Pharmacokinetics, Efficacy and Safety of BAX326, a Novel Recombinant Factor IX: A Prospective, Controlled, Multicenter Study in Previously Treated Patients with Severe (FIX Level < 1%) or Moderately Severe (FIX Level ≤ 2%) Hemophilia B.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2222-2222
Author(s):  
Jerzy Windyga ◽  
Toshko Lissitchkov ◽  
Oleksandra Stasyshyn ◽  
Vasily Mamonov ◽  
Luminita Rusen ◽  
...  
Keyword(s):  
Research Funding ◽  
Prophylactic Treatment ◽  
Hemophilia B ◽  
Control Group ◽  
On Demand ◽  
Previously Treated ◽  
Bleeding Episodes ◽  
The Mean ◽  
Hemostatic Efficacy ◽  
Level 2

Abstract 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<0.001) annualized bleed rate (ABR) during prophylaxis (mean ABR 4.20) compared to an on-demand treatment in a historical control group (mean ABR 20.0). Among the 56 subjects on prophylaxis, 24 subjects (43%) did not bleed; the mean ABR for joint bleeds was 2.79, and 1.70 for spontaneous bleeds. Of 238 total acute bleeds, 201 (84.4%) were controlled with 1–2 infusions of BAX326. Hemostatic efficacy at resolution of bleed was rated excellent or good in 95.4% of all treated bleeding episodes. The efficacy as related to degree of severity of bleeding episodes was excellent or good in 96.8 % of minor bleeds, 95 % of moderate bleeds and 92.9 % of major bleeding episodes. 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.

Pharmacokinetics, Efficacy and Safety Of a Recombinant Factor IX (BAX326) In Previously-Treated Pediatric Patients < 12 Years Of Age With Severe Or Moderately Severe Hemophilia B

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1118-1118 ◽  
Author(s):  
Tomasz Urasinski ◽  
Oleksandra Stasyshyn ◽  
Tatiana Andreeva ◽  
Luminita Rusen ◽  
Farida Perina ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Factor Ix ◽  
Hemophilia B ◽  
Ovary Cell ◽  
Animal Origin ◽  
Efficacy And Safety ◽  
On Demand ◽  
Previously Treated ◽  
The Mean ◽  
Hemostatic Efficacy

Abstract 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) <12 years of age with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B. After the initial PK assessment, BAX326 was administered as prophylaxis twice a week (median dose 56 IU/kg, range 43-75 IU/kg) over 6-months or for a minimum of 50 exposure days. 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 <12 years with hemophilia B. Disclosures: Oh: Baxter: Employment. Chapman:Baxter: Employment. Pavlova:Baxter: Employment. Wong:Baxter: Employment. Abbuehl:Baxter: Employment.

scholarly journals Safety, Immunogenicity, and Hemostatic Efficacy of Nonacog Gamma in Patients With Severe or Moderately Severe Hemophilia B: A Continuation Study

2020 ◽  
Vol 26 ◽  
pp. 107602962095083
Author(s):  
Jerzy Windyga ◽  
Oleksandra Stasyshyn ◽  
Toshko Lissitchkov ◽  
Vasily Mamonov ◽  
Margit Serban ◽  
...  
Keyword(s):  
Prophylactic Treatment ◽  
Phase 1 ◽  
Factor Ix ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
On Demand ◽  
Treatment Standard ◽  
Pediatric Study ◽  
Bleeding Episodes ◽  
Hemostatic Efficacy

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

scholarly journals Improvement of Efficacy Outcomes in Patients Who Switched from Sucrose-Formulated rFVIII to BAY 81-8973 Prophylaxis in the LEOPOLD Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Gili Kenet ◽  
Thomas Moulton ◽  
Erika Soltes Rak ◽  
Brian M. Wicklund ◽  
Sanjay P Ahuja
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Study Drug ◽  
Study Cohort ◽  
Efficacy And Safety ◽  
Old Patients ◽  
On Demand ◽  
Adults And Children ◽  
Previously Treated ◽  
Bleeding Episodes

Background BAY 81-8973 (Kovaltry®) is a full-length, unmodified, recombinant factor VIII (FVIII), indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding and routine prophylaxis to reduce the frequency of bleeding episodes in adults and children with hemophilia A. It has the same amino acid sequence as sucrose formulated FVIII (FVIII-FS; Kogenate® FS/Helixate® FS). Pharmacokinetic comparisons confirmed BAY 81-8973 to have a longer half-life and lower clearance than FVIII-FS. The objective of this analysis was to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS prior to enrolling into the LEOPOLD clinical studies receiving BAY 81-8973. Methods LEOPOLD I (NCT01029340) Part B and LEOPOLD Kids (NCT01311648) were Phase 3, multinational, open-label studies that included male patients with severe hemophilia A receiving on-demand or prophylactic therapy, with ≥50 exposure days to any FVIII product and no history of FVIII inhibitors. Patients in LEOPOLD I were &gt;12 years old and received 20-50 IU/kg BAY 81-8973 prophylaxis twice-weekly (2×W) or three times a week (3×W) for up to one year. Patients in LEOPOLD Kids were ≤12 years old and received 25-50 IU/kg BAY 81-8973 ≥2×W for six months. Dosing regimens for both studies were assigned by the investigator. In this analysis, efficacy and safety are assessed in the subset of patients in LEOPOLD I Part B and LEOPOLD Kids who were previously treated with FVIII-FS. Results In LEOPOLD I, 22 (35.5%) patients were previously treated with FVIII-FS with a median age of 27.0; in LEOPOLD Kids, 24 (47.1%) patients were previously treated with FVIII-FS with a median age of 5.0 (Table 1). In general, these switch cohorts had similar patient demographics to the whole study cohort (Table 1) and any differences did not affect the final analysis. Most patients did not change their dosing frequency when starting treatment with BAY 81-8973 but most increased their dose (FVIII-FS dose is 25 IU/kg 3×W [adults] or every other day [EOD; children]; BAY 81-8973 dose is 25-40 IU/kg 2×W or 3×W [&gt;12 years] or 25-50 IU/kg 2×W, 3×W or EOD [≤12 years]). Switching from FVIII-FS to BAY 81-8973 resulted in lower median annualized bleeding rates (ABRs) in the LEOPOLD studies. In LEOPOLD I, median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) in the 12 months of FVIII-FS treatment prior to study entry, to 1.0 (0.0; 6.8) (Figure 1). In LEOPOLD Kids, median total ABR decreased from 3.0 (1.0; 12.0) to 2.0 (0.0; 6.0) for 0-&lt;6 year old patients (n = 13) and from 4.0 (0.0; 10) to 0.0 (0.0; 2.1) for 6-12 year old patients (n = 11) after switching from FVIII-FS to BAY 81-8973 (Figure 1). Joint and spontaneous median ABRs were zero for &lt;12 year old patients treated with BAY 81-8973. There were no study-drug-related adverse events (AEs) or serious AEs (SAEs) reported in patients switching from FVIII-FS to BAY 81-8973 in either LEOPOLD I Part B or LEOPOLD Kids (Table 2). One patient in the LEOPOLD Kids main study discontinued BAY 81-8973 due to a central venous catheter-related infection after six months of treatment, which was not considered study-drug-related. No FVIII inhibitors developed in any patients in either study. Conclusions Switching from FVIII-FS to BAY 81-8973 resulted in improved bleeding control in adults and children with hemophilia A and was well-tolerated. Disclosures Kenet: PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Moulton:Bayer: Current Employment. Soltes Rak:Bayer: Other: Employee of Belcan, contracted with Bayer. Wicklund:Genentech: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Shire (Takeda): Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding.

Safety of Exposure to Recombinant Activated FVII (rFVIIa) Doses In Patients with Hemophilia and Inhibitors (CHwI) to Factors VIII or IX.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3675-3675 ◽  
Author(s):  
Amy D. Shapiro ◽  
Ellis J. Neufeld ◽  
David L. Cooper
Keyword(s):  
Clinical Trials ◽  
Single Dose ◽  
Research Funding ◽  
Prophylactic Treatment ◽  
Data Sources ◽  
On Demand ◽  
Frequency Of Use ◽  
The Us ◽  
Bleeding Episodes ◽  
Higher Doses

Abstract Abstract 3675 Background: The FDA-approved label for recombinant FVIIa (rFVIIa), for treatment of bleeding episodes and prevention of bleeding in surgical or invasive procedures in CHwI patients, recommends initial dosing with 90 mcg/kg as a bolus injection. Patients typically require 2–3 injections for bleed resolution. Based upon three clinical trials comparing a single dose of 270 mcg/kg to 3 doses of 90 mcg/kg, the single-dose 270 mcg/kg rFVIIa regimen was approved by the EMA in March 2007 for treatment of mild-to-moderate bleeds in hemophilic inhibitor patients. Published reports indicate that rFVIIa dosing utilized in clinical practice varies widely. Furthermore, the broad adoption of home treatment makes it difficult to estimate how frequently higher doses (doses > 90 mcg/kg) are used, particularly in the US, and whether or not higher doses pose safety concerns, namely development of thromboembolism. Objectives: To report the frequency of use of higher doses of rFVIIa for on-demand or prophylactic treatment in clinical trials and registries that included safety monitoring, particularly for occurrence of thromboembolic events (TEs). Methods: Data for on-demand treatment of bleeds with rFVIIa in patients with CHwI, were obtained from two published, prospective, randomized studies, one prospective, observational diary study in the US, and the ongoing US-based Hemophilia and Thrombosis Research Society (HTRS) registry database. Data on prophylactic use of rFVIIa in patients with CHwI were obtained from a published, prospective, randomized trial. Information on demographics, rFVIIa dosing, and frequency of TEs were collected and reported using descriptive statistics. Results: A total of 232 CHwI patients reported 20,496 rFVIIa doses administered either for on-demand treatment of 2,286 bleeding episodes or prophylactic treatment for 1,885 days. The majority (81%) of patients were diagnosed with hemophilia A and reported an inhibitor titer range of 0.5 – 20,000 BU, and 9% of patients were diagnosed with hemophilia B. Whites comprised 72% of patients for whom race information was available. Patient age ranged from < 1 year to 62 years, and adults (>18 years old) comprised 37% of the patients studied. All five data sources included use of rFVIIa doses > 90 mcg/kg, the dose recommended in the current US label. Doses of rFVIIa > 120 mcg/kg, > 160 mcg/kg and >240 mcg/kg comprised 40.2% (8,232 doses), 25.9% (5,316 doses) and 8.0% (1,644 doses), respectively, of the 20,496 doses administered to all patients, and comprised 30.8% (1,171 doses), 27.3% (1,037) and 12.1% (460), respectively, of the 3,800 doses administered specifically to adults (>18 years old). No TEs were reported across the five data sources irrespective of the dose administered. Conclusions: A comprehensive review of data of over 20,000 rFVIIa doses used for either prophylactic or on-demand treatment of bleeding episodes demonstrates the frequent use and safety of rFVIIa doses above the US FDA-approved dose. The absence of TEs in 8,232 higher doses (i.e. doses > 120 mcg/kg, including 460 doses > 240 mcg/kg in adults) suggests TEs are likely uncommon at doses up to 300 mcg/kg, and reaffirm the low TE incidence (0.2%) reported in CHwI trials at standard doses (≤ 90 mcg/kg). Substitution of fewer high doses in place of more frequent lower doses may provide improved compliance and avoid the need for short interval repetitive dosing. Evaluation of additional data sources such as the ongoing European ONE Registry, the recently completed PRO-PACT study (retrospective global chart review for assessment of prophylactic treatment), UKHCDO, and other global registries in countries where 270 mcg/kg dosing has been approved for clinical use, will enlarge the current data set and provide even better estimates of the frequency of use of higher doses of rFVIIa and occurrence of TEs across a larger, more global population. Disclosures: Shapiro: Novo Nordisk: Consultancy. Off Label Use: rFVIIa dosing for approved indications above the PI recommendations. Neufeld:Novo Nordisk: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Cooper:Novo Nordisk Inc.: Employment.

Efficacy and Safety Results of Prolong-9FP Clinical Program of Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Previously Treated Patients with Hemophilia B

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 548-548 ◽  
Author(s):  
Elena Santagostino ◽  
Christine Voigt ◽  
Denise Wolko ◽  
Grace Cole ◽  
Yanyan Li ◽  
...  
Keyword(s):  
Day Treatment ◽  
Hemophilia B ◽  
Spontaneous Bleeding ◽  
Safety And Efficacy ◽  
On Demand ◽  
Routine Prophylaxis ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Bleeding Episodes

Abstract A fusion protein genetically linking recombinant human coagulation FIX with recombinant human albumin (rIX-FP) has been developed with an improved PK profile, thus improving hemophilia B treatment by allowing less frequent dosing. Two Phase 3 studies (CSL654-3001 and CSL654-3002) were completed. CSL654-3001 study evaluated safety and efficacy of rIX-FP for prophylaxis treatment (PT) of every 7-, 10- and 14-day and on-demand (ODT) of bleeding episodes in 63 previously treated patients (PTP), 12-61 years of age with hemophilia B (FIX ≤ 2%). Subjects in the on-demand arm received only ODT for 6 months and then switched to every 7-day PT. Subjects in the prophylaxis arm received every 7-day PT, and eligible subjects switched to every 10- or 14-day PT for approximately 12-18 months. Annualized spontaneous bleeding rates (AsBR) were compared between ODT and PT periods (in on-demand arm), and between 7-day PT and 10- or 14-day PT (in prophylaxis arm). CSL654-3002 study evaluated safety and efficacy of rIX-FP for weekly prophylaxis regimen in 27 previously treated patients younger than 12 years with hemophilia B (FIX ≤ 2%) for approximately 12 months. Annualized spontaneous bleeding rates (AsBR) were calculated. The median annualized spontaneous bleeding rate were all 0.00 for all treatment interval (7-day, 10-day or 14-day) and in both studies age groups (1-11 years and 12-65 years) during the two completed phase 3 studies. Seventy-six subjects from both studies continued their prophylaxis regimen in the on-going extension study. In addition, subjects (including children), switched to longer treatment intervals of 10-day, 3 times per month or 14-day or lowered their weekly prophylaxis dose. Nine subjects switched to 21-day treatment interval with 100 IU/kg rIX-FP. As of 28 July 2015, at least 50 subjects (PTP) had achieved 100 EDs without developing an inhibitor to FIX or antibodies to rIX-FP. The long term safety and efficacy of rIX-FP will be presented. This presentation includes the new information regarding the change to longer than 7-day treatment regimens in the extension study, among those subjects (1-61 years of age) that previously participated in the lead in studies. Conclusion: The Prolong - 9FP clinical programdemonstrated the clinical efficacy of rIX-FP for routine prophylaxis every 7-, 10- and 14-day treatment intervals. Routine prophylaxis once every 21 days may be effective in preventing bleeding episodes in a selected patient population. In addition, rIX-FP demonstrated favorable long-term safety and tolerability. Disclosures Santagostino: Novo Nordisk: Speakers Bureau; Bayer: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Biogen/Sobi: Speakers Bureau; Biotest: Speakers Bureau; Kedrion: Speakers Bureau; Octapharma: Speakers Bureau; Roche: Speakers Bureau. Voigt:CSL Behring: Employment. Wolko:CSL Behring: Employment. Cole:CSL Behring: Employment. Li:CSL Behring: Employment. Jacobs:CSL Behring: Employment.

RESULTS OF AN OPEN, PROSPECTIVE, MULTICENTER, NONCOMPARATIVE STUDY OF THE PHARMACOKINETICS, EFFICACY AND SAFETY OF NONACOG ALFA IN PATIENTS AGED 6–12 YEARS WITH SEVERE AND MODERATE HEMOPHILIA B

2020 ◽  
Vol 99 (6) ◽  
pp. 190-198
Author(s):  
T.A. Andreeva ◽  
◽  
V.V. Lebedev ◽  
V.V. Vdovin ◽  
M.A. Timofeeva ◽  
...  
Keyword(s):  
Prophylactic Treatment ◽  
Study Drug ◽  
Factor Ix ◽  
Hemophilia B ◽  
Efficacy And Safety ◽  
Open Label ◽  
Time Curve ◽  
Entire Study ◽  
On Demand ◽  
Bleeding Episodes

Providing hemophilia patients with blood coagulation preparations is one of the priority tasks of the national health care system. In 2011, the first recombinant factor IX was created in Russia (rFIX, nonacog alpha, Innonafactor, GENERIUM JSC), that was previously studied for pharmacokinetic (PK) parameters, efficacy and safety in adult patients and adolescents over 12 years of age with severe and moderate hemophilia B. Objective of this open-label, prospective, multicenter, noncomparative clinical study was to study PK, efficacy and safety of Innonafactor in 12 patients aged 6 to 12 years with severe and moderate forms of hemophilia B (FIX activity less than 2%). The study included periods of screening, studies of PK parameters and treatment within 26±1 weeks, but not less than 50 days of administration of the studied drug. Nonacog alfa was administered in the study of PK parameters at a dose of 75 IU/kg, once, for prophylactic treatment – at a dose of 45±10 IU/kg, 2 times a week with an interval of 72–96 h. 30 minutes after administration of the studied drug, FIX activity increased to 73,93±13,35%, with a gradual decrease to 5,88±1,97% 72 hours after administration. The area under the «concentration ‒ time» curve in the section 0–72 h (AUC0–72) and with exponential extrapolation to infinity (AUC00‒∞) was 1573,41±407,16%*h and 1808,74 ± 437,59%*h respectively. Biological half-life (T1/2) was 28,11±8,60 hours. During preventive treatment there were 19 hemorrhagic episodes, 14 (74%) bleedings were post-traumatic and 5 (26%) bleedings were spontaneous. Mean number of bleeding episodes over the entire observation period was 1,9±1,4. Mean number of episodes of spontaneous bleeding that occurred within 72 hours after Innonafactor administration in patients with bleeding was 2,5±2,1. During the entire study period, patients received 942,5 thousand IU of the drug Innonafactor, 890,5 thousand IU were administered for prophylaxis and 52 thousand IU to stop bleeding on demand. Mean single dose of Innonafactor for prophylactic treatment was 46,24±5,86 IU/kg, for on-demand treatment – 49±13,1 IU/kg. Of the 19 registered bleeding episodes, 14 (73.7%) episodes required the administration of the studied drug; 5 (26,3%) bleedings stopped on their own. To stop one episode of bleeding, an average of 2,3±2,3 administration of nonacog alfa was required. At the end of the study, the proportion of hemophilia B patients with residual FIX activity of 2% or more was 92%. During the study, 14 adverse events (AEs) were registered in 7 (58,3%) patients. All reported AEs were not study drug related and did not require study drug withdrawal. Thromboembolic complications and immunogenic reactions were not registered. Thus, the data obtained indicate efficacy and safety of Innafactor both for prophylactic treatment and for on-demand treatment of bleeding in patients aged 6 to 12 years with severe and moderate hemophilia B.

Efficacy, PK and Safety Results of a Phase I/II Clinical Trial of Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Previously Treated Patients with Haemophilia B (PROLONG - 9FP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1121-1121 ◽  
Author(s):  
Uriel Martinowitz ◽  
Aaron Lubetsky ◽  
Elena Santagostino ◽  
Gantcho Jotov ◽  
Jacob Luboshitz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Prophylactic Treatment ◽  
Factor Ix ◽  
Bleeding Rate ◽  
On Demand ◽  
Routine Prophylaxis ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Bleeding Episodes

Abstract Abstract 1121 Factor IX (FIX) replacement therapy is the standard of care for patients with haemophilia B. FIX products currently available have a relatively short half-life, requiring 2–3 times a week intravenous prophylactic treatment to achieve a significant bleeding reduction. A recombinant FIX albumin fusion protein (rIX-FP) was generated by genetic fusion of human recombinant albumin to rFIX to extend the half life of FIX. A Phase I/II open-label, multicenter, clinical study of rIX-FP has been completed in previously treated patients with severe hemophilia B (FIX ≤ 2%) as part of the PROLONG - 9FP clinical developmental program. The objectives of the study were to evaluate the prevention of bleeding episodes during once weekly prophylaxis and to assess the hemostatic efficacy of rIX-FP for the treatment of bleeding, in addition to safety and pharmacokinetic (PK) assessments. The study consisted of a 10 to 14 day PK evaluation period, and a 3 to 12 month safety and efficacy evaluation period, during which subjects received either on-demand or prophylaxis treatment. Subjects receiving weekly prophylactic treatment were initially treated with a dose based upon the subject's PK profile, bleeding phenotype, and physical activity level. The dose could be adjusted based on clinical outcome, while maintaining a 7 day treatment interval. Subjects receiving on-demand treatment were treated with a dose based upon the subject's PK profile and WFH recommendations for treatment of bleeding episodes. Seventeen study subjects from hemophilia treatment centers in Israel and Bulgaria participated in the study, 13 of whom received weekly prophylaxis treatment and 4 of whom received on-demand treatment. Following a single infusion of 25 IU/kg rIX-FP (n=13), the PK parameters (t1/2 = 94 hrs, AUC0-inf= 3414 hr*IU/dL) were comparable to those previously reported from the Phase I study (Blood prepublished Aug 2, 2012). In addition, rIX-FP maintained a baseline-corrected mean trough level of 3.8% and 2.7% at Day 7 and Day 14, respectively, after 25 IU/kg rIX-FP administration. There were no AEs considered as possibly related to rIX-FP. There were no allergic reactions, inhibitors to FIX or antibodies to rIX-FP reported. All 10 prophylaxis subjects who were previously receiving routine prophylaxis with FIX were maintained successfully on weekly treatment with rIX-FP for the entire study. Furthermore, three prophylaxis subjects who were previously treated on-demand were maintained successfully on weekly prophylaxis treatment with rIX-FP with at least 85% reduction in the annualized spontaneous and total bleeding rate compared to the annualized bleeding rate prior to study entry. All of the bleeding events were treated successfully, including approximately 90% of the events with a single infusion of rIX-FP. The mean weekly product consumption of rIX-FP (IUs) was reduced compared to the consumption of the previous FIX product (IUs). No subject was withdrawn from the study due to safety concerns or lack of hemostatic efficacy. This Phase I/II study has demonstrated the clinical efficacy of rIX-FP for once weekly routine prophylaxis to prevent spontaneous bleeding episodes and treatment of bleeding episodes, in addition to the excellent safety characteristics and improved PK profile. A detailed analysis of the efficacy of weekly routine prophylaxis and treatment of bleeding episodes, improved PK and safety properties of rIX-FP will be presented. Disclosures: Martinowitz: CSL Behring: Honoraria, Investigator for CSL clinical study of rIX-FP Other. Lubetsky:CSL Behring: Investigator for CSL clinical trial of rIX-FP Other. Santagostino:CSL Behring: Honoraria, Investigator for CSL Behring clinical trial of rIX-FP Other, Research Funding, Speakers Bureau. Jotov:CSL Behring: sub-investigator for CSL clinical trial of rIX-FP Other. Barazani-Brutman:CSL Behring: study coordinator for CSL Behring clinical trial of rIX-FP Other. Voigt:CSL Behring: Employment. Moises:CSL Behring: Employment. Jacobs:CSL Behring: Employment. Lissitchkov:CSL Behring: Investigator for CSL Behgring clinical trial of rIX-FP Other.

Once-Weekly Prophylactic Treatment Versus on-Demand Treatment of Nonacog Alfa in Patients with Moderately Severe to Severe Hemophilia B

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1523-1523
Author(s):  
Kaan Kavakli ◽  
Lynne Smith ◽  
Kazimierz Kuliczkowski ◽  
Joan Korth-Bradley ◽  
Chur Woo You ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Research Funding ◽  
Prophylactic Treatment ◽  
Hemophilia B ◽  
Stock Ownership ◽  
Upper Respiratory Tract ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
On Demand ◽  
Scientific Congress

Abstract Introduction: Hemophilia B is characterized by a functional deficiency in factor IX (FIX), which results in spontaneous or trauma-induced bleeding into soft tissue, muscles, and joints. Replacing deficient FIX with plasma-derived or recombinant FIX products, either prophylactically or on an on-demand basis, is a mainstay in the prevention and treatment of bleeding episodes in patients with hemophilia B. A previous study of patients with moderately severe to severe hemophilia B compared the efficacy and safety of 2 secondary prophylaxis regimens of a recombinant coagulation FIX product (nonacog alfa, 50 IU/kg twice weekly or 100 IU/kg once weekly) with on-demand treatment. The study found a significant reduction (P<.0001) in the annualized bleeding rate (ABR) for the prophylaxis regimens compared with on-demand therapy. No significant differences in the ABR were observed between the once-weekly and twice-weekly prophylaxis regimens, and safety and tolerability profiles were similar for both. Objective: To demonstrate that once-weekly prophylaxis with nonacog alfa reduces the ABR compared with on-demand treatment in patients with moderately severe to severe hemophilia B. Methods: This open-label, 2-period study enrolled males aged 12 to 65 years with moderately severe to severe hemophilia B (FIX plasma activity ≤2%), ≥100 prior exposure days to FIX products, and no history of or current FIX inhibitor. Patients received on-demand therapy with nonacog alfa for 6 months (dose selected at the investigator's discretion) followed by prophylactic treatment with nonacog alfa 100 IU/kg once weekly for 12 months. Recovery was assessed on day 1, week 26, and week 78, after a 72-hour washout from any FIX product. Plasma samples were collected before administration and at 30 minutes after nonacog alfa infusion. The primary efficacy end point was the ABR (number of bleeding events/[days on treatment period/365.25]). Secondary end points included the response to on-demand treatment of a bleeding event, incidence of less-than-expected therapeutic effect (LETE) in the prophylaxis setting; and FIX inhibitor development. Safety was also assessed. Results: In total, 25 patients were enrolled and received at least 1 dose of study medication; all patients completed the study. Mean ±SD age was 31.3 ±12.6 years; 5 patients were <18 years; 9 patients were Asian and 16 were white. ABR results are summarized in the Table; ABR for the prophylaxis period was significantly lower (P<.0001) than the ABR for the on-demand period. Of the 507 bleeding events treated over the study, 271 (53.5%) first infusions resulted in an “excellent” response and 177 (34.9%) resulted in a “good” response; the majority of bleeding events (416/507; 82.1%) resolved with 1 infusion. Of the 1254 prophylaxis infusions administered during the study, none were associated with an occurrence of LETE. No patient developed a FIX inhibitor or experienced a thrombotic event during the study. The most commonly reported treatment-emergent AEs (≥20%) were inappropriate schedule of drug administration (24%), arthralgia (20%), upper respiratory tract infection (20%), and toothache (20%) during the prophylaxis period, and headache (32%) and arthralgia (20%) during the on-demand period. Five patients (20%) experienced a total of 6 serious AEs; blood pressure decreased, pain resulting in hospitalization, chicken pox, lipoma, and nephrolithiasis (2 events in 1 patient). Only the serious AE of blood pressure decreased was considered related to study drug. No deaths occurred during the study. Conclusions: Prophylactic treatment with nonacog alfa 100 IU/kg once weekly significantly reduced the number of bleeding events compared with on-demand treatment in patients with moderately severe to severe hemophilia B. Nonacog alfa 100 IU/kg once weekly was well tolerated; no new safety issues were observed. Table. Comparison of Annualized Bleed Rates Between On-Demand and Prophylaxis Regimens Parameter On-Demand (n=25) 100 IU/kg Once-Weekly Prophylaxis (n=25) Over 6 Months Mean (SD) 32.9 (17.4) 3.6 (4.6)* Median 33.6 2.0 Minimum, maximum 6.1, 69.0 0, 13.8 Spontaneous bleeding events Mean (SD) 23.1 (17.1) 2.6 (4.1) Median 22.4 1.0 Minimum, maximum 0, 54.2 0, 13.8 Traumatic bleeding events Mean (SD) 9.9 (14.5) 1.0 (1.6) Median 4.1 1.0 Minimum, maximum 0, 52.2 0, 6.9 *P<.0001 for comparison of on-demand vs prophylaxis treatment. Disclosures Kavakli: Pfizer Inc.: Honoraria; Pfizer Inc.: Scientific Congress Expenses, Scientific Congress Expenses Other; Pfizer Inc.: Research Funding; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees. Smith:Pfizer Inc.: Employment; Pfizer Inc.: Stock Ownership, Stock Ownership Other. Korth-Bradley:Pfizer Inc.: Employment; Pfizer Inc.: Stock Ownership, Stock Ownership Other. Fuiman:Pfizer Inc.: Stock Ownership, Stock Ownership Other; Pfizer Inc.: Employment. Zupancic-Salek:Pfizer Inc.: Research Funding. Rendo:Pfizer Inc.: Employment; Pfizer Inc.: Stock Ownership, Stock Ownership Other.

scholarly journals Characteristics of Patients without Bleeding in a Pivotal Trial of Extended Half-Life, Pegylated, Full-length Recombinant Factor VIII (BAX 855) in the Treatment of Hemophilia A

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1105-1105
Author(s):  
Alice D. Ma ◽  
Robert Klamroth ◽  
Marilyn J. Manco-Johnson ◽  
Werner Engl ◽  
Jacqueline A Dyck-Jones ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Prophylactic Treatment ◽  
Employment Equity ◽  
Advisory Committees ◽  
On Demand ◽  
Bleeding Episodes ◽  
Equity Ownership ◽  
The One

Abstract 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.

scholarly journals Safety and Longer-Term Efficacy of Concizumab Prophylaxis in Patients with Hemophilia a or b with Inhibitors: Results from the Extension Part of the Phase 2 explorer4 Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Amy D Shapiro ◽  
Giancarlo Castaman ◽  
Katarina Cepo ◽  
Sidsel Marie Tønder ◽  
Tadashi Matsushita ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Main Part ◽  
Prophylactic Treatment ◽  
Phase 2 ◽  
Advisory Committees ◽  
On Demand ◽  
Term Efficacy ◽  
Bleeding Episodes

Introduction Concizumab is a high-affinity, anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody currently in clinical investigation for the once-daily subcutaneous prophylactic treatment of patients with hemophilia. We present results from the combined main and extension parts (at least 76 weeks) of the phase 2 explorer4 trial (NCT03196284), which aimed to assess the safety and longer-term efficacy of concizumab in patients with hemophilia A with inhibitors (HAwI) and hemophilia B with inhibitors (HBwI). Methods explorer4 comprised a main part, which lasted at least 24 weeks for all patients, and an extension part, which lasted at least 52 weeks. The primary objective of the main part of explorer4 was to assess the efficacy of concizumab in preventing bleeds in patients with HAwI/HBwI, evaluated as annualized bleeding rate (ABR) at the last dose level after at least 24 weeks. This objective has been addressed in previous reporting of the main part of the trial (Shapiro A, et al. Blood 2019; 134[22]:1973-1982). During the main part of the trial, patients were randomized 2:1 to receive either concizumab prophylaxis or on-demand treatment with recombinant activated factor VII (rFVIIa). At the end of the main part, patients in the rFVIIa on-demand arm were switched to 0.15 mg/kg concizumab for the extension part. Concizumab dose was escalated to 0.20 and 0.25 mg/kg in both the main and extension parts if a patient experienced ≥3 treated spontaneous bleeding episodes within 12 weeks and if deemed safe by the investigator. The objective of the extension part of the trial was to assess safety and longer-term efficacy of concizumab. Endpoints included ABR after at least 76 weeks of treatment, concizumab and free TFPI concentrations prior to last dose administration at 76 weeks, number of adverse events (AEs) and occurrence of anti-drug antibodies (ADAs) during 76 weeks of treatment. ABR was estimated using LS-means estimates, based on a negative binomial regression with log of exposure time to concizumab in main and extension part as offset. Results Twenty-five patients with inhibitors were exposed to concizumab during the explorer4 trial; 15 with HAwI and 10 with HBwI. Eight of these patients received on-demand treatment with rFVIIa during the main part of the trial before receiving their first concizumab dose in the extension phase. The estimated ABR at the last dose level for all patients treated with concizumab during the main and extension parts was 4.8 (95% CI: 3.2-7.2), while during the trial this was 5.7 (95% CI: 4.2−7.8) (Table 1). During the main and extension parts, 4 (16%) patients had zero treated bleeding episodes on their last dose level. Plasma concentrations of concizumab were variable during the extension part of the trial (Table 2). Increased concizumab concentration was observed in patients who received concizumab 0.20 mg/kg; these patients also had lower concentrations of free TFPI (Table 2). There were no AEs leading to withdrawal, no thromboembolic events and no deaths during the main and extension parts of the trial. ADAs developed in 6 patients. Elevated prothrombin fragment 1+2 and D-dimer levels were observed in some patients treated with concizumab. Conclusions Results from the combined main and extension parts of the phase 2 explorer4 trial were in line with the clinical proof of concept established in the main part of the trial and provided further details of the safety and longer-term efficacy of subcutaneous prophylactic treatment with concizumab for at least 76 weeks in patients with HAwI and HBwI. Disclosures Shapiro: BioMarin: Research Funding; Agios: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; OPKO: Research Funding; Daiichi Sankyo: Research Funding; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Glover Blood Therapeutics: Research Funding; Octapharma: Research Funding; Pfizer: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding. Castaman:Uniqure: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ablynx: Honoraria; Alexion: Honoraria; Bayer: Honoraria; Baxalta/Shire: Honoraria; Sobi: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Werfen: Speakers Bureau; Kedrion: Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Cepo:Novo Nordisk: Current Employment. Marie Tønder:Novo Nordisk: Current Employment. Matsushita:Sysmex: Honoraria; Octapharm: Honoraria; Bayer: Consultancy, Honoraria; Novo Nordisk: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Shire/Takeda: Honoraria; Bioverative/Sanofi: Honoraria; CSL: Honoraria; JB: Honoraria; KMB: Honoraria; Kirin: Honoraria; Nichiyaku: Honoraria. Young:Bayer, CSL Behring, Freeline, UniQure: Consultancy; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria; Genentech/Roche, Grifols, and Takeda: Research Funding. Zupancic-Šalek:NovoNordisk Health Care AG: Honoraria, Speakers Bureau; Baxter: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Octapharma: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sobi: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau. Jimenez Yuste:NovoNordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Honoraria; Sobi: Consultancy, Honoraria, Research Funding; CSL: Honoraria; Octapharma: Honoraria.

Sign in / Sign up

Export Citation Format

Share Document