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Introduction Primary factor VIII (FVIII) prophylaxis is the optimal treatment in children with severe haemophilia A. They are expected to benefit from extended half-life (T1/2) FVIII coverage by reduced infusion frequency while maintaining haemostatic efficacy. Aims To determine immunogenicity, pharmacokinetics (PK), efficacy, safety and quality of life of prophylaxis with a polyethylene glycol (peg)-ylated FVIII (BAX 855) based on full-length recombinant FVIII (ADVATE) in paediatric previously treated patients (PTPs) with severe haemophilia A. Methods PTPs

Current management of hemophilia A includes prophylaxis with factor VIII (FVIII) replacement every 2 to 3 days. BAX 855, Baxalta's pegylated full-length recombinant FVIII (rFVIII), was designed to increase half-life and, thus, reduce the frequency of prophylactic infusions while maintaining hemostatic efficacy. BAX 855 was evaluated in previously treated patients with severe hemophilia A who were aged 12 to 65 years. A phase 1 study compared the pharmacokinetic (PK) profile of BAX 855 with that of licensed rFVIII (Advate). In a pivotal study, the annualized bleeding rate (ABR), PK parameters, and efficacy of bleeding treatment were assessed. In the phase 1 study, the mean half-life (T1/2) and the mean residence time of BAX 855 compared with Advate were 1.4- to 1.5-fold higher. These results were confirmed in the pivotal study. The pivotal study met its primary endpoint: Prophylaxis with BAX 855 resulted in an ABR that was significantly lower than half the ABR of on-demand treatment (P < .0001). The median ABR was 1.9, and 39.6% of compliant subjects had no bleeding episodes during prophylaxis, whereas subjects treated on-demand had a median ABR of 41.5. BAX 855 was also efficacious for the treatment of bleeding episodes, with 95.9% of bleeding episodes treated with 1 to 2 infusions and 96.1% having efficacy ratings of excellent/good. No FVIII inhibitory antibodies or safety signals were identified. These studies provide evidence that BAX 855 was safe and efficacious for on-demand treatment and prophylaxis administered twice weekly in patients with hemophilia A. The trials were registered at www.clinicaltrials.gov as #NCT01736475 and #NCT01599819.

A newly developed recombinant factor IX (BAX326(1) ) was investigated for prophylactic use in paediatric patients aged12 years with severe (FIX level1%) or moderately severe (FIX level 1-2%) haemophilia B. The aim of this prospective clinical trial was to assess the safety, haemostatic efficacy and pharmacokinetic profile of BAX326 in previously treated paediatric patients. BAX326 was administered as prophylaxis twice a week for a period of 6 months, and on demand for treatment of bleeds. Safety was assessed by the occurrence of related AEs, thrombotic events and immunologic assessments. Efficacy was evaluated by annualized bleeding rate (ABR), and by treatment response rating (excellent, good, fair, none). PK was assessed over 72 h. None of the 23 treated paediatric subjects had treatment-related SAEs or AEs. There were no thrombotic events, inhibitory or specific binding antibodies against FIX, rFurin or CHO protein. Twenty-six bleeds (19 non-joint vs. 7 joint bleeds) occurred (mean ABR 2.7 ± 3.14, median 2.0), of which 23 were injury-related. Twenty subjects (87%) did not experience any bleeds of spontaneous aetiology. Haemostatic efficacy of BAX326 was excellent or good for96% of bleeds (100% of minor, 88.9% of moderate and 100% of major bleeds); the majority (88.5%) resolved after 1-2 infusions. Longer T1/2 and lower IR were observed in younger children (6 years) compared to those aged 6 to 12 years. BAX326 administered as prophylactic treatment as well as for controlling bleeds is efficacious and safe in paediatric patients aged12 years with haemophilia B.

Rurioctocog alfa pegol (BAX 855) is a novel third-generation recombinant factor VIII whose active ingredient is chemically modified with polyethylene glycol. A global multicenter phase 2/3 study of the product in 137 patients (including 11 patients from Japan) with severe hemophilia A aged 12–65 years, reported an extended half-life and a good tolerability profile, as well as a significantly lower annualized bleeding rate in the prophylactic treatment arm than in the on-demand treatment arm. Using descriptive statistics, a post hoc analysis was performed to compare the pharmacokinetics, safety, and efficacy profiles of the product in the Japanese subpopulation and the overall population. Extended half-life was demonstrated in the Japanese subpopulation. The mean [standard deviation (SD)] annualized bleeding rates in the prophylactic treatment arm were 3.7 (4.7) for the overall population (n = 120) and 4.0 (3.4) for the Japanese subpopulation (n = 11). The proportion of bleeds reported as excellent or good was 94.9% (149/157) in the overall population, whereas that in the Japanese subpopulation was 92.3% (12/13). No FVIII inhibition or anaphylactic reaction was reported in the Japanese subpopulation. The post hoc comparisons demonstrated similar pharmacokinetic, safety, and efficacy profiles between the overall population and the Japanese subpopulation.

Individuals with hemophilia B experience frequent and spontaneous bleeding episodes into joints and muscles that can lead to severe arthropathy, chronic pain, disability, and diminished quality of life (QoL). Prophylaxis with factor nine (FIX) concentrates may reduce the frequency of bleeding events and improve QoL. Recombinant FIX (rFIX) concentrates are a potentially safer treatment option than plasma-derived FIX products with respect to pathogen transmission risk, but until recently, only one licensed rFIX product was available. We describe a newly approved rFIX concentrate, BAX326 (RIXUBIS; Baxter Healthcare Corporation). Phase III studies of BAX326 demonstrated its efficacy and safety in prophylactic, on-demand, and surgical settings and showed that its pharmacokinetic properties were comparable to those of the licensed comparator. Importantly, prophylaxis with BAX326 significantly improved physical health-related QoL, demonstrating that this new rFIX treatment that has the potential to improve outcomes in hemophilia B patients.

The ability to switch between coagulation factors safely is of common interest to haemophilia patients and treating physicians. This is the first formal prospective comparative evaluation of safety, efficacy and incremental recovery of a plasma-derived FIX (pdFIX) and a recombinant FIX (rFIX) in the same haemophilia B patients following a switch from pdFIX Immunine® to a recently developed rFIX Bax326 product. Patients (aged

Summary Haemostatic management of haemophilia B patients undergoing surgery is critical to patient safety. The aim of this ongoing prospective trial was to investigate the haemostatic efficacy and safety of a recombinant factor IX (rFIX) (Bax326) in previously treated subjects (12–65 years, without history of FIX inhibitors) with severe or moderately severe haemophilia B, undergoing surgical, dental or other invasive procedures. Haemostatic efficacy was assessed according to a predefined scale. Blood loss was compared to the average and maximum blood loss predicted preoperatively. Haemostatic FIX levels were achieved peri- and postoperatively in 100% of subjects (n = 14). Haemostasis was ‘excellent’ intraoperatively in all patients and postoperatively in those without a drain, and ‘excellent’ or ‘good’ at the time of drain removal and day of discharge in those with a drain employed. Following the initial dose, the mean FIX activity level rose from 6.55% to 107.58% for major surgeries and from 3.60% to 81.4% for minor surgeries. Actual vs. predicted blood loss matched predicted intraoperative blood loss but was equal to or higher than (but less than 150%) the maximum predicted postoperative blood loss reflecting the severity of procedure and FIX requirements. There were no related adverse events, severe allergic reactions or thrombotic events. There was no evidence that BAX326 increased the risk of inhibitor or binding antibody development to FIX. BAX326 was safe and effective for peri-operative management of 14 subjects with severe and moderately severe haemophilia B.

Introduction BAX 855 is a pegylated full-length recombinant factor VIII (rFVIII) with an extended half-life, built on a licensed rFVIII (ADVATE®). BAX 855 demonstrated efficacy and safety in prophylaxis and the treatment of bleeding episodes in previously treated patients (PTPs) with severe haemophilia A. Aim This phase 3 surgery study evaluates the haemostatic efficacy and safety of BAX 855 for perioperative haemostasis in PTPs with severe haemophilia A undergoing surgery. Methods Elective procedures were prospectively classified as major or minor. The dose and frequency of BAX 855 administered perioperatively were to be guided by each patient's pharmacokinetic profile for major procedures or BAX 855 incremental recovery for minor procedures. Haemostatic efficacy was evaluated using a predefined scale. Blood loss was compared to the expected average and maximum blood loss predicted preoperatively. Results A total of 15 male patients (aged 19–52 years) underwent 15 procedures (11 major and four minor). The overall intra- and perioperative haemostatic efficacy of BAX 855 was ‘excellent’ in all 15 subjects (100%). Postoperatively, evaluated at postoperative Day 1, all treatments were ‘excellent’ except for one minor (dental) procedure which was rated ‘good’. No related adverse events, allergic reactions, thrombotic events, nor signs of immunogenicity in terms of induction of binding antibodies to FVIII, PEG or PEG-VIII, or FVIII inhibitors were observed. Conclusion These results demonstrate that BAX 855 is safe and haemostatically effective in patients with severe haemophilia A undergoing surgery.

SummaryWe report a prospective trial of 55 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe/moderately severe haemophilia A (baseline factor VIII [FVIII] ≤2%) treated with a single FVIII replacement product. It was the objective of this study to evaluate the immunogenicity, efficacy, and safety of rAHF-PFM (Advate®). Ondemand or prophylactic treatment regimens were determined at the discretion of the investigator. rAHF-PFM was also permitted for perioperative management. There were 633 bleeding episodes (BEs), including 517 treated, and 466 rated for efficacy. Haemostatic efficacy was considered excellent/good in 93% of 466 rated treatments. Of 517 treated BEs, 463/517 (90%) were managed with one (356/517 [69%]) or two infusions (107/517 [21%]). There were 27 surgeries. Intraoperative (n=22) and postoperative (n=25) haemostatic efficacies were considered excellent or good in 100% of rated surgeries. Related serious adverse events (SAEs) were inhibitor development in 16/55 (29.1%) subjects who received at least one infusion of rAHF-PFM. Nonserious, related adverse events (AEs) were few in number (14 in eight subjects). The odds ratio (OR [95% Confidence Interval, CI]) of developing inhibitors was significantly higher in subjects with a family history of inhibitor (4.95 [1.29–19.06]), non-Caucasian ethnicity (4.18, [1.18–14.82]), and intensive treatment at high dose (4.5 [1.05–19.25]) within ≤20 exposure days (EDs). In conclusion, rAHF-PFM was safe and effective for the management and perioperative coverage of PUPs/MTPs with severe/moderately severe haemophilia A. This report supports previous findings from studies in which family history of inhibitor, non-Caucasian ethnicity, and high intensity treatment were associated with high risk of inhibitor development.

Introduction and Objective: Patients with severe hemophilia A repeatedly bleed into joints and subsequently develop target joints and arthropathy. BAX 855, a polyethylene glycol pegylated, full-length, recombinant factor VIII built on ADVATE, demonstrates an extended half-life, efficacy, and safety for prophylaxis and the treatment of bleeding in patients with severe hemophilia A. Target joint status was evaluated in an ad-hocanalysis of integrated efficacy data from previously treated adolescent and adult patients who participated in the pivotal (completed) and continuation (ongoing) studies. Methods: The number of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, were analyzed over 3 consecutive 6-month periods in patients who received twice weekly BAX 855 prophylaxis at 40-50 IU/kg. Results: After approximately 6 months of twice weekly prophylaxis during the pivotal study, 101 adolescent and adult patients continued treatment in the continuation study, 51 of whom were treated with twice weekly prophylaxis for 18 consecutive months. At screening 29.4% (15/51) of these patients had no target joints, 19.6% (10) had 1 target joint, 21.6% (11) had 2, and the remaining 29.4% (15) had 3 or more. After the first 6-month treatment period, the percent of patients with no target joints increased to 66.7% (34 patients), including 19 patients in whom 1 or more target joints had resolved and 15 patients who remained target joint-free from screening. Of note, for the 15 patients with 3 or more target joints at screening, all of their target joints resolved after the first 6 months of treatment with BAX 855. This trend was maintained after the second 6-month treatment period. After the third 6-month period of twice weekly prophylaxis, the percent of patients with no target joints further increased to 82.4% (42), which included the 15 patients who remained target joint-free from screening. Nine patients had 1 or more unresolved target joint after 18 months of twice weekly prophylaxis, and in 6 of these patients, 1 to 3 other target joints had resolved. Overall, there were 89 target joints at screening which reduced to 14 after 18 months of twice weekly prophylaxis. Of those, 10 target joints changed status (eg, were present, resolved, and then re-appeared) and only 4 target joints (in 4 patients) persisted as unresolved through each of the 3 consecutive 6-month treatment periods. Conclusions: These results demonstrate the efficacy of continuous twice weekly prophylaxis with BAX 855 for preventing and resolving the majority of target joints. Disclosures Engl: Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Patrone:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Abbuehl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership.

Management of hemostasis with factor IX replacement during surgical procedures on patients with hemophilia B is vital to patient safety. A recombinant factor IX (rFIX, nonacog gamma, RIXUBIS, BAX 326) presents a treatment alternative for hemophilia B; nonacog gamma is manufactured with no materials of human or animal origin, and includes as two-step virus inactivation (solvent/detergent treatment and nanofiltration). This multi-national clinical trial was conducted to investigate the efficacy and safety of nonacog gamma for perioperative use in previously-treated patients with severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B. Interim results of 14 (11 major) surgeries showed that nonacog gamma is safe and effective in maintaining hemostasis in the surgical setting;1 the results of all 38 surgeries are presented here. Previously-treated hemophilia B immunocompetent patients aged 12 to 65 years with no evidence of a history of FIX inhibitors were eligible for participation if they were either: 1) participating in another trial with nonacog gamma and required an emergency or elective major or minor surgical, dental, or other invasive procedure; or 2) if not participating in any other nonacog gamma clinical study, they required elective major surgery and had been treated previously with plasma-derived and/or recombinant FIX concentrate(s) for a minimum of 150 exposure days. Pre-operative FIX levels were targeted at 80%-100% of normal for major, and 30%-60% of normal for minor surgeries, through an individualized nonacog gamma dosing approach. Hemostatic efficacy was evaluated intra- and post-operatively by determination of actual versus predicted blood loss and a semi-quantitative 4-point hemostatic efficacy rating scale (excellent, good, fair, none); safety was assessed in terms of the occurrence of adverse events. Thirty patients participated in this study, 10 of whom underwent multiple surgeries and were re-enrolled for each surgery. Of a total of 38 surgeries performed, 21 were major (14 orthopedic) and 17 were minor. Hemostatic efficacy for 37/38 surgeries (including 20/21 major surgeries) had a rating of 'excellent' and one was 'good' (a knee joint replacement). At drain removal (n=14), the ratings for all major surgeries were either 'excellent' (10/14) or 'good' (4/14). On postoperative day 3, 6 of 7 major surgeries where no drain was employed had a rating of 'excellent', and one had a rating of 'good'. At discharge from hospital, 12/21 were 'excellent', 7/21 were 'good' and 2 were 'fair' (both had ratings of 'excellent' intraoperatively and at drain removal). For 16/21 major surgeries, the actual blood loss was below (n=8) or equal to (n=8) the average predicted blood loss and the mean post-operative blood loss was 552.4 mL (range: 11-1100 mL) in subjects who had a drain placed. For 12/17 minor surgeries, actual intraoperative blood loss was below the average predicted blood loss, for 4/17 minor surgeries, the actual intraoperative blood loss matched the average predicted blood loss, and for 1 minor surgery (intra-articular infiltration) actual blood loss was between the average predicted and maximum predicted blood loss. Nonacog gamma was safe and well tolerated. One possibly related AE (hemorrhagic anemia) was reported. This event was resolved at the completion of the study. No thrombogenic events or severe allergic reactions, nor induction of inhibitory antibodies to FIX or total binding antibodies to FIX were observed. Conclusion: Nonacog gamma provides a safe and effective treatment alternative for perioperative management of hemostasis in hemophilia B patients in a variety of surgical settings. References 1 Windyga J, Lissitchkov T, Stasyshyn O, et al. Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective, open-label, uncontrolled, multicentre, phase III study. Haemophilia. 2014 Sep;20(5):651-8. Disclosures Windyga: CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker's honorarium. Mamonov:Baxalta (Now part of Shire): Research Funding. Chapman:Baxalta (Now part of Shire): Employment, Equity Ownership. Tangada:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Abbuehl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership.

BAX 855 is an extended half-life, pegylated full-length recombinant factor VIII (PEG-rFVIII) built on ADVATE and is approved for prophylaxis and the treatment of bleeding in hemophilia A. Safety data from 7 clinical studies were integrated to evaluate single, short-term, and long-term exposure with BAX 855. These clinical trials included the following patients: previously treated adult, adolescent, and pediatric patients (PTPs) and previously untreated patients (PUPs). Immunogenicity, adverse events (AEs), and clinical laboratory parameters were assessed during prophylaxis, treatment of bleeding, perioperative management, and PK evaluations. Of 243 patients, the mean ±SD (range) age was 23.4 ±15.84 (0-61) years, there was 1 female; 74.9% of patients were White, 21.4% were Asian, and 2.5% were Black. Overall, 97 million IUs of BAX 855 were infused, resulting in a median (Q1; Q3) of 111 (73-196) exposure days (EDs) per patient, which ranged from 1 to 322 EDs. No patient developed inhibitory antibodies to FVIII (≥0.6BU) at any time. The 95% confidence intervals for developing inhibitory antibodies based on exposure are as follows: 0-0.19 for 191 PTPs with ≥50 EDs, 0-0.027 for 135 patients with ≥100 EDs, 0-0.37 for 98 patients with ≥150 EDs, and 0-0.68 for 52 patients with ≥200 EDs. At the time of the last blood sample analyzed, no patient had any antibodies to CHO proteins or persistent binding antibodies to FVIII, PEG-FVIII, or PEG. Binding antibodies were either pre-existing (28 patients) or transient (13 patients). No conclusion can be drawn as yet for 5 patients who developed binding antibodies shortly before or at the data cut-off for the analysis. The presence of binding antibodies could not be correlated to an altered PK or impaired efficacy. The only AE considered related to BAX 855 occurring in ≥1% of patients was headache; other related AEs (nausea; diarrhea, flushing, rash, and hypersensitivity) were observed in Disclosures Engl: Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Patrone:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Jacqueline:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Tangada:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Abbuehl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership.

Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

Background and objectives BAX 855 (Antihemophilic Factor [Recombinant] pegylated, rurioctocog alfa pegol) is an extended half-life (EHL) recombinant human coagulation factor VIII (rFVIII) modified with polyethylene glycol (PEG) (Turecek et al., 2012). It was recently approved in the US and Japan for on-demand treatment of bleeding events and for prophylactic treatment for patients with congenital severe hemophilia A. The efficacy and safety of BAX 855 were extensively studied during clinical development of this compound (Konkle et al., 2015). The assessment of BAX855 immunogenicity was of particular interest because the development of neutralizing antibodies (FVIII inhibitors) is the most serious complication following replacement therapies with FVIII products. FVIII inhibitors develop in about 20-32% of previously untreated patients (Gouw SC et al., 2013) and with a rate of 1.55- 3.8 per 1000 patients per year in previously treated patients (Kempton CL, 2010) with severe hemophilia A. To fully understand the potential of BAX855 to induce antibody responses, both FVIII inhibitors and total FVIII-binding antibodies were assessed. Furthermore, potential antibody development against PEG-FVIII, PEG and CHO proteins was investigated. Methods The clinical protocols (ClinicalTrials.gov identifier: NCT02585960, NCT02210091, NCT01736475, NCT01913405, NCT01945593, NCT01599819, NCT02615691) and the methods used for antibody analytics (Whelan et al 2013; Lubich et al 2016) were previously described. ELISA technologies were used for the analysis of total binding antibodies, the Nijmegen modification of the Bethesda assay was used for the detection of FVIII inhibitors. Correlation analyses were done to assess any potential correlation between the development of antibodies and potential adverse events. Results None of the 243 subjects (6 PUPs and 237 PTPs) included in the analysis developed FVIII inhibitors (≥ 0.6 BU/mL) A total of 44 subjects tested positive for binding antibodies against FVIII, PEG-FVIII or PEG at single time points. 28 of these 44 subjects showed pre-existing antibodies against FVIII, PEG-FVIII, or PEG prior to first exposure to BAX 855, which disappeared during the study. 13 subjects who tested negative at screening developed transient antibodies against FVIII, PEG-FVIII, or PEG at one or two consecutive study visits after exposure to BAX 855. Antibodies were transient and not detectable at subsequent visits or at completion of the study. Five subjects showed positive results for binding antibodies at study completion or at the time of the data cutoff. No conclusion can be drawn whether these antibodies are of transient or persistent nature. There was no confirmed causal relationship between the appearance of binding antibodies against FVIII, PEG or PEG-FVIII and adverse events, nor was there an impact on hemostatic efficacy in any of the 44subjects. No subject had pre-existing antibodies or developed de novo antibodies to CHO proteins during the study at any time point. Conclusion Our data indicate that BAX855 did not show an increased risk for PTPs to develop FVIII inhibitors. We did not see any FVIII inhibitor development in PUPs, but the small number of overall exposures does not allow general conclusions for PUPs. Importantly, the data suggest that BAX855 did not induce immune responses associated with impaired treatment efficacy or with altered PK parameters. Disclosures Horling: Shire: Employment. Allacher:IMC Krems: Research Funding. Koppensteiner:Shire: Employment. Engl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Scheiflinger:Shire: Employment, Research Funding. Abbuehl:Baxalta (now part of Shire): Employment. Reipert:Shire: Employment.

Introduction: Hemophilia A (HA) is an X linked recessive bleeding disorder characterized by frequent bleeding predominantly in joints. To avoid the sequelae of hemarthroses (e.g., target joints and arthropathy), timing of factor VIII (FVIII) infusions to cover periods of physical activity and adherence to a prophylactic schedule are particularly important in children with HA. BAX 8551, a polyethylene glycol (peg)ylated, extended half-life, full-length, recombinant FVIII built on ADVATE2, was developed to reduce infusion frequency while maintaining or improving therapeutic efficacy. Methods: Efficacy of twice-weekly prophylaxis with BAX 855 was evaluated in a phase 3, prospective, uncontrolled, multicenter study in pediatric previously treated patients with severe HA (FVIII level Results: Sixty-six patients, 32 aged ABRs were highest in the evening with point estimates (95% CIs) of the mean of 1.0 (0.7 - 1.5) compared to 0.6 (0.4 - 1.0) in the afternoon and 0.5 (0.3 - 1.1) in the morning. On weekdays, the point estimate (95% CI) of the mean ABR was 2.4 (1.7 - 3.5), on weekends it was 0.9 (0.6 - 1.2). For all periods assessed except for mornings, ABRs were higher in the older than in the younger cohort (Table 1). Seventy minor or moderate bleeding events in 34/66 (51.5%) patients were treated with a mean (SD) dose of 57.9 (31.0) IU/kg of BAX 855. Most treated bleeds occurred in the evening (34.3%; 24/70), fewer in the afternoon (22.9%; 16/70) and in the morning (14.3%; 10/70). The proportion of moderate bleeds increased during the day from 20.0% (2/10) in the morning to 31.3% (5/16) in the afternoon and 70.8% (17/24) in the evening. For 28.6% (20/70) of treated bleeds, the time of day of occurrence was unknown. The mean interval between the preceding prophylactic infusion and the bleeding event was similar for all times of day, ranging from 51.0 h to 54.6 h (median 51.4 h to 57.8 h). On weekends, the mean interval between prophylactic dose and bleeding event was lower (38.8 h; median 35.7 h) than on weekdays (54.6 h; median 52.9 h), suggesting that the time of infusion was chosen to cover for weekend activities. Bleeding severity was similar on weekdays and on weekends. Efficacy of bleed treatment with BAX 855 was rated excellent or good for ≥85% of bleeds and ≥85% were treated with 1 or 2 infusions, irrespective of the time of day/period of the week the bleeds occurred. Conclusions: In this study in pediatric patients with severe HA, bleeding was observed more frequently in the evening than during other times of day and more frequently on weekdays than on weekends. BAX 855 was shown to be effective for the prevention and treatment of bleeding in this patient population. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trademark of Baxalta US Inc., now part of Shire. Disclosures Mullins: Baxalta (now part of Shire): Honoraria; US WorldMeds: Membership on an entity's Board of Directors or advisory committees. Dunn:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Kedrion: Research Funding; NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12-65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC(0-72) h per dose. Twice-weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg(-1) per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.

BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on ADVATE (rFVIII) with an extended half-life and is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. In the pivotal trial, previously treated patients (PTPs) received BAX 855 prophylaxis with a twice-weekly 45 IU/kg dosing regimen. Of 101 patients in the per protocol analysis set, 40 (39.6%) patients achieved zero bleeding during 6 months of prophylactic treatment with BAX 855, compared with the on-demand treatment arm in which every patient (n=17) experienced at least 1 bleeding episode. Pharmacokinetic parameters were assessed in a subset of patients with zero bleeding (n=9). Assessments were performed for rFVIII, for an initial infusion of BAX 855 and for a repeat infusion of BAX 855 after 6 months of treatment. Using the one-stage clotting assay, BAX 855 demonstrated an extended circulation time compared to rFVIII with a mean (standard deviation [SD]) half-life (T1/2) of 16.13 (3.827) hours vs 11.44 (2.250) hours (ratio BAX 855/rFVIII: 1.4). Over time, the 6 month assessment of BAX 855 T1/2 remained stable at 16.30 (3.137) hours (ratio repeat/initial BAX 855: 1.0), based on the one-stage clotting assay. Incremental recovery (IR) measurements were comparable with 2.41 (0.454) IU/dL for rFVIII and 2.62 (0.684) IU/dL for BAX 855. As expected, clearance (CL) was higher for rFVIII compared to BAX 855: 0.0380 (0.009) vs 0.0205 (0.007) dL/(kg*h). Historical annualized bleeding rates (ABRs) in the 40 patients without bleeding during prophylactic treatment were calculated based on the previous 3-6 months of each patient's diary or recall. Historical ABRs ranged from 0-80 with a median ABR of 7. However, patients may have either been receiving on demand or prophylactic FVIII treatment prior to entering the prophylactic arm of the trial, accounting for the range in ABRs. The median pre-trial ABR of patients in the on-demand arm, all of whom experienced bleeding, was much higher at 41.5 (range: 12.9-67.9). Of the 40 patients without bleeding who were in the prophylaxis arm of the trial, 31 received prophylaxis in their previous pre-trial regimen, while 9 had received on-demand treatment prior to enrolling in the trial. A target joint was defined as a single joint (ankles, knee, hip, or elbow) with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period. At screening, 30% of patients without bleeding on the study had 0 target joints, while 37.5% had 1-2 and 32.5% had ≥3 target joints. Of the patients who had >3 target joints at screening, there were 4 (10%) patients with 4 and 1 (2.5%) patient with 6 target joints at screening. In contrast, patients in the on-demand group (who had all been treated on-demand prior to the trial) had a higher incidence of target joints at screening: 11.8% of patients had 0 target joints, while 52.9% had 1-2 and 28.3% had ≥3 target joints. The presence or absence of preexisting arthropathy did not seem to influence the likelihood of having zero bleeding during the trial. In 65% of the patients without bleeding, arthropathy was present at screening. This is higher than was found in the patients treated on-demand (47.1%) who all experienced bleeding. A patient was considered to have arthropathy if it was indicated in the medical history or if the patient had joint surgery. Blood group types were collected on the patients without bleeding. The results showed: A-50%; B-12.5%; AB-7.5%; O-15%; unknown 15%. This is rather different than the blood types of the 17 on demand patients who all experienced joint bleeding: A-35.3%; B-5.9%; AB-17.6%; O-35.3%; unknown 5.9%. There were fewer blood group O patients among the patients without bleeding. While some of the characteristics of patients on prophylaxis without bleeding episodes were similar to those of patients treated on-demand who all experienced bleeding, patients without bleeding had fewer target joints at screening, lower median historical ABR, and lower incidence of blood type O. Disclosures Ma: Kedrion: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Klamroth:Biogen and SOBI: Honoraria, Speakers Bureau; Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau. Manco-Johnson:Baxter/Baxalta, Bayer, CSL Behring, Biogen NovoNordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding. Engl:Baxalta: Employment, Equity Ownership. Dyck-Jones:Baxalta: Employment. Abbuehl:Baxalta: Employment, Equity Ownership.

BAX 855 is a pegylated, full-length, recombinant factor VIII (PEG rFVIII) built on ADVATE with an extended half-life that is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. This safety evaluation was derived from an integrated analysis of 5 clinical studies in previously treated patients (PTPs) who were treated with BAX 855 for prophylaxis, bleeding episodes, or perioperative management, or who received a single-dose for a pharmakokinetic (PK) evaluation. Two studies have been completed (pivotal phase 2/3 and phase 1) and 3 are ongoing (continuation, surgery, and pediatric). In all studies, adverse events (AEs) (including hematology and clinical chemistry laboratory values deemed AEs by the investigator) and immunogenicity (inhibitory and binding antibodies) were assessed. Shifts in laboratory values to clinically abnormal over the course of the study and changes in pre- and post-infusion vital signs were also assessed. Of the 169 unique patients (most participated in more than 1 study), 3 were A total of 300 AEs were reported in 96 of 169 patients during or after treatment with at least 1 infusion of BAX 855. The overall rate of AEs by infusion was 2.2% (300 AEs/13,579 infusions), the rate of nonserious AEs by infusion was 2.1% (283 AEs/13,579 infusions), and the rate of SAEs by infusion was 0.1% (16 SAEs/13,579 infusions). Common AEs considered related to BAX 855 (in ≥1% of patients) were headache and nausea; diarrhea, flushing, and blood pressure increase occurred once in 1 patient each. None of the 16 SAEs reported were considered related to the use of BAX 855. No treated patient has discontinued from a study due to a treatment related AE (or SAE). None of the patients exposed to BAX 855 developed an inhibitory antibody to FVIII of ≥0.6 BU/mL by the Bethesda assay, including 120 patients with ≥50 EDs (95% CI: 0.000 to 0.030) and 48 with ≥100 EDs (95% CI: 0.000 to 0.074). None of the 169 treated patients developed a persistent binding antibody against FVIII, PEG-FVIII, PEG, or CHO protein. Pre-existing and transient binding antibodies were detected in 21 patients; however, these were not detectable at subsequent visits or at completion of the study and appeared to have no apparent impact on efficacy or temporal association with an AE. No remarkable trends were observed in changes in laboratory parameters from baseline to last study visit or in vital signs evaluated pre- and post-infusions given at the study site (eg, PK assessments). From this integrated analysis, BAX 855 was safe and well tolerated in 169 PTPs with severe hemophilia A. The common adverse events considered related to BAX 855 treatment were consistent with the safety profile of ADVATE. Disclosures Chowdary: Sobi: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding. Konkle:Baxalta: Consultancy, Research Funding; CSL Behring: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy; Octapharma: Research Funding; Biogen: Consultancy, Research Funding. Matsushita:Baxalta: Research Funding. Engl:Baxalta: Employment, Equity Ownership. Patrone:Baxalta: Employment, Equity Ownership. Abbuehl:Baxalta: Employment, Equity Ownership.

BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on rFVIII (ADVATE) with an extended half-life and is intended for prophylaxis and the treatment of bleeding in patients with hemophilia A.1 This phase 3 surgery study is evaluating the efficacy and safety of BAX 855 for the perioperative control of hemostasis. Patients' informed consent and appropriate ethics committee approvals were obtained. Elective procedures were prospectively classified (major or minor) by the investigator/surgeon and major emergency surgeries were excluded. The target trough FVIII levels for major and minor surgeries were to be ≥80% and 30-60%, respectively. Each patient's pharmacokinetic (PK) profile was used to guide the BAX 855 dose and infusion frequency. BAX 855 PK were consistent with previous PK assessments with terminal half-life ranging from 8.81 to 18.06 hours for the 15 patients in this study. In this interim analysis, 15 male previously treated patients (PTPs) ranging from 19 to 52 years of age have undergone 15 procedures in 7 countries. Individual procedure profiles are compiled to evaluate the control of hemostasis for BAX 855. There were 11 major procedures: 6 orthopedic (3 knee replacements, 2 arthroscopic synovectomies, 1 elbow cyst extirpation) and 5 non-orthopedic procedures (3 dental [root canals for 2 teeth, 2 extractions of ≥4 teeth, 1 radicular cyst removal], 1 cardiovascular [mediport placement], 1 abdominal [gastric band insertion]). The 4 minor surgeries comprised 1 synoviorthesis, 1 dental, 1 dermatological and 1 endoscopy (radiosynovectomy) procedure. Efficacy was evaluated by the surgeon or investigator's rating of hemostatic control using 4-point scale which was based on blood loss and by comparing actual blood loss with predicted blood loss which was specified by the surgeon for non-hemophilia patients prior to the procedure. For all procedures, the hemostatic control of BAX 855 was rated "excellent" for the intraoperative (during the procedure), postoperative (24 hours after completion of the procedure), and perioperative (from start of the procedure until discharge or day 14) periods, except for 1 minor dental procedure in which postoperative efficacy was rated "good" and 1 minor procedure in which a postoperative rating was not provided (for both of these procedures intra- and perioperative ratings were "excellent"). Actual blood loss (ABL) for the intraoperative and postoperative periods were compared with predicted average and maximum values. Intraoperative ABL for all minor and major procedures was less than or equal to predicted averages and maximums, except for 1 minor procedure in which the ABL was greater than the predicted average and maximum and 1 major procedure which did not have ABL recorded. Postoperative ABL was less than or equal to predicted averages and maximums for 4/4 minor procedures and 5 major procedures. For 4 major procedures, postoperative ABL was greater than or equal to predicted average, but less than predicted maximums. For the remaining major procedure (synovectomy with general anesthesia) with reported ABL, postoperative ABL was greater than the predicted the average and maximum - the efficacy assessments at all periods for this procedure were considered "excellent". These results demonstrate the efficacy of BAX 855 for the perioperative control of hemostasis in patients with severe hemophilia A. 1 Konkle BA, Stasyshyn O, Chowdary P et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015; Link to Publisher's site: http://www.bloodjournal.org/content/bloodjournal/early/2015/07/08/blood-2015-03-630897.full.pdf Disclosures Brand: CSL Behring: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Baxalta: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biotest: Consultancy. Gruppo:Baxalta: Consultancy, Research Funding; Novo Nordisk: Consultancy; Pfizer: Consultancy; Alexion: Speakers Bureau. Wynn:Baxalta: Research Funding. Griskevicius:Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Fernanda Lopez Fernandez:Baxalta: Research Funding. Dvorak:Baxalta: Employment, Equity Ownership. Patrone:Baxalta: Employment, Equity Ownership. Abbuehl:Baxalta: Employment, Equity Ownership.

BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on ADVATE with an extended half-life and is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. In a pivotal trial, 101 previously treated patients (PTPs) received BAX 855 for prophylaxis twice weekly (in the per protocol analysis set). At screening, 67/101 (66.3%) of patients had arthropathy (reported in medical history or history of joint surgery) and 69/101 (68.3%) had at least 1 target joint. A target joint was defined as a single joint (ankle, knee, hip, or elbow) with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period. Overall, among these 101 PTPs, the mean (standard deviation) annualized joint bleeding rate (AJBR) was 1.8 (3.0) and 57.4% of patients had zero joint bleeding episodes. There were 32, 40, and 29 subjects with 0, 1-2, and ≥3 target joints, respectively, at screening. Patients with more target joints at screening experienced higher AJBRs: with mean AJBRs of 1.15, 1.84, and 2.58 for patients with 0, 1-2, and ≥3 target joints, respectively, at screening. Of the individual joints, ankle and knee joints had highest AJBRs. BAX 855 demonstrated efficacy in the treatment of joint bleeding, with the majority of joint bleeding episodes, irrespective of target joint status, treated with 1-2 infusions: 92.8%, 91.9% and 94.4% for patients with 0, 1-2, and ≥3 target joints, respectively, at screening. Hemostatic efficacy of BAX 855 at 24 hours was rated as excellent or good in >90% of patients, regardless of target joint status at screening. Patients with 0 target joints at screening had 57.1% of joint bleeding episodes considered mild in severity, while patients with 1-2 or ≥3 target joints had 59.5% and 66.7% of joint bleeding episodes, respectively, rated moderate in severity. There were few joint bleeding episodes considered severe. Similar doses per infusion of BAX 855 were used to treat joint bleeding episodes: the mean dose per BAX 855 infusion was 35, 33.8, and 36.2 IU/kg for patients with 0, 1-2, and ≥3 target joints, respectively. In conclusion, BAX 855 demonstrated a favorable efficacy profile in the treatment of breakthrough joint bleeding episodes, and twice-weekly use was efficacious in prevention of bleeding, with the lowest overall AJBRs achieved in patients in the trial without target joints. Disclosures Manco-Johnson: Baxter/Baxalta, Bayer, CSL Behring, Biogen NovoNordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding. Ma:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees. Klamroth:Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau; Biogen and SOBI: Honoraria, Speakers Bureau. Engl:Baxalta: Employment, Equity Ownership. Griparic:Baxalta: Employment. Dyck-Jones:Baxalta: Employment. Abbuehl:Baxalta: Employment, Equity Ownership.

Hemophilia B is an X-linked congenital bleeding disorder caused by defective or deficient levels of circulating coagulation factor IX (FIX). Adequate levels of FIX can be maintained in the plasma through routine prophylactic infusions, which can especially benefit pediatric patients if started early in order to prevent recurrent joint bleeding and severe joint disease. A recombinant FIX (BAX326, Rixubis®, Baxter) has been developed for the prophylaxis and control of bleeding in hemophilia B patients. BAX326 is manufactured without the addition of any materials of human or animal origin; solvent/detergent treatment as well as nanofiltration are used for viral inactivation/reduction. Safety and efficacy of BAX326 have already been demonstrated in hemophilia B patients aged 12 years and above.1 A prospective clinical trial was conducted to assess the pharmacokinetics (PK), hemostatic efficacy and safety of BAX326 in previously treated patients (PTPs) Twenty-three male subjects (median age 7.10 years, range 1.8 to 11.8 years, with 11 subjects < 6 years) were enrolled and treated with BAX326. Sixteen subjects (69.6%) had received previous treatment with FIX products by prophylaxis only, 6 (26.1%) by both prophylaxis and on-demand, and 1 subject (4.3%) had been treated on-demand only. BAX326 was safe and well-tolerated. No allergic reactions or thrombotic events occurred and there were no treatment-related adverse events. None of the subjects developed an inhibitory or positive binding antibody to FIX, Chinese hamster ovary cell protein or furin. PK assessments (N = 23) after one 75 ± 5 IU/kg infusion with BAX326 were performed up to 72 hours (median AUC0-inf. 802.9 IU hr/dL, MRT 26.77 hr, Cl 0.0935 dL/[kg.hr], half-life 24.48 hr, Vss 2.629 dL/kg) using a non-linear mixed model (population PK) approach. The mean incremental recovery (IR) 30 minutes after infusion was consistent over time (assessed after initial PK infusion, and at 5, 14 and 26 weeks of treatment). A tendency toward higher IR in association with increased patient age was observed, as previously described.2 BAX326 administered as prophylaxis was efficacious in preventing bleeds. Nine subjects (39.1%) did not experience any bleeds; the mean annualized bleeding rate (ABR) was 2.7 ±3.14 (median 2.0). Out of 26 total bleeds, only 2 (in 2 subjects) were spontaneous, and 1 was of unknown cause. Fewer bleeds occurred in joints than in non-joint sites (19 non-joint vs. 7 joint bleeds). Hemostatic efficacy at the resolution of a bleed was excellent or good in 96.2% of bleeds. The majority of bleeds were resolved after 1-2 infusions (88.5%) with BAX326; the mean total dose of rFIX administered per bleed was 94.4 (52.41) IU/kg. Hemostatic efficacy in terms of bleed severity was excellent or good in 100% of minor bleeds (N =15), 88.9% of moderate bleeds (N=9) and 100% of major bleeds (N=2). In summary, these data indicate that BAX326 is safe and efficacious in treating bleeding episodes and in routine prophylaxis in pediatric patients aged Disclosures: Oh: Baxter: Employment. Chapman:Baxter: Employment. Pavlova:Baxter: Employment. Wong:Baxter: Employment. Abbuehl:Baxter: Employment.

Abstract 2222 Hemophilia B is a congenital X-linked bleeding disorder whose severity is associated with diminished or absent levels of circulating FIX. Treatment with regular prophylactic FIX infusions has significant medical and quality of life benefits by maintaining adequate plasma levels of FIX for hemostasis approximating a non-diseased state. BAX326 nonacog gamma is a novel recombinant FIX (rFIX) that is manufactured without the addition of any materials of human or animal origin, and viral inactivation/reduction is achieved through solvent/detergent (S/D) treatment as well as 15nm nanofiltration. Pharmacokinetics, hemostatic efficacy and safety of BAX326 were assessed in a prospective clinical trial in patients aged 12 to 65 years with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B, previously treated with plasma-derived and/or recombinant FIX concentrates. PK parameters were compared with a commercially-available rFIX used as an active control in a crossover design. Hemostatic efficacy of BAX326 administered twice weekly as prophylaxis was compared with a historical control group treated on-demand. A total of 86 patients were enrolled and 73 were treated with BAX326. All subjects treated had previous exposure to a FIX concentrate for ≥ 150 days prior to entry into the study. Subjects included in the PK analysis (n=28) received one 75 ± 5 IU/kg infusion with BAX326 and one infusion with commercial rFIX in random order prior to receiving prophylactic treatment at a dose range from 40 to 60 IU/kg two times a week with BAX326. An additional 31 subjects also received prophylactic treatment (21–67 exposure days), and 14 subjects received BAX326 on-demand (5–25 exposure days). More than 70% of subjects had 50 or more exposure days to BAX326 during the study. PK equivalence between BAX326 and the comparator rFIX was confirmed as the 90% confidence intervals of the ratio (BAX326/comparator rFIX) of the geometric mean of AUC 0–72 h/dose (1.063 [1.03; 1.09]) was fully contained in the margins for equivalence (0.8 to 1.25). The mean half-life (T1/2) of BAX326 was 26.70h ± 9.55, and incremental recovery (IR) was 0.87 ± 0.22 IU/dL: IU/kg. Repeated PK analysis after 6 months of prophylactic treatment confirmed the results of the initial values. Twice weekly prophylactic treatment with BAX326 was effective in preventing bleeding episodes, with a significantly lower (79%, p BAX326 was safe and well-tolerated, with similar adverse reaction rates to the comparator rFIX. The safety assessments demonstrate the safety and tolerability of BAX326 in patients with moderately severe or severe hemophilia B. There were no product related SAEs, no inhibitory or binding FIX antibodies, no antibodies to CHO, and no allergic reactions or thrombotic events; AEs considered related to BAX326 (dysgeusia and pain in extremity) were transient and mild, and occurred with an overall incidence of 2.7%. There were no treatment-related AEs within 24 hours after infusion. Elevated pre- and post-infusion values for thrombogenic markers (TAT, F1.2 and D-dimer) in some subjects did not reveal any pattern indicative of clinically relevant thrombogenicity with either BAX326 or the comparator rFIX, and were not associated with AEs. These data indicate that BAX326 is safe and efficacious in treating bleeding episodes and in routine prophylaxis in patients aged 12 years and older with hemophilia B. None of the historical risk factors, such as hypersensitivity reactions, inhibitor formation or thrombotic events were observed and few related adverse events occurred. Disclosures: Windyga: Baxter: Research Funding. Lissitchkov:Baxter: Research Funding. Stasyshyn:Baxter: Research Funding. Mamonov:Baxter: Research Funding. Rusen:Baxter: Research Funding. Lamas:Baxter: Research Funding. Oh:Baxter: Employment. Chapman:Baxter: Employment. Fritsch:Baxter: Employment. Pavlova:Baxter: Employment. Wong:Baxter: Employment. Abbuehl:Baxter: Employment.