scholarly journals In silico evaluation of limited blood sampling strategies for individualized recombinant factor IX prophylaxis in hemophilia B patients

2017 ◽  
Vol 15 (9) ◽  
pp. 1737-1746 ◽  
Author(s):  
T. Preijers ◽  
H. C. A. M. Hazendonk ◽  
K. Fijnvandraat ◽  
F. W. G. Leebeek ◽  
M. H. Cnossen ◽  
...  
Keyword(s):  
In Silico ◽  
Factor Ix ◽  
Blood Sampling ◽  
Hemophilia B ◽  
Sampling Strategies ◽  
Recombinant Factor Ix

scholarly journals In silico evaluation of limited sampling strategies for individualized dosing of extended half-life factor IX concentrates in hemophilia B patients

2021 ◽  
Author(s):  
T. Preijers ◽  
M. W. F. van Spengler ◽  
K. Meijer ◽  
K. Fijnvandraat ◽  
K. Fischer ◽  
...  
Keyword(s):  
In Silico ◽  
Half Life ◽  
Factor Ix ◽  
Hemophilia B ◽  
Weekly Dose ◽  
Sampling Strategies ◽  
Time Profiles ◽  
Limited Sampling ◽  
Individualized Dosing ◽  
Life Factor

Abstract Purpose Hemophilia B is a bleeding disorder, caused by a factor IX (FIX) deficiency. Recently, FIX concentrates with extended half-life (EHL) have become available. Prophylactic dosing of EHL-FIX concentrates can be optimized by assessment of individual pharmacokinetic (PK) parameters. To determine these parameters, limited sampling strategies (LSSs) may be applied. The study aims to establish adequate LSSs for estimating individual PK parameters of EHL-FIX concentrates using in silico evaluation. Methods Monte Carlo simulations were performed to obtain FIX activity versus time profiles using published population PK models for N9-GP (Refixia), rFIXFc (Alprolix), and rIX-FP (Idelvion). Fourteen LSSs, containing three or four samples taken within 8 days after administration, were formulated. Bayesian analysis was applied to obtain estimates for clearance (CL), half-life (t1/2), time to 1% (Time1%), and calculated weekly dose (Dose1%). Bias and precision of these estimates were assessed to determine which LSS was adequate. Results For all PK parameters of N9-GP, rFIXFc and rIX-FP bias was generally acceptable (range: −5% to 5%). For N9-GP, precision of all parameters for all LSSs was acceptable (< 25%). For rFIXFc, precision was acceptable for CL and Time1%, except for t1/2 (range: 27.1% to 44.7%) and Dose1% (range: 12% to 29.4%). For rIX-FP, all LSSs showed acceptable bias and precision, except for Dose1% using LSS with the last sample taken on day 3 (LSS 6 and 10). Conclusion Best performing LSSs were LSS with samples taken at days 1, 5, 7, and 8 (N9-GP and rFIXFc) and at days 1, 4, 6, and 8 (rIX-FP), respectively.

scholarly journals Treatment of hemophilia B: focus on recombinant factor IX

2013 ◽  
pp. 33 ◽  
Author(s):  
Massimo Franchini ◽  
Frattini ◽  
Crestani ◽  
Sissa ◽  
Bonfanti
Keyword(s):  
Factor Ix ◽  
Hemophilia B ◽  
Recombinant Factor Ix

scholarly journals Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-Fc fusion protein: A randomized trial

2019 ◽  
Vol 3 (2) ◽  
pp. 268-276 ◽  
Author(s):  
Carmen Escuriola Ettingshausen ◽  
Inga Hegemann ◽  
Mindy L. Simpson ◽  
Adam Cuker ◽  
Roshni Kulkarni ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Randomized Trial ◽  
Protein A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Fc Fusion Protein ◽  
Recombinant Factor Ix

The Synonymous V107V Mutation In Factor IX Is Not So Silent and May Cause Hemophilia B In Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2197-2197 ◽  
Author(s):  
Chava Kimchi-Sarfaty ◽  
Vijaya L Simhadri ◽  
David Kopelman ◽  
Adam Friedman ◽  
Nathan Edwards ◽  
...  
Keyword(s):  
Codon Usage ◽  
In Silico ◽  
Synonymous Codon ◽  
Protein Translation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Structure Stability ◽  
Synonymous Mutation ◽  
Codon Substitution ◽  
In Silico Analyses

Abstract Abstract 2197 Hemophilia B is characterized by structural and functional defects in coagulation factor IX (FIX) caused by mutations in the F9 gene. Various mutations (nonsense, missense, etc.) are known to be associated with the disease, including a synonymous V107V mutation reported recently by Knobe and colleagues (Knobe et al., Hemophilia, 2008). However the mechanism by which this synonymous mutation contributes to the disease has not yet been elucidated. Earlier we have shown that synonymous codon substitutions in the mRNA of the multidrug resistance protein (MDR1) may change the conformation of the protein and result in altered functionality (Kimchi-Sarfaty et al., Science, 2008). Here we have performed in silico analyses of the synonymous codon substitution (GTGàGTA) leading to the V107V polymorphism and found that it may change the mRNA structure, stability, codon usage, and 3D structure of the encoded protein. We hypothesize that changes in codon usage might affect the rhythm of protein translation and thus result in slightly altered FIX conformation. In vitro analyses of FIX mRNA and protein expression supported our in silico analyses. The GTGàGTA (V107V) synonymous mutation results in reduced expression levels as well as an encoded protein with a slightly different conformation compared to wild-type FIX. These results show that the V107V polymorphism is not silent and might cause mild hemophilia B. This work sheds further light on ways in which synonymous mutations impact disease. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination policy Disclosures: No relevant conflicts of interest to declare.

Biochemical Characterization of a Recombinant FIX Drug Candidate for Treatment of Hemophilia B

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4658-4658
Author(s):  
Peter Turecek ◽  
Susanne Vejda ◽  
Katalin Varadi ◽  
Hanspeter Rottensteiner ◽  
Ernst Boehm ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Drug Product ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Drug Candidate ◽  
Alternative Drug ◽  
Recombinant Factor Ix ◽  
Fermentation Technology

Abstract Abstract 4658 Human coagulation factor IX (FIX) is a vitamin-K-dependent coagulation factor whose absence or dysfunction causes hemophilia B. Treatment of hemophilia B is based on replacement therapy using highly purified FIX concentrates. Baxter has developed a recombinant factor IX for treating hemophilia B patients that is produced in a CHO cell-line using a serum and protein-free fermentation technology. The purification process avoids the use of immune-affinity chromatography and includes two viral reduction steps. The final drug product is formulated in the absence of proteins of animal or human origin. Baxter's recombinant FIX resembles commercially available rFIX in most characteristics with the exception of a significantly lower FIXa content, which might improve standardization compared to commercial rFIX products. Preclinical and clinical lots of rFIX were characterized with respect to their hemostatic potency, efficiency of activation by FXIa and FVIIa in the presence of tissue factor, and capacity to bind to phospholipid vesicles. Three lots of commercial rFIX with different potencies and one lot of a plasma-derived FIX product were included in the study. Similarity could be shown between the preclinical and clinical lots of rFIX in all these assays. Furthermore, the functional and biochemical characterization of Baxter's recombinant FIX showed that it resembles the recombinant comparator product. The phase I clinical trial which has been initiated will now have to show whether Baxter's rFIX can become an alternative drug candidate product for treating patients suffering from hemophilia B. Disclosures: Turecek: Baxter Innovations GmbH: Employment. Vejda:Baxter Innovations GmbH: Employment. Varadi:Baxter Innovations GmbH: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Boehm:Baxter Innovations GmbH: Employment. Reiter:Baxter Innovations GmbH: Employment. Kaliwoda:Baxter Innovations GmbH: Employment. Mundt:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2407-2407 ◽  
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.

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

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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