scholarly journals Treatment With Efmoroctocog Alfa (Elocta®) in Hemophilia: A Case Series

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Ezio Zanon ◽  
Alberto Tosetto ◽  
Paolo Radossi ◽  
Samantha Pasca ◽  
Elisa Bonetti ◽  
...  
Keyword(s):  
Half Life ◽  
Soft Tissues ◽  
Hemophilia A ◽  
Case Series ◽  
Coagulation Factor ◽  
Phase Iii ◽  
Coagulation Cascade ◽  
Weekly Dose ◽  
Prophylactic Regimen ◽  
Joint Health

Hemophilia A is a rare X-linked disease that occurs as a result of a defect in the FVIII-encoding gene. The reduction or absence of plasma FVIII compromises the coagulation cascade, resulting in frequent bleeds, especially in joints or soft tissues. Currently, replacement therapy with coagulation factor concentrates is the gold standard for the treatment of FVIII deficiency.Herein, we report a case series of five hemophilia A patients treated with an extended half-life recombinant human coagulation factor, FVIII-Fc fusion protein (efmoroctocog alfa). The prophylactic regimen for each patient was individualized based on their pharmacokinetic profile.Compared to previous prophylactic treatments, most patients received a reduced weekly dose of concentrate, all underwent a reduced frequency of administration, the annualized bleeding rates (ABR) and hemophilia joint health scores (HJHS) were stable or improved. The half-life of efmoroctocog alfa and the 72-hour trough levels were higher than those observed in the A-LONG Phase III trial.In conclusion, all patients reported clinical improvements and general subjective wellbeing in the absence of significant safety concerns after switching to efmoroctocog alfa. 

scholarly journals Assessing the Performance of Extended Half-Life Coagulation Factor VIII, FC Fusion Protein by Using Chromogenic and One-Stage Assays in Saudi Hemophilia A Patients

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Tarek M. Owaidah ◽  
Hazzaa A. Alzahrani ◽  
Nouf S. Al-Numair ◽  
Abdulmjeed O. Alnosair ◽  
Amelita M. Aguilos ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Time Interval ◽  
One Stage ◽  
Chromogenic Assay ◽  
Significant Difference ◽  
Mean Differences ◽  
The One

Background. The one-stage assay is the most common method to measure factor VIII activity (FVIII : C) in hemophilia A patients. The chromogenic assay is another two-stage test involving purified coagulation factors followed by factor Xa-specific chromogenic substrate. Aim. This study aimed to assess the discrepancy and correlation between the chromogenic and one-stage assays in measuring FVIII : C levels in hemophilia patients receiving Extended Half-Life Elocta® as a recombinant extended half-life coagulation factor. Methods. We performed a study comparing the measurements of FVIII : C levels by the chromogenic versus the one-stage assays at different drug levels. Data of FVIII : C levels, dosage, and the time interval from administration to measurement were retrieved from the hospital records. The correlation, mean differences, and discrepancy between the two assays were calculated. The linear regression analysis was used to predict the time interval till reaching 1% FVIII : C. Results. Fourteen patients with 56 samples were included in the study. Of them, 13 patients were receiving Elocta® as a prophylactic, while one was receiving Elocta® on demand. One-third of these samples showed a discrepancy between the chromogenic and one-stage assays. The two assays were well correlated. Mean differences were significant at the individual and the time interval level. The time since the last Elocta® injection could significantly predict FVIII : C levels (β = 0.366, P<0.001). Conclusion. Our findings suggested a significant difference between both methods; the FVIII : C levels measured by the one-stage assay were less than those estimated by the chromogenic assay. However, the measurements of FVIII levels by the two assays were well correlated but discrepant in one-third of the samples. The levels of FVIII : C reach 1% after 5.4 days since the last Elocta® administration.

scholarly journals Surgical Experience from the Phase III STASEY Trial of Emicizumab Prophylaxis in Persons with Hemophilia A with FVIII Inhibitors: Final Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 344-344
Author(s):  
Giancarlo Castaman ◽  
Jerzy Windyga ◽  
Hazza Alzahrani ◽  
Susan Robson ◽  
Fabian Sanabria ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Knee Prosthesis ◽  
Coagulation Factor ◽  
Left Knee ◽  
Phase Iii ◽  
Postoperative Treatment ◽  
Research Centre ◽  
Case Report Form ◽  
Knee Arthrodesis

Abstract Background: Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX and FX, replacing the function of missing activated FVIII in persons with hemophilia A (PwHA). The Phase IIIb, multicenter, single-arm STASEY study (NCT03191799) assessed the safety and efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors. Surgical experiences in STASEY are reported here. Methods: Following informed consent and ethics committee approval, PwHA aged ≥12 years with FVIII inhibitors received 3 mg/kg/week emicizumab for 4 weeks (loading dose), then 1.5 mg/kg/week for the remaining 2-year treatment period. Minor and major surgeries were managed per the investigators' discretion. The type and number of procedures performed, additional prophylaxis, and frequency and management of postoperative bleeds were analyzed. Surgeries occurring up to 28 days after the last dose of emicizumab were included, due to emicizumab's ~28-day half-life (Emicizumab Prescribing Information, United States Food and Drug Administration, 2017). Surgeries were documented using an electronic case report form by the treating physicians and classified as minor or major based on manual medical review (Santagostino, et al. Haemophilia, 2015). Bleed and prophylactic hemophilia medication data were recorded in the electronic Bleed Medication Questionnaire by participants. Case narratives were provided by trial investigators. Results: Overall, 46 patients reported ≥1 on-study surgery. Thirty-seven patients had 56 minor surgeries (central venous access device [CVAD], n=9; dental, n=20; joint, n=4; other, n=23) (Figure), one of which (skin laceration and suture insertion on Day 9) was performed during the loading phase. Twenty-four surgeries (42.9%) were managed with additional prophylactic medications (Table). Of these, 11/24 (45.8%) resulted in postoperative bleeds, of which 6/11 were treated (54.5%). Of surgeries managed without additional prophylactic medications, 15/32 (46.9%) resulted in postoperative bleeds, of which 5/15 (33.3%) were treated. A total of 13 patients had 22 major on-study surgeries (arthroplasty, n=13; other, n=9). 'Other' included hemorrhoid operations, coronarography, sigmoidectomy, colostomy, laparotomy and polypectomy. Eighteen (81.8%) major surgeries, including all arthroplasties, were managed with additional prophylactic medications (Table). Of these, 12/18 (66.7%) resulted in postoperative bleeds (including 10/13 arthroplasties), of which six (50.0%) were treated (all arthroplasties). Four (18.2%) major surgeries were managed without additional prophylactic medication, including three hemorrhoid operations in one patient, and a coronarography in a patient with acute myocardial infarction. One hemorrhoid operation resulted in a postoperative treated bleed. Major surgeries included a 55-year-old male with Grade 4 device dislocation of left knee prosthesis on Day 7, who was diagnosed with recurrent infection and prosthesis misalignment on Day 62. Amputation of the left leg above the knee was performed, with treatment including tranexamic acid and rFVIIa. A 61-year-old male with left knee prosthesis infection underwent left knee arthrodesis on Day 457, vacuum-assisted closure therapy on Day 495, skin grafting on Day 512, and left knee arthrodesis with skin flap placement on Day 527. Throughout these surgeries, the individual experienced recurrent joint bleeding and received rFVIIa. Neither of these individuals had a change in their study treatment due to these events. No thrombotic events (TEs) or thrombotic microangiopathies (TMAs) related to surgeries were observed. Conclusions: In the STASEY study of PwHA with FVIII inhibitors receiving emicizumab prophylaxis, most minor surgical procedures were performed without additional prophylactic coagulation factor and did not result in postoperative treated bleeds. Therefore, emicizumab alone provided adequate hemostatic coverage for some PwHA undergoing certain types of minor surgery, such as tooth extraction and CVAD removal. Major surgeries were safely performed with additional coagulation prophylaxis. Management of surgeries with rFVIIa did not result in TE or TMA. In case of bleeds, a bleed management plan should be in place. Effects of emicizumab on coagulation and assays may persist for up to 6 months after the last dose, which may be relevant when planning postoperative treatment. Figure 1 Figure 1. Disclosures Castaman: Uniqure: Honoraria; Bayer: Honoraria; Sobi: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Kedrion: Honoraria; LFB: Honoraria; Grifols: Honoraria; Werfen: Honoraria; Biomarin: Honoraria; Sanofi: Honoraria; F Hoffmann-La Roche Ltd: Honoraria. Windyga: Swixx BioPharma: Honoraria; Octapharma: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; Werfen: Honoraria; Bayer AG: Honoraria; Aspen: Honoraria; Alfasigma: Honoraria; Takeda: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Alnylam Pharmaceuticals: Research Funding; Sanofi/Genzyme: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Alexion: Honoraria; CSL Behring: Honoraria; Rigel Pharmaceuticals: Research Funding; Novo Nordisk: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding. Alzahrani: Sobi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; King Faisal Specialist Hospital and Research Centre: Current Employment. Robson: F. Hoffmann-La Roche Ltd: Current Employment, Ended employment in the past 24 months. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Howard: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Jiménez-Yuste: Octapharma: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

scholarly journals Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A

2020 ◽  
Vol 120 (10) ◽  
pp. 1357-1370
Author(s):  
Georg Gelbenegger ◽  
Christian Schoergenhofer ◽  
Paul Knoebl ◽  
Bernd Jilma
Keyword(s):  
Clinical Trials ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Factor X ◽  
Current Standard ◽  
Bleeding Events ◽  
Recombinant Activated Factor Vii

AbstractHemophilia A, characterized by absent or ineffective coagulation factor VIII (FVIII), is a serious bleeding disorder that entails severe and potentially life-threatening bleeding events. Current standard therapy still involves replacement of FVIII, but is often complicated by the occurrence of neutralizing alloantibodies (inhibitors). Management of patients with inhibitors is challenging and necessitates immune tolerance induction for inhibitor eradication and the use of bypassing agents (activated prothrombin complex concentrates or recombinant activated factor VII), which are expensive and not always effective. Emicizumab is the first humanized bispecific monoclonal therapeutic antibody designed to replace the hemostatic function of activated FVIII by bridging activated factor IX and factor X (FX) to activate FX and allow the coagulation cascade to continue. In the majority of hemophilic patients with and without inhibitors, emicizumab reduced the annualized bleeding rate to almost zero in several clinical trials and demonstrated a good safety profile. However, the concurrent use of emicizumab and activated prothrombin complex concentrate imposes a high risk of thrombotic microangiopathy and thromboembolic events on patients and should be avoided. Yet, the management of breakthrough bleeds and surgery remains challenging with only limited evidence-based recommendations being available. This review summarizes published clinical trials and preliminary reports of emicizumab and discusses the clinical implications of emicizumab in treatment of hemophilia A.

scholarly journals The tertiary structure and domain organization of coagulation factor VIII

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1240-1247 ◽  
Author(s):  
Betty W. Shen ◽  
Paul Clint Spiegel ◽  
Chong-Hwan Chang ◽  
Jae-Wook Huh ◽  
Jung-Sik Lee ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Tertiary Structure ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Factor Viii Gene ◽  
C2 Domains ◽  
Activated Platelets ◽  
Membrane Bound ◽  
Domain Stabilization

AbstractFactor VIII (fVIII) is a serum protein in the coagulation cascade that nucleates the assembly of a membrane-bound protease complex on the surface of activated platelets at the site of a vascular injury. Hemophilia A is caused by a variety of mutations in the factor VIII gene and typically requires replacement therapy with purified protein. We have determined the structure of a fully active, recombinant form of factor VIII (r-fVIII), which consists of a heterodimer of peptides, respectively containing the A1-A2 and A3-C1-C2 domains. The structure permits unambiguous modeling of the relative orientations of the 5 domains of r-fVIII. Comparison of the structures of fVIII, fV, and ceruloplasmin indicates that the location of bound metal ions and of glycosylation, both of which are critical for domain stabilization and association, overlap at some positions but have diverged at others.

scholarly journals Pharmacokinetics of Extended Half-Life Factor VIII Products By myPKFiTR Is Useful for Personalized Treatment in Children with Severe Hemophilia a

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1127-1127
Author(s):  
Risa Matsumura ◽  
Keita Tomioka ◽  
Shiho Nishimura ◽  
Yoko Mizoguchi ◽  
Hiroshi Kawaguchi ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
After School ◽  
Severe Hemophilia ◽  
Prophylactic Regimen ◽  
Sports Activity ◽  
Prophylactic Administration ◽  
Single Center Experience

Prophylactic administration of factor VIII products is necessary to prevent bleeding and preserve normal musculoskeletal function in children with severe hemophilia A (HA). Recently, extended half-life recombinant factor VIII (EHL-rFVIII) products have been utilized in HA patients. Therefore, the pharmacokinetics (PK) of EHL-rFVIII in individuals is needed to determine the appropriate administration for personalized prophylaxis according to the age, bleeding phenotype, the presence of arthropathy, and physical activity. The myPKFiTR ver 3.0 has been developed as the device to estimate the personalized dosing with a 2 sample PK based on the population PK (Bayesian) tool. In this study we report our single-center experience to study PK profiles and to individualize dose and dosing interval based on myPKFiTR. Eight patients with severe HA aged from 10 to 20 years were enrolled in this study for personalized prophylaxis. The half-life of EHL-rFVIII was approximately 15 to 18 hours in all patients studied. The clearance of FVIII was inversely correlated with the half-life of EHL-rFVIII. The EHL-rFVIII products have been basically administered twice a week. The trough levels of FVIII were more than 3% in all patients. The prophylactic regimen in adolescents was individually determined according to the personal simulation of PK study and to patients' life style and physical activities. Adolescent patients actively participated in sports, such as track and field, basketball, and football after school. The FVIII level after school was easily estimated by the use of myPKFiTR according to the dose and duration of replacement. The doses of EHL-rFVIII products were individually determined to have more than 10 to 30% of FVIII level at the time of sports activity. During personalized prophylaxis (6 to 18 months), all of patients studied have been no bleeds during sports as well as no spontaneous bleeds. Additionally, myPKFiTR has the capability of presenting the real-time FVIII level on the screen of smartphone after the replacement of EHL-rFVIII based on the individual PK. Some patients have referred their own FVIII level before the beginning of sports through their smartphone and then have decided the necessity of the replacement. These experiences suggest the enhancement of treatment concordance in the supportive relationship between patients and medical staff. Thus, the use of myPKFiTR may be essential for the optimization of prophylactic administration of EHL-rFVIII and for the medical adherence and concordance in each individual. Disclosures No relevant conflicts of interest to declare.

scholarly journals Recombinant VWF Fragments Improve Bioavailability of Subcutaneous Factor VIII in Hemophilia A Mice

Blood ◽  
2020 ◽  
Author(s):  
Nadine Vollack-Hesse ◽  
Olga Oleshko ◽  
Sonja Werwitzke ◽  
Barbara Solecka-Witulska ◽  
Christoph Kannicht ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Dependent Manner ◽  
High Concentrations ◽  
Von Willebrand ◽  
Willebrand Factor

Conventional treatment of hemophilia A (HA) requires repetitive intravenous (IV) injection of coagulation factor VIII (FVIII). Subcutaneous (SC) administration of FVIII is inefficient because of binding to the extravascular matrix, in particular to phospholipids (PL), and subsequent proteolysis. To overcome this, recombinant dimeric fragments of von Willebrand factor (VWF) containing the FVIII stabilizing D3 domain were engineered. Two fragments, called VWF-12 and VWF-13, demonstrated high binding affinity to recombinant human FVIII (rhFVIII) and suppressed PL-binding in a dose-dependent manner. High concentrations of VWF fragments did not interfere with the functional properties of full-length VWF in vitro. The HA mouse model was used to study the effects of VWF-12 or VWF-13 on the in vivo pharmacokinetics of rhFVIII, demonstrating (i) no significant impact on rhFVIII recovery or half-life after a single IV administration; (ii) enhanced bioavailability (up to 18.5 %) of rhFVIII after SC administration; (iii) slow absorption (cmax 6h) and prolonged half-life (up to 2.5-fold) of rhFVIII after SC administration. Formation of anti-FVIII antibodies was not increased after administration of rhFVIII/VWF-12 SC compared to rhFVIII IV. A single SC dose of rhFVIII/VWF-12 provided protection in the HA tail bleeding model for up to 24h. In conclusion, recombinant VWF fragments support FVIII delivery through the SC space into vascular circulation without interfering with VWF or FVIII function. Slow resorption and excretion of FVIII after SC administration highlight the potential application of VWF fragments for SC FVIII prophylaxis in HA.

scholarly journals Changing the Paradigm in Hemophilia Care: Extended Half-Life Products (rFVIIIFc and rFIXFc)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3514-3514 ◽  
Author(s):  
Louis M. Aledort ◽  
Nisha Jain ◽  
Nanxin Li ◽  
Sangeeta Krishnan ◽  
Benjamin Hagberg ◽  
...  
Keyword(s):  
Half Life ◽  
Hemophilia A ◽  
The Other ◽  
Treatment Regimens ◽  
On Demand ◽  
Fda Approval ◽  
The Us ◽  
Joint Health ◽  
Viii And Ix ◽  
The Impact

Abstract Background: Prophylactic treatment with factor products has demonstrated superior outcomes and care compared to on-demand treatment in hemophilia patients, including patients with pre-existing joint diseases. However, 40% to 50% of severe or moderate hemophilia A and B patients are still treated on-demand in the US. Recombinant factor VIII and IX Fc fusion proteins (rFVIIIFc and rFIXFc) were the first extended half-life (EHL) products approved in the US (in 2014) with the promise of optimizing prophylactic regimens by achieving low bleeding rates and improving joint health with fewer injections overall. Objective: This is the first real-world study to assess the impact of EHL rFVIIIFc and rFIXFc on overall prophylaxis rates, particularly to understand how patients have transitioned from on-demand treatment. Methods: A retrospective analysis was conducted on aggregate, de-identified United States Specialty Pharmacy Provider (SPP) records from Jan 2014 to June 2018 (data pull on June 14th, 2018). Adult hemophilia patients (age 18 and above) were included for an analysis of treatment regimens prior to and after switching to EHL rFVIIIFc and rFIXFc (on-demand or prophylaxis). The results were descriptively compared to those who switch to the other EHL PEGylated rFVIII and rFIX albumin Fusion Protein (rFIX-FP) and conventional factors. Results: A total of 304 hemophilia A patients who switched to rFVIIIFc and 133 hemophilia B patients who switched to rFIXFc were included in this study. For the hemophilia A and B patients, the median age was 31 and 32 years and median weight was 82 and 79 kg. The proportion of patients who switched from on-demand treatment with conventional factors to prophylaxis treatment with EHL rFVIIIFc and rFIXFc among all patients who switched to these products increased over time since the FDA approval (3 time points: 2014-2015, 2016-2017, and 2018: rFVIIIFc: 13%, 20%, and 21%; rFIXFc: 25%, 29%, and 57%). Such proportions were higher compared to those who switched from on-demand with conventional factors to prophylaxis with the other EHLs (2016-2017, 2018: PEGylated rFVIII: 16%, 18%; rFIX-FP: 18%, 13%, see comparison in the Figure) and with conventional factors (2014-2015, 2016-2017, and 2018: conventional rFVIII: 10%, 7%, and 9%; conventional rFIX: sample size was too small and not suitable for analysis). Discussion: rFVIIIFc and rFIXFc have transformed the paradigm of hemophilia care by shifting on demand patients to prophylaxis significantly faster than conventional factors and any other EHLs to date. This shift is significant as it is helping more hemophilia patients achieve optimal protection through low bleeding rates and improved joint health over the long-term. Figure. Figure. Disclosures Jain: Bioverativ: Employment. Li:Bioverativ: Employment. Krishnan:Bioverativ: Employment. Hagberg:Bioverativ: Employment. Su:Bioverativ: Employment.

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 Current and emerging factor VIII replacement products for hemophilia A

2017 ◽  
Vol 8 (10) ◽  
pp. 303-313 ◽  
Author(s):  
Lorraine A. Cafuir ◽  
Christine L. Kempton
Keyword(s):  
Gene Therapy ◽  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Standard Of Care ◽  
Cross Reactivity ◽  
Life Extension ◽  
Past Century ◽  
Current Standard

Hemophilia A is a congenital X-linked bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. Routine infusion of factor replacement products is the current standard of care; however, the development of alloantibodies against FVIII remains a challenge. The treatment of hemophilia has undergone major advances over the past century to improve safety, effectiveness, manufacturing, and convenience of factor products. Major recent advances in the treatment of hemophilia A include the emergence of extended half-life products, factor VIII orthologs, and gene therapy products. Extended half-life products were designed to decrease the frequency of infusions, but only modest half-life extension is achieved. Factor VIII orthologs featuring lower cross-reactivity with anti-FVIII antibodies may be less susceptible to inactivation by inhibitors. Meanwhile, gene therapy may potentially provide a cure for hemophilia A, thus abrogating the need for protein-based factor replacement. This review aims to discuss current and emerging FVIII replacement products for hemophilia A.

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