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

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

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 ◽  
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)*

Pharmacokinetic Behavior of IB1001, An Investigational Recombinant Factor IX, in Patients with Hemophilia B: Repeat Pharmacokinetic Study and Subgroup Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2267-2267
Author(s):  
Uri Martinowitz ◽  
Amy D. Shapiro ◽  
Doris V. Quon ◽  
Miguel Antonio Escobar ◽  
Christine L Kempton ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Half Life ◽  
Biological Variation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Maximum Plasma ◽  
Recombinant Factor Ix ◽  
The Stability ◽  
Over Time ◽  
Group 1

Abstract Abstract 2267 Introduction IB1001 is an investigational recombinant factor IX for the treatment and prevention of bleeding in individuals with hemophilia B. A randomized cross-over pharmacokinetic (PK) study demonstrated that IB1001 (75 IU/kg) compared with nonacog alfa (BeneFIX®). was non-inferior (lower bound of the 1-sided 95% confidence interval for the area under the concentration curve [AUC0–∞] was 90%) and was well tolerated. Here we report the findings from a repeat PK assessment, in which a subset of patients underwent a second PK evaluation with IB1001 only. In addition, we present the results of an exploratory analysis of IB1001 PK parameters to assess the relationship between the degree of sialylation and the pharmacokinetics of recombinant factor IX. [Griffith MJ et al. J Thromb Haemost 5 (Suppl 1), PM–043, 2007]. Methods In the randomized PK study, patients were assigned to receive 75 ± 5 IU/kg of IB1001 or nonacog alfa following a washout period of ≥5 days. Factor IX levels were determined pre-infusion and at 30 minutes, 1, 3, 6, 9, 12, 24, 36, 48, 60, and 72 hours post-infusion. The evaluation was repeated 5–28 days later, when a 75 ± 5 IU/kg dose of the alternate therapy was administered. Factor IX levels were assessed at the same time points. The repeat PK assessment was planned to include patients who had received 3–6 months of IB1001 prophylaxis following their initial PK assessment. Calculated PK parameters were identical to those determined during the randomized PK study: half-life (β-phase t1/2, determined using a robust regression approach [Lee ML et al. XVIth ISTH Congress, Florence, Italy, 1997]), maximum plasma concentration (Cmax) and AUC(0-∞) (determined by the trapezoidal rule). To explore the association between sialylation level and the PK behavior of IB1001, patients in the randomized PK study (n=32) were allocated to one of three subgroups based on the sialylation levels of the IB1001 lots used (see Table). Results Thirty-two evaluable patients were enrolled in the randomized PK study (Feb 2009–Aug 2010). Of these, 13 underwent repeat PK assessments with IB1001 after receiving 4–18 months of prophylaxis with IB1001. The results demonstrate the stability of PK parameters following up to 18 months of exposure to IB1001. No significant reduction in factor IX recovery or elimination half-life occurred in any patients over time. The sialylation subgroup analysis revealed that the use of IB1001 lots with the lowest sialylation levels (Group 1) resulted in slightly lower AUC levels when compared with nonacog alfa (see Table). When lots with intermediate or the highest sialylation levels were used, the AUC of IB1001 appeared similar (Group 2), or slightly higher (Group 3), than the corresponding nonacog alfa values. Although Cmax of IB1001 was lower in Group 1, it appears comparable with the nonacog alfa controls in all groups, suggesting that this was not an effect of sialylation but of individual biological variation. Conclusions The stability of IB1001 PK profile during prophylactic use was demonstrated in 13 patients and supported observations of the lack of inhibitor development over this period. The continued PK stability of IB1001 over time is of interest for the prophylactic treatment of hemophilia B.Evaluation of IB1001 sialylation levels was consistent with observations from previously reported nonclinical studies [Griffith MJ et al. J Thromb Haemost 5 (Suppl 1). Although the level of sialylation resulted in slightly different PK behavior, these differences may simply reflect the biological variation between individuals. Disclosures: Gomperts: Inspiration Biopharmaceuticals Inc: Consultancy. Lee:Inspiration Biopharmaceuticals Inc: Consultancy.

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