which can provide better protection and better clinical outcomes.

Haemophilia A patients' medication adherence to prophylaxis with efmoroctocog alfa.

INTRODUCTION: Lightening the injection burden is commonly believed to improve prophylaxis adherence. Efmoroctocog alfa (rFVIIIFc) is the first recombinant FVIII-Fc fusion protein available in France. This clotting factor with an extended half-life could thus improve medication adherence. AIM: The study primarily aimed to assess the real-life impact on prophylaxis adherence of haemophilia A patients, when switching from a standard to an extended half-life FVIII. METHODS: This study was an observational, monocentre, non-interventional study aiming at assessing haemophilia A patients' real-life adherence during the first-year post-rFVIIIFc prophylaxis initiation. Medication adherence was assessed using two methods: the medication possession ratio (MPR), which is based on the hospital pharmacy dispensing data, and self-reported VERITAS-Pro® questionnaire. Patients on rFVIIIFc prophylaxis for at least 12 months, following a 12-month standard FVIII prophylaxis, were eligible for inclusion. RESULTS: In 2019, 47 male patients were undergoing rFVIIIFc prophylaxis in our Hemophilia Center, among which 36 meeting the inclusion criteria. Switching from standard to extended half-life FVIII prophylaxis resulted in increased mean dosing, while the mean number of weekly prophylactic injections (2.6 ± 0.5 vs 1.8 ± 0.3) decreased. Following rFVIIIFc initiation, a non-significant increase in median MPR occurred and the self-reported VERITAS-Pro® questionnaire demonstrated improved adherence to rFVIIIFc prophylaxis. Comparing adherent and non-adherent patients revealed age as the only factor likely to impact adherence (p = .07). CONCLUSION: Our patient cohort exhibited high adherence levels before and after FVIII switching, based on MPR and VERITAS-Pro® questionnaire. The latter is likely a useful tool to quantity prophylaxis adherence from a patient's perspective in daily use.

Recombinant factor VIII Fc for the treatment of haemophilia A.

Prophylaxis with factor VIII (FVIII) is the current therapeutic approach for people with haemophilia A. However, standard half-life (SHL) FVIII products must be injected frequently, imposing a substantial burden on the individual and making it difficult to tailor therapy according to patient need and lifestyle, which could impact adherence. Recombinant FVIII Fc fusion protein (rFVIIIFc; Elocta® , Sobi; Eloctate® , Sanofi) is a recombinant fusion protein that undergoes slower clearance from the body than SHL FVIII products. This pharmacokinetic property of rFVIIIFc allows prophylactic administration every 3-5 days, or once weekly in selected patients, with doses adjusted to patient needs and clinical outcomes. Higher FVIII levels can be achieved maintaining dosing frequency similar to that usually applied with SHL FVIII. This review provides a summary of recent data from the A-LONG, Kids A-LONG, ASPIRE and PUPs A-LONG studies and recently published real-world experience relevant to rFVIIIFc use in individualised regimens. The review also introduces ongoing studies of rFVIIIFc, including its use for induction of immune tolerance, and discusses some aspects to consider when switching patients to rFVIIIFc and managing ongoing treatment. In summary, rFVIIIFc is suitable for individualised prophylaxis regimens that can be tailored according to patient clinical needs and lifestyle.

Observational study of recombinant factor VIII-Fc, rFVIIIFc, in hemophilia A.

INTRODUCTION: rFVIIIFc (Eloctate) is an extended-half-life recombinant factor VIII-Fc fusion protein that may promote factor VIII (FVIII) tolerance through Fc immunoregulatory properties. Yet, little is known regarding its immunogenicity in patients with hemophilia A (HA) or in HA with inhibitors (HA-I), including tolerized, immune tolerance induction (ITI)-refractory, or ITI-naïve. METHODS: We reviewed medical records of 60 patients, including 2 previously-untreated patients (PUPs) and 58 previously-treated patients (PTPs), cared for between 01/01/06 and 06/01/17, on whom anti-FVIII antibody data were available before and after initiating rFVIIIFc. Continuous data were analyzed by student's t-test, and discrete data by chi square or Fisher's exact test. RESULTS: After initiating rFVIIIFc, one of two HA PUPs developed a low-responding (LR) inhibitor after 10 exposures, which resolved (anti-VIII<0.6 B.U.) within 8 additional exposures, while none of 41 HA PTPS developed an inhibitor. Among 19 HA-I PTPs with detectable inhibitors prior to rFVIIIFc, 5 developed an anamnestic response to rFVIIIFc, including 1 of 8 (12.5%) low-responding (LR), and 4 of 9 (44.9%) high-responding (HR), of whom 3 were ITI-naïve and 1 ITI-refractory. Inhibitors resolved in 4 HR within 2 months of continuing rFVIIIFc (median) but persisted in 1 LR at low titer. The remaining 11 HA-I PTPs, including 4 HR and seven LR, had no detectable inhibitor at the time of or after initiating rFVIIIFc. DISCUSSION: rFVIIIFc was immunogenic in HA PUPs and in HA-I PTPs persistently ITI-naïve or ITI-refractory, with inhibitor resolution in the majority. rFVIIIFc immunogenicity appears to be similar to other FVIII products.

Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: Final results from the ASPIRE extension study.

INTRODUCTION: The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half-life treatment for severe haemophilia A were demonstrated in the Phase 3 A-LONG and Kids A-LONG studies. Eligible subjects who completed A-LONG and Kids A-LONG could enrol in ASPIRE (NCT01454739), an open-label extension study. AIM: To report the long-term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. METHODS: Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. RESULTS: A total of 150 subjects from A-LONG and 61 subjects from Kids A-LONG enrolled in ASPIRE. Most subjects received the IP regimen (A-LONG: n = 110; Kids A-LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A-LONG and Kids A-LONG was 3.9 (0.1-5.3) years and 3.2 (0.3-3.9) years, respectively. No inhibitors were observed (0 per 1000 subject-years; 95% confidence interval, 0-5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was <1.0) and extended-dosing intervals were maintained (median of 3.5 days) for the majority of subjects in ASPIRE. CONCLUSION: ASPIRE results, which include up to 5 years of follow-up data, confirm earlier reports on the consistent and well-characterized safety and efficacy of rFVIIIFc treatment for severe haemophilia A.

Multicentre pharmacokinetic evaluation of rFVIII-Fc (efmoroctocog alfa) in a real life and comparison with non-extended half-life FVIII concentrates.

The use of enhanced half-life (EHL) FVIII has improved the quality of prophylaxis in haemophilia A, but with a benefit that may vary from one patient to another. We analysed the pharmacokinetic data obtained with efmoroctocog alfa (rFVIII-Fc) in 114 patients and, in 47 cases, compared them to those previously measured with non-EHL FVIII. The in vivo recovery (IVR) of rFVIII-Fc measured with one stage clotting assay (OSA) and chromogenic assay (CSA) was 2.2 and 2.8 IU/mL per IU/kg, respectively. The median half-life (T1/2 ) of rFVIII-Fc was 14.5 hours whatever the FVIII:C assay used, but variable and correlated with preinfusion VWF:Ag levels (r = .76). Both IVR and T1/2 were lower in patients under 12 years old (2.4 IU/mL per IU/kg and 11.1 hours, respectively; CSA). PK study of rFVIII-Fc vs non-EHL FVIII showed a T1/2 ratio of 1.4 in favour of rFVIII-Fc, regardless of the patient's age. However the relative increase in T1/2 with rFVIII-Fc was lower than 30% in one-third of patients evaluated, particularly when the previous FVIII administered was a BHK-derived product. This study therefore suggests that analysis of individual PK profile in response to a specific FVIII concentrate is potentially useful before a switch in haemophilia A patients.

rFVIIIFC for hemophilia A prophylaxis.

Introduction: rFVIIIFC was the first extended half-life product to complete the phase 3 development program and be registered. It was developed to reduce the high treatment burden imposed by prophylaxis. It is now one of four extended half-life products available for a variety of indications in hemophilia A. This article focus on the efficacy use of rFVIIIFC in the prevention of bleeds in hemophilia A. Areas covered: This article provides an update on efficacy data from three clinical studies describing the use of rFVIIIFC in the treatment and prevention of bleeds in hemophilia A. The update includes the efficacy use of rFVIII in all age groups, in the perisurgical setting, in immune tolerance induction, and in improving the quality of life of patients. The role of rFVIIIFC prophylaxis in the face of rapidly evolving non-replacement therapy and gene therapy is summarized. Expert commentary: The role of rFVIIIFC in hemophilia A prophylaxis is uncertain in the light of development of newer prophylaxis agents with better route of administration, improved pharmacokinetic and superior efficacy profiles. While rFVIIIFC was primarily developed for prophylaxis in hemophilia A, this role may change in the face of competitive extended half-life products and non-replacement therapies.

Budget impact analysis of the use of extended half-life recombinant factor VIII (efmoroctocog alfa) for the treatment of congenital haemophilia a: the Italian National Health System perspective.

BACKGROUND: Congenital haemophilia A (HA) is a rare, inherited, life-long bleeding disorder characterised by prolonged or spontaneous bleeding due to the lack of clotting factor VIII (FVIII) in the body. Treatment for HA involves FVIII replacement therapy and poses great economic burden to National Health Systems and to society. Availability of novel products as extended half-life clotting factor products might change treatment approches and their economic evaluation is essential for an informed treatment choice. Accordingly the objective of the present work is to analyse the economic impact of using efmoroctocog alfa (recombinant factor VIII-Fc fusion protein, rFVIIIFc) for the treatment of children and adults with severe congenital haemophilia A (HA). METHODS: A budget impact analysis was performed to estimate the economic impact of the introduction of rFVIIIFc in the market-mix of products for the treatment of HA. The analysis condidered a 3-year time horizon and the Italian National Health System (INHS) perspective. The model estimated drug costs associated with the treatment of HA in the current scenario - representing the marketplace forecast for the time period of interest assuming that rFVIIFc is not introduced - and a new scenario, assuming that rFVIIIFc is available in the market. The size of the target population was calculated using epidemiological national data. Univariate one-way sensitivity analyses and scenario analyses were performed. RESULTS: Overall 3-year costs of treating the HA population in the current scenario were 555,277,691 Euro for the INHS. With the introduction of rFVIIIFc, the costs were reduced to 541,897,466 Euro suggesting potential savings to the INHS of 13,380,255 Euro. Results were consistent at variation of most of the model's parameters; only in case of lower dosage of conventional products and higher dosage of rFVIIIFc, costs for the INHS increased, in both cases, of about 20 million Euro. CONCLUSIONS: The use of rFVIIIFc for the treatment of HA has been recently approved by the Italian Medicines Agency (AIFA) and this is the first study estimating the financial impact of this new therapeutic alternative in the Italian context. The analysis suggests that rFVIIIFc use does not result in higher expenditure for the INHS.

The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein.

Essentials Recombinant factor VIII (rFVIII) Fc fusion protein has a 1.5-fold longer half-life than rFVIII. Five orthogonal methods were used to characterize the structure of rFVIIIFc compared to rFVIII. The C-terminal Fc fusion does not perturb the structure of FVIII in rFVIIIFc. The FVIII and Fc components of rFVIIIFc are flexibly tethered and functionally independent. SUMMARY: Background Fusion of the human IgG1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. Objective To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. Methods rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen-deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), and electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). Results HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Conclusions The FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.

Budget Impact Analysis of Prolonged Half-Life Recombinant FVIII Therapy for Hemophilia in the United States.

BACKGROUND: Hemophilia A is a factor VIII deficiency, associated with spontaneous, recurrent bleeding episodes. This may lead to comorbidities such as arthropathy and joint replacement, which contribute to morbidity and increased health care expenditure. Recombinant factor VIII Fc fusion protein (rFVIIIFc), a prolonged half-life factor therapy, requires fewer infusions, resulting in reduced treatment burden. OBJECTIVE: Use a budget impact analysis to assess the potential economic impact of introducing rFVIIIFc to a formulary from the perspective of a private payer in the United States. METHODS: The budget impact model was developed to estimate the potential economic impact of adding rFVIIIFc to a private payer formulary across a 2-year time period. The eligible patient population consisted of inhibitor-free adults with severe hemophilia A, receiving recombinant-based episodic or prophylaxis treatment regimens. Patients were assumed to switch from conventional recombinant factor treatment to rFVIIIFc. Only medication costs were included in the model. RESULTS: The introduction of rFVIIIFc is estimated to have a budget impact of 1.4% ($0.12 per member per month) across 2 years for a private payer population of 1,000,000 (estimated 19.7 individuals receiving treatment for hemophilia A). The introduction of rFVIIIFc is estimated to prevent 124 bleeds across 2 years at a cost of $1891 per bleed avoided. CONCLUSIONS: Hemophilia A is a rare disease with a low prevalence; therefore, the overall cost to society of introducing rFVIIIFc is small. Considerations for comprehensively assessing the budget impact of introducing rFVIIIFc should include episodic and prophylaxis regimens, bleed avoidance, and annual factor consumption required under alternative scenarios.