Extended Half-life Products Research Articles

Phenotypic characterization of haemophilia B - Understanding the underlying biology of coagulation factor IX.

Haemophilia B is a recessive, X-linked bleeding disorder due to inherited deficiency in vitamin K-dependent coagulation factor IX (FIX). FIX activity levels, as a basis for the definition of disease severity, do not clearly correlate with bleeding phenotype, likely due to the multiple steps regulating coagulation. Timely, with the availability of extended half-life products and successful steps in gene therapy, haemophilia B therapy is in an active developmental phase. Therefore, increased knowledge of the factors contributing to the variation of haemostatic and clinical outcome and response to therapy is welcomed. FIX acts at the crossroads of both the extrinsic and intrinsic pathways, and on the platelet procoagulant membrane at the site of vascular injury, and therefore, FIX biology is targeted for multiple effectors and regulators. The synthesis, cellular and molecular interactions, and elimination routes of FIX are not as well studied as for FVIII. The specific roles of magnesium in both platelet adhesion and FIX activation, and of vascular collagen at the haemostatic site of platelet adhesion and FIX residence are of particular interest. Biochemical and translational research on these issues should improve our understanding of the mechanisms involved, leading to the development of relevant assays that measure both haemostasis and treatment response. The latter is becoming increasingly important in the new era of haemophilia management and ultimately may lead to improved treatment strategies individually tailored to a patient's needs and cost-efficiency.

Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP

Aims: Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals, and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients.Materials and methods: A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated hemophilia B patients aged ≥12 years (FIX ≤2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A z-test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated.Results: Seven articles investigating six rFIX products were identified. Median ABR, AsBR, and AjBR ranged from 0–3.0, 0–1.0, and 0–1.1 (means = 0.8–4.26, 0.13–2.6, and 0.34–2.85), respectively. rIX-FP achieved the lowest median and mean values in all three parameters. Z-tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products.Limitations: The low number of appropriate trials available for comparison limits the quantity of data available for comparison, and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field.Conclusion: This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably vs other rFIX products for prophylaxis in hemophilia B.

Extended Half-Life Coagulation Factors: A New Era in the Management of Hemophilia Patients

Despite effective factor replacement and various treatment schedules, there remain several challenges and unmet needs in the prophylactic treatment of hemophilia limiting its adoption and thereby posing an increased risk of spontaneous bleeding. In this regard, extended half-life (EHL) recombinant factor VIII (rFVIII) and factor IX (rFIX) products promise optimal prophylaxis by decreasing the dose frequency, increasing the compliance, and improving the quality of life without compromising safety and efficacy. EHL products might lead to higher trough levels without increasing infusion frequency, or could facilitate the ability to maintain trough levels while reducing infusion frequency. This paper aims to provide a comprehensive review of the rationale for developing EHL coagulation factors and their utility in the management of hemophilia, with special emphasis on optimal techniques for half-life extension and criteria for defining EHL coagulation factors, as well as indications, efficacy, and safety issues of the currently available EHL-rFVIII and EHL-rFIX products. Potential impacts of these factors on quality of life, health economics, and immune tolerance treatment will also be discussed alongside the challenges in pharmacokinetic-driven prophylaxis and difficulties in monitoring the EHL products with laboratory assays.

PRO5 REAL WORLD UTILIZATION OF FVIII PRODUCTS IN THE US: ANALYSIS OF THE CHESS US STUDY

Hemophilia A is characterized by factor VIII deficiency resulting in uncontrolled bleeding if untreated. The gold standard of management is prophylactic intravenous factor VIII replacement. Standard half-life products (SHL) are typically infused three times weekly. Currently marketed extended half-life products (EHL) aim to reduce dosing frequency, while optimizing protection against bleeding. However, due to limitations in claims data, little evidence is available to describe how these products are used in clinical practice. Our primary objective was to describe real world utilization of SHL/EHL in the USA. A descriptive analysis was conducted, utilizing data from the CHESS US study, a cross-sectional survey and chart review in 2018, replicating the methodology of previous European studies. Males aged 18+ years, with severe hemophilia A, treated with factor VIII continuous prophylaxis, and reside in the USA were included in the analysis. Included in the assessment were 200 patients. Patients were categorized by treatment with either EHL (n=70) or SHL (n=130). Mean age was 29.4 in both groups. More patients currently receiving EHL products vs. SHL products had sites of long-term joint damage (31.4% EHL vs. 19.2% SHL) and were more overweight/obese (57.1% EHL vs. 47.7% SHL). Additionally, the EHL group were more likely to have had a previous inhibitor (28.6% EHL vs. 12.3% SHL). Those currently using EHL products were found to use 9.0 IU/kg/week less than their SHL counterparts (70.2 IU/kg/week and 79.2 IU/kg/week respectively). Adherence rates were similar with 81.4% of EHL patients and 80% of SHL patients reporting ≥85% adherence. This analysis indicates that there may be a tendency for patients with greater ‘severity’ to receive EHL products (i.e. those with greater prevalence of chronic joint damage, obesity and history of inhibitors). Despite these likely confounding factors, there was less clotting factor consumption in patients receiving EHL products.

Regional variation and cost implications of prescribed extended half-life factor concentrates among U.S. Haemophilia Treatment Centres for patients with moderate and severe haemophilia.

Extended half-life (EHL) factor VIII (FVIII) and IX (FIX) products are intended to decrease the burden of prophylaxis for patients with haemophilia A or B. Whether these newer concentrates have led to meaningful clinical practice change remains vague. To characterize the longitudinal use of standard (SHL) and EHL factor concentrates at haemophilia treatment centres (HTCs), using the ATHNdataset, a US database of 138 ATHN-affiliated HTCs. Factor concentrate use among moderate and severe haemophilia A and B patients without inhibitors was analysed at three time points over 18months. Use of EHL concentrates rose from 10% of patients to 22% during this study. EHL FVIII prophylaxis is prescribed to the minority of patients, 28%; EHL FIX now predominates for prophylaxis, 52%. Rates of prescribed EHL products varied significantly by age group and HTC region. Median prescribed prophylaxis for SHL compared to EHL products was FVIII 6240 and 5200 and FIX 6968 and FIX 3900IU/kg/y, respectively. On-demand EHL use has grown but has minimal contribution to overall usage (2%). Haemophilia treatment centre region and patient age impact the rate of adoption of EHL products; however, EHL prescribing continues to rise nationally, particularly for EHL FIX. Careful attention to annual cost of prophylaxis is imperative as the decrease in median EHL prophylaxis consumption is not offset by the higher unit cost of these products. It is unclear how further growth in use of EHLs will be impacted by emerging non-factor replacement and gene therapies.

Real World Use of Extended Half-Life Products and the Impact on Bleeding Events and Joint Health in the United States

Real World Use of Extended Half-Life Products and the Impact on Bleeding Events and Joint Health in the United States

Analysis of US Claims Real World Data of Hemophilia a & B Patients: Units Dispensed & Expenditures Associated with Utilization of and Switching from Standard to Extended Half-Life Factor Products

Background:Both standard half-life (SHL) and extended half-life (EHL) factor replacement products are used to treat patients with hemophilia A (hem-A) and B (hem-B). A comparison of international unit (IU) utilization and expenditures ($USD) was made between patients on SHL and EHL factor replacement products to compare utilization and to determine the impact of switching from an SHL to an EHL product.Methods:De-identified claims data from both the Truven Health MarketScan® Research (Truven) and Optum® Clinformatics® (Optum) US claims databases included male patients with hem-A (Truven from Aug 2014-Apr 2018 and Optum from Aug 2014-Dec 2017) and hem-B (Truven from Jun 2014-Apr 2018 and Optum from Jul 2014-Dec 2017) who had data for at least 3 months of product dispensation. The SHL and EHL groups were compared. A separate “switch” analysis using the Truven database examined expenditures and IUs before and after switching from nonacog-α (SHL) to FIX-Fc (EHL). Descriptive statistics were used and medians reported for expenditures and IUs to accommodate for the skewness of data distribution.Results:Hem-A: The analysis included 896 SHL and 202 EHL patients, including those who switched from an SHL to an EHL product. Quarterly expenditures and IUs dispensed were analyzed. Both the Optum and Truven databases (see Table) demonstrated higher IU dispensation (Optum: 35%, Truven: 50% higher) and expenditures (Optum: 87%, Truven: 117%) associated with EHL products versus SHL products. In the switch analysis, 35 patients switched from nonacog-α to FIX-Fc; median IUs rose from 61,228 to 75,914 [24%] and median expenditures rose from $78,945 to $155,203 [97%].Hem-B: The analysis included 50 FIX-Fc, 13 FIX-Alb, and 132 nonacog-α patients. Both databases (see Table) demonstrated higher median expenditures for the EHL products compared with nonacog-α (Optum: 179% for FIX-Fc, 189% for FIX-Alb; Truven: 234% for FIX-Fc, 245% for FIX-Alb). The IU results varied in Optum: FIX-Fc was 23% higher than nonacog-α, but FIX-Alb was 9 % lower than nonacog-α. Similarly, in Truven, the IU results varied: IUs were mixed for the SHL product compared with the EHL products: 62% higher for FIX-Fc than nonacog-α, and approximately the same for FIX-Alb and nonacog-α. In the switch analysis, 16 patients switched from nonacog-α to FIX-Fc; median IUs rose from 62,857 (nonacog-α) to 69,816 (FIX-Fc) [11%], while expenditures rose from $75,064 (nonacog-a) to $210,482 (FIX-Fc) [180%].Conclusions:This analysis in more than 1000 patients, unadjusted for severity of disease or treatment scheme, demonstrated in hem-A that higher IU utilization and expenditures were associated with EHL use compared with SHL use, and in hem-B, that higher expenditures were seen with EHL products, while IU dispensation in some cases decreased, remained the same, or increased. In patients switching from the SHL to an EHL product, higher IU dispensation and expenditures were seen. These real-world data may challenge assumptions regarding typical factor usage and expenditures associated with EHL products in patients with hem-A and hem-B. Additional analyses with adjustment for treatment scheme and disease severity are needed. [Display omitted] DisclosuresTortella:Pfizer Inc.: Employment. Chhabra:Pfizer Inc.: Employment. Alvir:Pfizer Inc.: Employment. Rubinstein:Pfizer Inc.: Employment. Young:Pfizer Ltd.: Employment. Fogarty:Pfizer Inc.: Employment.

Adoption of Prophylaxis in the United States in the Era of Extended Half-Life Factor Concentrates

Background: Use of prophylaxis is the evidence-based strategy to prevent joint bleeds and reduce arthropathy for patients with severe hemophilia however, prophylaxis has not been universally adopted in the United States. Amongst patients with severe hemophilia enrolled in the ATHNdataset, the largest database of patients with disorders of hemostasis and thrombosis in the United States, as of 2015, 37% of patients with hemophilia A, and 45% of patients with hemophilia B do not receive prophylaxis. With the approval of extended half-life (EHL) factor products, patients and providers have options for less treatment-intense and burdensome prophylaxis. With the changing landscape of available hemophilia products, we aimed to quantify the number of patients treated at U.S. HTCs on prophylaxis utilizing the ATHNdataset with the objective determining the impact of EHL products on the proportion of patients with severe hemophilia receiving prophylaxis and to characterize use of prophylaxis according to age, race and ethnicity, geographic region, and payer.Methods: The ATHNdataset, a HIPAA compliant limited dataset sponsored by the American Thrombosis and Hemostasis Network (ATHN), was accessed as of June 30, 2018. The proportion of subjects with severe hemophilia on prophylaxis were compared to those on demand by age cohort. The proportion of subjects on prophylaxis was analyzed by race, ethnicity, insurance status, and hemophilia treatment center region. For each group receiving prophylaxis, the product (EHL versus standard half-life (SHL)), dose and frequency of treatment was analyzed.Results: ATHNdataset included 6,160 severe hemophilia patients using factor replacements, 5,234 individuals with hemophilia A and 926 individuals with hemophilia B. Overall, 76.0% (n=4,864) of patients with severe hemophilia are on prophylaxis whereas 24.0% (n=1426) are on demand; this included a total of 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B on prophylaxis. Treatment type (prophylaxis or not) had significant associations with age (p-value <0.001), ethnicity (p<0.001), race (p=0.005), hemophilia treatment center (HTC) region (p<0.001), and hemophilia type (p=0.015) (Table 1). Prophylaxis was not significantly correlated with payer (p=0.847) with a similar number of patients with Medicare/Medicaid or private insurance receiving prophylaxis.Among patients on prophylaxis, 30.8% (n=1,462) are prescribed EHL products including 27.4% of patients with hemophilia A and 50.4% with hemophilia B. In terms of dosing frequency (n=758), 73.8% of hemophilia A patients on prophylaxis receive EHL two times per week while 73.7% (n=1,906) receive SHL every other day (Table 2). Of hemophilia B patients using EHL products, 63.3% of patients receive prophylaxis once weekly, 12.7% every 10 days, and 15.0% every 2 weeks (Table 2).Discussion: The ATHNdataset highlights increased use of prophylaxis over the past 3 years in the U.S. with 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B currently receiving prophylactic therapy as compared to 63% and 55% of patients, respectively, in 2015. Further, the majority (83.7%) of patients are beginning prophylaxis according to the World Federation of Haemophilia recommendation to initiate prophylaxis by three years of age. There has been an uptake of the use of EHL factor products including a majority of patients (50.4%) with severe hemophilia B. Although not captured in the ATHNdataset, a plausible reason for the increased uptake of EHL in the hemophilia B population includes the data that 91% of patients are able to dose between weekly or less frequently. As the hemophilia treatment landscape continues to evolve, it is important to continue to understand the adoption of these new products into practice and to examine their real-world impact. [Display omitted] DisclosuresMalec:Shire: Consultancy; Bioverativ: Consultancy; Bayer: Consultancy; Bioverativ: Research Funding. White:Biomarin: Other: DSMB; Bioverativ: Other: DSMB; Bayer: Other: GRAC; Shire: Other: Physician Leadership Group; Novo Nordisk: Consultancy; Asklepios: Other: Scientific Advisory Board; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Croteau:Biomarin: Consultancy; Bioveritiv: Consultancy; Catalyst Biosciences: Consultancy; CSL-Behring: Consultancy; Genetech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Ragni:Sangamo: Research Funding; CSL Behring: Research Funding; Bioverativ: Consultancy, Research Funding; SPARK: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Shire: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

Bilateral, Simultaneous Total Knee Replacement (TKR) Surgery for Hemophilia a with Eloctate (Extended Half Life Product)—A Feasible and Cost Effective Approach

Abstract INTRODUCTION: The majority of bleeds experienced by people with Haemophilia occur into the joints or muscles.The joints most frequently involved are the knees, ankles, and elbows. The consequences of recurrent bleeding into a joint leads to chronic hemophilic arthropathy. Knee arthropathy is crippling situation affecting Quality of Life (QOL) for Patient with Hemophilia (PWH).With the advent of the availability of Clotting Factor Concentrates (CFC), Total Knee Replacement (TKR) can now be performed safely. TKR is performed using Total 2000IU/kg of Plasma Derived (PD) or Recombinant CFC. Literature recommends 1000-1200IU/kg of Total Eloctate for TKR. METHODS: Aim for feasible, safe &amp; cost effective CFC replacement policy for TKR 1) Use lower dose Eloctate during TKR 2) Perform Simultaneous Bilateral TKR Patients and Methods: Total 24 Severe Hemophilia A patients underwent 48 bilateral, simultaneous TKR. Age range was 28-51 years. Pre-operative 50IU/Kg Eloctate was infused. Pre-operative FVIIIc Level was median 108IU/kg (86-126 IU/dl). Post-operative Eloctate replacement was 40-50IU/kg once daily till day 5, then 30IU/kg once daily till Day15. FVIIIc assay was monitored at least once daily till day 10. Dose was tailored according to FVIIIc levels. Trough FVIIIc level was maintained above 60iu/dl for first 5 days. Average duration of surgery was 4 hours. Drains were removed after 48 hours. LMWH Thromboprophylaxis &amp; physiotherapy was started from post-operative Day 2. Clips were removed on Day 14. Eloctate was received through Humanitarian Aid Program of WFH. RESULTS: Total of 48 bilateral, simultaneous TKR were performed on 24 patients. 23 patients had no significant intra or post-operative bleeding &amp; no transfusion support was needed . One patient underwent pseudo tumour excision and TKR in the same sitting &amp; required extra 50IU/kg Eloctate+ 8 packed red cells + 8 FFP + 10 Cryoprecipitate intra operative during excision of Pseudo Tumour for total blood loss of 2200 ml as expected . He also experienced no post-operative bleeding till discharge. No wound or prosthesis infection was noted. Prosthesis survival was 100%. Total Eloctate used was 510- 640 IU/kg over 14 days. DISCUSSION: There was no excess bleeding in our patients. The results from our assessment are quite similar to the overall prosthetic survival rates reported for TKAs performed on patients without hemophilia.In our study there were no periprosthetic infections reported. Other studies have showed rates of periprosthetic infection after primary TKA in patients with hemophilia are much higher (up to 11%). Late infection is a major concern after TKA in patients with hemophilia, an important factor is the high rate of HIV-positive patients (3).Another important complication of TKA surgery is aseptic loosening of the prosthesis. Aseptic loosening was not found in any of our patients. Rates of this complication increase over follow-up (4). In our data the ROM improved and flexion contracture reduced significantly after arthroplasty following the scheduled physiotherapy.As mentioned in an article by Schild FJA et al the Median amount of CFC (Plasma derived &amp; recombinant) used for multi-joint procedure per patient was 57,680 IU; in another retrospective study by A Thes et al where the median CFC (Plasma derived &amp; recombinant) usage per patient was 1,500 IU/kg; whereas we used Total Eloctate of 510- 640 IU/kg and hence reduced CFC usage compared to western protocol. CONCLUSIONS : Low dose Eloctate replacement is safe and cost effective for TKA in PWH. Bilateral TKA in same sitting is feasible and increases cost effectiveness in PWH. Thrombo-prophylaxis with LMWH can be done safely in PWH. Bleeding events did not increase with low dose Eloctate &amp; LMWH. At these doses, total Eloctate replacement was 40-50% lower than previously reported for TKR surgery for PWH. Our protocol offers a cost effective and safe option in resource constraint countries. Disclosures No relevant conflicts of interest to declare.

Changing the Paradigm in Hemophilia Care: Extended Half-Life Products (rFVIIIFc and rFIXFc)

Background:Prophylactic treatment with factor products has demonstrated superior outcomes and care compared to on-demand treatment in hemophilia patients, including patients with pre-existing joint diseases. However, 40% to 50% of severe or moderate hemophilia A and B patients are still treated on-demand in the US. Recombinant factor VIII and IX Fc fusion proteins (rFVIIIFc and rFIXFc) were the first extended half-life (EHL) products approved in the US (in 2014) with the promise of optimizing prophylactic regimens by achieving low bleeding rates and improving joint health with fewer injections overall.Objective:This is the first real-world study to assess the impact of EHL rFVIIIFc and rFIXFc on overall prophylaxis rates, particularly to understand how patients have transitioned from on-demand treatment.Methods:A retrospective analysis was conducted on aggregate, de-identified United States Specialty Pharmacy Provider (SPP) records from Jan 2014 to June 2018 (data pull on June 14th, 2018). Adult hemophilia patients (age 18 and above) were included for an analysis of treatment regimens prior to and after switching to EHL rFVIIIFc and rFIXFc (on-demand or prophylaxis). The results were descriptively compared to those who switch to the other EHL PEGylated rFVIII and rFIX albumin Fusion Protein (rFIX-FP) and conventional factors.Results:A total of 304 hemophilia A patients who switched to rFVIIIFc and 133 hemophilia B patients who switched to rFIXFc were included in this study. For the hemophilia A and B patients, the median age was 31 and 32 years and median weight was 82 and 79 kg. The proportion of patients who switched from on-demand treatment with conventional factors to prophylaxis treatment with EHL rFVIIIFc and rFIXFc among all patients who switched to these products increased over time since the FDA approval (3 time points: 2014-2015, 2016-2017, and 2018: rFVIIIFc: 13%, 20%, and 21%; rFIXFc: 25%, 29%, and 57%). Such proportions were higher compared to those who switched from on-demand with conventional factors to prophylaxis with the other EHLs (2016-2017, 2018: PEGylated rFVIII: 16%, 18%; rFIX-FP: 18%, 13%, see comparison in the Figure) and with conventional factors (2014-2015, 2016-2017, and 2018: conventional rFVIII: 10%, 7%, and 9%; conventional rFIX: sample size was too small and not suitable for analysis).Discussion:rFVIIIFc and rFIXFc have transformed the paradigm of hemophilia care by shifting on demand patients to prophylaxis significantly faster than conventional factors and any other EHLs to date. This shift is significant as it is helping more hemophilia patients achieve optimal protection through low bleeding rates and improved joint health over the long-term. [Display omitted] DisclosuresJain:Bioverativ: Employment. Li:Bioverativ: Employment. Krishnan:Bioverativ: Employment. Hagberg:Bioverativ: Employment. Su:Bioverativ: Employment.

Bay 94-9027 Can be Accurately Measured across Regions with Appropriate One-Stage Assay Reagent Use

Introduction: Differences in coagulation assay reagents may lead to variable results for some extended-half-life (EHL) recombinant factor VIII (rFVIII) products, with the potential to adversely affect patient care. Laboratories assessing EHL-rFVIII activity can choose from many available one-stage assay and chromogenic assay reagents. A field study was conducted to evaluate the ability of clinical laboratories to accurately measure FVIII activity in plasma samples spiked with BAY 94-9027, an EHL rFVIII, when using diverse assay reagents and when guided in the choice of reagent. In a regional subanalysis, BAY 94-9027 field study results from clinical laboratories in the United States and Canada were compared with those from Europe and Israel.Methods: In this 2-part study, a broad range of laboratories in the United States, Canada, Europe (Austria, Germany, Italy, Romania, Spain, Switzerland, United Kingdom), and Israel were provided samples containing defined concentrations of BAY 94-9027 or an unmodified rFVIII (antihemophilic factor [recombinant] plasma/albumin-free method [rAHF-PFM]) as a control. In part 1, each laboratory measured FVIII activity using their routine methods (one-stage assay, chromogenic assay, or both); laboratories that had ≥2 routine one-stage assays were asked to perform sample testing with one of the less commonly used assays in the laboratory to ensure that part 1 captured both the prevalence and heterogeneity of one-stage assays used in the geographic regions studied. In part 2, laboratories used one-stage assays with SynthASil and Pathromtin SL reagents provided by Bayer; SynthASil and Pathromtin SL have previously been shown to accurately measure BAY 94-9027 and full-length rFVIII products. The field study data were analyzed to identify the most commonly used reagents in the 2 regions (United States/Canada and Europe/Israel) and to assess if regional differences resulted in differences in accuracy of FVIII activity measurement.Results: 52 laboratories (US/Canada, n=25; Europe/Israel, n=27) participated in the field study. The one-stage reagent SynthASil was commonly used in all countries (n=15) in part 1, but differences were seen in the frequency of use of other reagents. PTT-A (n=6) and Actin FSL (n=5) were frequently used in the US/Canada and Actin FS (n=6) and Pathromtin SL (n=6) in Europe/Israel. Regional differences in the choice of assay, with US/Canada more likely to use assays that did not accurately measure BAY 94-9027, affected the ability of laboratories to accurately measure FVIII activity in the spiked samples (Figure). In part 1 of the study, regional differences in median recovery of BAY 94-9027 were seen among laboratories when using their own in-house one-stage assays. These differences were not seen in part 2 of the study when laboratories used provided reagents (SynthASil and Pathromtin SL), despite using the same instrumentation as used in part 1. Regional differences in part 1 might have been exacerbated by use of less common, and potentially inappropriate, one-stage assay reagents, affecting the accuracy of BAY 94-9027 measurement. Chromogenic assay use was more common in Europe/Israel (n=11) than US/Canada (n=5). No regional differences in chromogenic assay results were observed.Conclusions: Most clinical laboratories were able to accurately measure BAY 94-9027 activity using their in-house assays. However, regional differences in the accurate measurement of BAY 94-9027 activity were influenced by regional choice of one-stage reagents used in part 1 of the study; the activity and accuracy differences were eliminated when all laboratories used the same provided one-stage reagents with their in-house instruments (part 2 of study). Therefore, standardization of laboratory procedures and use of newer, more accurate one-stage assay reagents should improve measurement of FVIII activity with EHL products. [Display omitted] DisclosuresCastellone:Bayer: Membership on an entity's Board of Directors or advisory committees; Wilmer-Hale: Consultancy. Church:Bayer: Employment. Leong:Bayer: Employment. Kitchen:Bayer: Consultancy, Other: travel reimbursement, Speakers Bureau.

Efficacy and Safety Results from a Phase 3b, Open-Label, Multicenter, Continuation Study of Rurioctocog Alfa Pegol for Prophylaxis in Previously Treated Patients with Severe Hemophilia A

Background: Patients with severe hemophilia A experience substantial morbidity and mortality due to frequent spontaneous and traumatic bleeding episodes, especially in joints. Prophylaxis with standard half-life factor VIII (FVIII) is the standard of care to prevent bleeds. Extended half-life products benefit patients by reducing the number of infusions without impacting the treatment efficacy.Methods: This phase 3b, prospective, open-label, multicenter, continuation study (NCT# 01945593) investigated the safety and efficacy of a PEGylated recombinant FVIII with an extended half-life, rurioctocog alfa pegol (SHP660, BAX 855, ADYNOVATE®, Shire, Lexington, MA, USA), for prophylaxis and treatment of bleeding in patients with severe hemophilia A (FVIII <1%). Eligible children and adults were ≤75 years of age and had either completed a previous rurioctocog alfa pegol study (NCT# 01599819, 01736475, 02210091, 02615691, 01913405, or 02585960) and were willing to immediately transition to the continuation study, or were naïve to rurioctocog alfa pegol but had received treatment with plasma-derived or recombinant FVIII for ≥150 (in patients ≥6 years of age) or ≥50 (in patients <6 years of age) exposure days. Patients received prophylactic rurioctocog alfa pegol at least twice weekly, either at a fixed dose (FD; 45 ± 5 IU/kg in patients ≥12 years of age; 50 ± 10 IU/kg in those <12 years of age; dose adjustment ≤80 ± 5 IU/kg allowed) or with pharmacokinetically (PK)-tailored dosing (≤80 ± 5 IU/kg) to maintain FVIII trough levels ≥3%. The co-primary endpoints assessed were the incidence of FVIII inhibitory antibody development (as measured by ≥0.6 BU in the Nijmegen modification of the Bethesda assay) and the spontaneous annualized bleed rate (ABR). Secondary endpoints included overall hemostatic efficacy ratings and occurrence of adverse events (AEs).Results: The study began in October 2013 and completed in March 2018. Overall, 216 patients receiving prophylaxis were eligible and included in the safety/full analysis dataset (≥1 dose received). Of these, 215 were male, the mean (SD) age at enrollment was 22.8 (15.7) years, the mean (SD) number of documented previous rurioctocog alfa pegol exposure days was 57.0 (39.6), the total ABR over 3-6 months prior to enrollment in the continuation study (including patients naïve to rurioctocog alfa pegol or receiving on-demand or prophylactic treatment with rurioctocog alfa pegol) was mean (SD) 4.7 (12.6), median (range) 0.0 (0-69). Most patients (206; 95.4%) had participated in a previous rurioctocog alfa pegol study. Overall, 215 patients received ≥1 dose in the FD regimen and 25 received ≥1 dose in the PK regimen. These patients received a mean (SD) of 1.72 (0.29) and 2.11 (0.61) prophylactic infusions per week, respectively, with a mean (SD) dose per infusion of 51.15 (8.11) IU/kg and 52.14 (17.03) IU/kg, respectively.None of the patients developed a confirmed FVIII inhibitor in this study and only 1 treatment-related allergic or hypersensitivity reaction (a nonserious mild AE) was reported. Nonserious AEs assessed by the investigators to be related to treatment occurred in 11/216 (5.1%) patients. Serious AEs (SAEs) occurred in 33 (15.3%) patients; there were no SAEs assessed by the investigators to be related to treatment. Descriptive statistics on spontaneous, joint, and total ABR by prophylactic regimen are shown in the Table. The overall total ABR in all patients was mean (SD) 2.5 (3.1), median (range) 1.6 (0.0-19.5). Overall hemostatic efficacy was rated as good or excellent in 88.5% of all bleeds and 89.4% of all bleeds were treated with 1 or 2 infusions.Conclusions: These results show that in previously treated patients with severe hemophilia A, rurioctocog alfa pegol prophylaxis in FD- and PK-tailored regimens was well tolerated and effective. None of the patients developed FVIII inhibitory antibodies, and a decrease in mean total ABR was reported in these patients compared with baseline. [Display omitted] DisclosuresMullins:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konkle:Genentech: Consultancy; CSL Behring: Consultancy; Gilead: Consultancy; Pfizer: Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy; Bioverativ: Research Funding; Shire: Research Funding; Sangamo: Research Funding. McGuinn:CSL Behring: Consultancy; BioMarin: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark: Consultancy, Research Funding; Genentech: Consultancy; Shire: Research Funding; Pfizer: Research Funding. Engl:Shire: Employment, Equity Ownership. Tangada:Shire: Employment, Equity Ownership.

IX因子活性に基づいた半減期延長型第IX因子製剤（エフトレノナコグアルファ）による定期補充療法の有用性

IX因子活性に基づいた半減期延長型第IX因子製剤（エフトレノナコグアルファ）による定期補充療法の有用性

PSY65 - REAL-WORLD DATA ANALYSIS OF US CLAIMS DATA ON COAGULATION FACTOR IX DISPENSATION AND EXPENDITURES IN PATIENTS WITH SEVERE HEMOPHILIA B: STANDARD HALF-LIFE VS. EXTENDED HALF-LIFE PRODUCTS

Management of hemophilia B requires factor IX (FIX) infusions to replenish missing coagulation factor. Newer extended half-life (EHL) replacement products with longer half-lives compared to standard half-life (SHL) products are available in the US. In this exploratory analysis of US claims data, we compared the expenditures and dispensation of two EHL products versus an SHL product for hemophilia B treatment. De-identified claims from a large national specialty pharmacy dispensation claims database were used to identify male patients with severe hemophilia B who received FIX replacement from May 2016 (first month of albutrepenonacog alfa dispensation) to September 2017 and had ≥1 month of dispensation data. Two patient groups (SHL vs. EHL) were compared. Key outcome measures were direct expenditures and factor IUs dispensed, measured over monthly increments. Descriptive statistics were used to analyze results. Medians for expenditures and IUs were used to accommodate data distribution skewing. 213 Hem B patients met the inclusion criteria and were included in the analysis, including patients who were dispensed >1 FIX product. The SHL (nonacog alfa) group comprised 133 patients; the EHL group included 72 patients in the eftrenonacog alfa group and 39 patients in the albutrepenonacog alfa group. The median per-patient-per-calendar-month FIX product dispensation was 20,456 IU (interquartile range [IQR], 28,896 IU; nonacog) versus 17,438 IU (IQR, 16,483 IU; eftrenonacog) and 10,453 IU (IQR, 8377 IU; albutrepenonacog). Median per-patient-per-calendar-month expenditures were higher for EHLs (eftrenonacog: $51,986, IQR, $49,520; albutrepenonacog: $44,425, IQR, $35,602) than for SHL ($28,025, IQR, $39,587). A consistent pattern of decreased eftrenonacog vs. nonacog unit utilization was not demonstrated. This real-world data analysis showed higher expenditures in US hemophilia B patients who received EHL products. Further analyses, incorporating essential clinical characteristics and drug regimens, should be explored.

Practical aspects of extended half-life products for the treatment of haemophilia.

Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients' quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5-1.8 times that of standard products for FVIII and 3-5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.

PSY34 - Factor Dispensation and Expenditures in Hemophilia B Patients Switching from Standard Half-Life to Extended Half-Life Recombinant Factor IX Replacement Products: Real-World Analysis in Japan

Management of hemophilia B requires replacement therapy with factor IX (FIX) coagulation products. Extended half-life (EHL) recombinant FIX products are now available along with existing standard half-life (SHL) FIX products. The aim is to examine factor dispensation and expenditure for Japanese patients who switched from SHL to EHL product in a real world setting. Japanese real world data provided by Medical Data Vision Co., Ltd (MDV) were used to compute number of IUs dispensed, direct product and total health care expenditure (¥)among individuals with data for ≥3 months before and after switching from an SHL (nonacog alfa, nonacog gamma, freeze-dried human blood-coagulation factor IX) to EHL (eftrenonacog alfa) product (April 2010–November 2017). MDV is a commercially available large scale real-world hospital medical administrative and claims database in Japan, that includes claims data from hospitals, regardless of insurance types, from >10 million inpatients and outpatients. We report medians for IUs and expenditures to accommodate for skewness of data distribution. Seventeen patients switched from an SHL to EHL product and had ≥3 months of data pre and post switch. Median quarterly IUs dispensed increased from 29,600 IUs on SHL to 36,750 IUs on EHL when considering available data on the 4 quarters pre and post switch. Median FIX expenditures increased 398% from ¥1,522,368 to ¥7,589,255. FIX replacement expenditures represented 96% of total expenditures pre and 99% post switch. Similar patterns held when analyses were limited to 7 individuals who switched from nonacog alfa (Medians= 18,000 IUs; ¥1,896,510) to eftrenonacog alfa (Medians=36,000 IUs; ¥7,480,296) (294% increase in expenditures). This analysis shows that switching from an SHL to EHL product increased FIX replacement IUs dispensed. Expenditures on FIX replacement products increased post switch by 294% - 398%. Further analyses in larger patient populations should be explored.

GlycoPEGylated recombinant factor IX for hemophilia B in context

Decisions over hemophilia treatment selection and switching involve balancing many clinical and patient-related factors. The current standard of care for patients with hemophilia B is prophylaxis with plasma-derived or recombinant factor IX (rFIX) concentrates. However, several extended half-life (EHL) rFIX products have recently been developed to improve treatment convenience and clinical outcomes for these patients. Nonacog beta pegol, an rFIX product that combines the FIX protein with a 40 kDa polyethylene glycol moiety, has been evaluated in 115 previously treated patients with hemophilia B (including 25 children) in the paradigm clinical trial program. FIX activity levels and pharmacokinetics were monitored throughout these trials and showed that nonacog beta pegol offers significant pharmacological improvements over standard FIX products. Once-weekly prophylaxis with nonacog beta pegol 40 IU/kg resulted in fewer bleeds in all patients (median annualized bleeding rate of 1.0 across all ages), resolved 90% of target joints, and improved health-related quality of life. No patients developed FIX inhibitors, and there were no thromboembolic events or unexpected safety concerns. Nonacog beta pegol was also safe and effective in the perioperative setting. These findings show that nonacog beta pegol is highly effective, while also offering more convenient dosing than standard FIX products. Nonacog beta pegol represents a significant advance in the current context of treatment for hemophilia B, offering effective management across several treatment modalities and settings, and potentially easing the treatment burden for patients of all ages. Meanwhile, the development of novel treatment strategies, such as gene therapy, anti-tissue factor pathway inhibitor antibodies, and RNA interference therapy, may provide patients with additional therapeutic options, which would require reassessment of the role of EHL products in the future.

PSY110 - Real World Data Analysis of US Claims Database on Coagulation Factor IX Expenditures in Patients with Hemophilia B: Standard half-Life Vs. Extended Half-Life Products

Management of Hemophilia B requires intravenous factor IX (FIX) infusions to replenish missing coagulation factor. The introduction of extended half-life (EHL) replacement products in the US, with longer half-lives compared to standard half-life (SHL) product enabled comparison of expenditures and dispensation of clotting factor concentrates for the treatment of Hemophilia B with two EHL products versus an SHL product. De-identified claims from a large national specialty pharmacy claims database were used to identify male patients with severe or moderate hemophilia B who received FIX replacement from Apr 2015 (month first EHL FIX dispensed) to Sep 2017 and had data for at least 1 month of dispensation. SHL vs EHL groups were compared. Key outcome measures were direct expenditures and factor IUs dispensed. Expenditures and IUs dispensed were measured over monthly increments. Descriptive statistics were used to analyze results. Medians for expenditures and IUs were used to accommodate for the skewness of data distribution. 386 Hemophilia B patients met the inclusion criteria and were included in the analysis. The SHL group comprised of 293 nonacog alfa patients and the EHL group included 107 eftrenonacog alfa patients and 45 albutrepenonacog alfa patients. The albutrepenonacog group had a proportionately higher number of pediatric patients. The median FIX product dispensation per patient per calendar month was 16,134 IU (IQR, 26,903 IU) (nonacog) versus 16,380 IU (IQR, 17,287 IU) (eftrenonacog) and 10,039 IU (IQR, 10,620 IU) (albutrepenonacog). Median expenditures per patient per calendar month were higher for EHLs (eftrenonacog $48,336; IQR, $49,970; and albutrepenonacog $42,664; IQR, $45,135) than for SHL ($21,849; IQR, $36,102). This real-world data analysis, unadjusted for treatment regimen, showed higher expenditure among U.S. moderate/severe hemophilia B patients who used EHL, compared to SHL FIX. Further analyses, incorporating essential clinical characteristics and drug regimen, should be explored.

Novel therapies and current clinical progress in hemophilia A.

The evolution of hemophilia treatment and care is a fascinating one but has been fraught with many challenges at every turn. Over the last 50 years or so patients with hemophilia and providers have witnessed great advances in the treatment of this disease. With these advances, there has been a dramatic decrease in the mortality and morbidity associated with hemophilia. Even with the remarkable advancements in treatment, however, new and old challenges continue to plague the hemophilia community. The cost of factor replacement and the frequency of infusions, especially in patients with severe hemophilia on prophylaxis, remains a significant challenge for this population. Other challenges include obtaining reliable venous access, especially in younger patients, and the development of neutralizing alloantibodies (inhibitors). The development of extended half-life products, a bispecific antibody which mimics the coagulation function of factor VIII (FVIII) and inhibition of anticoagulation proteins such as antithrombin with antibodies, aptamers or RNA interference technology have offered novel therapeutic approaches to overcome some of these existing challenges. Additionally, ongoing gene therapy research offers a way to possibly cure hemophilia. These novel treatment tools in conjunction with the establishment of an increasing number of comprehensive hemophilia centers and worldwide advocacy efforts have continued to push the progress of hemophilia care to new frontiers. This review highlights and summarizes these novel therapeutic approaches and the current clinical progress of hemophilia A.

Real-World Health Care Expenditure In Hemophilia A Patients Using Standard And Extended Half-Life Recombinant Factor VIII Products

Management of hemophilia A includes replacement of factor VIII (FVIII) by intravenous infusion. The recent introduction of extended half-life (EHL) FVIII products has enabled comparison of health care expenditure and volumes of factor dispensed for hemophilia A patients switching from a standard half-life (SHL) to EHL FVIII product. The Truven Health MarketScan® Research US claims databases (Aug 1, 2014 to Jan 31, 2017) were used to identify direct expenditures and international units (IUs) dispensed for all patients who used SHL (SHL group) and/or EHL (EHL group). Data on patients who switched from an SHL to an EHL FVIII product were captured up to one year before and after the switch. Patients with at least 1 pre and post-calendar quarter of claims available were included in the switching analysis. Cross-sectional analysis: In the SHL group (N=415), Six distinct SHL FVIII products were dispensed, with two EHL FVIII products dispensed in the EHL group (N=91). Median FVIII product dispensation per calendar quarter was 46,409 IU (IQR, 12,760-87,670 IU) (SHL) versus 67,375 IU (IQR, 50,524-98,264 IU) (EHL). Median expenditures per calendar quarter were higher for EHL ($135,519; IQR, $100,320-186,557) than for SHL ($61,152; IQR, $18,593-115,845). Switching analysis: In the EHL group, 29 patients switched from one of three SHL FVIII products to one of two EHL FVIII products during the study period. Total median IU dispensation per calendar quarter increased following the switch from 58,598 IU (pre-switch, SHL) to 68,036 IU (post-switch, EHL; 16% increase). Factor-related expenditure also increased 84% ($76,553, SHL, versus $141,101, EHL). This analysis suggests that switching from an SHL to an EHL product is associated with increased IU dispensation, expenditures and variability, including more EHL IU dispensed post-switch than SHL in quarters pre-switch. Further real world analyses incorporating larger numbers of patients should be explored.