Pharmacokinetic Profile of Nonacog Gamma (recombinant factor IX) in Previously-Treated Patients with Severe or Moderately Severe Hemophilia B

Abstract Pharmacokinetic (PK) parameters are important surrogate indicators for hemostatic efficacy replacement therapy in the treatment of haemophilia patients. Nonacog gamma (Rixubis) is a recombinant factor IX (rFIX) concentrate that is manufactured using two viral inactivation steps (solvent/detergent treatment and nanofiltration) and without any materials of animal origin. Clinical trials of nonacog gamma included a comprehensive evaluation of PK in hemophilia B patients across multiple age groups and a direct comparison to determine equivalence with another licensed, commercially-available factor IX product. The objective of this evaluation was to assess the factor IX activity across clinical development with nonacog gamma. PK parameters for nonacog gamma were evaluated in a non-bleeding state in previously-treated patients with severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B in three prospective clinical trials (a pivotal trial in adults,1 a pediatric trial in children aged 2 to 12 years,2 and a third trial in patients undergoing surgical procedures3). Factor IX activity was determined using a one-stage clotting assay. In the pivotal trial, PK equivalence with a comparator recombinant factor IX product (nonacog alfa) was determined by the ratio of AUC0-72 h (area under the plasma concentration versus time curve from 0 to 72 hours post-infusion), per dose with a type I error of 5% for the two-sided 90% confidence interval (equivalence margin: 80% to 125%). Windyga et al. (2014) established bioequivalence of nonacog gamma with a comparator recombinant factor IX in the pivotal trial (N=27), as the 90% CI for the ratio of the AUC0-72 h per dose ranged from 103% to 109%.1 A plot of mean factor IX activity levels versus time after start of infusion on a linear scale and log scale (figure 1a and 1b) depicts the equivalence throughout the 72-hour follow-up period. A similar pattern can be observed in the linear and log regression for mean factor IX activity in pediatric patients (N=23). These results are further supported by consistent PK parameters determined prior to surgical intervention in the surgery trial (N=12).3 Two important PK parameters determined in each study were as follows: mean [STD] T ½ 26.70h (9.55), incremental recovery (IR) 0.87 (0.22) for nonacog gamma and 27.87h (9.22), IR 0.76 (0.20) for the comparator rFIX in the pivotal trial, 25.31h (3.130), IR 0.67 (0.16) in the pediatric trial, and 23.60h (3.60), IR 1.06 (0.35) in the surgery trial. Conclusion Factor IX activity of nonacog gamma throughout its clinical development support previous finding of its equivalence with another licensed recombinant factor IX concentrate in patients with severe to moderately severe hemophilia B. References 1. Windyga J, Lissitchkov T, Stasyshyn O, et al. Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B. Haemophilia. 2014 Jan;20(1):15-24. 2. Urasinski T, Stasyshyn O, Andreeva T, et al. Recombinant factor IX (BAX326) in previously treated paediatric patients with haemophilia B: a prospective clinical trial. Haemophilia. 2015 Mar;21(2):196-203. 3. Windyga J, Lissitchkov T, Stasyshyn O, et al. Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective, open-label, uncontrolled, multicentre, phase III study. Haemophilia. 2014 Sep;20(5):651-8. Disclosures Windyga: Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker's honorarium; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Chapman:Baxalta (Now part of Shire): Employment, Equity Ownership. Tangada:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Chatterjee:Baxalta (Now part of Shire): Employment, Equity Ownership.

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Recombinant Factor IX in Surgical Management of Hemostasis in Hemophilia B Patients: A Prospective Clinical Trial

Blood ◽

10.1182/blood.v128.22.2585.2585 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2585-2585

Author(s):

Jerzy Windyga ◽

Toshko Jelev Lissitchkov ◽

Vasily Mamonov ◽

Miranda Chapman ◽

Srilatha D. Tangada ◽

...

Keyword(s):

Blood Loss ◽

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Employment Equity ◽

Advisory Committees ◽

Recombinant Factor Ix ◽

Previously Treated ◽

Equity Ownership

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

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Spontaneous Bleeding and Poor Bleeding Response with Extended Half-Life Factor IX Products: A Survey of Select US and Canadian Hemophilia Treatment Centers

Blood ◽

10.1182/blood-2019-126196 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2407-2407 ◽

Cited By ~ 2

Author(s):

Lynn M Malec ◽

Stacy E. Croteau ◽

Michael Callaghan ◽

Davide Matino ◽

Kenneth Dale Friedman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Bleeding Events ◽

Advisory Committees ◽

Spontaneous Bleeding ◽

Recombinant Factor Ix ◽

Traumatic Bleeding ◽

Hemophilia Treatment Centers

Background: Factor IX (FIX) has distinct pharmacokinetic properties compared to factor VIII including significant distribution to the extravascular space. Extravascular distribution and binding to type IV collagen is important in hemostasis but not readily measureable in clinical practice for patients with hemophilia B receiving factor products. We previously reported data regarding use of EHL-FIX products in a cohort of patients who demonstrated issues with spontaneous bleeding and poorly controlled bleeding events; we now report data from an expanded cohort including performance of all EHL-FIX products available in US and Canada. Aims: To characterize the use and performance of EHL-FIX in clinical practice at six hemophilia treatment centers (HTCs). Methods: An electronic survey regarding center specific use of EHL-FIX amongst patients with severe hemophilia B (HB) was sent in summer 2019, including 4 previously surveyed centers and 2 additional centers. Providers were asked if patients utilizing EHL-FIX for prophylaxis had experienced 1) spontaneous/minimally traumatic bleeding events at factor levels >10% or 2) poorly controlled bleeding events requiring more frequent/higher doses of EHL-FIX than anticipated in addition to patterns of EHL-FIX product switching. Results: Surveyed HTCs cared for 90 patients with HB including 67 (74%) who utilized EHL-FIX, including 26 (39%) recombinant factor IX (FIX) albumin fusion protein (rFIX-FP), 37 (55%) recombinant factor IX Fc fusion protein (rFIXFc), and 4 (6%) received glycopegylated recombinant FIX (rFIX-GP). All patients had severe hemophilia B with the exception of one smaller center also contributing data regarding moderate HB patients on prophylaxis. All centers reported having patients with unexpected spontaneous/minimally traumatic bleeding and poorly controlled bleeding which did not seem to be dependent on age (median age 14.5 years, range 1.4-44). This occurred in 18 patients on prophylaxis, including 16 of 26 (62%) patients using rFIX-FP, and 2 of 4 (50%) of patients using rFIX-GP. Conclusions: Although plasma FIX activity levels have driven prophylaxis and bleed management decisions, clinical experience suggests novel properties of EHL-FIX may impact hemostasis. Although achieving seemingly adequate FIX plasma troughs (>10%), limited clinical experience suggests patients with SHB may have a differential response to EHL-FIX, noted in our cohort with FIX-FP and rFIX-GP. Successful bleed prevention or control in SHB may be predicted by the distribution of FIX in circulation and extravascular space, and the presence of FIX in tissues at time of injury. These data demonstrate the importance of real-world monitoring of efficacy of new FIX products and suggest the need for more robust mechanisms to understand the hemostatic performance of products. Disclosures Malec: Bayer: Honoraria; Spark: Honoraria; CSL: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria. Croteau:Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Octapharma: Honoraria; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Callaghan:Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Alnylum: Equity Ownership; Bayer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Global Blood Therapeutics: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy; Pfizer: Research Funding; Roche: Research Funding; Shire/Takeda: Speakers Bureau; Roche/Genentech: Speakers Bureau. Matino:Bayer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Bioviiix: Honoraria; Sanofi: Honoraria. Friedman:CSL: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Instrumentation Laboratory: Consultancy; Siemens: Consultancy. Sidonio:Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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Pharmacokinetics Of Recombinant Factor IX Fc Fusion Protein (rFIXFc) In Pediatric Subjects With Hemophilia B: An Interim Analysis Of The Kids B-LONG Study

Blood ◽

10.1182/blood.v122.21.3599.3599 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3599-3599

Author(s):

Kathelijn Fischer ◽

Roshni Kulkarni ◽

Myles Bradbury ◽

Margaret V. Ragni ◽

Savita Rangarajan ◽

...

Keyword(s):

Board Of Directors ◽

Half Life ◽

Interim Analysis ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Employment Equity ◽

Advisory Committees ◽

Age Cohorts ◽

Equity Ownership

Abstract Introduction Prophylaxis with factor IX (FIX) is the optimal treatment for patients with hemophilia B; however, due to the short half-life of currently available FIX products, frequent injections may be required to prevent bleeding episodes. To prolong half-life and reduce injection frequency, a long-acting recombinant FIX Fc fusion protein (rFIXFc) consisting of one rFIX molecule covalently linked to the Fc domain of immunoglobulin G1 (IgG1) was developed. In a phase 3 study in adults and adolescents, rFIXFc had a 2.43-fold increase in half-life and 50% reduction in clearance (CL) compared with FIX (BeneFIX®) (J Thromb Haemost. 2013;11[2]:241). The Kids B-LONG study (NCT01440946) was designed to evaluate the pharmacokinetics (PK), safety, and efficacy of rFIXFc prophylaxis in previously treated pediatric subjects with hemophilia B. The objective of this planned interim analysis was to determine the PK parameters of rFIXFc in subjects enrolled in Kids B-LONG and compare these parameters to their pre-study FIX PK parameters. Methods This multicenter, open-label, phase 3 study is currently enrolling previously treated subjects aged<12 years with severe hemophilia B (≤2 IU/dL endogenous FIX), at least 50 exposure days (EDs) to FIX products, and no inhibitors to FIX. Subjects are stratified into two age cohorts (<6 and 6 to<12 years of age). A weekly prophylactic regimen of 50-60 IU/kg of rFIXFc is administered to all subjects, with subsequent dose and interval adjustments based upon PK data and bleeding frequency. Subjects will continue treatment until they achieve 50 EDs. The primary endpoint is the incidence of inhibitor formation. A sequential PK analysis is performed to compare the PK parameters of rFIXFc with that of pre-study FIX products. PK sampling of pre-study FIX occurs at baseline prior to first dose of FIX (50 IU/kg) and at 5 additional time points through 48 hours. PK sampling of rFIXFc occurs prior to first dose of 50 IU/kg rFIXFc and at 7 additional time points through 168 hours following the first dose; a washout period of 96 hours is required before the first dose of both pre-study FIX and rFIXFc. Plasma FIX activity is measured using the one-stage clotting assay calibrated against a commercially available FIX plasma standard and the FIX activity-over-time profiles are analyzed by non-compartmental analysis (NCA) using the PK data analysis software Phoenix™ WinNonlin 6.2.1.51. A data cut-off date of 23 April 2013 was used to report PK data in this interim analysis. Results At the time of this interim analysis, 24 subjects were enrolled and had received at least one dose of pre-study FIX and/or rFIXFc. Of 18 subjects with evaluable PK profiles, 15 had complete PK profiles for both pre-study FIX (BeneFIX®, Haemosolvex®, or Alphanine®) and rFIXFc. A comparison of PK parameters for rFIXFc versus FIX for both age cohorts is presented in Table 1. rFIXFc had a more than 3-fold prolongation in half-life and a more than 60% reduction in CL compared to the FIX products. Conclusion In comparison to currently available FIX products, rFIXFc had a prolonged half-life and reduced CL in pediatric subjects, which was similar to previous observations in adults and adolescents. The final analysis of the Kids B-LONG study will provide further PK information and evaluate the safety and efficacy of rFIXFc in children. Disclosures: Fischer: Biogen Idec, Baxter, Novo Nordisk, Bayer: Membership on an entity’s Board of Directors or advisory committees; Baxter, Bayer, Novo Nordisk, Pfizer: Research Funding. Kulkarni:Biogen Idec, Novo Nordisk, Baxter : Membership on an entity’s Board of Directors or advisory committees. Ragni:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb, Smith Kline Glaxo, Tacere Benitec: Consultancy; Baxter, Bayer, Biogen Idec, Bristol Myers Squibb, CSL Behring, Merck, Novo Nordisk, Pfizer, Smith Kline Glaxo: Research Funding. Rangarajan:Baxter, Pfizer: Research Funding; Biogen Idec : Membership on an entity’s Board of Directors or advisory committees. Dong:Biogen Idec: Employment, Equity Ownership. Li:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment, Equity Ownership. Nugent:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Allen:Biogen Idec: Employment, Equity Ownership.

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Long Term Safety and Efficacy of Recombinant Factor IX Fc Fusion Protein (rFIXFc) Prophylaxis in Children with Hemophilia B: Interim Results of the B-Yond Extension Study

Blood ◽

10.1182/blood.v128.22.4976.4976 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4976-4976 ◽

Cited By ~ 1

Author(s):

Jonathan M. Ducore ◽

Kathelijn Fischer ◽

Roshni Kulkarni ◽

Beatrice Nolan ◽

Carolyn M. Bennett ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Advisory Committees ◽

Safety And Efficacy ◽

Treatment Groups ◽

Recombinant Factor Ix ◽

Bleeding Episodes

Abstract Introduction: The phase 3 Kids B-LONG study (NCT01440946) demonstrated the safety, efficacy, and pharmacokinetics of prophylactic recombinant factor IX Fc fusion protein (rFIXFc) for the prevention and treatment of bleeding episodes in children with severe hemophilia B. The ongoing rFIXFc extension study B-YOND (NCT01425723) is evaluating long-term safety and efficacy of rFIXFc in children and adults with hemophilia B. The safety and efficacy data for pediatric subjects from the second B-YOND interim data cut (11 Sep 2015) are reported here. Methods: The Kids B-LONG study enrolled males aged <12 years with severe hemophilia B (≤2 IU/dL endogenous factor IX [FIX] activity) who had ≥50 exposure days (EDs) of a prior FIX product. Subjects completing Kids B-LONG (median time on study: 49.4 wk) could enroll in 1 of 3 prophylactic treatment groups in B-YOND: weekly prophylaxis (WP; 20-100 IU/kg every 7 d), individualized prophylaxis (IP; 100 IU/kg every 8-16 d), or modified prophylaxis (MP, to optimize prophylaxis with IP or WP). Subjects could change treatment groups at any point in B-YOND. The primary endpoint was development of inhibitors (neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay). Secondary outcomes included annualized bleeding rate (ABR) and rFIXFc exposure days (EDs). Additional outcomes included adverse events (AEs) and evaluation of treatment of bleeding episodes. This analysis reports data for pediatric B-YOND subjects (includes subjects who were <12 y at enrollment into Kids B-LONG) treated with ≥1 dose of rFIXFc. Results: At the time of the second B-YOND interim data cut, 27 subjects had completed Kids B-LONG and enrolled in B-YOND (<6 y cohort, n=13; 6 to <12 y cohort, n=14). Ten subjects had completed (ie, ended participation in the study without premature discontinuation), 16 subjects were ongoing in B-YOND, and 1 subject withdrew due to subject request. From the start of Kids B-LONG to the second B-YOND interim data cut, subjects had a median (range) 2.3 y (0.9-3.0 y) of treatment with rFIXFc, and a median (range) 127.0 (50.0-183.0) cumulative rFIXFc EDs.No inhibitors were observed. AEs were generally typical of the pediatric hemophilia B study population. There were no reports of serious allergic reactions or anaphylaxis associated with rFIXFc, and no vascular thrombotic events; no subjects had AEs related to the study drug. Median (interquartile range [IQR]) overall, spontaneous, and traumatic ABRs were low in both age groups for subjects in the IP and WP treatment groups (Figure; 1 subject in each age cohort was in the MP group [data not shown]). Median (IQR) joint ABRs were 0.0 (0.0-2.2) for subjects < 6 years in the WP treatment group and 0.9 (0.0-2.7) and 1.1 (0.0-2.4) for subjects 6 to <12 years in WP and IP treatment groups, respectively. Regardless of age or treatment group, the majority of bleeding episodes were controlled with 1-2 intravenous injections (<6 y, 97.3%; 6 to <12 y, 97.2%). At the end of Kids B-LONG, 26/27 subjects were dosing once weekly and 1/27 subject was dosing every 5 days. Compared with these dosing intervals, 14.8% of subjects lengthened, 77.8% of subjects did not change, and 7.4% of subjects decreased their prophylactic dosing interval during B-YOND. The median (IQR) dosing interval during B-YOND for pediatric subjects in the IP treatment groups was 10.0 [10.0, 10.7] days. Compared with the end of B-LONG, the median (IQR) total weekly prophylactic dose of rFIXFc was similar at the second B-YOND interim data cut (60.0 [50.0-60.0] vs 60.0 [57.0-70.0]). Conclusion: These data confirm the long-term safety of rFIXFc with maintenance of low ABRs and extended-interval prophylaxis in children with hemophilia B. This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content. Disclosures Ducore: Octapharama: Membership on an entity's Board of Directors or advisory committees; Baxalta (Shire): Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Fischer:Baxter: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Speakers Bureau; Biogen: Consultancy; Biotest: Consultancy, Speakers Bureau; Baxalta/Baxter: Consultancy, Research Funding, Speakers Bureau; Wyeth: Research Funding; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy. Kulkarni:Kedrion: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: 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, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nolan:Sobi: Research Funding; Biogen: Research Funding. Perry:Biogen: Consultancy, Honoraria; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yuan:Biogen: Employment, Equity Ownership. Ramirez-Santiago:Biogen: Employment, Equity Ownership. Ferrante:Sobi: Employment. Lethagen:Sobi: Employment.

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Spk-9001: Adeno-Associated Virus Mediated Gene Transfer for Hemophilia B Achieves Sustained Mean Factor IX Activity Levels of >30% without Immunosuppression

Blood ◽

10.1182/blood.v128.22.3.3 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3-3 ◽

Cited By ~ 13

Author(s):

Lindsey A. George ◽

Spencer K. Sullivan ◽

Adam Giermasz ◽

Jonathan M. Ducore ◽

Jerome M. Teitel ◽

...

Keyword(s):

Immune Response ◽

Gene Transfer ◽

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: Earlier data demonstrated long-term expression of factor IX (mean FIX:C ~5.1%) following AAV8-mediated gene transfer at 2 x1012 vg/kg in hemophilia B (Nathwani et al., 2014). While the clinical improvement imparted by stable FIX levels is clear, these levels of expression fall short of trough values obtained by long-acting FIX prophylaxis (Santagostino et al. 2016), and of natural history data suggesting that levels of ~12% are required to eliminate spontaneous hemarthroses (den Uijl et al. 2011). Achieving higher levels of FIX:C with dose escalation has not been possible without eliciting a dose-dependent, capsid-specific immune response that may prevent sustained expression and efficacy (Mingozzi et al. 2007, Monahan et al. 2015). We sought to develop a highly efficient vector capsid and expression cassette that could be administered at low doses to achieve hemostatic FIX expression without need for immunosuppression. Methods: The investigational product, SPK-9001, utilizes a bioengineered AAV capsid (Spark100) with liver specific tropism. The prevalence of neutralizing antibodies (NAb) to Spark100 among sampled hemophilia B sera was 40% (Anguela et al. 2015). The expression cassette is a codon-optimized, single-stranded transgene encoding FIX Padua, a naturally occurring variant with a single amino acid substitution (R338L) that confers ~8-fold greater specific activity compared to wild-type FIX (Simioni et al. 2009). Data on bleeding and factor infusions in the year prior to enrollment were retrospectively compiled. Laboratory values, bleeding frequency, FIX consumption, changes in activity and quality-of-life via Haem-A-QoL were prospectively evaluated after vector infusion. Results: We enrolled 9 subjects, of whom 2 failed screening for liver fibrosis and 7 were infused with SPK-9001 at a dose of 5 x1011 vg/kg. Infused subjects were adult males ages 18-52 years with baseline FIX:C </=2% and Spark100 NAb titer of <1:1 or 1:1. Table 1 outlines infused subject data with a follow up interval of >2-34 weeks after vector infusion. Figure 1 outlines subject vector-derived FIX:C for the first 12 weeks. There have been no vector or procedure related adverse events. Steady-state FIX expression is reached by 12 weeks after vector infusion, resulting in a mean FIX:C of 32.3% ±6.5%. To date, no subjects required immunosuppression or demonstrated evidence of a cytotoxic immune response (characterized by loss of FIX activity, elevation of transaminase values >/=1.5-times the upper limit of normal, and positive IFN-gammaELISPOT response to capsid peptides). No subjects developed a FIX inhibitor or demonstrated ELISPOT reactivity to the FIX (R338L) gene product. Subject 3 infused with FIX concentrate for a suspected ankle bleed 2 days after vector infusion. Beyond this, no subjects required factor or experienced any bleeding events. The 4 subjects previously maintained on prophylaxis safely stopped without break-through bleeding. As of today (cumulative 724 days post vector infusion), total factor consumption was reduced by 543,589 IU, tantamount to a cumulative savings of $1,182,298 USD.Six of 7 subjects report increased physical activity and improved quality of life. Conclusion: As of 8/4/2016, we report the highest and most consistent levels of sustained vector-derived FIX:C following FIX gene transfer. Levels of FIX:C achieved by SPK-9001 permitted termination of prophylaxis, prevention of bleeding, and nearly complete cessation of factor use. Despite the heterogeneity in subjects with respect to presence and extent of hemophilic arthropathy, age, and co-morbidities, consistency of transgene expression and clinical outcomes have been observed in all participants studied to date. A vector dose of 5x1011 vg/kg is the lowest dose currently reported in hemophilia gene transfer trials; the absence of any observed CD8+ T cell immune response supports the hypothesis that lowering the dose can reduce or eliminate the risk of a capsid-specific immune response and maximize efficacy. In summary, preliminary data suggest SPK-9001 safely and consistently produces sustained elevation in FIX:C levels sufficient to prevent spontaneous hemarthroses without the need for factor consumption or immunosuppression. Disclosures Ducore: Octapharama: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; 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 (Shire): Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Cuker:Biogen-Idec: Consultancy, Research Funding; T2 Biosystems: Research Funding; Genzyme: Consultancy; Stago: Consultancy; Amgen: Consultancy. McGuinn:Spark: Research Funding; Biogen: Research Funding; Novo Nordisk: Research Funding; Baxalta: Research Funding. Luk:Spark Therapeutics, Inc.: Employment. Wright:Spark Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties: SPK-9001. Chen:Spark Therapeutics, Inc.: Employment. Hui:Spark Therapeutics, Inc.: Employment. Wachtel:Spark Therapeutics, Inc.: Employment. Urich:Spark Therapeutics, Inc.: Employment. Takefman:Spark Therapeutics, Inc.: Employment. Couto:Spark Therapeutics, Inc.: Employment. Carr:Pfizer, Inc.: Research Funding. Anguela:Spark Therapeutics, Inc.: Employment, Patents & Royalties: SPK-9001. High:Spark Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties: SPK-9001.

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Analysis of Target Joint Bleeding with Prophylactic Use of Recombinant Factor IX Fc Fusion Protein in Patients with Severe Hemophilia B

Blood ◽

10.1182/blood.v126.23.2294.2294 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2294-2294

Author(s):

Amy D Shapiro ◽

David J Perry ◽

Ross I Baker ◽

Elisa Tsao ◽

Baisong Mei

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Severe Hemophilia ◽

Bleeding Events ◽

Advisory Committees ◽

Recombinant Factor Ix ◽

Bleeding Episodes ◽

Dosing Intervals

Abstract Background: The phase 3 B-LONG study demonstrated the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) for the prevention and treatment of bleeding episodes in subjects with severe hemophilia B. For people with hemophilia, frequent bleeding events occur in target joints, which are a known precursor to hemophilic arthropathy (chronic joint disease). There is currently limited information available on the outcomes of prophylaxis in subjects with target joints who have severe hemophilia B. Aims: To assess the frequency of bleeding events and the dosing of rFIXFc in subjects who had ≥1 target joint at baseline in the B-LONG study. Methods: B-LONG was a Phase 3, multicenter, open-label study that enrolled males aged ≥12 years with severe hemophilia B (≤2 IU/dL endogenous FIX activity) who had received prior treatment with FIX. Subjects in B-LONG were enrolled into 1 of 4 arms: Arm 1, weekly prophylaxis; Arm 2, individualized interval prophylaxis; Arm 3, episodic treatment; or Arm 4, perioperative management. For the current post-hoc analysis, subjects with ≥1 target joint at baseline (per protocol, a target joint was defined as a major joint with ≥3 bleeding episodes in a 3-month period) and who received on-study rFIXFc prophylaxis (Arms 1 and 2 only) were included. On-study per subject target joint ABR (annualized number of bleeding episodes per year in all target joints combined), including overall, spontaneous, and traumatic target joint ABR, were assessed. In subjects with available prestudy and on-study ABR data, prestudy 12-month bleeding rates were compared with on-study overall ABR. Results: Forty-three subjects from the prophylaxis arms had target joints at entry into B-LONG and data collected during the efficacy period of the study (weekly prophylaxis, n = 35; individualized interval prophylaxis, n = 8). Of these, 40 subjects had both prestudy and on-study bleeding information available. Regardless of prestudy treatment regimen (prophylactic or episodic rFIX), on-study median ABRs were low among subjects with target joints at baseline compared with prestudy ABRs (Fig. 1). The on-study overall target joint, spontaneous target joint, and traumatic target joint median (interquartile range, [IQR]) ABRs were low for subjects in the weekly prophylaxis arm (1.03 [0.00, 3.07], 0.00 [0.00, 1.10], and 0.00 [0.00, 1.11], respectively) and for subjects in the individualized interval prophylaxis arm (2.20 [0.00, 3.75], 2.20 [0.00, 3.75], and 0.00 [0.00, 0.00], respectively; Fig. 2). A total of 17 (48.6%) subjects receiving weekly prophylaxis and 3 (37.5%) subjects receiving individualized interval prophylaxis had no target joint bleeding episodes on-study. The average weekly prophylactic rFIXFc dose for subjects with target joints at baseline was (median [IQR]) 46.26 (37.98, 54.55) IU/kg and 69.48 (57.28, 77.45) IU/kg for those receiving weekly prophylaxis and individualized interval prophylaxis, respectively. The median (IQR) average on-study dosing intervals for these groups were 6.98 (6.88, 7.00) days and 10.25 (9.45, 12.72) days, respectively. Among subjects with target joints at baseline who received prestudy rFIX and on-study rFIXFc prophylaxis (n = 6, weekly prophylaxis arm only; no subjects from the individualized interval prophylaxis arm who met these criteria had available data), the on-study median (IQR) average weekly prophylactic dose of 50.61 (39.61, 60.61) IU/kg with rFIXFc was lower than the prestudy median (IQR) average weekly prophylactic dose of 111.28 (95.56, 116.76) IU/kg with rFIX. Additionally, the on-study median (IQR) dosing interval (6.92 [6.79, 6.97]) with rFIXFc prophylaxis was longer than the pre-study median (IQR) dosing interval among these 6 subjects (3.50 [2.33, 3.50] days). Summary/Conclusion: For subjects in the current analysis with severe hemophilia B who entered B-LONG with target joints, rFIXFc prophylaxis was effective for reducing the frequency of bleeding episodes overall and in target joints. Furthermore, in subjects who received prestudy and on-study prophylaxis, rFIXFc was associated with reduced consumption and prolonged dosing intervals compared with conventional prestudy rFIX products. These results suggest that target joints can be effectively managed and controlled with rFIXFc dosed prophylactically every 1 to 2 weeks. Disclosures Shapiro: Baxalta, Novo Nordisk, Biogen, ProMetic Life Sciences, and Kedrion Biopharma: Consultancy; Biogen: Speakers Bureau; Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, and Selexys: Research Funding; Baxalta, Novo Nordisk, Biogen,: Membership on an entity's Board of Directors or advisory committees. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Baker:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: conference travel support, 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, Research Funding; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Portola Pharmaceuticals: Research Funding; Astellas: Research Funding; CSL Behring: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support; Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support; Bristol- Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Other: conference travel support. Tsao:Biogen: Employment, Equity Ownership. Mei:Biogen: Employment, Equity Ownership.

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Clinical Study to Investigate the Efficacy and Safety of Wilate during Prophylaxis in Previously Treated Patients with Von Willebrand Disease (VWD)

Blood ◽

10.1182/blood-2019-128339 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4931-4931

Author(s):

Robert F. Sidonio ◽

Bruce A. Schwartz

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Prophylactic Treatment ◽

Von Willebrand Disease ◽

Advisory Committees ◽

Previously Treated Patients ◽

Previously Treated ◽

Type 3 ◽

Von Willebrand

Background: Inherited von Willebrand disease (VWD) is the most common inherited hemorrhagic disorder, with an estimated prevalence of 1 in every 100 individuals. Type 1 and type 3 (the most severe form) are characterized by a quantitative deficiency of von Willebrand factor (VWF) and type 2 arises from a qualitative deficiency of VWF. Treatment of VWD depends on the type and severity of the disease. Severe bleeding is reported in patients with all subtypes, leading to progressive joint disease as well as diminished quality of life (QoL). VWF/factor VIII (FVIII) concentrates have become the mainstay of VWD treatment for these patients with severe disease or for those patients in whom other treatments (e.g., desmopressin) are ineffective or contraindicated but this is broadly applicable only for on demand treatment. Aims: The primary objective of this study is to determine the efficacy of VWF/FVIIII concentrate in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD. Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time and, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication. The study will also examine, the efficacy of VWF/FVIIII concentratein the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the QoL during prophylaxis with VWF/FVIIII concentrate. Methods: The study is planned to enroll 28 patients aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run-in observational study to collect the bleeding profile prior to the start of prophylaxis. From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated. Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none) In patients that undergo surgeries, efficacy of VWF/FVIIII concentratewill be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator. Results: Data will be monitored on an ongoing basis and the study is expected to end Q2 2021. Conclusions: Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve QoL in patients but to date, this form of treatment in VWD is not well characterized. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the QoL in VWD patients. Disclosures Sidonio: Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: 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; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees. Schwartz:Octapharma: Employment.

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99.3% of Inhibitors in Severe Hemophilia a Develop before Exposure Day 75. Time to Change Definition of Previously Treated Patients; Data from 1038 Patients with Severe Hemophilia a of the Pednet Registry

Blood ◽

10.1182/blood-2018-99-114518 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2472-2472

Author(s):

Marijke Van den Berg ◽

Kathelijn Fischer ◽

Elena Santagostino ◽

Herve Chambost ◽

Karin Kurnik ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Advisory Committees ◽

Inhibitor Development ◽

Previously Treated Patients ◽

Previously Treated ◽

Definition Of

Abstract Introduction.In patients with hemophilia treated with factor VIII products, the development of inhibitory antibodies poses the largest safety risk. Especially during the first 50 exposure days (EDs), up to 37% of patients with severe hemophilia A have been reported to develop an inhibitor. To study neo-immunogenicity of products and new treatment strategies, patients have been distinguished into previously untreated (PUPs) and previously treated patients (PTPs); the latter defined as patients treated for more than 150 EDs. The number of 150 EDs was established in the eighties during a time when most patients received on-demand treatment and testing for inhibitors was not frequently performed. More recent studies on inhibitor incidence in PUPs with severe hemophilia A report that 50% of inhibitors develop within 14-15 EDs, however the cut-off number of EDs for a PUP to become a PTP is not well defined. The aim of this study was to define the number of EDs for PUPs to become PTPs based on long-term follow-up of patients with severe hemophilia A Methods.All patients with severe hemophilia A born after January 1, 2000, treated for at least 1 ED and followed prospectively until inhibitor development or the number of EDs at last follow-up, were included. The number of EDs at inhibitor development is the last exposure day before the first positive titer was reported. An inhibitor was defined as positive when at least two positive inhibitor titers were measured. Positivity was defined according to the cut-off level in each individual center's laboratory. Results.Of 1,038 PUPs with severe hemophilia A, 930 (89.6%) were followed until 75 EDs, 429 until 500 EDs and 212 until 1000 EDs. In total, 300 inhibitors developed, of which 298 (99.3%) within the first 75 EDs. Thereafter only two inhibitors developed, both low titer: after 249 and 264 EDs. Conclusion.Almost all inhibitors develop during the first 75 EDs. Patients with severe hemophilia A can be defined as PTP after 75 instead of 150 exposure days. A change of definition of PTP will increase the number of severe hemophilia A patients eligible for new therapies. Disclosures Santagostino: Bioverativ: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Male:SOBI: Speakers Bureau; Shire: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Speakers Bureau; Novo Nordisk: Speakers Bureau; Biotest: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oldenburg:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liesner:Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Sobi: Speakers Bureau; Bayer: Consultancy, Research Funding; Roche: Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau. Carcao:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nolan:CSL Behring: Research Funding; Sobi: Research Funding; Bayer: Research Funding. Álvarez-Roman:Shire: Consultancy; NovoNordisk: Consultancy; SOBI: Consultancy. Koenigs:Gilead: Research Funding; CSL Behring: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Intersero: Research Funding; Bioverativ: Consultancy; Roche/Chugai: Consultancy; EU (IMI, FP7): Research Funding; Sobi: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding; Novo Nordisk: Consultancy, Speakers Bureau; Biotest: Research Funding, Speakers Bureau; Jansen: Research Funding.

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Phase 3 Clinical Trial: Perioperative Use of Nonacog Gamma, a Recombinant Factor IX, in Previously Treated Patients With Moderate/Severe Hemophilia B

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029620946839 ◽

2020 ◽

Vol 26 ◽

pp. 107602962094683

Author(s):

Jerzy Windyga ◽

Margarita Timofeeva ◽

Oleksandra Stasyshyn ◽

Vasily Mamonov ◽

José Luis Lamas Castellanos ◽

...

Keyword(s):

Elective Surgery ◽

Study Drug ◽

Factor Ix ◽

Hemophilia B ◽

Severe Hemophilia ◽

Phase 3 ◽

Recombinant Factor Ix ◽

Previously Treated Patients ◽

Previously Treated ◽

Hemostatic Efficacy

Hemostatic management is essential for ensuring the safety of patients with hemophilia during surgery. This phase 3, prospective, uncontrolled trial, evaluated hemostatic efficacy, consumption, and safety of a recombinant factor IX concentrate, nonacog gamma (BAX 326, Rixubis® [Baxalta US Inc., a Takeda company, Lexington, MA, USA]), in intraoperative and postoperative settings in previously treated patients (PTPs) with severe or moderately severe hemophilia B undergoing elective surgery (N = 38 surgeries; 21 major, 17 minor). Predefined preoperative hemostatic factor IX levels (80-100% of normal for major and 30-60% for minor surgeries) were maintained for each patient. Intraoperative efficacy was rated as “excellent” or “good” for all surgeries. Postoperative hemostatic efficacy on day of discharge was rated as “excellent,” “good,” and “fair,” respectively, for 29 (76.3%), 7 (18.4%), and 2 (5.3%) surgical procedures. All adverse events were considered unrelated to study drug; most frequently reported was mild procedural pain (9 patients). No thrombotic events, severe allergic reactions, or inhibitor formation were observed. Nonacog gamma was well tolerated and effective for intraoperative and postoperative hemostatic management of PTPs with hemophilia B. NCT01507896, EudraCT: 2011-000413-39

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A Pharmacokinetic Study of the Plasma-Derived Factor IX AlphaNine® and Its Comparison with the Recombinant Factor IX BeneFIX®, in Previously Treated Patients with Severe Hereditary Hemophilia B.

Blood ◽

10.1182/blood.v110.11.3955.3955 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3955-3955

Author(s):

Vicente R. Cortina ◽

T. Lissichkov ◽

K. Zavilska ◽

M. Matysiak ◽

L. Gercheva ◽

...

Keyword(s):

Half Life ◽

Factor Ix ◽

Hemophilia B ◽

Severe Haemophilia ◽

Open Label ◽

Recombinant Factor Ix ◽

Previously Treated Patients ◽

Previously Treated ◽

In Vivo Recovery

Abstract Objectives The objective of the present study was two fold: first, to determine the pharmacokinetic (PK) profile of the plasma-derived FIX concentrate AlphaNine® in patients with congenital severe haemophilia B (FIX:C 2%). To do this, two PK studies were carried out one six months after the first. The second objective was a comparison of the Alphanine® PK profile with the recombinant Factor IX, BeneFIX®. Patients and methods The first study was a prospective, five-center, open-label, comparative, PK study carried out in 25 severe hemophilia B patients who received 2 single doses of 65–75 IU/kg of AlphaNine® within 6 months (t=0 and t=6). The following parameters were assessed: in vivo recovery, half-life, AUC, mean residence time and clearance. As an extension of the study, a single dose of 65–75 IU/kg of BeneFIX® was administered in 9 out of 25 patients, after a wash-out period of 7–15 days. Results Table 1 summarizes the results obtained when comparing AlphaNine® within a period of time of 6 months (PK1 vs PK2) in 25 patients. Table 2 shows the results obtained when comparing the in vivo recovery of AlphaNine ® vs BeneFIX ® in the 9 patients studied. Conclusions These results confirm that AlphaNine® PK has similar profile as other plasma derived FIX products presently available to treat Hemophilia B patients. In addition, our results show that the recombinant FIX studied, BeneFIX® has a reduced in vivo recovery when is compared to AlphaNine®. Table 1 Parameter AlphaNine® (PK1) t=0 m AlphaNine® (PK2) t=6 m Results are expressed as Mean (SD) In vivo recovery (IU/dl:IU/kg) 1.0 (0.2) 1.2 (0.4) Half-life (h) 34.5 (6.2) 33.7 (5.4) Clearance (ml/min) 0.07 (0.01) 0.07 (0.01) AUC0-inf (IUxh/dl) 1602 (312) 1644 (360) MRT0-inf (h) 35.8 (5.4) 34.6 (5.2) Table 2 Parameter AlphaNine® (PK2) BeneFIX® Results are expressed as Mean (SD); * p<0.05 for the comparison of the in vivo recovery for the BeneFIX® group with the AlphaNine® PK2 In vivo recovery (IU/dl:IU/kg) 1.3 (0.5) 0.8 (0.2)*

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