Pharmacokinetics, Efficacy and Safety Of a Recombinant Factor IX (BAX326) In Previously-Treated Pediatric Patients < 12 Years Of Age With Severe Or Moderately Severe Hemophilia B

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1118-1118 ◽  
Author(s):  
Tomasz Urasinski ◽  
Oleksandra Stasyshyn ◽  
Tatiana Andreeva ◽  
Luminita Rusen ◽  
Farida Perina ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Factor Ix ◽  
Hemophilia B ◽  
Ovary Cell ◽  
Animal Origin ◽  
Efficacy And Safety ◽  
On Demand ◽  
Previously Treated ◽  
The Mean ◽  
Hemostatic Efficacy

Abstract Hemophilia B is an X-linked congenital bleeding disorder caused by defective or deficient levels of circulating coagulation factor IX (FIX). Adequate levels of FIX can be maintained in the plasma through routine prophylactic infusions, which can especially benefit pediatric patients if started early in order to prevent recurrent joint bleeding and severe joint disease. A recombinant FIX (BAX326, Rixubis®, Baxter) has been developed for the prophylaxis and control of bleeding in hemophilia B patients. BAX326 is manufactured without the addition of any materials of human or animal origin; solvent/detergent treatment as well as nanofiltration are used for viral inactivation/reduction. Safety and efficacy of BAX326 have already been demonstrated in hemophilia B patients aged 12 years and above.1 A prospective clinical trial was conducted to assess the pharmacokinetics (PK), hemostatic efficacy and safety of BAX326 in previously treated patients (PTPs) <12 years of age with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B. After the initial PK assessment, BAX326 was administered as prophylaxis twice a week (median dose 56 IU/kg, range 43-75 IU/kg) over 6-months or for a minimum of 50 exposure days. Twenty-three male subjects (median age 7.10 years, range 1.8 to 11.8 years, with 11 subjects < 6 years) were enrolled and treated with BAX326. Sixteen subjects (69.6%) had received previous treatment with FIX products by prophylaxis only, 6 (26.1%) by both prophylaxis and on-demand, and 1 subject (4.3%) had been treated on-demand only. BAX326 was safe and well-tolerated. No allergic reactions or thrombotic events occurred and there were no treatment-related adverse events. None of the subjects developed an inhibitory or positive binding antibody to FIX, Chinese hamster ovary cell protein or furin. PK assessments (N = 23) after one 75 ± 5 IU/kg infusion with BAX326 were performed up to 72 hours (median AUC0-inf. 802.9 IU hr/dL, MRT 26.77 hr, Cl 0.0935 dL/[kg.hr], half-life 24.48 hr, Vss 2.629 dL/kg) using a non-linear mixed model (population PK) approach. The mean incremental recovery (IR) 30 minutes after infusion was consistent over time (assessed after initial PK infusion, and at 5, 14 and 26 weeks of treatment). A tendency toward higher IR in association with increased patient age was observed, as previously described.2 BAX326 administered as prophylaxis was efficacious in preventing bleeds. Nine subjects (39.1%) did not experience any bleeds; the mean annualized bleeding rate (ABR) was 2.7 ±3.14 (median 2.0). Out of 26 total bleeds, only 2 (in 2 subjects) were spontaneous, and 1 was of unknown cause. Fewer bleeds occurred in joints than in non-joint sites (19 non-joint vs. 7 joint bleeds). Hemostatic efficacy at the resolution of a bleed was excellent or good in 96.2% of bleeds. The majority of bleeds were resolved after 1-2 infusions (88.5%) with BAX326; the mean total dose of rFIX administered per bleed was 94.4 (52.41) IU/kg. Hemostatic efficacy in terms of bleed severity was excellent or good in 100% of minor bleeds (N =15), 88.9% of moderate bleeds (N=9) and 100% of major bleeds (N=2). In summary, these data indicate that BAX326 is safe and efficacious in treating bleeding episodes and in routine prophylaxis in pediatric patients aged <12 years with hemophilia B. Disclosures: Oh: Baxter: Employment. Chapman:Baxter: Employment. Pavlova:Baxter: Employment. Wong:Baxter: Employment. Abbuehl:Baxter: Employment.

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.

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

RESULTS OF AN OPEN, PROSPECTIVE, MULTICENTER, NONCOMPARATIVE STUDY OF THE PHARMACOKINETICS, EFFICACY AND SAFETY OF NONACOG ALFA IN PATIENTS AGED 6–12 YEARS WITH SEVERE AND MODERATE HEMOPHILIA B

2020 ◽  
Vol 99 (6) ◽  
pp. 190-198
Author(s):  
T.A. Andreeva ◽  
◽  
V.V. Lebedev ◽  
V.V. Vdovin ◽  
M.A. Timofeeva ◽  
...  
Keyword(s):  
Prophylactic Treatment ◽  
Study Drug ◽  
Factor Ix ◽  
Hemophilia B ◽  
Efficacy And Safety ◽  
Open Label ◽  
Time Curve ◽  
Entire Study ◽  
On Demand ◽  
Bleeding Episodes

Providing hemophilia patients with blood coagulation preparations is one of the priority tasks of the national health care system. In 2011, the first recombinant factor IX was created in Russia (rFIX, nonacog alpha, Innonafactor, GENERIUM JSC), that was previously studied for pharmacokinetic (PK) parameters, efficacy and safety in adult patients and adolescents over 12 years of age with severe and moderate hemophilia B. Objective of this open-label, prospective, multicenter, noncomparative clinical study was to study PK, efficacy and safety of Innonafactor in 12 patients aged 6 to 12 years with severe and moderate forms of hemophilia B (FIX activity less than 2%). The study included periods of screening, studies of PK parameters and treatment within 26±1 weeks, but not less than 50 days of administration of the studied drug. Nonacog alfa was administered in the study of PK parameters at a dose of 75 IU/kg, once, for prophylactic treatment – at a dose of 45±10 IU/kg, 2 times a week with an interval of 72–96 h. 30 minutes after administration of the studied drug, FIX activity increased to 73,93±13,35%, with a gradual decrease to 5,88±1,97% 72 hours after administration. The area under the «concentration ‒ time» curve in the section 0–72 h (AUC0–72) and with exponential extrapolation to infinity (AUC00‒∞) was 1573,41±407,16%*h and 1808,74 ± 437,59%*h respectively. Biological half-life (T1/2) was 28,11±8,60 hours. During preventive treatment there were 19 hemorrhagic episodes, 14 (74%) bleedings were post-traumatic and 5 (26%) bleedings were spontaneous. Mean number of bleeding episodes over the entire observation period was 1,9±1,4. Mean number of episodes of spontaneous bleeding that occurred within 72 hours after Innonafactor administration in patients with bleeding was 2,5±2,1. During the entire study period, patients received 942,5 thousand IU of the drug Innonafactor, 890,5 thousand IU were administered for prophylaxis and 52 thousand IU to stop bleeding on demand. Mean single dose of Innonafactor for prophylactic treatment was 46,24±5,86 IU/kg, for on-demand treatment – 49±13,1 IU/kg. Of the 19 registered bleeding episodes, 14 (73.7%) episodes required the administration of the studied drug; 5 (26,3%) bleedings stopped on their own. To stop one episode of bleeding, an average of 2,3±2,3 administration of nonacog alfa was required. At the end of the study, the proportion of hemophilia B patients with residual FIX activity of 2% or more was 92%. During the study, 14 adverse events (AEs) were registered in 7 (58,3%) patients. All reported AEs were not study drug related and did not require study drug withdrawal. Thromboembolic complications and immunogenic reactions were not registered. Thus, the data obtained indicate efficacy and safety of Innafactor both for prophylactic treatment and for on-demand treatment of bleeding in patients aged 6 to 12 years with severe and moderate hemophilia B.

scholarly journals Safety, Immunogenicity, and Hemostatic Efficacy of Nonacog Gamma in Patients With Severe or Moderately Severe Hemophilia B: A Continuation Study

2020 ◽  
Vol 26 ◽  
pp. 107602962095083
Author(s):  
Jerzy Windyga ◽  
Oleksandra Stasyshyn ◽  
Toshko Lissitchkov ◽  
Vasily Mamonov ◽  
Margit Serban ◽  
...  
Keyword(s):  
Prophylactic Treatment ◽  
Phase 1 ◽  
Factor Ix ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
On Demand ◽  
Treatment Standard ◽  
Pediatric Study ◽  
Bleeding Episodes ◽  
Hemostatic Efficacy

This phase 3, prospective, open-label, multicenter, continuation study (NCT01286779) investigated the use of a recombinant factor IX (FIX), nonacog gamma (BAX 326, RIXUBIS®) in patients with severe or moderately severe hemophilia B. The study population included 85 patients transitioning from a phase 1/3 pivotal study (NCT01174446), a pediatric study (NCT01488994), and 30 newly recruited patients, naïve to nonacog gamma. Patients received nonacog gamma as prophylaxis treatment (standard, modified or PK-tailored) or on-demand, as determined by the investigator. Treatment was assessed for safety, immunogenicity, hemostatic efficacy and consumption. In this study, after ≥100 exposure days, nonacog gamma resulted in no treatment-related serious adverse events, and no patients developed inhibitory antibodies to FIX. Nonacog gamma was efficacious at controlling bleeding episodes, with an 89.1% overall hemostatic efficacy rating of excellent or good, and 56% of bleeds resolved with one infusion. The annualized bleeding rate was considerably lower during prophylactic treatment (median ABR of 1.3 in 108 patients) than during on-demand treatment (median ABR of 16.5 in 13 patients). These results show that in previously treated patients and nonacog gamma-naïve patients, long-term use of nonacog gamma had acceptable safety and tolerability, and was efficacious as a prophylactic treatment for the management of bleeding episodes. NCT01286779, EudraCT: 2010-022726-33

Nonacog Alfa: Analysis Of Safety Data From 6 Prospective Clinical Studies In Different Patient Populations With Hemophilia B Treated With Different Therapeutic Modalities

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3604-3604
Author(s):  
Pablo Rendo ◽  
Lynne Smith ◽  
Lee Hsiao-Yu ◽  
Frank E. Shafer
Keyword(s):  
Clinical Studies ◽  
Safety Data ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Efficacy And Safety ◽  
Open Label ◽  
Inhibitor Development ◽  
Nonrandomized Study ◽  
On Demand ◽  
Previously Treated

Abstract Background The safety of recombinant coagulation factor IX (FIX) nonacog alfa (BeneFIX; Pfizer) has been shown in studies across a range of patient (pt) populations. This pooled analysis aimed to evaluate the safety of nonacog alfa from a 16-y database of 6 key clinical studies in pts with hemophilia B. Methods This retrospective post hoc analysis pooled data from 6 prospective, clinical, non-interventional (n=1) and interventional (n=5) studies that utilized on-demand, prophylactic, and preventive (surgical procedure) nonacog alfa regimens in previously treated, minimally treated, and untreated pts. This analysis comprised data from an open-label nonrandomized study evaluating efficacy and safety in pts with moderately severe or severe hemophilia B (Study 300); an open-label nonrandomized study evaluating efficacy and safety in children<6y with severe hemophilia B (Study 301); an open-label nonrandomized study evaluating efficacy and safety in pts ≥12y with moderately severe or severe hemophilia B (Study 302); a double-blind, randomized, crossover pharmacokinetic study followed by a 6–12-mo open-label, on-demand treatment extension in pts ≥12y with moderately severe or severe hemophilia B (Study 304); a randomized, open-label crossover study evaluating efficacy and safety in pts 6-65y with moderately severe or severe hemophilia B (Study 400); and an open-label safety registry (Study 101038). Nonacog alfa doses were determined by investigators except for the randomized, open-label crossover study, wherein pts received 2 prophylaxis regimens (50 IU/kg biweekly and 100 IU/kg once weekly). Pt demographics and clinical characteristics, nonacog alfa consumption, and safety data, including adverse events (AEs) and events of special interest, were collected and pooled. Results In total, 412 pts received treatment with nonacog alfa. Median age was 21y (range, 0-79y; 3 pts were aged 0-27d, 47 pts were 28d to<1y); 96.1% were male; 75.7% were white; and 66.5% (273/412) were previously treated pts. Pts may have received on-demand, prophylaxis, and preventive (surgical procedure) treatment in the same study. Pts received a mean (SD) dose per infusion of 64.9 (42.8) IU/kg of nonacog alfa, with 29.2 (46.3) infusions and 28.2 (44.5) exposure days per pt. In total, 220 pts (53.4%) reported AEs; the most common (≥3%) are summarized in the Table. Treatment-related AEs were reported in 48 (11.7%) pts; the most common (≥1%) included hypersensitivity (n=6; 1.5%), urticaria (n=6;1.5%), FIX inhibition (n=5; 1.2%), and pyrexia (n=4; 1.0%). Serious AEs were reported in 74 (18.0%) pts; the most common (≥1%) included hemarthrosis (n=6; 1.5%), pyrexia (n=6; 1.5%), FIX inhibition (n=5, 1.2%), device-related infection (n=4; 1.0%), hematoma (n=4; 1.0%), and arthropathy (n=4; 1.0%). Thirty-seven events of special interest occurred in 31 (7.5%) pts: 15 pts experienced allergic-type manifestations, 5 had inhibitor development , 8 reported lack of effect, 7 reported red blood cell agglutination in the tubing or syringe, and 2 experienced thrombogenicity. Seven pts (1.7%) were withdrawn from the studies due to AEs of hypersensitivity (n=3), drug eruption, rash pruritic, urticaria, and therapeutic response decreased (n=1 each). Conclusions In this pooled safety analysis of pts with hemophilia B that represents a total of 11,588 exposure days, nonacog alfa was generally well tolerated, with a low rate of inhibitor development and allergic-type manifestations. The safety profile was consistent with previous studies. No new or unexpected safety signals were observed across various pt populations, including minimally treated, previously treated, and untreated pts, adults as well as children<18y, pts with mild, moderate, or severe hemophilia B, and pts receiving on-demand , prophylactic, and preventive treatment. Disclosures: Rendo: Pfizer Inc.: Employment. Smith:Pfizer Inc.: Employment. Hsiao-Yu:Pfizer Inc.: Employment. Shafer:Pfizer Inc.: Employment.

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.

scholarly journals Pharmacokinetic Results of Two Phase III Clinical Studies of Coagulation Factor IX (Recombinant) Albumin Fusion Protein (rIX-FP) in Previously Treated Patients with Hemophilia B (PROLONG-9FP)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1491-1491 ◽  
Author(s):  
Elena Santagostino ◽  
Iris C. Jacobs ◽  
Christine Voigt ◽  
Annettee Feussner ◽  
Tharin Limsakun
Keyword(s):  
Half Life ◽  
Age Groups ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Phase Iii ◽  
On Demand ◽  
Routine Prophylaxis ◽  
Clinical Program ◽  
The Mean

Abstract A recombinant fusion protein linking recombinant coagulation factor IX (FIX) with recombinant human albumin (rIX-FP) has been developed to extend the plasma half-life of FIX, thus 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 aims to evaluate the use of rIX-FP for prophylaxis and on-demand treatment of bleeding in patients with severe hemophilia B. In a completed Phase I pharmacokinetic (PK) study in subjects aged 15 to 58 years (y), the mean half-life of rIX-FP was 92 hours, 5 times longer than the half-life of the FIX products previously used by the subjects. The mean trough FIX activity after injection of rIX-FP was 7.4% (day 7) at a dose of 25 IU/kg, and 13.4% (day 7) and 5.5% (day 14) at a dose of 50 IU/kg (Santagostino E, et al. Blood 2012; 120:2405-11). A Phase II study demonstrated the efficacy of weekly prophylaxis with rIX-FP, with excellent safety and an improved PK profile. Following completion of these studies, 2 Phase III, open-label, multicenter studies have been conducted in previously treated patients (PTPs) with severe hemophilia B, aged 12 to 65 years (NCT01496274) and < 12 years (NCT01662531). Both studies, which were designed to evaluate the long term safety and efficacy of rIX-FP for both prophylaxis and on-demand treatment of bleeding episodes, consisted of an initial PK evaluation period followed by a treatment period during which subjects were administered rIX-FP as prophylaxis and on-demand treatment. Subjects from 42 hemophilia treatment centers in 12 countries participated; to date, the PROLONG-9FP clinical program encompasses over 100 hemophilia B subjects for the PK evaluation. Here, we report on the PK results from these 2 studies. During the 14-day PK evaluation periods, blood samples for PK analysis were taken before dosing, and then at 30 minutes, 3, 24, 48, 72, 120, 168, 240 and 336 hours after injection of 50 IU/kg rIX-FP. A subgroup of subjects also completed a PK evaluation of their previously used Factor IX products (pdFIX and rFIX), with sampling before dosing, and then at 30 minutes, 3, 6, 12, 24 and 48 hours after 50 IU/kg FIX injection. Plasma FIX activity (FIX:C) was measured by a one-stage clotting assay (CSL Behring central laboratory). The mean plasma FIX half-life after injection of 50 IU/kg rIX-FP was 105, 92 and 84 hours in the respective age groups of 12 to 61 years (n = 46), 6 to 11 years (n = 15) and 1 to 5 years (n = 12); the baseline corrected mean incremental recovery (IR) was 1.3, 1.1 and 1.0 IU/dL per IU/kg, the mean area under the curve (AUC) was 7,360, 4,949 and 4,358 IU*hr/dL, and the clearance was 0.7, 1.1 and 1.3 mL/h/kg in the respective age groups. The time to 5% FIX:C after injection of 50 IU/kg rIX-FP administration was Day 10 for children and Day 14 for adults; at Day 14, the mean trough FIX activity in children was 3%. Compared with the FIX products previously used by the subjects, rIX-FP had a 30 to 40% higher incremental recovery, > 5-times longer half-life, larger AUC and lower clearance. In conclusion, compared with standard FIX products, rIX-FP demonstrated an improved PK profile with a prolonged half-life in all age groups (1 to 61 years). At 14 days after injection of rIX-FP, the mean trough FIX activity is 3% in children and above 5% in adults, supporting a treatment interval of 14 days for routine prophylaxis. Treatment intervals of 7-, 10- and 14 days for routine prophylaxis were tested in the pivotal Phase III studies; every 21 day regimen will be tested in selected age groups during the Phase IIIb extension study. Detailed PK results will be presented during the meeting. Disclosures Santagostino: CSL: Honoraria, Speakers Bureau. Jacobs:CSL Behring: Employment. Voigt:Csl Behring: Employment. Feussner:CSL Behring: Employment. Limsakun:CSL Behring: Employment.

scholarly journals Impact of Systematic Pharmacokinetic (PK) Profiles in a Cohort of 29 Patients Treated with Conventional and Extended-Half Life (EHL) Products

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1123-1123
Author(s):  
Teresa Ceglie ◽  
Berardino Pollio ◽  
Irene Ricca ◽  
Maria Messina ◽  
Claudia Linari ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Null Mutation ◽  
Severe Hemophilia ◽  
Factor Level ◽  
On Demand ◽  
Active Life ◽  
Genetic Assessment

Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.

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