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This phase 3, prospective, open-label, multicenter, continuation study (NCT01286779) investigated the use of a recombinant factor IX (FIX), nonacog gamma (BAX 326, RIXUBIS®) in patients with severe or moderately severe hemophilia B. The study population included 85 patients transitioning from a phase 1/3 pivotal study (NCT01174446), a pediatric study (NCT01488994), and 30 newly recruited patients, naïve to nonacog gamma. Patients received nonacog gamma as prophylaxis treatment (standard, modified or PK-tailored) or on-demand, as determined by the investigator. Treatment was assessed for safety, immunogenicity, hemostatic efficacy and consumption. In this study, after ≥100 exposure days, nonacog gamma resulted in no treatment-related serious adverse events, and no patients developed inhibitory antibodies to FIX. Nonacog gamma was efficacious at controlling bleeding episodes, with an 89.1% overall hemostatic efficacy rating of excellent or good, and 56% of bleeds resolved with one infusion. The annualized bleeding rate was considerably lower during prophylactic treatment (median ABR of 1.3 in 108 patients) than during on-demand treatment (median ABR of 16.5 in 13 patients). These results show that in previously treated patients and nonacog gamma-naïve patients, long-term use of nonacog gamma had acceptable safety and tolerability, and was efficacious as a prophylactic treatment for the management of bleeding episodes. NCT01286779, EudraCT: 2010-022726-33

Introduction BAY 81-8973 (Kovaltry®), a recombinant factor VIII (rFVIII) product, was efficacious and well tolerated in paediatric previously treated patients (PTPs) with severe haemophilia A for ≥50 exposure days (EDs) in the LEOPOLD Kids study. Because long-term prophylaxis (≥100 EDs) can provide substantial patient benefits, FVIII products should demonstrate long-term safety and efficacy. Aim To demonstrate long-term (≥100 EDs) efficacy and safety of BAY 81-8973 in paediatric PTPs. Methods PTPs aged ≤12 years with severe haemophilia A without inhibitors could continue in the ongoing open-label extension study after completing ≥50 EDs in the LEOPOLD Kids main study. Patients received BAY 81-8973 for prophylaxis (25–50 IU/kg ≥2×/week), bleed treatment, and surgery. Bleeds were documented in electronic patient diaries. Inhibitor development was monitored every 6 months. Results At the August 2017 interim data cutoff, 46 patients (median [range] age at enrolment, 6.0 [1.0–11.0] years) had spent a median (range) of 602.5 (148–1069) EDs and 4.6 (1.0–5.9) years in the main plus extension studies. Median (quartile [Q]1; Q3) annualised bleeding rate for bleeds within 48 h after a prophylaxis infusion and total bleeds was 1.0 (0.2; 1.9) and 2.0 (0.4; 3.6), respectively. Most (>94%) bleeds were mild or moderate; 71.8% were treated with ≤1 infusion. BAY 81-8973 was also well tolerated with only one treatment-related adverse event (transient, low-titre inhibitor which did not require treatment adjustment). Conclusion BAY 81-8973 was efficacious for prophylaxis and treatment of bleeds during >4.5 years in paediatric PTPs with severe haemophilia A.

INTRODUCTION For individuals with haemophilia A, prophylaxis with factor VIII (FVIII) is typically directed towards trough activity >1 IU/dL; however, some patients still experience spontaneous bleeding events (sBEs). AIM Aims were to evaluate relationships of endogenous thrombin potential (ETP) and FVIII:C with occurrence of clinical bleeding. METHODS GENA-21 was a prospective, open-label, phase IIIb study investigating the safety and efficacy of Nuwiq® (human-cl rhFVIII) in previously treated adults with severe haemophilia A. The study included a 72-hour pharmacokinetic (PK) evaluation phase and a 6-month personalized prophylaxis phase in which treatment was guided by PK parameters. This subanalysis assessed FVIII:C by one-stage assay and ETP by thrombin generation assay in blood samples. RESULTS Baseline mean ETP was lower in the 7 patients who experienced sBEs during personalized prophylaxis versus 25 who did not (n = 32 with data from PK phase and prophylaxis phase; P = .0002). During personalized prophylaxis (n = 49), only patients with lower median trough ETP experienced sBEs (8/49 patients; ROC AUC = 0.9421; P

WOS: 000442583600048, PubMed ID: 29582525, IntroductionThe pharmacokinetics (PK), efficacy and safety of moroctocog alfa (AF-CC) have been demonstrated in haemophilia A patients aged 6years. AimThese studies aimed to further describe moroctocog alfa (AF-CC) experience in paediatric patients (, PfizerPfizer, Pfizer

Introduction Nuwiq® (human-cl rhFVIII) is a 4th generation recombinant human FVIII, without chemical modification or protein fusion, produced in a human cell-line. Aims/Methods This study (NuPreviq) was a prospective, open-label, multicentre, phase IIIb study of the efficacy and safety of personalized prophylaxis with Nuwiq® in 66 previously treated adults with severe haemophilia A. NuPreviq had three phases: (i) a 72-h pharmacokinetic (PK) phase; (ii) a 1–3 month standard prophylaxis phase; and (iii) a 6-month personalized prophylaxis phase. The personalized prophylaxis regimen was based on individual PK modelling for each patient according to whether their PK profile most closely fitted a two- or one-compartment model (NuPreviq approach). In cases of uncertainty, a noncompartment model was applied. Results The median dosing interval during personalized prophylaxis was 3.5 days, with 57% of patients on ≤2 weekly dosing. Mean annualized bleeding rates during personalized prophylaxis were 1.45 (median [interquartile range, IQR]: 0 [0, 1.9]) for all bleeds, 0.79 (median [IQR]: 0 [0, 0]) for spontaneous bleeds, and 0.91 (median [IQR]: 0 [0, 0]) for joint bleeds. During personalized prophylaxis, 83.1% of patients were spontaneous bleed-free. Compared with standard prophylaxis, median weekly prophylaxis dose was reduced by 7.2% from 100.0 to 92.8 IU kg−1 during the last 2 months of personalized prophylaxis. There were no FVIII inhibitors or treatment-related serious or severe adverse events. Conclusion PK-guided personalized prophylaxis with Nuwiq® provided bleeding protection and enabled the dosing interval to be extended to twice weekly or less in many patients and an overall dose reduction.

For individuals with haemophilia A, prophylaxis with factor VIII (FVIII) is typically directed towards trough activity1 IU/dL; however, some patients still experience spontaneous bleeding events (sBEs).Aims were to evaluate relationships of endogenous thrombin potential (ETP) and FVIII:C with occurrence of clinical bleeding.GENA-21 was a prospective, open-label, phase IIIb study investigating the safety and efficacy of NuwiqBaseline mean ETP was lower in the 7 patients who experienced sBEs during personalized prophylaxis versus 25 who did not (n = 32 with data from PK phase and prophylaxis phase; P = .0002). During personalized prophylaxis (n = 49), only patients with lower median trough ETP experienced sBEs (8/49 patients; ROC AUC = 0.9421; P .0001); there was no significant relationship for FVIII:C in predicting sBEs (ROC AUC = 0.5838; P = .4750). Directly following infusion of human-cl rhFVIII, ETP was lower in patients who experienced sBEs versus those who did not (P = .0002), whereas FVIII:C did not differ significantly between these groups.In adults with severe haemophilia A and reduced thrombin generation, increased frequency of spontaneous bleeding was observed irrespective of trough FVIII levels. Thus, personalized prophylaxis should take into account variables other than FVIII:C. Large prospective trials are needed to verify ETP as a marker for spontaneous bleeding.

WOS: 000350548500005, PubMed ID: 25546368, BackgroundBAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. ObjectivesTo demonstrate superiority of prophylaxis vs. on-demand therapy with BAY 81-8973 in patients with severe hemophilia A. Patients/MethodsIn this multinational, randomized, open-label crossover study (LEOPOLD II; ClinicalTrials.gov identifier: NCT01233258), males aged 12-65years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30IUkg(-1)), 3-times-weekly prophylaxis (30-40IUkg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs) andimmunogenicity were also assessed. ResultsEighty patients (on demand, n=21; twice-weekly prophylaxis, n=28; 3-times-weekly prophylaxis, n=31) were treated and analyzed. MeanSD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 +/- 7.2; 3-times-weekly, 4.3 +/- 6.5; combined, 4.9 +/- 6.8) vs. on-demand treatment (57.7 +/- 24.6; P, Bayer HealthCare AG, Leverkusen, GermanyBayer AGBayer Healthcare Pharmaceuticals; Bayer HealthCare PharmaceuticalsBayer AGBayer Healthcare Pharmaceuticals, This study was funded by Bayer HealthCare AG, Leverkusen, Germany. Medical writing assistance was provided by Erin P. Scott for Complete Healthcare Communications, Inc. (Chadds Ford, PA) and was fully funded by Bayer HealthCare Pharmaceuticals.

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.

NuwiqThis study (NuPreviq) was a prospective, open-label, multicentre, phase IIIb study of the efficacy and safety of personalized prophylaxis with NuwiqThe median dosing interval during personalized prophylaxis was 3.5 days, with 57% of patients on ≤2 weekly dosing. Mean annualized bleeding rates during personalized prophylaxis were 1.45 (median [interquartile range, IQR]: 0 [0, 1.9]) for all bleeds, 0.79 (median [IQR]: 0 [0, 0]) for spontaneous bleeds, and 0.91 (median [IQR]: 0 [0, 0]) for joint bleeds. During personalized prophylaxis, 83.1% of patients were spontaneous bleed-free. Compared with standard prophylaxis, median weekly prophylaxis dose was reduced by 7.2% from 100.0 to 92.8 IU kgPK-guided personalized prophylaxis with Nuwiq

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 Few randomized studies have reported on the use of factor IX (FIX) for secondary prophylaxis in haemophilia B patients. This study aimed to evaluate the efficacy and safety of two secondary prophylaxis regimens of recombinant coagulation FIX, nonacog alfa, compared with on-demand therapy. Male subjects aged 6–65 years with severe or moderately severe haemophilia B (FIX:C ≤ 2, n = 50) and ≥12 bleeding episodes (including ≥6 haemarthroses episodes) within 12 months of study participation were enrolled in this multicentre, randomized, open-label, four-period crossover trial. The primary measure was the annualized bleeding rate (ABR) of two prophylactic regimens vs. on-demand therapy. In the intent-to-treat group, mean ABR values were 35.1, 2.6 and 4.6 for the first on-demand period, the 50 IU kg−1 twice-weekly period, and the 100 IU kg−1 once-weekly period respectively. Differences in ABR between the first on-demand period and both prophylaxis regimens were significant (P

Essentials: High-quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy. SPINART was a 3-year randomized clinical trial of late/tertiary prophylaxis vs on-demand therapy. Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI. Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy. Summary: Background: Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease. Objectives: To describe 3-year bleeding, joint health and structure, health-related quality-of-life (HRQoL) and other outcomes from the open-label, randomized, multinational SPINART study. Patients/Methods: Males aged 12-50 years with severe hemophilia A, ≥ 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose-formulated recombinant FVIII prophylaxis or on-demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging [MRI]), joint health (Colorado Adult Joint Assessment Scale [CAJAS]), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction. Results: Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre-existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed-free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares [LS] mean, - 0.31 [n = 42] versus + 0.63 [n = 42]) and HAEMO-QoL-A scores (LS mean, + 3.98 [n = 41] versus - 6.00 [n = 42]), less chronic pain (50% decrease), and approximately two-fold less HRU; activity, Euro QoL-5D-3L (EQ-5D-3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 [n = 41] versus + 0.96 [n = 38]). Conclusions: Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre-existing joint arthropathy may be irreversible. (Less)

Recombinant VIII (rVIII)-SingleChain is a novel B-domain–truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII

Summary. Moroctocog alfa (AF-CC) (Xyntha™, BDDrFVIII) is manufactured by a process designed to enhance the theoretical viral safety profile relative to ReFacto®, its predecessor, and to provide alignment with clinical monitoring by the one-stage clotting assay. To evaluate the efficacy and safety of B-domain-deleted recombinant factor VIII (BDDrFVIII) was given as bolus injection (BI) or continuous infusion (CI) in haemophilia patients undergoing major surgery. BDDrFVIII was administered by BI or CI per investigator discretion peri-operatively for at least 6 days. Thirty patients enrolled and were treated with at least one dose of BDDrFVIII. Twenty-five patients were evaluable for efficacy. Outcomes were favourable against a background of multiple major surgical procedures. All haemostatic efficacy ratings were ‘excellent’ or ‘good’. End-of-surgery haemostasis ratings, the primary efficacy endpoint, were excellent for 72% (18/25) and good for 28% (7/25) of patients. Haemostasis ratings following the initial postoperative period were excellent for 92% (23/25) and good for 8% (2/25) of patients. Intra-operative blood loss was rated as normal in all patients. Thirteen patients had postoperative blood loss; in 10, this was rated as normal. A low frequency of transfusion was reported in both the intra-operative and postoperative settings. Adverse events (AEs) were consistent with surgery; three were considered related to BDDrFVIII. One patient had a related AE of postoperative haemorrhage. A clinically silent low-titre inhibitor was detected in one patient, and one patient had a false-positive inhibitor titre. This study demonstrates that BDDrFVIII is safe and efficacious for surgical prophylaxis in haemophilia A patients undergoing major surgery.

Summary. Background: Hemophilic patients with factor VIII (FVIII) and FIX inhibitors suffer from frequent bleeding episodes and reduced quality of life. Objectives: To evaluate whether secondary prophylaxis with activated recombinant factor VII (rFVIIa) can safely and effectively reduce bleeding frequency as compared to conventional on-demand therapy. Methods: Thirty-eight male patients entered a 3-month preprophylaxis period to confirm high baseline bleeding frequency (mean ≥ 4 bleeds per month). Twenty-two patients were randomized 1:1 to receive daily rFVIIa prophylaxis with either 90 or 270 μg kg−1 for 3 months, followed by a 3-month postprophylaxis period. Results: Bleeding frequency was reduced by 45% and 59% during prophylaxis with 90 and 270 μg kg−1, respectively (P

BAY 81-8973, a full-length, unmodified, recombinant factor VIII (FVIII) in development for treatment of haemophilia A, has the same primary amino acid sequence as Bayer's sucrose-formulated recombinant FVIII but is produced with more advanced manufacturing technologies.To demonstrate safety and efficacy of BAY 81-8973 for prophylaxis and treatment of bleeds in previously treated children.In this phase III, multicentre, open-label, nonrandomized study, boys aged ≤12 years with severe haemophilia A and ≥50 exposure days (EDs) to FVIII products received prophylaxis with BAY 81-8973 25-50 IU kg(-1) ≥2 times weekly for ≥50 EDs. The efficacy endpoint was annualized number of total bleeds. Adverse events (AEs) and immunogenicity were assessed.Fifty-one patients were treated (age:6 years, n = 25; 6-12 years, n = 26) with a 2× per week (43%) or2× per week (57%) regimen at study start. Median [quartile 1; quartile 3 (Q1; Q3)] annualized number of bleeds for the combined age groups was 1.90 (0; 6.02) for total bleeds, 0 (0; 2.01) for joint bleeds and 0 (0; 0) for spontaneous bleeds. Median (Q1; Q3) annualized number of total bleeds within 48 h of previous prophylaxis infusion was 1.88 (0; 3.97) for children aged6 years and 0 (0; 1.96) for children aged 6-12 years. No drug-related serious AEs or inhibitors were reported.Prophylaxis with BAY 81-8973 using individualized prophylaxis regimens of 2× per week, 3× per week and every-other-day infusions was efficacious in prevention and treatment of bleeds in children with severe haemophilia A. Treatment with BAY 81-8973 was well tolerated.

Background and objectives In apharmacokinetic (PK)-guided personalized prophylaxis study with human-cl rhFVIII(Nuwiq®), a factor VIII (FVIII) concentrate from a human cell line,58% of the previously treated adult patients (PTPs) with severe hemophilia A received 2 or fewer prophylactic infusions per weekwith a median dosing interval of3.5 days. Seventy-three percent (73%) of patients did not experience any bleeding and 83% had no spontaneous bleeding episodes during the 6-month personalized prophylaxis period. The objective of this analysis was to evaluate the relationship between endogenous thrombin generation (TG) as well as FVIII plasma concentrations with the bleeding phenotype. Study design and methods This prospective, open-label, multicenter study included 66 adult PTPs with severe hemophilia A. After the previously given FVIII concentrate was washed out, patients received human-cl rhFVIII(60 IU/kg) for PK evaluation. Individual PK data were analyzed to determine doses and injection intervals that would theoretically result in a trough FVIII plasma level of ≥1%. Individualized prophylaxis lasted 6 months. TG and FVIII:C plasma concentrations were measured before and during the PK assessment, and trough TG and FVIII:C levels were measured 2, 4 and 6 months after the start of personalized prophylaxis. For TG, blood was drawn in trisodium citrate tubes (0.106 M) containing 1.45 µM corn trypsin inhibitor, centrifuged twice to obtain platelet poor plasma, and stored frozen until central analysis. TG was initiated by adding tissue factor (1 pM), and endogenous thrombin potential (ETP) was measured using the calibrated, automated TG assay.FVIII:C was measured using one-stage (automated APTT, Trinity Biotech, Siemens BCX-XP) and chromogenic assays (Coatest SP FVIII Kit, Chromogenix, Siemes BCS-XP). Results Data on both baseline ETP and bleeding rate during PK-guided individualized prophylaxis were available for 32 patients. Twenty-one patients did not experience any bleeding episode, and 25 patients had no spontaneous bleeding episodes. The mean baseline ETP did not differ between patients with and without any bleeding (373 ± 334 vs 367 ± 168 nmol*min), but was considerably lower in patients who had spontaneous bleeding episodes compared with those without spontaneous bleeding episodes (164 ± 66 vs 426 ± 231 nmol*min). Data on trough ETPs and FVIII:C during personalized prophylaxis were available for 34 patients.Patients with low TG potential tended to experience more frequent spontaneous bleeding episodes during this phase of the protocol (Figure 1), while low FVIII:C levels seemed to be less related to spontaneous bleeding episodes. Conclusions Low TG capacity seems to be correlated with increased frequency of spontaneous bleeding episodes, irrespective of trough FVIII plasma levels. Further prospective studies should be carried out to evaluate the value of this global coagulation parameter in the personalization prophylactic treatment in patients with hemophilia A in comparison with trough FVIII coagulant activity. Figure 1 Figure 1. Disclosures Klamroth: Biogen Idec: Other: honoraria for advisory boards and speaker fees; Baxalta: Other: honoraria for advisory boards and speaker fees ; Bayer: Other: honoraria for advisory boards and speaker fees; CSL Behring: Other: honoraria for advisory boards and speaker fees; NovoNordisk: Other: honoraria for advisory boards and speaker fees; SOBI: Other: honoraria for advisory boards and speaker fees; pfizer: Other: honoraria for advisory boards and speaker fees; Octapharma: Other: honoraria for advisory boards and speaker fees; uniqure: Other: honoraria for advisory boards and speaker fees. Windyga:Biogen: 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; Nordisk: 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; Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, 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; 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; CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Bichler:Octapharma: Employment. Knaub:Octapharma: Employment. Negrier:NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; LFB: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Pfizer: Research Funding; SOBI: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees.

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.

SummaryBackground The benefits of routine prophylaxis vs. on-demand treatment with factor VIII products have not been evaluated in controlled clinical trials in older patients with hemophilia A. Objectives To report results from a preplanned analysis of data from the first year of the 3-year SPINART study, which compares routine prophylaxis with on-demand treatment with sucrose-formulated recombinant FVIII (rFVIII-FS). Patients/Methods SPINART is an open-label, randomized, controlled, parallel-group, multinational trial. Males aged 12–50 years with severe hemophilia A, ≥ 150 days of exposure to FVIII, no FVIII inhibitors, no prophylaxis for > 12 consecutive months in the past 5 years and 6–24 bleeding episodes in the preceding 6 months were randomized 1 : 1 to rFVIII-FS prophylaxis (25 IU kg−1, three times weekly) or on-demand treatment. The primary efficacy endpoint, number of total bleeding episodes in the intent-to-treat population, was analyzed after the last patient had completed 1 year of follow-up. A negative binomial model was used for the primary endpoint analysis; analysis of variance was used for confirmatory analysis of annualized bleeding rates. Results Eighty-four patients were enrolled and analyzed (n = 42 per group; mean age, 30.6 years; median treatment duration, 1.7 years). The median number of total bleeding episodes and total bleeding episodes per year were significantly lower with prophylaxis than with on-demand treatment (total, 0 vs. 54.5; total per year, 0 vs. 27.9; both P

Background Prophylactic therapy aims to maintain sufficient factor VIII (FVIII) plasma levels to prevent bleeding. FVIII plasma trough level and time spent above a certain threshold are mainly determined by the half-life of the FVIII concentrate and the injection interval. Aims A clinical study was conducted to investigate the efficacy of individually PK-tailored prophylaxis with Human-cl rhFVIII. Methods This prospective, open-label, multicenter phase 3b study included previously treated immunocompetent adult patients with severe hemophilia A without past or present inhibitors. Each patient started with a PK evaluation (single dose of 60 ± 5 IU/kg) followed by 1-3 months of routine prophylaxis (i.e. 30-40 IU/kg every other day or 3 times per week, Phase I) until individual PK data was analyzed. It was calculated, which dose and injection interval would theoretically result in a trough FVIII level of ≥1%. Then, prophylaxis was continued for 6 months using the individually recommended treatment scheme (Phase II). Results The study enrolled 66 patents from 20 centers across 8 countries. The majority of patients (62.1%) had been treated on-demand only before study entry. Their median annualized bleeding rate (ABR) was 41. Key outcomes of the personalized prophylaxis are: The prophylactic injection interval was extended from usually 3 times per week in Phase-I to twice per week or less in 58% of patients.The median dosing interval was 3.5 days.73% of patients did not experience any bleeding episode.The mean ABR in phase-II was 1.45 (3.16 in Phase-I).The median weekly prophylactic dose decreased by nearly 10% compared to Phase-I.There were no inhibitors and related serious adverse events. Conclusion The data suggest that personalized prophylaxis with Human-cl rhFVIII results in a more convenient treatment for more than half of the patients with lower factor consumption and a lower ABR while remaining safe and efficacious. Disclosures Klamroth: Biogen and SOBI: Honoraria, Speakers Bureau; Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau. Rusen:Octapharma: Other: Investigator. Walter:Octapharma: Employment. Bichler:Octapharma AG: Employment. Pasi:Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria; Octapharma: Research Funding. Tiede:Octapharma: Other: Investigator, Speakers Bureau; Leo Pharma: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy, Honoraria; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Investigator, Research Funding; Baxter: Consultancy, Honoraria, Research Funding; Coachrom: Research Funding. Knaub:Octapharma: Employment.

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.

Introduction: Hemophilia patients with inhibitors experience frequent bleeds and reduced quality of life (QoL). This trial evaluated whether once−daily prophylaxis therapy with activated recombinant factor VII (rFVIIa; 90 or 270 μg/kg) for 3 months can effectively reduce bleed frequency compared with on−demand therapy, without compromising safety. Methods: Thirty−eight hemophilia inhibitor patients with frequent bleeds entered a 3−month observation period where on−demand therapy was continued according to local practice. Twenty−two patients with a stable bleed frequency (≥4 bleeds/month) were randomized 1:1 to once−daily dosing with 90 or 270 μg/kg rFVIIa in a double−blind, parallel−group design. To maintain blinding, the same volume was administered in both groups. Patients then entered a 3−month post−treatment observation period, where on−demand therapy was resumed. Results: The number of bleeds per month was significantly reduced by 45% and 59% with 90 or 270 μg/kg rFVIIa prophylaxis, respectively, compared with the observation period (Fig.). Similar reductions were seen for all bleeds, irrespective of site or cause. The majority of this reduced bleeding frequency was maintained in the 3 month post−treatment period (27% and 50% reductions, respectively). There were no treatment− or dose−dependent patterns in the number or type of adverse events. No thromboembolic events or withdrawals due to adverse events or ineffective treatment were reported. The benefits of reducing bleeding frequency in this trial translated into improvements in QoL. Conclusions: These results support the concept of secondary rFVIIa prophylaxis in inhibitor patients with frequent bleeds. Clinically relevant reductions in number of bleeds and improvements in quality of life were observed during prophylaxis compared with conventional on−demand therapy without raising any safety concerns. Figure Figure

ReFacto AF (Albumin-Free Cell Culture Process) is a BDDrFVIII manufactured by a modified process designed to enhance viral safety relative to currently licensed ReFacto. Efficacy and safety of ReFacto AF for management of surgical hemostasis has been evaluated in an ongoing open label study of at least 25 efficacy evaluable previously treated patients, age ≥12 years, with severe hemophilia A [FVIII:C ≤ 2%] undergoing elective major surgery. ReFacto AF was to be administered for at least 6 postoperative days by bolus injection (BI) or by continuous infusion (CI) at the investigator’s discretion, and up to a maximum of 6 weeks following surgery. An interim analysis has been performed on the initial 22 patients. Fourteen (14) patients treated by BI received a total of 647 infusions (range 17 to 72 infusions per patient) for a cumulative total dose of 1,279,150 IU over 457 exposure days (ED), while 8 patients assigned to treatment by CI, including 1 patient who received only 1 dose for PK assessment, received a total dose of 348,618 IU over 140 total ED (range 1 to 64 ED per patient). Of the 21 patients who underwent major surgery, 18 were evaluable for efficacy and had the following procedures: 11 total knee replacements, 3 synovectomies, 1 left ulnar nerve transposition/release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, and 1 revision/debridement of the knee after total knee replacement. Investigator ratings of efficacy at the end of surgery and the initial postoperative period were all excellent or good [72% excellent (13/18) and 28% good (5/18) at the end of surgery; and 94% excellent (15/16) and 6% good (1/16) at the end of the initial postoperative period]. Blood loss was assessed for the intra- and post- operative periods. Sixteen (16) efficacy-evaluable patients had intraoperative blood loss; for all subjects, blood loss was rated normal. Ten (10) efficacy-evaluable patients had postoperative blood loss; in 9 cases the postoperative blood loss was rated normal, 1 case was rated abnormal due to hemorrhage following surgical trauma to the epigastric artery. Eleven (11) of 18 efficacy-evaluable patients were predicted to require transfusions during the intraoperative period; only 2 were transfused. No intraoperative transfusions were administered to the other 7 efficacy-evaluable patients. During the postoperative period 2 efficacy-evaluable patients received transfusions. One (1) of these had excessive hemorrhage following trauma to the epigastric artery during surgery, the other received 2 units of PRBCs in the postoperative period following normal blood loss. The most frequently reported treatment emergent adverse events (AEs) were fever, anemia and pain, not unexpected in the perioperative setting. Only one AE was related to ReFacto AF: a clinically silent low titer inhibitor was detected in one patient during a routine protocol-specified surveillance test before his surgery, after several injections of a plasma derived FVIII product that were preceded by only 1 dose of ReFacto AF. This patient had a left knee synovectomy, both of his hemostatic efficacy assessments were excellent, and he had less intraoperative blood loss than predicted. These interim data demonstrate that ReFacto AF is effective and safe when used for surgical prophylaxis in hemophilia A patients undergoing major surgery.

BDDrFVIII [moroctocog alfa (AF-CC), Xyntha] is manufactured by a modified process designed to enhance viral safety relative to currently licensed ReFacto. Efficacy and safety of BDDrFVIII for management of surgical hemostasis has been evaluated in a completed, open-label study of previously treated patients, age 12 years or older, with severe hemophilia A (FVIII:C ≤ 2%) undergoing elective major surgery. BDDrFVIII was to be administered for at least 6 postoperative days by bolus injection (BI) or by continuous infusion (CI) at the investigator’s discretion, and up to a maximum of 6 weeks following surgery. Twenty-two (22) patients treated by BI received a median of 42 infusions per patient (range 16 to 72) for a median total dose of 85,008 IU per patient (range 36,500 to 231,044) over a median 33 total exposure days (EDs) per patient (range 15 to 40). Eight (8) patients designated for treatment by CI, including 1 patient who received 1 dose for PK assessment only, received a median total dose of 74,409 IU per patient (range 4,405 to 96,251) over a median 29 total EDs per patient (range 1 to 37). Of the 30 patients treated with BDDrFVIII, 29 patients underwent major surgery and completed the study; 25 were evaluable for hemostatic efficacy. These 25 patients had the following procedures: 11 total knee replacements, 5 synovectomies, 1 left ulnar nerve transposition/release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 stapes replacement, 1 ankle arthrodesis, 1 pseudotumor excision, 1 hip arthroplasty, 1 hip arthroplasty revision, and 1 revision/debridement of the knee after total knee replacement. Investigator ratings for surgical hemostasis efficacy at the end of surgery, the primary efficacy endpoint, were 72% excellent (18/25) and 28% good (7/25). At the end of the initial postoperative period, postsurgical day 7, the surgical hemostasis efficacy ratings were 92% excellent (23/25) and 8% good (2/25). Blood loss was assessed for the intra- and post-operative periods. Twenty-four (24) efficacy-evaluable patients had intraoperative blood loss; for all subjects, blood loss was rated normal. Thirteen (13) efficacy-evaluable patients had postoperative blood loss; in 10 cases the postoperative blood loss was rated normal, 1 case was rated abnormal due to hemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL blood loss after hip replacement surgery and 1 after an elbow synovectomy, but the blood loss could not be quantitated by the investigator. Nine (9) of 25 efficacy-evaluable patients were prospectively predicted to require transfusions during the intraoperative period; of those 9 only 1 was transfused. Of the other 16 efficacy-evaluable patients, 2 had intraoperative transfusions of packed red blood cells (PRBCs), for both, blood loss was reported as normal. During the postoperative period 4 efficacy-evaluable patients received transfusions, including 1 patient who received PRBCs following excessive hemorrhage associated with trauma to the epigastric artery during surgery. All 30 patients were assessed for safety. Treatment emergent adverse events (AEs) reported in 3 or more patients were fever, pain, infection, headache, flu syndrome, hypertension, nausea, anemia, thrombocythemia, peripheral edema, arthralgia, upper respiratory infection, and local reaction to procedure. The general AE profile was considered consistent with AEs reported in the surgical setting. Three (3) AEs were reported as related to BDDrFVIII. There was an AE of hemorrhage at the operative site during the postoperative period in 1 patient, and clinically silent low titer inhibitors were detected in two patients during routine protocol-specified surveillance testing. One inhibitor was detected pre-operatively (maximum observed titer 1.51 BU/mL) and the other inhibitor (0.63 BU/mL) was detected only on the patient’s final study visit with corresponding negative ELISA tests for anti- Factor VIII antibodies. This study has demonstrated that BDDrFVIII is effective and safe when used for surgical prophylaxis in hemophilia A patients undergoing major surgery.