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Background Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. Objectives To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept™2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg−1) or rFVIIa (one to three doses at 90 μg kg−1). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. Results In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24–48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. Conclusions This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit–risk profile is unlikely to be achieved with vatreptacog alfa.

The Generic Enterprise Reference Architecture and Methodology (GERAM) defines those methods, models and tools which are needed to identify and carry out change in enterprises. Enterprises need a life-cycle architecture that describes the progression of an enterprise from the point of realisation that change is necessary through setting up a project (or enterprise integration programme) and to implementing the change based on a thorough analysis and design. GERAM is a framework in which all necessary ingredients of this process are identified. GERAM allows one to characterise and compare all particular change methodologies and architectures, or helps in deciding how to combine ingredients of individual architectures and methods. GERAM is the result of generalisation, based on the three most complete enterprise reference architectures: CIM-OSA (Vernadat, 1992), the GRAI Integrated Methodology, GIM (Vallespir et al 1991), and the Purdue Enterprise Reference Architecture, PERA (Williams, 1992), but GERAM extends the scope of enterprise architecture to the life-cycle of Products, Enterprises, Enterprise Integration Projects, and Strategic Enterprise Management. It is also proposed which details of GERAM could be standardised.

The generic enterprise reference architecture and methodology is about those methods, models and tools which are needed to build the integrated enterprise. The architecture is generic because it applies to most, potentially all types of enterprise. The coverage of the framework spans products, enterprises, enterprise integration and strategic enterprise management. The proposal for the architecture follows the architecture itself improving the quality of the presentation and of the outcome. Definitions of generic enterprise reference architecture, enterprise engineering/integration methodology, enterprise modelling languages, enterprise models, and enterprise modules are given. It is proposed how the above could be developed on the basis of previously analysed architectures (and other results too), such as the purdue enterprise reference architecture (PERA) 1 , the GRAI integrated methodology 2 , CIM-OSA 3 , and TOVE 4 . GERAM is meant to unify existing architectures rather than intending to replace them. This is achieved by ensuring that the scope of GERAM spans all areas of consideration in an enterprise.

In multiphoton dissociation experiments on ketene (CH 2 CO) using a UV dye laser emission spectra were observed in the 360–370 nm range. The spectra were seen only with a focused laser beam and consist of lines attributable to emission from rotational levels in the ν ′ = 1 vibrational state of the B 2 Σ − electronic state of the methylidyne (CH) radical. In these spectra rotational transitions to the N ′ = 7 level of the B state from the ground (X) state, ν ″ = 0, were observed. Time-resolved fluorescence measurements on the N ′ = 1, 2, 3, 4, 5 and 6 levels yielded lifetime data contributing to the existing values in the literature. Based on line broadening a lifetime estimate is given for the strongly predissociated N ′ = 7 level.

This paper is a summary of the major technical report (Williams et al., 1993) of the IFAC/IFIP Task Force on Architectures for Integrating Manufacturing Activities and Enterprises. It presents a synopsis of the investigations of pertinent architectures undertaken, and the findings generated relating to the suitability of various architectures for the integration task. It also presents the Task Force's recommendations for achieving a “complete” architecture in terms of the necessary capabilities by “completing” a currently available architecture. The Task Force also outlined how a “best” architecture could be achieved by selecting and combining the best features of the available architectures.

Information Communication Technology (ICT) infrastructures supporting complex operations require collaborative effort to integrate a range of standalone software products into a coordinated system. However, the standalone products are normally developed with specific objectives and do not interoperate with each other. In a virtual enterprise environment, this imposes major challenges to ICT managers to manage o large variety of software products whereby each product only satisfies the unique requirements of a small portion of the user community. This paper discusses the development of the ICT infrastructure for a tooling virtual enterprise) using the open protocol standards as well as a new ICT infrastructure development tool known as Dynamic Network System (DNS). DNS models the operating characteristics of the ICT environment and generates the integrated internet web portal quickly from the system designer’s view. It is built on standard JSP server capabilities using open source system that has the normal server security facilities.

Under the IMS (Intelligent Manufacturing Systems) program, CSIRO assisted the ANZAC Ship Alliance in Australia to establish a framework for coordinating team members working in a cross company project from different locations. The ANZAC Ship Alliance is a virtual enterprise formed by 3 major partners with the aim to provide management and implementation of capability changes in ANZAC class frigates. Our earlier study proved that significant modifications are essential in order to adapt project operations to different practices of individual companies. This paper describes the study of the actual processes within an ANZAC Ship Alliance project, the techniques used to identify the information and workflow as well as the relationships with the stakeholders. Development of a web-based system that significantly enhances the effectiveness of collaboration within the virtual enterprise is presented.

This paper presents the design of a typical virtual enterprise (VRIDGE Inc.), as well as an integrated software environment for supporting the design, implementation and operation of the virtual enterprise (VRIDGE Workbench). The Purdue Enterprise Reference Architecture (PERA) methodology has been applied in combination with enterprise modelling tools, and extended with the STEP methodology. This has led to the specification of information requirements of the Vridge Inc. for developing the Vridge Workbench.

Customer service is essential to maintain good and lasting relationships. Many companies would like to reduce the cost of such support services. They have been looking for solutions many of which are created using IT tools. This paper will discuss a generic approach using IDEF3 process modelling methodology to provide such services in a flexible fashion. The approach results in the definition of a framework consisting of generic modelling methodology and software systems which captures the knowledge of experts and generates customer support systems tailored to the application requirements. The framework allows personnel, who do not have computer programming background, to generate such systems easily and the information can be accessed anywhere in the world.

We investigate essential properties of virtual enterprises and the consequent modeling requirements. Agent autonomy is defined. Virtual enterprises are treated as autonomous entities built out of autonomous entities. Requirements are derived from two types of virtual enterprises, a repetitive and a one-of-akind production or service enterprise. Properties that need to be represented in virtual enterprise models include the dynamics of decision making, the negotiations among participants for the delineation of domains of autonomy, authority, beliefs and responsibilities, the mapping of organizational entities to decisional roles, the ability to identify and analyze a variety of conflict types and the existence of conflict resolution paths. These properties have to be analyzed by matching enterprise engineering tools. An ontological theory is also needed to systematize the concepts that must be supported by the protocol languages for parallel distributed planning, scheduling and control algorithms in the virtual enterprise.

An account is given of the possibilities and limitations of reusing Enterprise Models (EM)1. Special difficulties are discussed which arise from the fact that stake-holders in the enterprise engineering process do not belong to a single homogeneous language community. Measures are proposed which ensure that models are interpreted as intended, thereby controlling the quality of the processes using enterprise models — such as enterprise engineering. A practical definition of model completeness is presented, based on a pragmatic theory of meaning and theory of communication.

With the globalisation of economies, enterprises are more viewed as ‘products’ themselves. This is quite obvious for green field companies as they are designed, built and put into operation as the customer requires. The product view, however, is also true for already existing enterprises. New business priorities have to be analysed, changes have to be specified, designed and carried out, and the design of an enterprise may take a considerable effort.

Managers and information scientists, control engineers and others have long been intrigued by the concept that one should be able to correlate and use, at any one time, all of the information then available concerning an enterprise, to systematically improve the operability, profitability, agility, competitivity (and many other important characteristics) of these systems.

A new type of cooperative engineering has appeared on the horizon. Notwithstanding geographical separation designers can share design data and model, cooperate through interactions on-line. In this paper the major issues of this method are examined, together with its impact on the design process. An overview of several typical cooperative design systems is also given.

The conclusions below are drawn from a review of the answers given to each of the three Questionnaires by the Purdue, CIMOSA and GRAI-GIM teams.

Abstract 719 Introduction: Current treatment options for the management of bleeds in hemophilia patients with inhibitors are primarily with bypassing agents, either recombinant activated factor VII (rFVIIa, NovoSeven®) or plasma-derived activated prothrombin complex concentrates. Whilst these products are efficacious, an improvement in the time to hemostasis could lead to better efficacy and improved quality of life. NN1731 was developed with the aim to provide a safe, rapid and sustained resolution of bleeds in patients with hemophilia and inhibitors. NN1731 is a recombinant factor VIIa analog with three point mutations in the protease domain at amino acid positions 158, 296 and 298, thereby stabilizing the active conformation of the molecule (Persson et al. PNAS 2001). It is produced without any human- or animal-derived raw materials. The aim of this phase 2 dose-escalation trial was to evaluate the safety and preliminary efficacy of NN1731 for the treatment of acute joint bleeds in subjects with congenital hemophilia A or B with inhibitors. Methods: This was a prospective, multi-center, randomized, double-blinded, active-controlled, dose-escalation trial evaluating 1–3 doses of NN1731 at 5, 10, 20, 40, and 80 mcg/kg bw vs. 1–3 doses of rFVIIa at 90 mcg/kg bw with a randomization ratio of 4:1 NN1731:rFVIIa for all dose tiers. Enrolled male patients ≥12 years of age experiencing a joint bleed were asked to report to the hemophilia center and were randomized to treatment within 3 hours of onset if the bleed met entry criteria. After first trial product administration (TPA), subjects were assessed at 3-hourly intervals and up to two additional doses of trial product could be given 3 and 6 hours later. Other hemostatic agents could be given as per local standard of care if, according to the investigator, the bleed was not controlled after three doses of trial product. The primary endpoint was number of adverse events, including non-serious adverse events (AEs) occurring within seven days of first TPA, and serious adverse events (SAEs) from first TPA to the end of subjects' participation in the trial. Secondary safety endpoints included evaluation of immunogenicity, biochemistry, hematology, and coagulation parameters. Efficacy endpoints included the number of doses needed to control bleeding, need for additional hemostatic medication, and improvement of symptoms (pain, swelling and range of motion). Furthermore, pharmacokinetic (PK) parameters were evaluated based on FVIIa activity. An independent Data Monitoring Committee (DMC) reviewed all data throughout the trial period, and made assessments after the first 10 bleeding episodes in each dose tier before allowing escalation to the next dose tier. Results: 96 bleeding episodes in 50 patients from 18 countries were dosed. Baseline demographic characteristics of the patients were comparable between NN1731 and the active control group. There were more target joints (defined as three bleeding episodes or more in the same joint in the past six months) treated in the NN1731 groups combined vs. rFVIIa (49% vs. 32%, respectively). Fewer AEs, including SAEs, were reported in the NN1731 groups vs. rFVIIa. AE rates, including SAEs rates, were similar for all dose levels of NN1731 studied, with no safety concerns. No antibody formation was detected in any patient treated with trial product. The PK profile of NN1731 observed in these actively bleeding hemophilia patients confirmed the PK seen in healthy subjects (Moss et al. J Thromb Haemost 2009). Initial analysis of the efficacy results show that 98% of the joint bleeds were controlled with NN1731 in a combined evaluation of 20 to 80 mcg/kg dose groups. The efficacy of rFVIIa was similar to that observed and reported in clinical studies and practice. Remaining data analyses are ongoing at the time of submission but will be completed for presentation at the meeting. Conclusion: In this largest prospective, randomized, controlled clinical trial of recombinant bypassing agents ever conducted in actively bleeding hemophilia patients with inhibitors, NN1731 was well tolerated, with no safety concerns observed at any dose levels. In particular, no antibodies were detected in any exposed patient. Preliminary results confirm the fast acting pharmacokinetic profile of NN1731 and show a high efficacy rate of NN1731 in controlling acute joint bleeds. Disclosures: de Paula: Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau, Traveling cost to scientific events; Bayer: Honoraria, Speakers Bureau, Traveling cost to scientific events; Baxter: Traveling cost to scientific events; Octapharma: Traveling cost to scientific events. Kavakli:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahlangu:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Maxygen: Membership on an entity's Board of Directors or advisory committees. Ayob:Novo Nordisk: Research Funding. Lentz:Novo Nordisk: Consultancy, Research Funding; Celgene: Equity Ownership; Schering-Bayer: Research Funding. Morfini:Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Baxter: Honoraria, Speakers Bureau; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Wyeth: Membership on an entity's Board of Directors or advisory committees. Nemes:Novo Nordisk: Research Funding. Zupancic Salek:Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Baxter: Consultancy, Speakers Bureau. Shima:Novo Nordisk: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Windyga:Novo Nordisk: Honoraria, Research Funding, Speakers Bureau, Travel to attend scientific meetings. Ehrenforth:Novo Nordisk: Employment. Andersen:Novo Nordisk: Employment. Chuansumrit:Novo Nordisk: Honoraria, Research Funding. behalf of 1804 (ADEPT-1) Investigators:Novo Nordisk: Research Funding.

Abstract 717 Between 2003 and 2009 42 pregnant females were diagnosed with acquired haemophilia A (AHA) and included in the European Acquired Haemophilia A (EACH2) Registry. They constituted 8 % of the total number of admitted patients to the registry (n=501). In one female the diagnosis was made 36 days before delivery and the rest were diagnosed postpartum. One female had an autoimmune disorder, the others were without any associated disease. In 31 cases AHA occurred associated with the 1st pregnancy, in 7 the 2nd, in 2 the 3rd and in 2 the 4th pregnancy. Data are given as median and inter quartile ranges: Reference Age at pregnancy of interest 34 (30–37) Days after delivery until diagnosis 89 (25–180) Days between first abnormal APTT to diagnosis 1 (0–8) Factor VIII at diagnosis 2.5 (1–8) 50–200 IU/dL Anti Factor VIII antibody titre 7.8 (2.4–31.3) All the diagnoses were triggered by bleeds. Cause of bleed: spontaneous 24, trauma 1, surgery 4, peri postpartum 15. Site of bleed: deep (musculoskeletal, retroperitoneal) 14, haemarthroses 2, mucosa 18, skin 19, CNS none. In 11 females the bleeds started on day of diagnosis. In 22 females the bleeds started between 0 and 7 days before diagnosis and in 20 females the bleeds were reported to have started more than 7 days before the diagnosis suggesting a significant delay in diagnosis. In 25 the bleed was considered as severe (a drop of Hb >2 g/dL or received red cell transfusions) – in 7 of these no haemostatic treatment was given. 21/41 of first bleed required haemostatic treatment, 12 with rFVIIa (recombinant activated factor VII), 5 aPCC (activated prothrombin complex concentrate), 2 FVIII concentrate, 2 desmopressin. In addition, 6 received antifibrinolytics. Ten needed red cell transfusions. The bleeds were controlled in all cases and there was no fatality. First line immunosuppressive (IS) treatment: Regimen CR* n (%) NR** n (%) Treatment changed n (%) Days from start of IS Relapse n (%) Inhib 70 IS stopped Steroids only n=31 22 (71) 8 (26) 1 (3) 47 (29–112) 40 (25–160) 105 (63–236) 2/20 (10) Steroids and Cytotoxics n=6 5 (83) 1 0 9, 35, 175, 261 12, 60, 175, 261 57, 60, 265, 363 0/5 Steroids and rituximab n=2 2 (100) 0 0 11, 76 11, 138 43, 53 0/2 * CR = complete remission i.e. FVIII >70 IU/dL and no antibodies ** NR = no complete remission Summing up, AHA is a rare but severe bleeding condition in pregnancy/postpartum and is often overlooked. The diagnosis should be considered when screening tests show an abnormal APTT which indicates an immediate specific coagulation analysis. Acute bleeds are effectively treated with rFVIIa or aPCC. Immunosuppression with steroids to eliminate the anti FVIII inhibitor activity should be instituted as soon as possible after confirmation of AHA and this treatment seems to give a better response compared to older patients with AHA. Disclosures: Nemes: Novo Nordisk: Tengborn: Novo Nordisk: Collins: NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees. Knoebl:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marco:Novo Nordisk:Levesque:NovoNordisk

Abstract 1398 Acquired Haemophilia (AH) is an autoimmune disorder, characterized by autoantibodies against the coagulant activity of Factor VIII: C. Is a rare (estimated frequency 1.5 cases per million/year), but severe hemorrhagic condition. EACH2 is a multinational European registry from 90 centres in 11 countries that recruited between 2003–2009, This abstract describes the demographic, clinical and aetiological data recorded in a web database from EACH2 from the largest cohort described in the literature to date. Outcomes of haemostatic therapy, immunosuppression and during pregnancy are described elsewhere. Data were recorded on consecutive patients from each centre. Informed consent was taken as appropriate to each country. Parametric and non-parametric test, were used to analyse the study. There were 501 AH patients included in the registry. The basic demographic data are shown in Table 1. Table 1: . Demographic data of the whole group expressed in median, interquartile range (IQR) and range Age FVIII at diagnosis IU/dL Inhibitor titre at diagnosis BU/mL Hb g/L Female/Male ratio Whole group n=501 74 2 12.8 9 235/266 (62–80) (1–5) (4.3–42.5) (7.5–11.3) 1:1.3 13–104 0–40 0.1–2800 3–15.7 In 93 % of the patients the diagnosis was triggered by bleeding in a variety o locations, these were and mainly spontaneous (details will presented in another abstract).). There was no correlation between FVIII level or titre inhibitor and type or severity of bleeding. Aetiology of AH Table 2 The delay in diagnosis, stratified in etiologic groups, after detecting abnormal APTT is shown in Table 3 Table 3: . Time (days) between abnormal APTT and diagnosis All group Idiopathic Autoimmune disease Malignancy Pregnancy Evaluable patients n=499 21.6 24 36 10 8 Mean 1 1 0.5 1 1 Median (0–8) (0–9) (0–5) (0–7) (0–9) IQR 0–1091 0–796 0–1091 0–93 0–60 Range Survival analysis (Kaplan-Meyer curves), after 5 years of follow-up was: 71.5% in patients who had eradicated the inhibitor, 47.7% in patients dependent immunosuppressive therapy, and 37.6% in those who had not eradicated the inhibitor In conclusion this prospective multinational European registry (EACH2) includes a large number of patients affected of AH. Idiopathic remains the more frequent aetiological association. Bleeding is the principal clinical manifestation but in a proportion of patients there is a considerable delay in diagnosis. The finding of an abnormal APTT in a bleeding patient with no history of hemorrhagic condition should raise suspicion of AH. Survival in this patient cohort is clearly related to response to immunosuppressive therapy. Disclosures: Marco: Novo Nordisk: Consultancy. Collins: NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knoebl: Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levesque: NovoNordisk:. Baudo: NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Nemes: Novo Nordisk: Consultancy. Tengborn: Novo Nordisk: Consultancy. Huth-Kuehne: NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pellegrini: Novonordisk: Consultancy, Honoraria, Speakers Bureau, The EACH2 registry is funded by Novonordisk.

Abstract 715 The optimal first line immunosuppression (IS) for eradicating factor (F)VIII inhibitors in acquired haemophilia A (AHA) is controversial. Steroids and cyclophosphamide are commonly used and there has been recent interest in the role of rituximab. Prospective randomised controlled trials (RCTs) would be challenging and in their absence registries may provide useful data to guide clinical practice. EACH2 collected data on 281 analysable patients who received first line IS. Complete remission (CR) was defined as inhibitor undetectable, FVIII>70IU/dL and IS stopped. Stable CR was defined as CR without relapse. A higher proportion of patients achieved CR with steroids and a cytotoxic (predominantly cyclophosphamide) (77%) than those treated with steroids alone (58%) (P Table. Outcome of first line immunosuppression (IS) for AHA. Regimen Age Years FVIII at diagnosis (IU/dL) Inhibitor titre at diagnosis (BU/mL) CR after 1st line IS N (%) Days from start of IS Relapse (%) Stable CR after 1st line IS % Alive and in CR at final FU % Inhibitor -ve FVIII >70 IU/dL IS stopped Steroids alone n=142 75 (63–81) 3 (1–6) 13 (5–43) 83 (58) 34 (17–76) 32 (15–51) 108 (55–208) 19 48 60 13–104 0–28 0.1–1020 5–321 3–551 11–1169 Steroids and cytotoxics n=88 76 (63–80) 1 (1–4) 22 (8–67) 68 (77) 32 (12–77) 40 (18–81) 74 (52–151) 14 67 60 16–101 0–34 0.4–2800 0–386 2–386 1–386 All rituximab regimen n=51 74 (5–78) 2 (0–7) 16 (6–62) 31 (61) 65 (29–144) 64 (28–206) 43 (22–96) 4 59 67 14–104 0–20 0.1–2176 10–436 10–569 17–257 Rituximab plus another IS n=39 75 (57–78) 2 (0–7) 16 (9–62) 26 (67) 47 (28–96) 38 (28–141) 55 (26–96) 4 64 61 14–104 0–20 0.1–2176 10–436 10–569 17–257 Rituximab alone n=12 69 (65–77) 1 (0–8) 16 (3–71) 5 (42) 53, 145, 209, 334* 145, 209, 252, 334* 21, 21, 21, 21, 22* 0 42 70 50–85 0–15 1–460 Data are median, interquartile range (IQR) and range, * actual days due to low number of patients. Disclosures: Collins: NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: The use of Rituximab for the treatment of acquired haemophilia. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Knoebl:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levesque:NovoNordisk: NovoNordisk fund the EACH2 registry. Nemes: NovoNordisk: Novonordisk fund the EACH2 registry. Pellegrini:Novonordisk: Consultancy, Honoraria, Speakers Bureau, The EACH2 registry is funded by Novonordisk. Tengborn:NovoNordisk: NovoNordisk fund the EACH2 registry. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees.

ReFacto AF (Albumin-Free Cell Culture Process) is a BDDrFVIII manufactured using an albumin-free cell culture process and purified using a chemically synthesized peptide affinity ligand instead of a murine monoclonal antibody. A virus-retaining filtration step has been included as an additional safety precaution during manufacture. The potency assignment of ReFacto AF has been aligned to the one-stage clotting assay, to permit routine clinical monitoring, as for other rFVIII products, without specialized standards. The pharmacokinetic (PK) profile of ReFacto AF vs. Advate was assessed in a randomized double blind crossover fashion, in 30 previously treated patients (PTPs) (≥ 12 years; FVIII:C ≤1%) using the standard bioequivalence approach based upon the one-stage clotting assay. Safety and efficacy of ReFacto AF was also assessed in a total of 94 PTPs (FVIII ≤2%), which included the PK subjects, during 6 months of open label routine prophylaxis supplemented with on-demand treatment as necessary. A follow-up PK assessment with ReFacto AF was performed in the PK subjects after 6 months. Pharmacokinetic equivalence of ReFacto AF and Advate was demonstrated (n = 30 subjects). The ratios of geometric least-square means for K-value, AUCt, AUC∞ were 100%, 89.8%, and 88.0%, respectively, and associated 90% confidence intervals were within the bioequivalence window of 80%–125%. Twenty five (25) subjects had a baseline and 6 month follow-up PK assessment with ReFacto AF. Mean K-value and t1/2 for ReFacto AF were 2.23 (± 0.39) IU/dL per IU/kg and 11.8 (± 5.1) hours, respectively at baseline and the 6 month follow-up PK profile was unchanged. Of the 94 patients, 89 accrued at least 50 ReFacto AF exposure days. Median routine prophylaxis dose was 30.2 IU/kg. During routine prophylaxis, the median annualized bleed rate was 1.9 (mean 3.9, range 0 to 42.1), and 43 of 94 (45.7%) patients experienced no bleeding episodes. A total of 187 bleeding episodes were treated on-demand with a median dose of 30.6 IU/kg, and 92.5% resolved with 1 or 2 infusions. The overall adverse event (AE) profile was consistent with the AE profile of ReFacto and other rFVIII products. Two of the 94 patients had transient, low-titer, clinically silent inhibitors (0.98 BU/mL and 1.21 BU/mL), each detected by routine surveillance on a single occasion and each was negative on follow-up testing. The corresponding ELISAs for FVIII antibodies were negative for both patients. No patient in the study had a positive ELISA immune response to CHO cell protein or to the peptide affinity ligand used for ReFacto AF purification. ReFacto AF is pharmacokinetically equivalent to Advate based on one-stage FVIII activity assessments, and ReFacto AF PK is stable over 6 months of use. The product is effective in the prevention and treatment of bleeding episodes. Inhibitor safety results show no evidence of neoantigenicity and the AE profile demonstrates safety in PTPs with hemophilia A.