Evaluation of Two Secondary Prophylaxis Regimens of Recombinant Factor IX(r-IX) in Moderately Severe to Severe( FIX ≤2%) Hemophilia B Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4628-4628
Author(s):  
Pablo Rendo ◽  
Mary-Kate Barrette-Grischow ◽  
Lynne Smith ◽  
JM Korth-Bradley ◽  
Robert Charnigo ◽  
...  
Keyword(s):  
Venous Access ◽  
Factor Ix ◽  
Hemophilia B ◽  
World Health ◽  
Coagulation Disorder ◽  
Severe Hemophilia ◽  
Prophylactic Regimen ◽  
On Demand ◽  
Significant Difference ◽  
Bleeding Episodes

Abstract Abstract 4628 Background: Hemophilia B is an X-linked coagulation disorder characterized by a deficiency in factor IX (FIX), which results in spontaneous or trauma-induced bleeding primarily in joints, muscles, and soft tissues. Prevention and treatment of bleeding episodes in patients with hemophilia B is based upon replacing deficient FIX, either prophylactically or on an on-demand basis, with plasma-derived or recombinant FIX products. Prophylaxis therapy (ie, long-term, regular treatment) with FIX products is endorsed by the World Health Organization, World Federation of Hemophilia, and National Hemophilia Foundation as a primary therapeutic option for individuals with severe hemophilia B. Still, the use of prophylaxis is underutilized, as shown in data from North American and European hemophilia centers, where only 21% to 55% of individuals with hemophilia B were identified as receiving prophylactic FIX therapy (Rocca A et al. Blood Transfus 2011;9:60; Aznar JA et al. Haemophilia 2011;17:542; Biss TT et al. Haemophilia 2008;14:923). Factors implicated for this phenomenon include difficulty in venous access (particularly with primary prophylaxis in children), as well as overall adherence and willingness to commit to a highly demanding treatment schedule (Valentino LA. Haemophilia 2004;10:147; Collins PW et al. Haemophilia 2011;17:2; Santagostino E. Haemophilia 2010;16:13). The potential benefits of utilizing a once-weekly prophylactic regimen versus a more frequent dosing regimen include increased convenience for patients and their caregivers owing to fewer infusions and less preparation and infusion time, and the preservation of venous access. Objective: This study aimed to compare the safety and efficacy results for 2 prophylaxis regimens of nonacog alfa in moderately severe and severe hemophilia B patients. Methods: This multicenter, open-label crossover study enrolled 50 patients with moderately severe or severe (FIX C ≤ 2%) hemophilia B. Patients were treated on demand for 16 weeks, and 47 were subsequently randomized to 1 of 2 prophylactic regimens (nonacog alfa 100 IU/kg once weekly or 50 IU/kg biweekly) for 16 weeks. Following the initial prophylactic regimen, patients underwent an 8-week washout period of on-demand (OD) therapy then were crossed over to receive the other prophylactic regimen. The primary end point was the annualized number of bleeding episodes, expressed as the annualized bleeding rate (ABR). The results of this study were previously reported (Valentino LA, et al, 2011 ISTH abstract 1293). Results: Comparisons between once-weekly and twice-weekly prophylaxis regimens are given in Tables 1 and 2 and in Figure. No thrombosis, inhibitor, or allergic reactions were reported. Survival curve analysis comparing 100 IU once weekly to 50 IU twice weekly using the Kaplan-Meier technique showed no significant difference in the timing or extent of either type of treatment failure (p=0.14 for joint, p=0.61 for soft tissue/muscle by the Chi-squared [log-rank] analysis). Conclusions: Once-weekly prophylaxis with nonacog alfa 100 IU/kg is a safe and effective alternative to twice-weekly prophylaxis at 50 IU/kg. Once-weekly dosing may present a reasonable option for patients with severe hemophilia B, offering more convenience to patients and their caregivers compared with more frequent prophylactic dosing regimens. Disclosures: Rendo: Pfizer Inc.: Employment. Barrette-Grischow:Pfizer Inc.: Employment. Smith:Pfizer Inc.: Employment. Korth-Bradley:Pfizer Inc.: Employment. Charnigo:Pfizer Inc.: Employment. Shafer:Pfizer Inc.: Employment.

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

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.

Lack of Seasonal Variation in Bleeding and Patient-Assessed Pain Patterns in Patients with Hemophilia B Receiving On-Demand Therapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1136-1136
Author(s):  
Frank E. Shafer ◽  
Lynne Smith ◽  
Nicholas Vendetti ◽  
Pablo Rendo ◽  
Marcus E. Carr
Keyword(s):  
Seasonal Variation ◽  
Pain Score ◽  
Temporal Pattern ◽  
Hemophilia B ◽  
Bleeding Events ◽  
Prophylactic Regimen ◽  
On Demand ◽  
Significant Pain ◽  
Patient Reported ◽  
Bleeding Episodes

Abstract Abstract 1136 Background: Bleeding events associated with hemophilia are characterized by spontaneous or trauma-related hemorrhage into soft tissue, muscles, and joints. Spontaneous hemorrhage in patients with hemophilia is generally considered to occur randomly and without a predictable temporal or seasonal pattern. While there are a few reports that have examined the effects that weather, temperature, and atmosphere might have on spontaneous bleeding, there is a lack of evidence in the medical literature for consistent seasonal variation in bleeding risk in patients with hemophilia (Linde P & Syrbe G, Gesamte Inn Med 1990;45:657–9; Linde P & Syrbe G, Folia Haematol Int Mag Klin Morphol Blutforsch 1990;117:519–25; Rainsford SG & Hall A, Br J Haematol 1973;24:539–51; Benbassat J, Br Med J 1971;3:771; van Dijk K et al, Blood 2004). Objective: This post hoc analysis of a randomized controlled trial examined the influence of seasonality on bleeding frequency and patient-assessed pain in patients with hemophilia B. Methods: In a multicenter, open-label crossover study, 50 patients with moderately severe and severe (FIX C ≤ 2%) hemophilia B were enrolled and treated on demand for 16 weeks, and 47 were subsequently randomized to 1 of 2 prophylactic regimens (100 IU/kg once weekly or 50 IU/kg biweekly) for 16 weeks. Following the initial prophylactic regimen, and before crossing over to the other prophylactic regimen, patients underwent an 8-week washout period of on-demand (OD) therapy. The primary end point was the annualized number of bleeding episodes, expressed as the annualized bleeding rate (ABR). The results of this study were previously reported (Valentino LA, et al, 2011 ISTH poster 1293). This post hoc analysis presents, as a scatterplot, the ABR during the calendar months when the patients were receiving OD therapy. Also presented as scatterplots are results of a patient-reported measure of pain completed during every joint bleeding event (spontaneous or traumatic) during the OD periods (Brief Pain Inventory; 0 [“no pain”] to 10 [“pain as bad as you can imagine”]). The OD periods were selected for this analysis in order to evaluate bleeding events without the influence of the prophylactic regimens. Results: Figure 1 shows the ABR for each patient for each OD period with data. Because most patients had relatively similar ABR values for both OD periods, the data were combined. Data for OD1 and OD2 are included in Figure 1, up to 2 values per patient. The time point shown for each patient's ABR is the midpoint of that patient's participation in that period. The observed ABRs during the OD periods showed no distinguishable trend over time. The proportion of joint bleeding episodes during which a patient reported pain is shown in Figure 2. Each point represents the proportion of joint bleeding events for which the patient answered “Yes” to question 1 on the Brief Pain Inventory (“Have you experienced significant pain today?”) plotted at the midpoint of the patient's participation in that period. For patients reporting significant pain as a result of a joint bleeding episode, no distinguishable temporal pattern was observed in the raw pain score (plotted on the day the episode occurred; Figure 3A) reported for each episode. A pain score of 0 was then imputed for any joint bleeding episode for which a patient reported no significant pain. The median pain score (plotted at the midpoint of the patient's participation in that period; Figure 3B) recorded by each patient for all joint bleeding episodes during the OD periods likewise showed no distinguishable temporal pattern. Conclusions: In this analysis, no discernible seasonal or temporal pattern was observed with respect to the frequency of bleeding episodes, as assessed by the ABR during the calendar months when patients were receiving OD treatment. Likewise, no pattern was observed in patient-reported occurrence or intensity of pain during joint bleeding episodes. These results support the observation that there is no apparent seasonal variation in bleeding pattern or patient-reported pain in patients with hemophilia B. Disclosures: Shafer: Pfizer: Employment. Smith:Pfizer, Inc: Employment. Vendetti:Pfizer, Inc: Employment. Rendo:Pfizer, Inc: Employment. Carr:Pfizer, Inc: Employment.

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 Bleeding Risk Reduction in Relation to Predicted Factor IX Levels in Hemophilia B Patients Receiving Idelvion (rIX-FP)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1411-1411
Author(s):  
John Roberts ◽  
Cecilia Fosser ◽  
Michael Tortorici ◽  
Alex Veldman ◽  
Iris C. Jacobs ◽  
...  
Keyword(s):  
Risk Reduction ◽  
Bleeding Risk ◽  
Factor Ix ◽  
Hemophilia B ◽  
Phase Iii ◽  
Activity Levels ◽  
Bleeding Events ◽  
On Demand ◽  
Bleeding Episodes ◽  
Trough Levels

Abstract Factor IX (FIX) replacement is an effective therapy for hemophilia B patients. The current clinical rationale for maintaining higher trough levels of FIX is to transition patients from a severe hemophilia phenotype (eg. FIX <1% of normal) to a moderate (FIX of 1-5%) or mild disease state (FIX >5%), thereby reducing the total number of bleeding events. Although there is a tentative linkage between trough FIX levels and bleeding tendency which guides hemophilia B management, a thorough quantitative analysis was undertaken for rIX-FP (Idelvion) to robustly define the FIX exposure versus clinical outcome relationship. Pooled adult hemophilia B data from the rIX-FP Phase III development program was utilized for the analysis. A Cox proportional hazards model was employed to relate time-to-bleed event data and various individual measures of exposure (FIX activity) and dosing regimen, while testing the influence of covariates (e.g. baseline FIX). FIX activity levels were simulated using a validated rIX-FP population pharmacokinetic (PK) model. The analysis included all recorded bleeding episodes in subjects receiving either prophylaxis and/or on-demand regimens. Dose amounts and intervals included 50 IU/kg (every 1 week) and 75 IU/kg (every 2 weeks, or every 10 days). A total of 478 bleeding episodes (267 spontaneous bleeds, 190 traumatic bleeds, 21 other bleeds) from 57 adult patients were included in the primary analysis. The highest proportion of bleeds occurred during the on-demand portion of the clinical studies. Patients maintaining cumulative FIX activity trough levels above 5% and 10% were predicted to have significant reductions in bleeding risk of 83% and 81%, respectively, per 1 year above these levels, compared to patients not maintaining these FIX activity trough levels. Cumulatively, maintaining FIX levels above 2% was not statistically significant for risk reduction. Furthermore, a time-direct evaluation relating daily FIX trough activity to daily bleeding risk found that >2%, >5% and >10% FIX activity thresholds were significant predictors of bleeding events with 69% (95% CI, 53 to 80) 77% (95% CI, 67 to 84) and 78% (95% CI, 69 to 85) risk reductions, respectively. Although >2% was significant, the wider confidence intervals suggest a more reliable risk reduction at the >5% and >10% levels. This in-depth exposure-response analysis of rIX-FP determined a strong relationship between FIX activity levels and hemophilia B bleeding risk reduction. Trough FIX activity above 5% (either cumulatively or on any given day) was identified as a statistically significant and overall sufficient pharmacological threshold for reduction of bleeding risk in adult hemophilia B patients receiving rIX-FP. Trough FIX activity > 10% was also a predictor of significant risk reduction, and the magnitude of risk reduction was similar to that of achieving levels > 5%. These results are aligned with existing World Hemophilia Foundation (WFH) hemophilia severity definitions where patients with a range of observed FIX activity 5-40% are categorized as a single mild hemophilia phenotype. Post-approval clinical exposure versus response relationships may also be affected by an individual's level of physical activity which was not assessed in the current analysis. Overall, this analysis demonstrates the quantitative clinical rationale for optimization of adult rIX-FP dose regimens through targeting and maintaining FIX activity trough levels above 5% to 10%. Disclosures Roberts: CSL Behring: Employment. Fosser:CSL Behring: Consultancy; Cytel: Employment. Tortorici:CSL Behring: Employment. Veldman:CSL Behring: Employment. Jacobs:CSL Behring: Employment. Sidhu:CSL Behring: Employment.

Pharmacokinetic/Pharmacodynamic Assessment of Reformulated Recombinant Coagulation Factor IX in Adults and Children with Severe Hemophilia B

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1190-1190
Author(s):  
JM Korth-Bradley ◽  
Leonard A. Valentino ◽  
Pablo Rendo ◽  
Frank E. Shafer ◽  
Lynne Smith ◽  
...  
Keyword(s):  
Medical Center ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Pharmacokinetic Data ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
On Demand ◽  
Coagulation Factor Ix ◽  
Weekly Group

Abstract Abstract 1190 Introduction: The goal of this study was to evaluate the efficacy and safety of two prophylaxis regimens of reformulated recombinant coagulation factor IX (rFIX-R), 100 IU/kg once weekly and 50 IU/kg twice weekly, compared with on-demand treatment in subjects with severe hemophilia B. Patients and Methods: Pharmacokinetic data were collected for 47 subjects aged 6 to 64 years with severe hemophilia B. Factor IX activity (FIX:C) measurements were made immediately before rFIX-R administration and at 0.5 hours post-administration of either 100 IU/kg or 50 IU/kg doses, to assess recovery before the initiation of each weekly regimen. Another FIX:C sample was collected at least 72 hours after dosing during each regimen. All samples were analyzed at local laboratories. Results: The mean prophylactic doses of rFIX-R administered were 86 ± 29 IU/kg in the 100 IU/kg once-weekly group and 53 ± 14 IU/kg in the 50 IU/kg twice-weekly group. The treatment comparison between the two prophylaxis regimens for annualized bleeding rate was not significant (LS mean = 2.0; 95% CI, −1.2 – 5.2; n=43), although both were significantly different from the on-demand treatment period (both, P<.0001). The number of new bleeding events in each group was 51 and 35, respectively, with only 12/51 new hemorrhages occurring within 72 hours of dosing in the 100 IU/kg once-weekly group compared with 29/35 in the 50 IU/kg twice-weekly group. The pharmacokinetic results are shown in the Table. The number (%) of observed trough plasma concentrations (Ctrough) that fell into the mild (>5%) range for hemophilia were 18 (45%) and 19 (48%) for the r-FIX-R 100 IU/kg once-weekly and 50 IU/kg twice-weekly groups, respectively. However, the severe phenotype was observed in 4 (10%) and 3 (7%) subjects, respectively. Conclusions: The pharmacokinetics of r-FIX-R are dose proportional. The C0.5hr increased in proportion to the dose administered. Recovery was consistent between the two prophylaxis regimens. Both regimens provided similar therapeutic results for Ctrough. The apparent difference in time after dose of new bleeding events between the 2 regimens is intriguing and deserves further study. Disclosures: Korth-Bradley: Pfizer Inc: Employment. Valentino:Inspiration Bioscience: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; CSL Behring: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center; Pfizer: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center; NovoNordisk: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; GTC Biotherapeutics: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; Bayer Healthcare: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; Baxter Bioscience: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; Biogen: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center; Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees, Past-President. Rendo:Pfizer Inc: Employment. Shafer:Pfizer Inc: Employment. Smith:Pfizer Inc: Employment. Baumann:Pfizer Inc: Employment. Charnigo:Pfizer Inc: 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

A Novel Case of Hemophilia B Due to a Partial Duplication of the Factor 9 Gene

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4423-4423
Author(s):  
Ruth Wheeler ◽  
Jayanthi Alamelu ◽  
Jacqueline Cutler
Keyword(s):  
De Novo ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Gene Copy Number ◽  
Factor Ix ◽  
Hemophilia B ◽  
Gene Copy ◽  
Coagulation Disorder ◽  
Severe Hemophilia ◽  
Bleeding Events

Abstract Abstract 4423 Hemophilia B is an X-linked recessive coagulation disorder. The disease is caused by a deficiency of procoagulant Factor IX and is characterised by easy bruising and prolonged bleeding and oozing after injury or surgery. The severity of the disease and the frequency of bleeding events vary, depending on the FIX clotting activity, and in severe cases males suffer from spontaneous joint and muscle bleeds which significantly impact on their health and quality of life. Hemophilia B is less common than Hemophilia A, with a frequency of approximately 1 in 25000 males worldwide. The F9 gene is located on the long arm of the × chromosome at Xq27. The gene comprises 8 exons, spanning approximately 33.5 kb DNA. The molecular basis of Hemophilia B is heterogeneous and to date over a 1000 different mutations have been reported, including missense and nonsense mutations, splicing mutations and large deletions. Here we report the identification of a previously uncharacterised duplication spanning a large part of the F9 gene in a patient with severe Hemophilia B. The patient, a 6 year old male of mixed Iranian and UK origin, was referred to the centre with severe Hemophilia B. He had a FIX level of less than 1iu/dL. No family history of bleeding diathesis could be confirmed due to loss of maternal family members in an earthquake. Mutation analysis of all exons including immediate flanking regions to allow detection of splice site mutations, and the 5’ and 3’ untranslated regions was performed by direct sequencing but no changes from the normal sequence were identified. There have been several reports of Hemophilia B being associated with partial duplications of the F9 gene so we analysed gene copy number using multiplex ligation-dependant probe amplification (MLPA). A large duplication, involving exons 2 to 6 was identified in the affected male. Subsequent analyses of maternal samples were normal, indicating that the mutation arose de novo. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2294-2294
Author(s):  
Amy D Shapiro ◽  
David J Perry ◽  
Ross I Baker ◽  
Elisa Tsao ◽  
Baisong Mei
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Factor Ix ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Recombinant Factor Ix ◽  
Bleeding Episodes ◽  
Dosing Intervals

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

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