Recombinant Factor VIII Fc Fusion Protein Research Articles

Factor VIII moiety of recombinant Factor VIII Fc fusion protein impacts Fc effector function and CD16+ NK cell activation.

Recombinant Factor VIII-Fc fusion protein (rFVIIIFc) is an enhanced half-life therapeutic protein product used for the management of hemophilia A. Recent studies have demonstrated that rFVIIIFc interacts with Fc gamma receptors (FcγR) resulting in the activation or inhibition of various FcγR-expressing immune cells. We previously demonstrated that rFVIIIFc, unlike recombinant Factor IX-Fc (rFIXFc), activates natural killer (NK) cells via Fc-mediated interactions with FcγRIIIA (CD16). Additionally, we showed that rFVIIIFc activated CD16+ NK cells to lyse a FVIII-specific B cell clone. Here, we used human NK cell lines and primary NK cells enriched from peripheral blood leukocytes to study the role of the FVIII moiety in rFVIIIFc-mediated NK cell activation. Following overnight incubation of NK cells with rFVIIIFc, cellular activation was assessed by measuring secretion of the inflammatory cytokine IFNγ by ELISA or by cellular degranulation. We show that anti-FVIII, anti-Fc, and anti-CD16 all inhibited indicating that these molecules were involved in rFVIIIFc-mediated NK cell activation. To define which domains of FVIII were involved, we used antibodies that are FVIII domain-specific and demonstrated that blocking FVIII C1 or C2 domain-mediated membrane binding potently inhibited rFVIIIFc-mediated CD16+ NK cell activation, while targeting the FVIII heavy chain domains did not. We also show that rFVIIIFc binds CD16 with about five-fold higher affinity than rFIXFc. Based on our results we propose that FVIII light chain-mediated membrane binding results in tethering of the fusion protein to the cell surface, and this, together with increased binding affinity for CD16, allows for Fc-CD16 interactions to proceed, resulting in NK cellular activation. Our working model may explain our previous results where we observed that rFVIIIFc activated NK cells via CD16, whereas rFIXFc did not despite having identical IgG1 Fc domains.

Comparison of one-stage and chromogenic factor VIII assays to tailor the dose of recombinant factor VIII-Fc fusion protein (rFVIIIFc, efmoroctocog alfa) in adult patients with haemophilia A: Single-centre, real-world experience of surgery.

Efmoroctocog alfa (rFVIIIFc) is an extended half-life FVIII used notably in surgery for patients with haemophilia A. More information is needed of its usage in real-life. Adult patients with HA followed at the Lyon Comprehensive Hemophilia Care Center who underwent a surgery with rFVIIIFc were included in this retrospective analysis. The pharmacokinetics of rFVIIIFc was assessed by plasma factor VIII clotting activity (FVIII:C) using both one-stage (OSA) and chromogenic substrate (CSA) assays. A total of 39 major and 31 minor surgeries were performed in 49 patients treated with rFVIIIFc. The median dose of rFVIIIFc infused before major and minor surgeries respectively was 67.5 ((interquartile range [IQR] 52.6-76.9) and 48.0 (38.5-51.8) IU/kg. For major surgeries, during the first postoperative week, the median residual FVIII:C was 78 (64.5-101.5) IU/dL with OSA and 99 (71-118) IU/dL with CSA (p<.0001). After surgery, rFVIIIFc doses were adjusted according to CSA results. This led to a significant decrease of rFVIIIFc consumption compared to what would have been proposed according to the OSA assay, without unusual bleeding or appearance of inhibitor. Considering the high price of the molecule, this was also associated with a significant cost reduction. Dose adjustment of rFVIIIFc according to FVIII: C measured by CSA is effective, safe and well tolerated in patients with haemophilia A undergoing invasive surgery.

Recombinant factor VIII Fc fusion protein for first-time immune tolerance induction: final results of the verITI-8 study

AbstractInhibitor development remains a major challenge in factor VIII (FVIII) replacement therapy. verITI-8 is the first prospective study of a recombinant FVIII Fc fusion protein (rFVIIIFc; efmoroctocog alfa) for first-time immune tolerance induction (ITI) in males with severe hemophilia A and high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL). In this single-arm, open-label, multicenter study, screening was followed by ITI (rFVIIIFc 200 IU/kg per day until tolerization or maximum of 48 weeks). Those who achieved ITI success entered a tapering period, returning to standard prophylaxis, and then entered follow-up. Primary end point was time to tolerization with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg), and half-life (t½) ≥7 hours within 48 weeks. Sixteen patients received ≥1 rFVIIIFc dose. Twelve (75%), 11 (69%), and 10 patients (63%), respectively, achieved negative inhibitor titers, an IR ≥66%, and a t½ ≥7 hours (ie, tolerance) within 48 weeks. Median times in weeks to achieve these markers of success were 7.4 (interquartile range [IQR], 2.2-17.8), 6.8 (IQR, 5.4-22.4), and 11.7 (IQR, 9.8-26.2), respectively. All patients experienced ≥1 treatment-emergent adverse event (TEAE), and 1 reported ≥1 related TEAE (injection site pain). Nine patients experienced ≥1 treatment-emergent serious AE. No thrombotic events, discontinuations because of AEs, or deaths were reported during the study. As the first extended half-life rFVIII with prospective data in ITI, rFVIIIFc offered short time to tolerization with durable responses in almost two-thirds of patients and was well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT03093480.

New opportunities in Haemophilia treatment: Efmoroctocog Alfa for patients with Haemophilia A

&#x0D; Recently new opportunities are emerging for improving the way patients with Haemophilia A are treated. Among these opportunities, efmoroctocog alfa is a first-in-class recombinant factor VIII-Fc fusion protein (rFVIIIFc) produced by recombinant DNA technology with an extended half-life compared with conventional FVIII preparations. The available evidence coming from an Italian HTA report indicates that efmoroctocog alfa provides an effective alternative to conventional FVIII preparations (including standard rFVIIIs) for the management of Haemophilia A. Moreover, by reducing the frequency of injections required, it has the potential to reduce treatment burden, and hence improve adherence to prophylaxis and patient Quality-of-Life. &#x0D;

Monitoring of different factor VIII replacement products using a factor VIII one-stage clotting assay on cobas t 511/711 analysers.

IntroductionRecombinant coagulation factor VIII (FVIII) products are the standard of care for patients with haemophilia A. The development of modified FVIII products has provided benefit for patients but presented challenges for monitoring FVIII activity.AimThis single‐centre study evaluated the Roche FVIII one‐stage clotting assay (OSA) in measuring FVIII activity in plasma samples spiked with seven FVIII products at clinically relevant concentrations.MethodsFVIII‐deficient plasma samples were spiked with two batches of recombinant FVIII products (octocog alfa, moroctocog alfa, simoctocog alfa, efmoroctocog alfa, damoctocog alfa pegol, rurioctocog alfa pegol, lonoctocog alfa) at 1–120 IU/dL FVIII activity, according to their labelled potency. Measurement was conducted on the cobas t 511/711 analysers using the Roche FVIII OSA and the Technoclone TECHNOCHROM FVIII:C chromogenic substrate assay (CSA).ResultsUsing the OSA, FVIII activity was close to labelled potency for most analysed FVIII products including a recombinant FVIII Fc fusion protein. PEGylated FVIII product, damoctocog alfa pegol, was marginally above and single‐chain product, lonoctocog alfa, below the predefined acceptance criteria: for FVIII activity < 25 IU/dL: ± 5 IU/dL; for FVIII activity ≥ 25 IU/dL: ± 20% (relative). The different principles of OSA and CSA led to discrepancies in the estimation of all analysed FVIII products. Additionally, in vitro recovery was increased at lower levels of FVIII activity using the OSA, whereas recovery was more consistent using the CSA.ConclusionThese data allow the interpretation of FVIII activity results for different FVIII products using the Roche FVIII OSA on the cobas t 511/711 analysers.

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.

Efficacy of rFVIIIFc versus Emicizumab for the Treatment of Patients with Hemophilia A without Inhibitors: Matching-Adjusted Indirect Comparison of A-LONG and HAVEN Trials.

PurposePrimary prophylaxis, using factor VIII replacement, is the recognized standard of care for severe hemophilia A. Recombinant factor VIII-Fc fusion protein (rFVIIIFc) and emicizumab, a humanized, bispecific antibody, are approved for routine prophylaxis of bleeding episodes in severe hemophilia A. These products have different mechanisms of action, methods of administration and treatment schedules. In the absence of head-to-head trials, indirect treatment comparisons can provide informative evidence on the relative efficacy of the two treatments. The aim of the study was to compare the approved dosing regimens for each product, rFVIIIFc individualized prophylaxis and emicizumab administered once every week (Q1W), every 2 weeks (Q2W) or every 4 weeks (Q4W), based on clinical trial evidence.Patients and MethodsThe comparison was conducted using matching-adjusted indirect comparison since clinical evidence did not form a connected network. Individual patient data for rFVIIIFc (A-LONG) were compared with data for emicizumab (HAVEN trial program) for mean annualized bleeding rate (ABR) and proportion of patients with zero bleeds. Safety data reported across the analyzed treatment arms were tabularized but not formally compared.ResultsAfter matching, no significant differences were observed between mean ABR for rFVIIIFc and emicizumab administered Q1W, Q2W or Q4W. The proportion of patients with zero bleeds was significantly higher with rFVIIIFc compared with emicizumab administered Q4W (51.2% versus 29.3%, respectively; odds ratio 2.53; 95% confidence interval 1.09–5.89); no significant differences noted when rFVIIIFc was compared with emicizumab administered Q1W or Q2W. The mean number of adverse events expressed per participant was 1.9 for individualized prophylaxis with rFVIIIFc and 3.7–4.0, 4.1 and 3.6 for emicizumab administered Q1W, Q2W or Q4W, respectively.ConclusionThis indirect treatment comparison suggests that rFVIIIFc individualized prophylaxis is more efficacious than emicizumab Q4W, and at least as effective as more frequent emicizumab regimens, for the management of hemophilia A.

PSY7 Cost-Minimisation Analysis of Recombinant Factor VIII FC Fusion Protein Versus Emicizumab for Haemophilia a Prophylaxis in Europe

Indirect treatment comparisons have shown that recombinant factor VIII-Fc fusion protein (rFVIIIFc) is at least as effective as emicizumab for haemophilia A (HA) prophylaxis. This cost-minimisation model evaluates rFVIIIFc versus emicizumab for HA prophylaxis over 5 years in 100 people, from a healthcare payer perspective, in the UK, France, Germany, Italy and Spain. Doses used in the model were based on the A-LONG study for rFVIIIFc and the summary of product characteristics for emicizumab. Bodyweight was based on data from the A-LONG (adults/adolescents, >12 years) and Kids A-LONG (children, ≤12 years) studies. Other model inputs included costs associated with: drug acquisition; emicizumab wastage according to bodyweight (manufacturer’s recommendations); increased emicizumab dose in hypo-responders; wasted on-demand factor VIII (FVIII) due to expired shelf life; and additional FVIII for treatment of bleeds for both groups. In the UK, total 5-year costs for adolescents/adults were €150.0 million for rFVIIIFc and €272.9 million for emicizumab, a total incremental saving with rFVIIIFc of €122.9 million. In children, total 5-year costs were €51.0 million and €115.8 million, respectively, a total incremental saving with rFVIIIFc of €64.8 million. Most of the excess cost with emicizumab reflects its higher acquisition cost and emicizumab wastage; the latter can be substantial, corresponding to up to 13% of used drug in adults/adolescents and >50% in children. At maximal wastage (bodyweight set at 81 kg and 41 kg for adult/adolescents and children, respectively), cost of wasted drug increased by 87% in adolescents/adults and 101% in children compared with the base-case analysis. In other European countries, cost savings associated with rFVIIIFc use ranged from €119.1–159.2 million in adolescents/adults and €63.8–76.1 million in children. The cost of HA prophylaxis in Europe would be substantially higher if patients were treated with emicizumab compared with rFVIIIFc.

A Physiologically Based Pharmacokinetic (PBPK) Model for Adults to Characterize BIVV001 Activity, a New Class of Factor VIII (FVIII) with High Sustained Factor Activity

Introduction PBPK models incorporate complex drug and system (ie, physiology) information into a mathematical framework to support dose selection while considering various patient factors (eg, age, sex, and comorbidity). Through "predict-learn-confirm cycles," PBPK models enable dose prediction to optimize clinical study design. BIVV001 (rFVIIIFc-VWF-XTEN), a new class of FVIII replacement therapy designed to break the von Willebrand factor (VWF) half-life ceiling (Chhabra et al.Blood. 2020; Konkle et al.Blood. 2018), consists of a single recombinant FVIII fused to dimeric Fc (to permit recycling of BIVV001 by a naturally occurring pathway via Fc neonatal receptors [FcRn]), a VWF D′D3 domain, and two XTEN® polypeptides (XTEN® is a registered trademark of Amunix Pharmaceuticals, Inc.). In a Phase 1 study (Lissitchkov et al.Blood. 2019), four once-weekly BIVV001 50 IU/kg infusions provided high sustained FVIII activity with a mean half-life of 41.3 hours. We aimed to build and verify an initial PBPK model to characterize BIVV001 activity levels in adults with severe hemophilia A. Methods To our knowledge, this is the first time that a PBPK model has been studied in hemophilia. We assumed that the distribution of BIVV001 and recombinant FVIII Fc fusion protein (rFVIIIFc) (Eloctate®) involves the FcRn recycling pathway that is similar to monoclonal antibodies. First, to evaluate the feasibility of the modeling approach, we built a PBPK model (Simcyp, Sheffield, UK) that captured FcRn-dependent recycling of Fc fusion proteins. Model input parameters were adjusted to capture observed rFVIIIFc activity levels with a prediction error of &amp;lt;1.35 by fitting values for the physiological parameters, equilibrium dissociation constant for FcRn binding (KD1), endothelial uptake rate (Kup), rate of recycling (Krc), and clearance by catabolism (CLcat). Next, a similar approach was used to characterize FVIII activity levels during the Phase 1 BIVV001 repeat-dose study (BIVV001 50 IU/kg and 65 IU/kg). The PBPK model virtual trial simulations were conducted at both BIVV001 doses using 100 virtual male subjects with an age range of 18-51 years. Results To fit the BIVV001 data, the PBPK model input parameters, KD1, vascular reflection coefficient (σv), and Kup, were modified compared with those used for the rFVIIIFc PBPK model. The PBPK model captured observed BIVV001 exposure with a low prediction error (&amp;lt;1.30) for maximal FVIII activity and area under the activity-time curve (Figure 1). The predicted inter-subject variability was lower than that for the observed data, which is likely due to the inability to include coefficients of variation for all parameters in the current Simcyp biologics module. Conclusions We have developed a PBPK model that accurately predicts the high sustained FVIII activity levels observed with BIVV001 exposure in adults with severe hemophilia A. The PBPK model framework can be a useful tool in the development of FVIII replacement therapies for hemophilia A. Disclosures Xia: Sanofi:Current Employment, Current equity holder in publicly-traded company.Katragadda:Sanofi:Current Employment, Current equity holder in publicly-traded company.Teutonico:Sanofi:Current Employment, Current equity holder in publicly-traded company.Macha:Sanofi:Current Employment, Current equity holder in publicly-traded company.Demissie:Sanofi:Current Employment, Current equity holder in publicly-traded company.Benson:Sanofi:Current Employment, Current equity holder in publicly-traded company.

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

IntroductionrFVIIIFc (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. MethodsWe 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. ResultsAfter 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. DiscussionrFVIIIFc 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.

Development of a Pegylated Dimeric Recombinant Factor VIII-Fc Fusion Protein for the Treatment for Hemophilia a Patients

▪Hemophilia A is a hereditary bleeding disorder resulting from reduced factor FVIII activity. It occurred in 1/5000 male. Currently, the treatment option is with the factor FVIII replacement therapy. A long-acting recombinant monomeric FVIII-Fc fusion protein product (Eloctate®) has been approved in 2014 by the US FDA, it requires to infuse the drug for every 3 days or twice a week. There is a clinical need to develop longer half-life product to extend the treatment option to once a week infuse for hemophilia A patients. Recently, we have developed a dimeric recombinant factor VIII-Fc (drFVIII-Fc) fusion protein therapeutic candidate, which is entering the clinical development in China. To generate a longer half-life recombinant FVIII product, we have developed a PEGylation method to PEGylated this drFVIII-Fc fusion protein to PEGdrFVIII-Fc. We have analyzed and characterized the fusion protein by various analytic methods, as well as in vivo animal tests. It was shown that PEGdrFVIII-Fc fusion protein has been modified with about five Y type of 40kd PEG; the remaining activity is around 700 IU/mg, and the in vivo tests in cynomolgus monkey demonstrated that the fusion protein has a half-life of about 37 hours. The data also showed that there was no detectable affinity binding activity of vWF to a PEGdrFVIII-Fc fusion protein, as compared with the binding activity of 5.16X10-4M for the molecule of a drFVIII-Fc fusion protein. In conclusion, we are able to generate a PEGylated form of a drFVIII-Fc molecule with the relevant specific activity and has been shown the molecule with the prolonger half-life in the in vivo tests. The further biochemical analysis demonstrated PEGdrFVIII-Fc fusion protein with no detectable vWF binding activity, which might explain why its half-life is longer than vWF's ~15hours half-life in vivo. This molecule is likely to be used as a once-weekly treatment option for hemophilia A patients. Currently, we are in the development stage of an IND filing in China. DisclosuresNo relevant conflicts of interest to declare.

BIVV001: The First Investigational Factor VIII Therapy to Break Through the VWF Ceiling in Hemophilia A, with Potential for Extended Protection for One Week or Longer

Introduction: The standard of care for patients with severe hemophilia A is prophylactic factor VIII (FVIII) replacement. Conventional recombinant FVIII products are efficacious but require frequent administration because of their short half-life, which reflects the dependence of FVIII on von Willebrand factor (VWF). Recombinant FVIII Fc fusion protein (rFVIIIFc) provides an extended dosing interval, as well as joint protection and improved quality of life (Oldenburg et al, Haemophilia, 2018; Wang et al, Blood, 2016), with a well-characterized safety profile. While rFVIIIFc reduces the required administration frequency, longer prophylactic dosing intervals that also offer maximum overall protection are still an unmet need for patients with severe hemophilia A. Increasing the half-life of rFVIII is ultimately dependent upon decoupling FVIII and endogenous VWF.BIVV001 (rFVIII-VWF-XTEN) is a novel investigational rFVIII therapy with single-chain FVIII, the Fc domain of human immunoglobulin G1, 2 XTEN polypeptides, and the FVIII-binding D′D3 domain of VWF, designed to circulate in plasma independently of VWF, thereby breaking the VWF half-life ceiling. Here, we present the low-dose cohort results of EXTEN-A, a Phase 1/2a study assessing the safety and tolerability of a single dose of BIVV001, and the pharmacokinetic (PK) characteristics of a single dose of BIVV001 compared with rFVIII.Methods: EXTEN-A (NCT03205163) is an open-label, dose-escalation, multicenter study. Previously treated adult males with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII activity) with ≥150 exposure days to FVIII products were included. Patients were assigned to either the low-dose cohort (25 IU/kg of rFVIII and 25 IU/kg of BIVV001; n≥6) or the high-dose cohort (65 IU/kg of rFVIII and 65 IU/kg of BIVV001; n≥8). Escalation from the low-dose cohort, and enrolment of patients to the high-dose cohort was undertaken after assessment of available data from the low-dose cohort.After a screening and washout period of up to 28 days, patients received a single dose (25 or 65 IU/kg) of rFVIII. After a 3- to 4-day washout period, patients received a single dose of BIVV001 at the same dose level as rFVIII. Blood samples for PK analysis were collected for 3 days after dosing of rFVIII and up to 14 days after dosing of BIVV001. Inhibitor testing was performed 14 and 28 days following BIVV001 administration. Adverse events, clinical abnormalities in laboratory tests (including inhibitor development), and PK parameters were assessed. An interim analysis is planned, including the first 2 patients of the high-dose cohort.Results: Out of 7 patients enrolled in the low-dose cohort (25 IU/kg), 6 patients were dosed with BIVV001. Patients in this group were primarily white, with 1 patient of Asian descent, and 1 of Hispanic/Latino ethnicity. Patient ages ranged from 19 to 60 years. Low-dose BIVV001 was well tolerated and no inhibitors were detected through 28 days after BIVV001 dosing. Low-dose BIVV001 demonstrated an extended half-life of 37.6 hours, compared with a 12.1-hour half-life for rFVIII. Average FVIII activity post-infusion of BIVV001 was 12.2% at 5 days and 5.3% at 7 days.At least 8 patients will be enrolled in the high-dose cohort (65 IU/kg); preliminary data for the first 2 patients will be reported.Conclusions: BIVV001 was well tolerated in 6 patients with severe hemophilia A who were treated with a single low dose (25 IU/kg). No patient developed an inhibitor to FVIII. Low-dose cohort data demonstrated a breakthrough in the half-life of rFVIII therapy, with BIVV001 providing sustained FVIII levels that could potentially allow for more optimal, extended protection for patients. DisclosuresKonkle:Genentech: Consultancy; Spark: Consultancy, Research Funding; Pfizer: Research Funding; Gilead: Consultancy; CSL Behring: Consultancy; Bioverativ: Research Funding; BioMarin: Consultancy; Sangamo: Research Funding; Shire: Research Funding. Shapiro:Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioMarin: Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo Biosciences: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; OPKO: Research Funding; Octapharma: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Daiichi Sankyo: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding. Quon:Bioverativ, a Sanofi Company: Speakers Bureau; Octapharma: Consultancy; Genetech: Consultancy, Speakers Bureau; Bayer: Consultancy; NovoNordisk: Consultancy, Speakers Bureau; Shire: Speakers Bureau. Staber:uniQure: Honoraria; NovoNordisk: Consultancy; Bayer: Honoraria. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Poloskey:Bioverativ: Employment. Rice:Bioverativ: Employment. Katragadda:Bioverativ: Employment. Rudin:Bioverativ: Employment, Equity Ownership. Fruebis:Bioverativ: Employment, Other: Clinical Development.

ASPIRE Final Results Confirm Established Safety and Sustained Efficacy for Up to 4 Years of Treatment With rFVIIIFc in Previously Treated Subjects With Severe Hemophilia A

Introduction: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care in hemophilia A, given its natural mechanism of action, strict homeostatic regulation, and consistent safety profile. Recombinant FVIII Fc fusion protein (rFVIIIFc) is an extended half-life therapy that demonstrated safety and efficacy in previously treated pediatric, adolescent, and adult subjects with severe hemophilia A in the Phase 3 A-LONG and Kids A-LONG trials (NCT01181128 and NCT01458106, respectively) (Young et al, J Thromb Haemostas, 2015; Mahlangu et al, Blood, 2014). Herein, the final results are reported from ASPIRE (NCT01454739), the long-term extension trial of those 2 studies.Methods: This was an open-label, multicenter, long-term trial of previously treated subjects of all ages with severe hemophilia A. Subjects received 1 of the 4 following regimens: individualized prophylaxis (IP; rFVIIIFc 25‒60 IU/kg every 3-5 days, or twice weekly), weekly prophylaxis (WP; rFVIIIFc 65 IU/kg every 7 days), modified prophylaxis (MP; personalized dosing), or episodic treatment (ET; on-demand dosing based on bleeding episodes). Subjects <12 years of age were eligible for only IP or MP. Investigators could switch a subject's treatment group at any time; therefore, each subject may appear in >1 treatment group. The primary endpoint was development of inhibitors. Secondary endpoints included annualized bleeding rates (ABRs), joint ABRs, spontaneous joint ABRs, exposure days (ED), and factor consumption. Descriptive statistics were used for analysis. Analyses were performed separately based on parent study.Results: A total of 211 subjects (150 were from A-LONG and 61 were from Kids A-LONG) enrolled in ASPIRE, and 186 subjects (132 from A-LONG and 54 from Kids A-LONG) completed the study. Subjects from Kids A-LONG had a median (range) age of 6.0 (2-12) years. Of the subjects from the A-LONG study enrolled to ASPIRE, the median (range) age was 31.0 (13-66) years. Most subjects received IP regardless of parent study (Kids A-LONG: IP [n=59], MP [n=3]; A-LONG: IP [n=110], WP [n=27], MP [n=21], ET [n=13]).No inhibitors were observed throughout the study, and the overall safety profile of rFVIIIFc was consistent with the parent studies and prior interim analyses. ABRs remained low throughout the entirety of ASPIRE in subjects prescribed IP (Table 1). For subjects from the Kids A-LONG study, the median (range) number of ED during ASPIRE was 332.0 (18.0-467.0) days. Total median (range) treatment duration was 166.6 (14.4-203.0) weeks. The median (range) number of ED for A-LONG subjects was 267.5 (8.0-660.0) days. Total median treatment duration was 201.4 (5.1-274.6) weeks. Overall, the median (range) duration of treatment with rFVIIIFc was 4.1 (0.4, 5.9) years.From the end of the parent study to the end of ASPIRE, the rFVIIIFc dosing interval increased for 6.6% and 21.1% of subjects from Kids A-LONG and A-LONG, respectively (Table 2). There was no change in median weekly factor consumption from the end of either parent study to the end of ASPIRE. For subjects from Kids A-LONG, the median (IQR) was 0.0 (0.0‒3.2), while the median (IQR) for those from A-LONG was 0.0 (0.0‒0.0).Conclusions: Throughout up to 4 years of treatment with rFVIIIFc in the ASPIRE extension study, no inhibitors were reported, and low ABRs and extended dosing intervals were sustained. These data are consistent with the well-characterized safety profile and durable efficacy of rFVIIIFc prophylaxis in previously treated subjects of all ages with hemophilia A. [Display omitted] DisclosuresNolan:Bayer: Research Funding; CSL Behring: Research Funding; Sobi: Research Funding. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Alnylam: Consultancy, Research Funding, Speakers Bureau; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Amgen: Consultancy; Biomarin: Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Young:Bayer: Consultancy; Bioverativ: Consultancy, Honoraria; Kedrion: Consultancy; Novo Nordisk: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Konkle:Sangamo: Research Funding; Gilead: Consultancy; Spark: Consultancy, Research Funding; BioMarin: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Bioverativ: Research Funding; Pfizer: Research Funding; Shire: Research Funding. Pasi:Shire: Speakers Bureau; Alnylam: Honoraria, Research Funding; Bayer: Speakers Bureau; Octapharma: Honoraria; Pfizer: Speakers Bureau; Biomarin: Honoraria, Research Funding; Sobi: Honoraria; Bioverativ: Honoraria, Research Funding; NovoNordisk: Speakers Bureau; Catalyst Bio: Honoraria; Apcintex: Honoraria. Oldenburg:Novo Nordisk: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Tripkovic:Sobi: Employment. Rudin:Bioverativ: Employment, Equity Ownership.

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

BackgroundCongenital 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).MethodsA 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.ResultsOverall 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.ConclusionsThe 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

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.

Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Children with Severe Hemophilia a

Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Children with Severe Hemophilia a

Predicting the outcomes of using longer‐acting prophylactic factor VIII to treat people with severe hemophilia A: a hypothetical decision analysis

Essentials No randomized trials have compared long-acting factor VIII (FVIII) with currently used products. A comparison was undertaken using a decision model to predict FVIII use and number of bleeds. In the base case, longer acting FVIII reduced factor use by 17% while resulting in similar bleeds. The value of longer acting FVIII will be largely determined by existing regimens and unit price. Click to hear Prof. Makris's presentation on new treatments in hemophilia SUMMARY: Background Recently, factor VIII (FVIII) products with longer half-lives, such as recombinant FVIII Fc fusion protein (rFVIIIFc), have become available. Use of longer-acting FVIII products will largely depend on effectiveness and cost; no direct evaluations have compared these parameters between conventional and longer-acting FVIII therapies. Objectives To present a hypothetical decision analysis, combining evidence from multiple sources to estimate bleeding frequency, resource use and cost of longer-acting prophylactic products, such as rFVIIIFc, vs. conventional recombinant FVIII (rFVIII). Patients/Methods The decision model used published pharmacokinetic parameters, bleeding frequency vs. time information below a 1-IU dL-1 FVIII trough level, and adherence. Prophylactic treatment scenarios were modelled for a hypothetical patient with severe hemophilia A (<1 IU/dL) receiving rFVIIIFc or rFVIII. Results Infusing twice weekly with rFVIIIFc 42.7 IU kg-1 per dose required less clotting factor than infusing every 56 h with rFVIII 33.75 IU kg-1 per dose; annual bleeding rates were similar. Base case analysis suggested that total FVIII costs were equated when rFVIIIFc cost 1.18 times more per IU than rFVIII, assuming similar adherence. Other modelled scenarios produced similar results, although differences in FVIII consumption were particularly sensitive to assumptions regarding frequency and dose of the rFVIII and rFVIIIFc regimens. For example, decreasing rFVIII from 33.75 IU kg-1 to 30 IU kg-1 per dose decreased the price factor to 1.05. Conclusions Longer-acting FVIII products may reduce FVIII consumption and infusion frequency without compromising hemostatic effect; this should be considered along with other factors (e.g. adherence and underlying FVIII regimen) when evaluating a suitable price for these agents.

Efmoroctocog Alfa: A Review in Haemophilia A.

Efmoroctocog alfa (Elocta(®), Eloctate(®), Eloctate™), a first-in-class recombinant factor VIII-Fc fusion protein (rFVIIIFc), has an extended half-life compared with conventional factor VIII (FVIII) preparations, including recombinant FVIII (rFVIII) products. It is approved for the treatment and prophylaxis of bleeding in patients with haemophilia A in multiple countries worldwide. Data accumulated from pivotal phase III studies (A-LONG in adults and adolescents aged ≥12years; Kids A-LONG in children aged <12years) and their ongoing extension study (ASPIRE) have demonstrated the long-term effectiveness of efmoroctocog alfa for the treatment of acute bleeding episodes, perioperative management and routine prophylaxis in previously treated males with severe haemophilia A. Among patients on individualized efmoroctocog alfa prophylaxis who had previously received FVIII prophylaxis, all but one of those aged ≥12years and three-quarters of those aged <12years reduced their injection frequency compared with their pre-study regimen. FVIII replacement therapy with efmoroctocog alfa was generally well tolerated in previously treated patients, with no evidence of increased immunogenicity. The safety and efficacy of FVIII replacement therapy with efmoroctocog alfa in previously untreated males aged <6years with severe haemophilia A are currently being evaluated. Although there are no direct, head-to-head studies, the available clinical trial evidence indicates that efmoroctocog alfa provides an effective alternative to conventional FVIII preparations (including rFVIIIs) for the management of haemophilia A. Moreover, by reducing the frequency of injections required, it has the potential to reduce treatment burden, and hence improve adherence to prophylaxis.

Long-Term Safety and Efficacy of rFVIIIFc in Adults and Adolescents with Severe Hemophilia A: A Longitudinal Analysis of A-LONG and ASPIRE

Long-Term Safety and Efficacy of rFVIIIFc in Adults and Adolescents with Severe Hemophilia A: A Longitudinal Analysis of A-LONG and ASPIRE

FcRn Rescues Recombinant Factor VIII Fc Fusion Protein from a VWF Independent FVIII Clearance Pathway in Mouse Hepatocytes.

We recently developed a longer lasting recombinant factor VIII-Fc fusion protein, rFVIIIFc, to extend the half-life of replacement FVIII for the treatment of people with hemophilia A. In order to elucidate the biological mechanism for the elongated half-life of rFVIIIFc at a cellular level we delineated the roles of VWF and the tissue-specific expression of the neonatal Fc receptor (FcRn) in the biodistribution, clearance and cycling of rFVIIIFc. We find the tissue biodistribution is similar for rFVIIIFc and rFVIII and that liver is the major clearance organ for both molecules. VWF reduces the clearance and the initial liver uptake of rFVIIIFc. Pharmacokinetic studies in FcRn chimeric mice show that FcRn expressed in somatic cells (hepatocytes or liver sinusoidal endothelial cells) mediates the decreased clearance of rFVIIIFc, but FcRn in hematopoietic cells (Kupffer cells) does not affect clearance. Immunohistochemical studies show that when rFVIII or rFVIIIFc is in dynamic equilibrium binding with VWF, they mostly co localize with VWF in Kupffer cells and macrophages, confirming a major role for liver macrophages in the internalization and clearance of the VWF-FVIII complex. In the absence of VWF a clear difference in cellular localization of VWF-free rFVIII and rFVIIIFc is observed and neither molecule is detected in Kupffer cells. Instead, rFVIII is observed in hepatocytes, indicating that free rFVIII is cleared by hepatocytes, while rFVIIIFc is observed as a diffuse liver sinusoidal staining, suggesting recycling of free-rFVIIIFc out of hepatocytes. These studies reveal two parallel linked clearance pathways, with a dominant pathway in which both rFVIIIFc and rFVIII complexed with VWF are cleared mainly by Kupffer cells without FcRn cycling. In contrast, the free fraction of rFVIII or rFVIIIFc unbound by VWF enters hepatocytes, where FcRn reduces the degradation and clearance of rFVIIIFc relative to rFVIII by cycling rFVIIIFc back to the liver sinusoid and into circulation, enabling the elongated half-life of rFVIIIFc.