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.

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.

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.

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

Efficacy, PK and Safety Results of Clinical Study Of Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) In Previously Treated Patients With Hemophilia B

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1109-1109 ◽  
Author(s):  
Aaron Lubetsky ◽  
Toshko Lissitchkov ◽  
Elena Santagostino ◽  
Gantcho Jotov ◽  
Tami Barazani-Brutman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Half Life ◽  
Factor Ix ◽  
Hemophilia B ◽  
Bleeding Events ◽  
Spontaneous Bleeding ◽  
Previously Treated Patients ◽  
Bleeding Episodes ◽  
The Mean

Abstract Background The standard of care for patients with severe hemophilia B is replacement treatment with Factor IX (FIX) 2-3 times a week. A fusion protein genetically linking recombinant human coagulation FIX with recombinant human albumin (rIX-FP) was developed with the aim to extend the half-life of FIX. In the completed Phase I pharmacokinetic study, the mean half-life of rIX-FP was found to be over 5 times longer than the subjects’ previous FIX. Thus, rIX-FP has potential to prevent bleedings for longer periods, allowing reduction in the frequency of injections compared to standard FIX and to reduce the number of injections required to treat a single bleed. Aims This was a Phase I/II open-label, multicenter study of rIX-FP in previously treated patients 12-65 years of age with severe hemophilia B (FIX ≤ 2%). The study evaluated the safety and efficacy of rIX-FP, including prevention of bleeding episodes during weekly prophylaxis of rIX-FP. Methods After completion of a 14-day rIX-FP pharmacokinetic assessment, 13 subjects in the prophylaxis arm received weekly prophylaxis of rIX-FP for approximately 11 months, and 4 subjects in the on-demand arm received rIX-FP upon occurrence of bleeding events. The treatment doses were initially selected based upon the pharmacokinetic profile of rIX-FP and subject’s bleeding phenotype, and doses could be adjusted at the Investigator’s discretion. Results Seventeen subjects were enrolled from hemophilia treatment centers in Israel and Bulgaria; the mean age was 26 years (range 13 to 46 years). Following a single injection of 25 IU/kg rIX-FP (n=13), the mean FIX activity level was 3.75% and 2.67% above baseline at Day 7 and Day 14, respectively, and the mean half-life of rIX-FP was 95 hours (comparable to the previously reported Phase I data). Over the 11 month treatment period, rIX-FP demonstrated a good safety profile with a total of over 700 EDs. The treatment was well tolerated and no FIX inhibitor formation was observed. There was no AE considered to be related to treatment with rIX-FP. No subject was withdrawn from the study due to safety concerns or lack of hemostatic efficacy. All 13 prophylaxis subjects were successfully maintained on a weekly routine regimen of rIX-FP for the entire duration of the study, with annualized spontaneous bleeding rates of 1.255 and 1.134 (mean and median respectively). Furthermore, three prophylaxis subjects who received only on-demand treatment prior to study entry had greater than 80% reduction in the annualized bleeding rate compared to their annualized bleeding rate prior to study entry. All bleeding events were treated successfully with ≤ 2 injections of rIX-FP, with approximately 90% of bleeds treated with a single injection of rIX-FP. The mean weekly consumption of rIX-FP was reduced markedly compared to the subjects’ weekly consumption of the previous FIX product. Conclusion This Phase I/II study demonstrated the clinical efficacy of rIX-FP for once weekly routine prophylaxis to prevent spontaneous bleeding episodes and for the treatment of bleeding episodes. In addition, rIX-FP showed an excellent safety and an improved PK profile over currently marketed factor IX products. Disclosures: Lubetsky: CSL Behring: Investigator for CSL clinical trial of rIX-FP Other. Lissitchkov:CSL Behring: Investigator for CSL Behring 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 Begring trial of rIX-FP Other. Barazani-Brutman:CSL Behring: study coordinator for CSL Behring rIX-FP trials Other. Voigt:CSL Behring: Employment. Moises:CSL Behring: Employment. Jacobs:CSL Behring: Employment. Martinowitz:CSL Behring: Honoraria, Investigator for CSL rIX-FP trials Other, Speakers Bureau.

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.

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.

Prophylaxis for Hemophilia in the Era of Extended Half-Life Factor VIII/Factor IX Products

2016 ◽  
Vol 42 (05) ◽  
pp. 518-525 ◽  
Author(s):  
Erik Berntorp ◽  
Nadine Andersson
Keyword(s):  
Half Life ◽  
Safety Margin ◽  
Clinical Development ◽  
Factor Ix ◽  
Life Extension ◽  
Bleeding Events ◽  
Treatment And Prevention ◽  
Trough Levels ◽  
Life Factor

There are two main bioengineering approaches to extending the half-life of factor (F)VIII or FIX products used for hemophilia replacement therapy. These are fusion to Fc-immunoglobulin G (FVIII and FIX) or to albumin (FIX) or pegylation/glycopegylation (FVIII and FIX). Four FVIII and three FIX products are in clinical development or have recently been licensed in regions of the world. The reported half-life extension is approximately 1.5-fold for FVIII and 2.5-fold, or even longer, for FIX. Clinical trials have shown promising results with respect to extension of dose intervals and efficacy in the treatment and prevention of bleeding events. The role of these products in clinical practice has been discussed in terms of either improving convenience and adherence through prolongation of the interval between infusions or maintaining current intervals thereby increasing trough levels and the safety margin against bleeds. This review of extended half-life products addresses the possibilities and problems of their introduction in hemophilia treatment.

scholarly journals Peak Thrombin and D-Dimer Levels in Subjects with Severe Hemophilia Receiving Acute Treatment for Bleeding Episodes Experienced during Prophylactic Marstacimab Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Satyaprakash Nayak ◽  
Sangeeta Raje ◽  
John Teeter ◽  
Lutz Harnisch ◽  
Steven Arkin
Keyword(s):  
Bleeding Episode ◽  
Phase 2 ◽  
Bleeding Events ◽  
Post Hoc Analysis ◽  
On Demand ◽  
Increased Risk ◽  
Phase 2 Study ◽  
Bleeding Episodes ◽  
Post Hoc ◽  
D Dimer

Introduction: Marstacimab is a fully humanized monoclonal immunoglobulin G1 that targets the shared K2 domains of tissue factor pathway inhibitor (TFPI)α and (TFPI)β and is currently in phase 3 development. The intended indication is routine prophylaxis treatment to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B (with or without inhibitors). Factor replacement or bypass treatment for bleeding events may lead to increased levels of peak thrombin and D-dimer associated with an increased risk of thrombosis . In this post hoc analysis of data from a phase 2 study in patients with hemophilia with and without bleeding episodes, receiving prophylactic marstacimab treatment, peak thrombin and D-dimer levels were investigated to assess the changes in these biomarker levels observed after bleeding episodes. Methods: Individual subject data from the phase 2 study (clinicaltrials.gov identifier: NCT02974855)were used for this analysis. Biomarker data for healthy volunteers who received single doses of marstacimab in a phase 1 dose escalation study (clinicaltrials.gov identifier: NCT02531815) were used as control data, as these subjects represent an intact and uncompromised coagulation system. Study subjects in the phase 2 study received subcutaneous (SC) marstacimab at doses of (1) 150 mg once weekly (QW), with a loading dose of 300 mg, (2) 300 mg QW, and (3) 450 mg QW. All subjects with bleeding episodes were identified, along with on-demand treatment administered for each bleeding episode. Treatments permitted for bleeding episodes included activated coagulation factor VIIa, factor VIII, or factor IX; use of activated prothrombin complex concentrate was prohibited. D-dimer and peak thrombin data collected within 3 days after each bleeding episode were used for this analysis. Time profiles of peak thrombin and D-dimer levels were analyzed to assess the effect of bleed treatment. Biomarker profiles were compared between subjects with and without bleeding episodes, as well as with the data from healthy volunteers (n=41). Results: A total of 15 bleeding episodes were reported in 8 of 26 subjects during the study (excluding screening and follow-up). No subject participating in the study showed any relevant increases in D-dimer levels after receiving on-demand treatment for a bleeding episode while receiving regular prophylaxis with marstacimab, compared with levels seen in subjects who did not experience a bleeding episode. Based on the peak thrombin data (see Figure), 150 nM was observed as the upper limit for 18 of 26 subjects who did not experience any bleeding episodes, which was approximately 50% of the 300 nM observed in healthy volunteer controls treated with 450 mg intravenous marstacimab. Transient increases in peak thrombin of &gt;150 nM were observed at several time points in 3 of 8 subjects who experienced bleeding episodes. The highest peak thrombin level reported was approximately 211 nM in one subject receiving marstacimab 300 mg SC QW and factor VIII concentrate on demand during the study. Conclusions: No transient increases in D-dimer could be attributed to the administration of bleeding episode treatment. The transient increases in peak thrombin levels following on-demand treatment for bleeding episodes did not exceed peak thrombin levels seen in subjects without bleeding events or the levels seen in healthy volunteer controls receiving single doses of marstacimab. Based on peak thrombin and D-dimer levels observed in this post hoc analysis, there does not appear to be any indication of an increased risk of thrombosis post administration of acute on-demand bleeding episode treatment while on prophylactic marstacimab therapy at the doses studied. Disclosures Nayak: Pfizer Inc.: Current Employment, Other. Raje:Pfizer Inc.: Current Employment, Other. Teeter:Pfizer Inc.: Current Employment. Harnisch:Pfizer Inc.: Current Employment, Other. Arkin:Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: own stock/options in the company.

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