scholarly journals Factor VIII Use in the Treatment of Breakthrough Bleeds in Hemophilia A Patients without Inhibitors on Emicizumab Prophylaxis: The Phase 3 HAVEN 3 Study Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2395-2395
Author(s):  
Michael Callaghan ◽  
Benjamin Trzaskoma ◽  
Richard H. Ko ◽  
Lucy Lee ◽  
Anisha M. Patel ◽  
...  
Keyword(s):  
Factor Viii ◽  
Exposure Time ◽  
Cumulative Dose ◽  
Research Funding ◽  
Hemophilia A ◽  
Phase 3 ◽  
Breakthrough Bleeding ◽  
On Demand ◽  
Equity Ownership ◽  
The Individual

Introduction HAVEN 3 was a phase 3 study investigating the use of emicizumab as prophylaxis in adult and adolescent (≥12 years old) persons with hemophilia A (PwHA) without factor VIII (FVIII) inhibitors (NCT02847637; Mahlangu et al. 2018). HAVEN 3 demonstrated that emicizumab prophylaxis once weekly or every two weeks was safe and highly effective in bleed prevention. The primary analysis of HAVEN 3 included an intrapatient comparison of 48 participants who received FVIII prophylaxis in a non-interventional study (NIS) prior to enrollment in HAVEN 3. Compared with emicizumab prophylaxis during the HAVEN 3 study, emicizumab prophylaxis resulted in an annualized bleed rate that was 68% lower than the rate with previous FVIII prophylaxis (1.5 vs 4.8, p<0.001). No dosing guidance was provided regarding the use of on-demand FVIII in HAVEN 3, and investigators prescribed FVIII at their own discretion. In this subsequent analysis, we characterize the dose and frequency of replacement FVIII used for the treatment of breakthrough bleeding in these 48 participants. Methods The primary comparisons in our analyses are focused on on-demand FVIII use for breakthrough bleeding while participants were on FVIII prophylaxis during the NIS versus its use while on emicizumab prophylaxis during HAVEN 3. Any use of on demand FVIII other than to manage breakthrough bleeding (e.g. prior to activity) was not included in our analyses. Given that, collectively, the total exposure time to emicizumab during HAVEN 3 was more than twice the exposure time to FVIII prophylaxis during the NIS (75.8 vs 28.6 years respectively), any treatment comparisons are drawn on an annualized basis. Annualized on-demand FVIII use was calculated by dividing by the number of days in the efficacy period and multiplying the resulting daily consumption by 365.25 days. The number of infusions and cumulative doses of on-demand FVIII use are described at the participant level as well as at the individual bleed level and are presented descriptively for both the NIS and HAVEN 3 exposure periods. No formal statistical inferences (i.e. calculation of p-values) have been conducted. All analyses were based on an October 2018 data cutoff. Results A total of 48 participants who were treated with FVIII prophylaxis during the NIS were then treated with emicizumab prophylaxis during HAVEN 3 and thus make up the total cohort for our analyses. Annualized infusion rates of on-demand FVIII per participant and cumulative doses of on-demand FVIII (in international units [IU] per kilogram) per participant were higher during the FVIII prophylaxis period when compared with the emicizumab exposure period (mean 15.3 vs 7.2; median 3.6 vs 0.6 annual infusions per participant and mean 602.4 IU/kg vs 209.0 IU/kg; median 75.5 IU/kg vs 19.1 IU/kg, respectively). At the individual bleed level, FVIII infusions and total cumulative dose suggested that participants were administered a similar amount of medication to treat bleeds during both the NIS and HAVEN 3 study periods: median number of infusions per bleed were 1.0 (interquartile range [IQR]=1.0) versus 2.0 (IQR=3.0) and median cumulative doses were 43.5 (IQR=35.1) versus 50.0 (IQR=72.7) IU/kg, respectively (Table 1). Conclusions This analysis revealed a lower annualized infusion rate and a correspondingly lower annualized cumulative dose of FVIII for treatment of breakthrough bleeds during emicizumab prophylaxis compared with FVIII prophylaxis. At the individual bleed level, the amount of on-demand FVIII used per bleeding episode was comparable between NIS and HAVEN 3 exposure periods. Thus, based on this single analysis, it appears that patients received less on-demand FVIII during emicizumab prophylaxis compared with FVIII prophylaxis, as a result of overall reduction of bleed frequency, while the treatment of individual bleeds appeared similar regardless of the prophylaxis therapy administered. Disclosures Callaghan: Octapharma: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Bayer: Consultancy, Speakers Bureau; Alnylum: Equity Ownership; Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Roche/Genentech: Speakers Bureau; Shire/Takeda: Speakers Bureau; Pfizer: Research Funding; Roche: Research Funding. Trzaskoma:Genentech: Employment, Equity Ownership. Ko:Genentech, Inc.: Employment. Lee:Genentech, Inc.: Employment. Patel:Genentech: Employment; Roche/Genentech: Equity Ownership. Tzeng:Genentech, Inc.: Employment. Shah:Genentech: Employment. Chang:Genentech, Inc.: Employment; Genentech/Roche: Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Dhalluin:F. Hoffmann-La Roche Ltd: Employment. Mahlangu:Sanofi: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Biomarin: Research Funding; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; Unique: Research Funding.

Perioperative Efficacy of an Extended Half-Life, Pegylated, Full-Length, Recombinant Factor VIII (BAX 855) in Individual Procedures

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2299-2299
Author(s):  
Brigitte Brand ◽  
Ralph A. Gruppo ◽  
Tung T. Wynn ◽  
Laimonas Griskevicius ◽  
Maria Fernanda Lopez Fernandez ◽  
...  
Keyword(s):  
Blood Loss ◽  
Factor Viii ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Full Length ◽  
Recombinant Factor Viii ◽  
Employment Equity ◽  
Major Procedure ◽  
Equity Ownership

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

scholarly journals Breakthrough Bleeding in Hemophilia a Patients on Prophylaxis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2581-2581 ◽  
Author(s):  
Beth Boulden Warren ◽  
Taylor Blades ◽  
Natalie L Smith ◽  
Michael Wang ◽  
Marilyn J. Manco-Johnson
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Breakthrough Bleeding ◽  
University Of Colorado ◽  
The University

Abstract Background: Patients with severe hemophilia A (factor VIII (FVIII)<1%), as well as many patients with moderate hemophilia A (FVIII 1-5%), are treated intravenously with FVIII prophylaxis to prevent bleeding. However, breakthrough bleeding occurs in many patients. Methods: To better understand breakthrough bleeding, we evaluated the effect of hemophilia severity, prophylaxis adherence, and replacement FVIII utilization on bleeding rates in patients with hemophilia A on prophylaxis. Data on hemophilia severity and bleeding rates were collected from subjects with hemophilia A, ages 2-30 years, treated at the University of Colorado for hemophilia A, using the University of Colorado Clinical Research Bleeding Disorders Database (UCBDD). Adherence and FVIII utilization data were collected from a subset of subjects with hemophilia A on prophylaxis without active inhibitors who participated in the Centers for Disease Control/American Thrombosis and Hemostasis Network Community Counts (CDCCC) registry between December 2013 and June 2016, which surveyed participants about their estimated percentage of missed prophylaxis doses. The CDCCC registry was also used to corroborate bleeding rates. The effect of hemophilia severity and missed prophylaxis doses (percentage of prescribed doses) on bleeding rates were analyzed using logistic regression, with bleeding rates dichotomized as high or low relative to study population median bleeding rates. The relationship between weekly factor utilization and annualized bleeding rates was evaluated using Pearson's correlation. Results: Of 89 patients with severe hemophilia A in the UCBDD, 86.5% of patients were on continuous prophylaxis, with an additional 7.9% on immune tolerance induction. The 5.6% of patients with severe hemophilia on episodic treatment had been encouraged to use prophylaxis but had declined. Of 37 patients with moderate hemophilia A, 48.7% were on continuous prophylaxis. Sixty-nine subjects on prophylaxis had data in the UCBDD and the CDCCC registry collected during the defined time period. Bleeding rates are shown in Table 1. Prophylaxis doses in this population had an interquartile range of 74.3 to 120 units/kg/week (mean 96.9 units/kg/week), dosed 2-7 times per week depending on activities and historic bleeding patterns. Eighty-two percent of patients rated their percentage of missed prophylaxis doses at <10%, 11.6% rated their missed doses at 10-20%, 2.9% rated their missed doses at 21-50%, and 2.9% rated missed doses at >50%. There was not a statistically significant relationship between any bleeding rate and percentage of missed doses, hemophilia severity, or factor utilization, as shown graphically in figures 1 and 2. Conclusion: Although prophylaxis usage and adherence were excellent, breakthrough bleeding was common, with breakthrough joint bleeding occurring in 36% of subjects, and was not related to FVIII dose per week. Prospective studies are needed to better determine individually tailored prophylaxis regimen using dose, product class, and timing with activities, in order to achieve more effective prophylaxis. Table 1 Bleeding Rates on Continuous Prophylaxis. No intracranial or gastrointestinal hemorrhages were recorded in this population. Table 1. Bleeding Rates on Continuous Prophylaxis. No intracranial or gastrointestinal hemorrhages were recorded in this population. Figure 1 Relationship between Bleeding Rates, Hemophilia Severity and Adherence Figure 1. Relationship between Bleeding Rates, Hemophilia Severity and Adherence Figure 2 No correlation was found between bleeding rates and factor VIII utilization as measured in units per kg per week. Figure 2. No correlation was found between bleeding rates and factor VIII utilization as measured in units per kg per week. Disclosures Warren: HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program: Research Funding. Wang:Biogen: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Baxalta: Honoraria; NovoNordisk: Honoraria; BiogenIdec: Honoraria; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria.

scholarly journals Patterns of Prior Treatment and Bleeds Among Patients with Severe Hemophilia a: Impact on Frequency of Dosing with Bay 81-8973 in the Leopold I Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1103-1103 ◽  
Author(s):  
Nikki Church ◽  
Rajeev Ayyagari ◽  
Jennifer Pocoski ◽  
Gautam Sajeev ◽  
Sneha S Kelkar ◽  
...  
Keyword(s):  
Factor Viii ◽  
Research Funding ◽  
Hemophilia A ◽  
Prior Treatment ◽  
Recombinant Factor Viii ◽  
Average Dose ◽  
Severe Hemophilia ◽  
On Demand ◽  
Dosing Frequency ◽  
The Impact

Abstract Background: BAY 81-8973 is an investigational recombinant factor VIII (FVIII) product with recommended prophylactic dosing of 20-40 IU/kg at least 2x or 3x weekly for patients with severe hemophilia A. The frequency of dosing with FVIII is among several decisions made by treating physicians and potentially affects effectiveness and cost. The impact of prior bleeds or prior FVIII treatment on the choice of BAY 81-8973 dosing frequency has not been studied previously and may help clarify the association of dosing frequency with effectiveness. This study examines the association between prior treatment patterns and bleeds with dose frequency assignment in patients from the LEOPOLD I (LEO I) trial. Methods: Data from part B of the phase II/III randomized, open-label crossover LEO 1 trial were analyzed. The sample consisted of patients who received prophylactic treatment with BAY 81-8973 during the 12-month LEO I study period. At study start, patients were assigned to a dose and a frequency of either 2x/week or 3x/week at the investigator's discretion; once assigned, the dose and frequency were unchanged through the study period. This analysis compared physician-recorded pre-enrollment FVIII treatment frequencies and bleeds during the last 12 months prior to enrollment between the 2x/week and 3x/week groups. Wilcoxon rank sum tests were used to compare average dose per FVIII injection and number of bleeds, and chi-square tests were used for mode of treatment (on-demand or prophylaxis) and FVIII treatment frequencies. Results: Among 62 patients in the trial, mean age was 31.5 years and 89% were Caucasians. FVIII prophylaxis frequencies ranged from daily to 1x/week prior to enrollment. 11 patients in the 2x/week group had received pre-enrollment FVIII prophylaxis at a frequency of 2x/week (Table 1). 28 patients in the 3x/week group had received FVIII injections at a frequency of 3x/week prior to enrollment. Some of these patients in each group had also received pre-enrollment FVIII prophylaxis at other frequencies. Average FVIII doses per injection in IU/kg were higher in the 2x/week group for prior on-demand and prophylactic therapy, but these differences were not statistically significant. The majority of patients in the 2x/week group (56%) and the 3x/week group (59%) had received Bayer's sucrose-formulated recombinant factor VIII prior to enrollment. Regardless of prior mode of treatment, the average number of bleeds in the last 12 months before enrollment was higher in the 3x/week group (13.4 bleeds) than in the 2x/week group (7.1 bleeds). Conclusions: Investigator selection of 2x/week or 3x/week dosing frequency was correlated with the regimen patients were on prior to enrollment. Patients receiving FVIII 3x/week had, overall, more frequent bleeding episodes than patients in the 2x/week group in the year prior to enrollment, suggesting that a phenotypic approach can well be used for dosing with Bay 81-8973. Disclosures Church: Bayer Healthcare Pharmaceuticals: Employment. Ayyagari:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Pocoski:Bayer Healthcare Pharmaceuticals: Employment. Sajeev:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Kelkar:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Du:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Mass-Enriquez:Bayer Healthcare Pharmaceuticals: Employment. Xie:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding.

Improved Factor VIII Expression with the Introduction of a PACE-Furin Variant into Codon-Optimized Human Factor VIII

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3498-3498
Author(s):  
Liron Elkouby ◽  
Robert J. Davidson ◽  
Paris Margaritis ◽  
Katherine A. High ◽  
Denise E. Sabatino
Keyword(s):  
Biological Activity ◽  
Factor Viii ◽  
Research Funding ◽  
Hemophilia A ◽  
Recognition Site ◽  
Wild Type ◽  
Aav Vector ◽  
Equity Ownership ◽  
Transgene Cassette

Abstract Adeno-associated viral (AAV) vector delivery of canine factor VIII (cFVIII) results in long-term dose dependent expression of FVIII in hemophilia A dogs for >8 years (Sabatino 2011). These data demonstrate that AAV-FVIII can significantly improve the disease phenotype. Interestingly, we found that cFVIII is inherently more stable than human FVIII (hFVIII), resulting in increased biological activity (Sabatino 2009). Thus, the AAV dose of cFVIII does not predict the efficacy of hFVIII and preclinical studies with hFVIII will be important for predicting the therapeutic dose of AAV-hFVIII. Furthermore, recent clinical trials for AAV-mediated gene transfer for hemophilia B have demonstrated sustained long-term expression of therapeutic levels of factor IX (FIX) but established that the AAV vector dose may be limiting due to anti-AAV immune responses to the AAV capsid. Therefore, our goal is to generate a novel hFVIII transgene cassette that increases hFVIII expression so that we can achieve therapeutic FVIII levels with a lower AAV dose. In our efforts to develop a hFVIII transgene cassette, we addressed this systematically by comparing different codon-optimized B-domain deleted (BDD) hFVIII genes, alternate promoters as well as hFVIII variants of the PACE-furin cleavage recognition site. We identified a novel codon-optimized hFVIII-BDD transgene (CO3) that expresses 15-fold higher than wild-type hFVIII-BDD. CO3 was introduced into a minimal expression cassette driven by the liver-specific transthyretin (TTR) promoter. At 4 weeks after delivery of AAV8-TTR-hFVIII-BDD and AAV8-TTR-hFVIII-CO3 (1x1011 vector genomes/mouse), the hFVIII expression in the peripheral blood based on ELISA was 35 ± 5 ng/ml and 492 ± 72 ng/ml, respectively. Using a modified transthyretin (TTRm) promoter (222bp), hFVIII expression further increased 2-fold compared to a wild type TTR promoter. In our previous work, we demonstrated that the R1645H substitution in the PACE-furin (P/F) cleavage recognition site (hFVIII-R1645H) confers increased stability and higher biological activity (Siner 2013). More recently, we have characterized a series of deletion variants at this P/F site in hFVIII with similar properties to R1645H. Therefore, in an effort to further enhance the efficacy of our hFVIII gene therapy approach, we introduced the R1645H or a 4 amino acid deletion (residues 1645-1648) of the P/F site (delP/F) into our hFVIII-CO3 transgene. Administration of AAV8-TTR-hFVIII-CO3, AAV8-TTR-hFVIII-CO3-R1645H and AAV8-TTR-hFVIII-CO3-delP/F in hemophilia A mice (1x1011vg/mouse) demonstrated that the hFVIII expression from R1645H (528 ± 30 ng/ml) was higher than CO3 (378 ± 75 ng/ml) at this vector dose. However, introduction of delP/F (TTR-hFVIII-CO3-delP/F) resulted in hFVIII expression that was 1.8-fold higher (685 ± 93 ng/ml)(p = 0.036) than CO3 alone. Importantly, the introduction of the deletion of the PACE-furin recognition site into the codon-optimized hFVIII resulted in an additive effect on the hFVIII expression. Delivery of AAV8-TTRm-hFVIII-CO3-delP/F using the modified TTR promoter resulted in 1018 ± 117 ng/ml hFVIII demonstrating that the TTRm promoter further enhances transgene expression. Notably, the AAV8-TTRm-hFVIII-CO3-delP/F construct results in hFVIII expression that is 30-fold higher than the wild type hFVIII-BDD. Our studies demonstrate that a combination of a liver-specific promoter, codon-optimization and modification of hFVIII at the PACE-furin recognition site (delP/F) significantly increases hFVIII expression in the setting of gene transfer. This work supports the feasibility of lowering the AAV vector dose for a gene-based therapeutic application for hemophilia A. Disclosures Elkouby: Spark Therapeutics: Research Funding. High:Bluebird Bio: Consultancy, Equity Ownership; Alnylam: Consultancy; Spark Therapeutics: Consultancy, Equity Ownership. Sabatino:Spark Therapeutics: Research Funding; Pfizer, Inc.: Research Funding.

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.

scholarly journals Patient satisfaction and acceptability of an on-demand and on-prophylaxis device for factor VIII delivery in patients with hemophilia A

2019 ◽  
Vol Volume 13 ◽  
pp. 233-240 ◽  
Author(s):  
Giovanni Di Minno ◽  
Elena Santagostino ◽  
Massimo Morfini ◽  
Cosimo Ettorre ◽  
Dorina Cultrera ◽  
...  
Keyword(s):  
Patient Satisfaction ◽  
Factor Viii ◽  
Hemophilia A ◽  
On Demand

Steady-State Imatinib Trough Levels as Well as Dose Interruptions Are Associated with Clinical Response (CCyR and MMR) and Adverse Events (AEs) in Patients with Chronic Myeloid Leukemia (CML) Receiving IM as Frontline Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2213-2213
Author(s):  
Richard A. Larson ◽  
Yen Lin Chia ◽  
Camille Granvil ◽  
François Guilhot ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Steady State ◽  
Clinical Response ◽  
Cumulative Dose ◽  
Research Funding ◽  
Risk Scores ◽  
Employment Equity ◽  
Risk Patients ◽  
Equity Ownership ◽  
Grade 3 ◽  
Trough Levels

Abstract Abstract 2213 Poster Board II-190 Background: Correlations between IM trough plasma levels (Cmin) and clinical response have been previously reported [Picard et al. Blood 2007; Larson et al. (IRIS) Blood 2008; Guilhot et al. (TOPS) ASH 2008]. This analysis correlates IM Cmin on Day 29 of initial treatment with complete cytogenetic response (CCyR) and major molecular responses (MMR) at 12 months and with cumulative Grade 3&4 toxicity over 12 months based on data pooled from 2 studies, IRIS (400 mg qd) and TOPS (400 mg bid (800 mg/daily) vs 400 mg qd), in newly diagnosed, previously untreated, Ph+ CML-CP. Methods: Steady-state Cmin was defined as predose blood level collected within ±3 hours of the scheduled dosing time on Day 29 without any dose interruptions within 5 days prior to PK sampling. The correlation between IM Cmin and CCyR and MMR at 12 months was studied by two approaches: 1) analysis of outcomes by quartile groups based on patients' IM Cmin levels; 2) logistic regression analysis with Cmin as a continuous variable plus Sokal risk scores and cumulative days with any dose interruptions during the initial 12 months. Safety parameters included Grade 3&4 AEs, as well as all frequently-occurring (>10%) AEs of any grade that occurred during the 12 months. Patients with missing covariates were excluded. Results: Steady-state IM Cmin trough levels were available in 526 patients: 319 in IRIS and 207 from TOPS. At the time of assessment most patients received either 400 mg or 800 mg; 8 patients received reduced doses (6 at 300 mg; 2 at 600 mg). The median IM Cmin [25-75% quartiles] for 400 mg in the pooled dataset was 943 ng/mL [688-1280 ng/mL], and that for 800 mg was 2910 ng/mL [2333-3900 ng/mL]. IM Cmin showed large inter-patient variability for both 400 mg and 800 mg dose groups (52.7% and 39.9%, respectively). Both CCyR and MMR rates at 12 months were significantly correlated with IM Cmin on Day 29. Besides Cmin on Day 29, Sokal risk scores and cumulative dose interruptions (due either to treatment-related toxicities or non-adherence) were significant covariates for 12 month CCyR and MMR. Patients with high Sokal scores (H) had lower CCyR and MMR rates than those with low Sokal scores (L), 64% (H), 69% (intermediate (I)), and 83% (L), respectively, for CCyR, and 37%, 48%, and 59%, respectively, for MMR. Response rates at 12 months were significantly lower for patients with cumulative dose interruptions > 28 days (in the first 12 months): 45% vs 76% for CCyR, and 27% vs 48% for MMR. Modeling predicts that at a Cmin level of 1000 ng/mL and assuming no or minimal dose interruptions, the CCyR at 12 months would be 85%, 78%, and 68% for L, I, and H Sokal risk patients, respectively, and for MMR 55%, 45% and 36%, respectively. If the Cmin were 2000 ng/mL, the CCyR at 12 months would be 93%, 89%, and 83% for L, I, and H Sokal risk patients, respectively, and for MMR 65%, 55% and 44%, respectively. The predicted CCyR and MMR would be lower if there were dose interruptions. Patients who had Grade 3&4 AEs over first 12 months period (n=136) had a higher IM Cmin on Day 29 (median [25-75% quartiles], 1985 [982-2943] ng/mL vs 1010 [728-1468] ng/mL, P<0.001), than those without (n=390) as well as longer cumulative dose interruptions (20 [8-41] days vs 0 [0-2] days, P<0.001), lower CCyR rate (66%; 77/117 vs 75%; 277/369, P=0.05), and lower MMR rate (37%; 49/131 vs 48%; 155/323, P=0.006). Most Grade 3&4 AEs were treatment-related hematologic AEs with median times to onset between 50-63 days. Regression analysis showed the correlation between hematologic Grade 3&4 AEs and IM Cmin level for the population (Figure). Among all-grade non-hematologic AEs, rash and vomiting were associated with higher IM Cmin levels. Conclusion: IRIS+TOPS pooled data confirmed earlier findings that higher steady-state IM levels correlate with better CCyR and MMR responses but also with more Grade 3&4 treatment-related toxicities. Dose interruptions compromise CCyR and MMR rates at 12 months. IM Cmin levels provide additional information together with clinical response and tolerability to inform dose changes for individual patients. Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding. Chia:Novartis: Employment. Granvil:Novartis: Employment. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. O'Brien:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Nedelman:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment, Equity Ownership.

Efficacy and Safety of Secondary Prophylactic Versus On-Demand Sucrose-Formulated Recombinant Factor VIII Treatment in Adults with Severe Hemophilia A: Results from a 13-Month Crossover Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 516-516 ◽  
Author(s):  
Peter Collins ◽  
Albert Faradji ◽  
Massimo Morfini ◽  
Monika Maas Enriquez ◽  
Eduard Gorina ◽  
...  
Keyword(s):  
Health Economics ◽  
Factor Viii ◽  
Crossover Study ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Joint Function ◽  
On Demand ◽  
History Of ◽  
Male Patients

Abstract Many of the physical, psychosocial, and financial difficulties associated with severe hemophilia can be attributed to the effects of recurrent joint bleeds and chronic arthropathy. Regimens for clotting factor replacement treatment for hemophilia include prophylactic and on-demand therapy. A study in pediatric male patients with severe hemophilia A showed that prophylactic treatment with sucrose-formulated recombinant factor VIII (rFVIII-FS) resulted in prevention of joint damage and a decrease in the frequency of joint and other bleeds compared with on-demand therapy (Manco-Johnson MJ, et al. N Engl J Med.2007;357:535). A clinical trial was conducted in adult patients with severe hemophilia A and history of frequent bleeding to evaluate the effect of secondary rFVIII-FS prophylaxis on the number of joint bleeds after switching from on-demand rFVIII-FS therapy. Secondary study objectives were to compare these treatment strategies with regard to joint function, number of all bleeds, health-related quality of life, health economics, and safety. Male patients who were aged 30–45 years, had a negative inhibitor status, had a history of FVIII treatment (&gt;100 exposure days), and were using on-demand FVIII treatment before the study were eligible to participate in this prospective 13-month crossover study. During the first 6 months, all patients received on-demand rFVIII-FS treatment. Patients were then switched to prophylactic rFVIII-FS treatment (20–40 IU/kg 3 times per wk at a stable dose as determined by investigators based on the patient’s bleeding history) for the remaining 7 months, with the first month constituting a washout/stabilization run-in period. Patients were monitored throughout the 13 months for bleeds and health-economics parameters and were evaluated by the Gilbert score (joint function) and the Haemo-QoL questionnaire at baseline and at the end of the on-demand (at 6 mo) and prophylactic (at 13 mo) treatment periods. A total of 20 patients from 9 international sites participated in the study. Patients received a mean dose of 31 IU/kg/wk during the on-demand period, which increased to 86 IU/kg/wk during the prophylaxis period. Although 16/20 patients already had 1 to 4 target joints, mean (±SD) numbers of joint and total bleeds per patient significantly decreased during the prophylaxis period (1.5±2.1 and 1.9±3.3, respectively) compared with the on-demand period (18.5±11.6 and 23.7±13.3; P&lt;0.001 for both). Mean (±SD) total Gilbert scores indicated better joint function at the end of prophylaxis (19.8±11.7) vs on-demand (25.3±11.7; P&lt;0.001) treatment. During this short observation period, there was no statistically significant difference between treatments in the pharmacoeconomic variables assessed (days off work, general practitioner visits, and hospitalization days) or in the mean total Haemo-QoL score, although patients reported significantly fewer restrictions at work or school by the end of the prophylaxis period compared with the end of the on-demand period (P=0.016). There was a trend toward improved patient activity levels with prophylaxis. Similar numbers of patients reported adverse events (AEs) during on-demand (n=9, 45.0%) and prophylactic (n=10, 52.6%) treatment; AEs occurring in 2 patients (dysgeusia and headache) were considered treatment related. Serious AEs were reported by 1 patient during each treatment; neither serious AE was related to treatment. No de novo inhibitor development was observed during either treatment. In summary, prophylaxis with rFVIII-FS was well tolerated and reduced the frequency of joint and other bleeds compared with on-demand treatment in previously treated adults with severe hemophilia A and target joints.

Analysis of Second Primary Malignancies in Lenalidomide-Treated Patients with IPSS Low- or Int-1-Risk Myelodysplastic Syndromes

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1704-1704 ◽  
Author(s):  
Aristoteles Giagounidis ◽  
Azra Raza ◽  
Alan F. List ◽  
Pierre Fenaux ◽  
Bouchra Benettaib ◽  
...  
Keyword(s):  
Research Funding ◽  
Prior History ◽  
Second Primary ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Increased Risk ◽  
History Of ◽  
Equity Ownership ◽  
Rbc Transfusion

Abstract Abstract 1704 Background: Lenalidomide (LEN) is approved in the US for the treatment of RBC transfusion-dependent patients with IPSS Low- or Int-1-risk myelodysplastic syndromes (MDS) with del(5q), with or without other cytogenetic abnormalities. In a phase 3 trial, treatment with LEN 5 mg and 10 mg resulted in RBC transfusion independence (TI) for ≥ 26 weeks in 43% and 56% of such patients, cytogenetic response in 25% and 50%, and a significant improvement of health-related quality of life (p <.05 for both 5 mg and 10 mg). Achievement of RBC-TI ≥ 8 weeks was associated with a significantly reduced risk of AML progression and death (p <.05 for both) (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). In newly diagnosed multiple myeloma patients, results of phase 3 trials showed a numerical imbalance in the occurrence of second primary malignancies (SPMs) between patients treated with LEN (in combination with melphalan or immediately after high-dose melphalan therapy and stem cell transplantation) and control cohorts. SPMs were analyzed in clinical trials of LEN across indications, including MDS. Methods: This was a single arm analysis of SPM data retrieved from RBC transfusion-dependent patients with IPSS Low- or Int-1-risk MDS with or without del(5q) who received LEN as monotherapy in 5 studies (MDS-001, -002, -003, -004, and -007). The cutoff date was February 28, 2011. SPMs were defined using MedDRA (Medical Dictionary for Regulatory Activities) categories of invasive SPMs (hematologic malignancies and solid tumors) and non-melanoma skin cancers (NMSC). Acute myeloid leukemia (AML) is considered part of the natural history of disease progression in MDS. Although further follow-up is needed, results of a phase 3 study showed no obvious evidence for an increased risk of AML progression in LEN-treated RBC transfusion-dependent patients with IPSS Low- or Int-1-risk MDS and del(5q) (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). AML was not included in the present analysis. The overall number of SPMs (invasive malignancies and NMSC), and the number and incidence rate (IR) of all invasive SPMs were evaluated, with IR defined as the number of new events per 100 person-years (pys). The IR of invasive SPMs was compared with the IR of new events of invasive cancer as reported from the SEER (Surveillance, Epidemiology, and End Results) cancer registry (2.1/100 pys for persons aged ≥ 65 years) (Howalder N et al. National Cancer Institute, 2011). Results: The combined population of all 5 studies comprised 557 LEN-treated patients. The median age was 71 years (range 27–95 years) and 72% of patients were aged ≥ 65 years. 88 patients (15.8%) had a prior history of cancer including malignant melanoma, meningioma, breast cancer, lung cancer, squamous cell carcinoma, and basal cell carcinoma. A total of 28 patients (5.0%) developed ≥ 1 SPM, including 17 (3.1%) with an invasive SPM and 12 (2.2%) with NMSC; 1 patient had both an invasive malignancy and a NMSC. Two of the 17 patients with invasive SPMs had a B-cell malignancy and 15 had solid tumors of heterogeneous type. Of the 28 patients with SPMs in total, 5 patients had a prior history of cancer. The IR of invasive SPMs was 2.60/100 pys (95% confidence interval 1.56–4.07), which is consistent with the IR reported in the SEER database among patients in this age group (2.1/100 pys for persons aged ≥ 65 years). The median time to onset of SPMs was 13.5 months (range 0.3–48.6 months). Conclusion: There was no clear evidence to associate LEN treatment with an increased risk of developing SPMs in patients with Low- or Int-1-risk MDS with or without del(5q). The IR of invasive SPMs among these LEN-treated patients is what would be expected from population-based estimates of invasive cancer incidence among persons in this age group. The collection of data on SPMs in LEN-treated patients including post-marketing information is ongoing. Disclosures: Giagounidis: Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy, Honoraria, Research Funding. Fenaux:Merck: Honoraria; Johnson & Johnson: Honoraria; Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Cephalon: Honoraria; Novartis: Honoraria. Benettaib:Celgene Corporation: Employment, Equity Ownership. Brown:Celgene Corporation: Employment, Equity Ownership. Zhong:Celgene Corporation: Employment, Equity Ownership. Brandenburg:Celgene Corporation: Employment, Equity Ownership. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Treatment Of Serious Bleeds With a B-Domain Deleted Recombinant Porcine Sequence Factor VIII (OBI-1) In Patients With Acquired Hemophilia A: A Prospective Clinical Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 206-206 ◽  
Author(s):  
Rebecca Kruse-Jarres ◽  
Jean St. Louis ◽  
Anne Greist ◽  
Amy D. Shapiro ◽  
Hedy Smith ◽  
...  
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Positive Response ◽  
Acquired Hemophilia A ◽  
Advisory Committees ◽  
Baxter Healthcare ◽  
Bayer Healthcare ◽  
Travel Grant

Abstract Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder, resulting from auto-antibodies to human factor VIII (hFVIII). The challenges created by the management of AHA and the co-morbidities present in this typically elderly population, can be managed by a recombinant, highly pure, B-domain deleted, porcine sequence FVIII (OBI-1) that is not generally susceptible to the inhibitory activity of anti-human FVIII antibodies. Treatment with OBI-1 allows for monitoring of FVIII levels which provides a reproducible and objective surrogate predictor of hemostasis. Eradication of hFVIII inhibitors with immunosuppressive therapy is critical for disease management. During immunosuppression, the patient transitions from a bleeding state at initial presentation to a relative hypercoagulable state which can be an issue in patients who are susceptible to thromboembolic events due to their comorbidities. This transition period is of most concern especially when using traditionally utilized bypassing agents that cannot be monitored. OBI-1 enables measurement of FVIII levels, guiding dosing and enhancing treatment safety during this critical period. Methods This global, prospective, multi-center phase 2/3 open label clinical trial investigates the efficacy and safety of OBI-1 in the treatment of serious bleeds in adults with AHA conducted under ICH guidelines and local IRB/Ethics Committee oversight. Primary efficacy endpoint was assessed at 24 hours (eg. effective, partially effective). All subjects (N= 18) presented with a serious bleed and were treated with an initial dose of OBI-1 (200 U/kg), followed by additional doses based on the subject's target factor VIII levels, anti-OBI-1 titer, and clinical factors. Results In all 18 subjects, a positive response (14 effective/4 partially effective) to treatment was observed at 24 hours. This positive response to OBI-1 treatment was seen by 8 hours in 14/18 of the subjects and at 16 hours in 16/18 of the subjects. Median total exposure to OBI-1 per subject was 1782.5 U/kg. The median total first dose was 14,000 U. For subjects who received additional doses of OBI-1, the median dose was reduced from the initial dose, but did not differ considerably over subsequent doses (9180 to 13561 U; median 11000 U). The majority of subjects (17/18) received concomitant immunosuppressive therapies. No related serious adverse reactions occurred. Non-serious adverse events related to treatment were noted in 5/18 (27.8%) subjects. One subject had mild tachycardia, hypotension and constipation. One subject had 2 instances of mild PICC line occlusion. One subject had a mild hypofibrogenemia. All of these adverse effects completely resolved. Three subjects developed anti-porcine inhibitors after infusion of study drug (range 8-108 BU) and two were discontinued from treatment. Anti-porcine inhibitors were detected prior to infusion in 6/18 patients (range 0.8-29 BU). All of these subjects had a favorable clinical response at 24 hours post-OB-1 infusions. Conclusions Data from this prospective study demonstrate OBI-1 as a safe and effective treatment of bleeding episodes in patients with AHA, with the added advantage over other bypass therapies of allowing FVIII monitoring throughout treatment and healing phase. Disclosures: Kruse-Jarres: Baxter Healthcare: Consultancy; Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy. St. Louis:CSL Behring: Research Funding; Octapharma: Consultancy, Research Funding; Baxter: Consultancy; Novo Nordisk: Honoraria. Shapiro:Kedrion Biopharma: Consultancy; Chugai Pharma USA: Consultancy; Biogen IDEC: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Baxter Healthcare: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Chowdary:Baxter Healthcare: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel grant Other; Novo Nordisk: Honoraria, Research Funding, Travel grant, Travel grant Other; Bayer HealthCare: Honoraria, Travel grant, Travel grant Other; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; CSL Behring: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant Other; Biogen IDEC: Honoraria, Travel, Travel Other. Drebes:Octapharma: Travel grant Other; CSL Behring: Travel grant, Travel grant Other; Leo-pharma: Travel grant, Travel grant Other; Bayer Healthcare: Consultancy, Honoraria. Gomperts:Baxter Healthcare: Consultancy; Asklepios Biopharmaceutoicals Inc: Consultancy; Cangene Inc: Consultancy. Chapman:Baxter Healthcare: Employment. Mo:Baxter Healthcare: Employment. Novack:Baxter Healthcare: Employment. Farin:Baxter Healthcare: Employment.

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