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

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

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

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

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

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

scholarly journals Long-Term Safety and Efficacy of Nonacog Beta Pegol (N9-GP) Administered for at Least 5 Years in Previously Treated Children with Hemophilia B

2020 ◽  
Vol 120 (05) ◽  
pp. 737-746
Author(s):  
Manuel Carcao ◽  
Susan Kearney ◽  
Meng Yao Lu ◽  
Masashi Taki ◽  
Daniel Rubens ◽  
...  
Keyword(s):  
Factor Ix ◽  
Hemophilia B ◽  
Phase Iii ◽  
Open Label ◽  
Safety And Efficacy ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Inhibitory Antibodies

AbstractLong-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis (N = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%).

scholarly journals Long-Term Safety and Efficacy of Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Previously Treated Pediatric Patients with Hemophilia B: Results from a Phase 3b Extension Study

2020 ◽  
Vol 120 (04) ◽  
pp. 599-606
Author(s):  
Gili Kenet ◽  
Hervé Chambost ◽  
Christoph Male ◽  
Susan Halimeh ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Extension Study ◽  
Safety And Efficacy ◽  
Coagulation Factor Ix ◽  
Previously Treated ◽  
Bleeding Episodes

Abstract Introduction A phase 3b extension study evaluated the long-term safety and efficacy of a recombinant fusion protein-linking coagulation factor IX (FIX) with albumin (rIX-FP) for the routine prophylaxis and on-demand treatment of bleeding in pediatric hemophilia B patients. Methods Previously treated patients aged <12 years with moderate to severe hemophilia B enrolled in a 3-year extension study following a phase 3 pivotal study in which they received weekly rIX-FP prophylaxis. In the extension study, they could maintain or extend their prophylaxis interval to every 10 or 14 days if they were well controlled on the 7-day regimen. Results Compared with their initial regimen, by the end of the study, dosing intervals were the same, extended, and shortened in 16, 4, and 4 patients, respectively. Very low annualized spontaneous bleeding rates (AsBRs) were observed; median AsBR was 0.0 for the 7- and 10-day regimens, and 1.1 for the 14-day regimen. The 7- and 14-day regimens were comparable in preventing spontaneous bleeds; mean (95% confidence interval) difference in AsBR of −1.2 (−2.6 to 0.3) bleeding episodes/year/subject. Overall, 96% of bleeding episodes were successfully treated with one or two injections of rIX-FP. Patients on a 14-day regimen maintained a mean steady-state trough FIX level of >7.2 IU/dL. No patient developed an inhibitor. Conclusion This extension study demonstrated the long-term safety and efficacy of weekly rIX-FP in pediatric patients. Additionally, it showed that adequate bleed protection can be achieved with 10- or 14-day rIX-FP regimens in selected pediatric patients while maintaining safety.

Latest Results From The PUP-GCP Clinical Trial: A Low Inhibitor Rate In Previously Untreated Patients With Severe Hemophilia A Treated With Octanate

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3596-3596
Author(s):  
Anna Klukowska ◽  
Martina Jansen ◽  
Vladimir Komrska ◽  
Pawel Laguna ◽  
Vladimir Vdovin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rating Scale ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Observational Period ◽  
Adverse Event Profile ◽  
On Demand ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Bleeding Episodes

Abstract Background Octanate is a highly purified, double virus inactivated, human plasma-derived factor VIII (FVIII) concentrate with all coagulation FVIII bound to its natural stabilizer VWF in a VWF:RCo/FVIII:C ratio of approximately 0.4. Five prospective GCP studies with octanate were conducted in 77 previously treated patients (PTPs) with severe hemophilia A. None of these 77 PTPs developed an inhibitor while treated exclusively with octanate. Aim To assess the immunogenicity in previously untreated patients (PUPs), a prospective clinical trial has been initiated in 2000. This included 50 PUPs with severe hemophilia A for an observational period of 100 exposure days with octanate, for at least 6 months. Methods Patients with severe hemophilia A without previous exposure to FVIII or FVIII-containing products were enrolled. Efficacy and tolerability were assessed by a 4-point verbal rating scale. Inhibitors were assessed according to modified Bethesda method prior to treatment every 3-4 exposure days (ED 1-20), and after treatment every 10 EDs (ED 21-100), but at minimum every three months. Results Two of 50 (4%) subjects developed clinically relevant inhibitor titers over the course of the study. Another two displayed inhibitors that disappeared spontaneously without change of dose or dosing interval. All inhibitors developed under on-demand treatment and before ED 50. From the 50 subjects, 42 had exceeded 50 EDs at the time of this analysis. Octanate was well-tolerated and the adverse event profile was consistent with the population studied. The hemostatic efficacy in prophylaxis and treatment of bleeding episodes was generally rated as “excellent” and no complication was reported for any surgical treatment. Conclusion Despite frequent inhibitor testing and predominant on-demand treatment, the data indicate a low overall inhibitor rate for octanate in patients who exceeded 50 exposure days (4/42) of which only 2 (4.8%) were clinically relevant. Disclosures: Klukowska: Octapharma AG: Investigator Other. Jansen:Octapharma AG: Employment. Komrska:Octapharma AG: Investigator Other. Laguna:Octapharma AG: Investigator Other. Vdovin:Octapharma AG: Investigator Other. Knaub:Octapharma AG: Employment.

scholarly journals Long-Term Use of Coagulation Factor IX (Recombinant) Albumin Fusion Protein (rIX-FP) in Previously Treated Patients with Hemophilia B in the Prolong-9FP Program

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1096-1096
Author(s):  
Aaron Lubetsky ◽  
Uri Martinowitz ◽  
Toshko Lissitchkov ◽  
Christine Voigt ◽  
Denise Wolko ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Phase Ii ◽  
Clinical Studies ◽  
Hemophilia B ◽  
Phase Iii ◽  
Safety And Efficacy ◽  
On Demand ◽  
Clinical Program ◽  
Over Time

Abstract A fusion protein genetically linking recombinant human coagulation FIX with recombinant human albumin (rIX-FP) has been developed with an improved PK profile, improving hemophilia B treatment by allowing less frequent dosing than required with standard plasma-derived (pd) and recombinant (r) FIX products. The PROLONG-9FP clinical program has evaluated the use of rIX-FP for prophylaxis and on-demand treatment of bleeding in patients with severe hemophilia B. The clinical program is comprised of 5 clinical studies, including four completed studies (a Phase I pharmacokinetic (PK) study, a Phase II study, and two Phase III studies in adults and children), and an ongoing extension study, which includes previously untreated patients. Over 100 subjects from 42 hemophilia treatment centers in 12 countries have participated in the PROLONG-9FP clinical program. Here, we report on the long-term safety and efficacy of rIX-FP in 15 subjects who have continuously participated in 3 clinical studies (Phase II, Phase III and the on-going Phase III extension studies) over a period of 4 years. Subjects began either weekly prophylaxis treatment or on-demand treatment with rIX-FP in the Phase II 2004 study, and continued that treatment regimen in the Phase III 3001 study. The Phase III global study evaluated safety and efficacy of rIX-FP for prophylaxis treatment (PT) of every 7-, 10- and 14-days and on-demand treatment (ODT) of bleeding episodes. Subjects in the on-demand arm received only ODT for 6 months and then switched to 7-day PT. Subjects in the prophylaxis arm received 7-day PT for 6 months, and eligible subjects switched to 10- or 14-day PT interval. Upon completion of the 3001 study, subjects entered the on-going extension study 3003 and either continued the treatment regimen or switched to a longer prophylaxis interval of 10-, 14- or 21-days. Within subject comparisons of the annualized spontaneous bleeding rates (AsBR), total ABR over time and other efficacy parameters between regimens will be presented. Long-term use of rIX-FP is safe and well-tolerated. No subjects developed inhibitors to FIX or antibodies to rIX-FP during the 4 year treatment period, with a mean of 180 exposure days (EDs) for PT subjects and 125 EDs for ODT subjects. ABR decreased over time with rIX-FP prophylaxis, and longer treatment intervals were possible with no increase in consumption. Disclosures Lubetsky: CSL Behring: Consultancy. Martinowitz:CSL Behring: Honoraria, Speakers Bureau. Voigt:CSL Behring: Employment. Wolko:CSL Behring: Employment. Jacobs:CSL Behring: Employment. Santagostino:Biotest: Speakers Bureau; Kedrion: Speakers Bureau; Roche: Speakers Bureau; Octapharma: Speakers Bureau; Novo Nordisk: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Bayer: Speakers Bureau; Biogen/Sobi: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; CSL Behring: Speakers Bureau.

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

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

Abstract Abstract 2222 Hemophilia B is a congenital X-linked bleeding disorder whose severity is associated with diminished or absent levels of circulating FIX. Treatment with regular prophylactic FIX infusions has significant medical and quality of life benefits by maintaining adequate plasma levels of FIX for hemostasis approximating a non-diseased state. BAX326 nonacog gamma is a novel recombinant FIX (rFIX) that is manufactured without the addition of any materials of human or animal origin, and viral inactivation/reduction is achieved through solvent/detergent (S/D) treatment as well as 15nm nanofiltration. Pharmacokinetics, hemostatic efficacy and safety of BAX326 were assessed in a prospective clinical trial in patients aged 12 to 65 years with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B, previously treated with plasma-derived and/or recombinant FIX concentrates. PK parameters were compared with a commercially-available rFIX used as an active control in a crossover design. Hemostatic efficacy of BAX326 administered twice weekly as prophylaxis was compared with a historical control group treated on-demand. A total of 86 patients were enrolled and 73 were treated with BAX326. All subjects treated had previous exposure to a FIX concentrate for ≥ 150 days prior to entry into the study. Subjects included in the PK analysis (n=28) received one 75 ± 5 IU/kg infusion with BAX326 and one infusion with commercial rFIX in random order prior to receiving prophylactic treatment at a dose range from 40 to 60 IU/kg two times a week with BAX326. An additional 31 subjects also received prophylactic treatment (21–67 exposure days), and 14 subjects received BAX326 on-demand (5–25 exposure days). More than 70% of subjects had 50 or more exposure days to BAX326 during the study. PK equivalence between BAX326 and the comparator rFIX was confirmed as the 90% confidence intervals of the ratio (BAX326/comparator rFIX) of the geometric mean of AUC 0–72 h/dose (1.063 [1.03; 1.09]) was fully contained in the margins for equivalence (0.8 to 1.25). The mean half-life (T1/2) of BAX326 was 26.70h ± 9.55, and incremental recovery (IR) was 0.87 ± 0.22 IU/dL: IU/kg. Repeated PK analysis after 6 months of prophylactic treatment confirmed the results of the initial values. Twice weekly prophylactic treatment with BAX326 was effective in preventing bleeding episodes, with a significantly lower (79%, p<0.001) annualized bleed rate (ABR) during prophylaxis (mean ABR 4.20) compared to an on-demand treatment in a historical control group (mean ABR 20.0). Among the 56 subjects on prophylaxis, 24 subjects (43%) did not bleed; the mean ABR for joint bleeds was 2.79, and 1.70 for spontaneous bleeds. Of 238 total acute bleeds, 201 (84.4%) were controlled with 1–2 infusions of BAX326. Hemostatic efficacy at resolution of bleed was rated excellent or good in 95.4% of all treated bleeding episodes. The efficacy as related to degree of severity of bleeding episodes was excellent or good in 96.8 % of minor bleeds, 95 % of moderate bleeds and 92.9 % of major bleeding episodes. BAX326 was safe and well-tolerated, with similar adverse reaction rates to the comparator rFIX. The safety assessments demonstrate the safety and tolerability of BAX326 in patients with moderately severe or severe hemophilia B. There were no product related SAEs, no inhibitory or binding FIX antibodies, no antibodies to CHO, and no allergic reactions or thrombotic events; AEs considered related to BAX326 (dysgeusia and pain in extremity) were transient and mild, and occurred with an overall incidence of 2.7%. There were no treatment-related AEs within 24 hours after infusion. Elevated pre- and post-infusion values for thrombogenic markers (TAT, F1.2 and D-dimer) in some subjects did not reveal any pattern indicative of clinically relevant thrombogenicity with either BAX326 or the comparator rFIX, and were not associated with AEs. These data indicate that BAX326 is safe and efficacious in treating bleeding episodes and in routine prophylaxis in patients aged 12 years and older with hemophilia B. None of the historical risk factors, such as hypersensitivity reactions, inhibitor formation or thrombotic events were observed and few related adverse events occurred. Disclosures: Windyga: Baxter: Research Funding. Lissitchkov:Baxter: Research Funding. Stasyshyn:Baxter: Research Funding. Mamonov:Baxter: Research Funding. Rusen:Baxter: Research Funding. Lamas:Baxter: Research Funding. Oh:Baxter: Employment. Chapman:Baxter: Employment. Fritsch:Baxter: Employment. Pavlova:Baxter: Employment. Wong:Baxter: Employment. Abbuehl:Baxter: Employment.

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 ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4976-4976 ◽  
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.

Investigator-Prescribed Prophylaxis of rFIX (BeneFIX®) in Children <6 Years of Age: Efficacy and Safety Outcomes.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1221-1221
Author(s):  
Paul E. Monahan ◽  
Raina Liesner ◽  
Sharon Sullivan ◽  
Brooke Hayward ◽  
Maria E. Ramirez ◽  
...  
Keyword(s):  
Hemophilia B ◽  
Patient Treatment ◽  
Prospective Clinical Study ◽  
Severe Hemophilia ◽  
Efficacy And Safety ◽  
Spontaneous Bleeding ◽  
Bleeding Rate ◽  
On Demand ◽  
Bleeding Episodes ◽  
Infusion Schedule

Abstract Prophylaxis is increasingly prescribed in treatment of hemophilia. The therapeutic benefit is believed to be most significant for the youngest patients since hemophilic arthropathy may be prevented if prophylaxis is initiated prior to recurrent hemarthroses. While clinical prophylaxis data is readily available for hemophilia A, analogous data for hemophilia B is limited. A prospective clinical study of recombinant human FIX (rFIX; BeneFIX®) was recently completed in which the efficacy and safety of rFIX were evaluated in children &lt;6 years of age with severe hemophilia B (FIX activity £1%). In this study, subjects received rFIX according to investigator-prescribed modality (on-demand or prophylaxis) and regimen (dose and infusion schedule). Nearly all children who participated in the study were prescribed prophylaxis (22/25; 88%) at a schedule of 1 or 2 infusions per week over a mean of 6.6 months (range, 1.9–11.4 months). The median prophylactic dose per infusion was 57.6 IU/kg. Spontaneous bleeding was rare (rate, 0.05 per month) with 77% (17/22) of subjects experiencing no spontaneous breakthrough bleeding episodes. Most bleeding episodes, when they did occur, were due to injury (84%; 37/44), involved soft tissue/muscle sites (68%; 30/44), and started more than 48 hours after an rFIX infusion (61%; 27/44). Nearly all hemorrhages were resolved with 1 or 2 infusions of rFIX (39/44; 89%). The observed data predict &lt;1 spontaneous bleed per year for either prophylaxis infusion schedule (0.84 and 0.34 per year, for 1 and 2 infusion per week schedules, respectively). Although not a randomized study designed for a direct comparison, patients prescribed on-demand therapy had a higher annualized spontaneous bleeding rate of 3.9 per year. Prophylaxis infusion schedules were well tolerated by these young children, including the youngest subjects (6 subjects were &lt;2 years of age). During the course of their treatments, there was no thrombosis and only 2 of 22 (9%) children prescribed prophylaxis had adverse events related to rFIX. For 1 subject, who was a previously untreated patient (treatment naïve) at study entry, the events, which occurred on the 13th rFIX exposure day, constituted allergic reaction (concurrent rash and urticaria), and were later confirmed to be associated with FIX inhibitor development. The low-titer inhibitor (peak titer, 2.4 Bethesda units) developed in the context of on-demand treatment and then resolved in the setting of prophylaxis; the subject received 19 subsequent infusions following premedication (antihistamine and corticosteroid), with no allergic manifestations or anamnestic inhibitor response. The other subject had mild rash. Nine (9; 41%) children practicing prophylaxis were known to have an implanted venous access device for administrations, and there was 1 report of a catheter infection. Four (4) subjects who were initially prescribed on-demand regimens were later switched to prophylaxis during the study. Prescribed prophylaxis infusion schedules were not changed during the course of treatment for any subjects, consistent with patient/caregiver and study investigator satisfaction with the therapeutic response and tolerability provided by 1 or 2 infusions of rFIX per week. The choice of prophylaxis for nearly all subjects reflects the increasing use of this treatment modality for children with severe hemophilia B. The data from this investigation support both the safety and efficacy of rFIX in children &lt;6 years old with severe hemophilia B, with routine regimented administration of rFIX preventing spontaneous bleeding in the majority of children. Table 1. Bleeding Rate During Prophylaxis by Infusion Schedule Bleeding Rate (per 30 Days) Infusion Schedule No. Patients Patient Age (years) (median, range) Duration of Prophylaxis (mean ± SD months) Spontaneous Injury Related Total NA = not applicable; No. = number. 1 per week 9 2.5 (0.6-4.3) 8.0 ± 2.7 0.07 0.18 0.25 1−2 per week 1 1.0 (NA) 2.5 ± (NA) 0 0.40 0.40 2 per week 12 3.6 (1.2-4.8) 5.9 ± 1.1 0.03 0.33 0.35 All Schedules 22 2.9 (0.6-4.8) 6.6 ± 2.3 0.05 0.26 0.30

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