scholarly journals Multicenter Pharmacokinetic Evaluation of rFVIII-Fc (Elocta) in a Real Life and Comparison with Non-Extended Half-Life FVIII Concentrates

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1196-1196 ◽  
Author(s):  
Claire Pouplard ◽  
Laurent Sattler ◽  
Anne Ryman ◽  
Valérie Eschwege ◽  
Emmanuel De Maistre ◽  
...  
Keyword(s):  
Half Life ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Phase 1 ◽  
Real Life ◽  
Strongly Correlated ◽  
Chromogenic Assay ◽  
Significant Prolongation ◽  
Previously Treated ◽  
The Impact

Abstract Background: The use of extending half-life (EHL) FVIII or FIX products is today a current strategy in Hemophilia A (HA) patients for improving prophylaxis and reducing the number of IV injections. Fc fusion technology is based on the use of the neonatal Fc receptor and endogenous Fc recycling pathway, thereby prolonging the half-life (T1/2) of rFVIII-Fc. A single dose phase 1/2 pharmacokinetic (PK) study performed in 16 severe HA patients demonstrated a prolonged T ½ of rFVIII-Fc equal to 18.8 hours (mean) compared to 12.2 hours with one conventional rFVIII (Malhangu et al. Blood 2014). The aim of the present study was to analyze PK data collected with Elocta® in "real life" i.e. in a large cohort of patients treated in 13 different French hemophilia care centers, and results were compared to those obtained with conventional FVIII, when available. Importantly, this study was performed without any involvement of Sobi, the pharmaceutical company that provides Elocta® in France. Patients and methods: 113 severe Hemophilia A (HA) patients with the following characteristics were included: mean age 30 years (range 3 - 70); weight 65 Kg (17-125); total FVIII-Fc dose injected 2650 IU (500-5750); FVIII-Fc IU/Kg: 41 (25 - 59); VWF Ag 98% (41-279). The FVIII recovery (R) was calculated as follows: (body weight (Kg) x observed increased in FVIII (%))/administered dose (IU/Kg). The T1/2 was calculated with the following formula: Ln2/((Ln FVIII% T1 - Ln FVIII%T2)/T2 - T1)), with T1 ≥ 4 hours and T2 ≥ 24 hours. Results were compared to those performed with conventional FVIII (non EHL-FVIII) in 48 patients (Advate® n = 14, Refacto® n = 2, Helixate®/Kogenate®/Kovaltry® n = 29, Factane® n = 3) Results: rFVIII-Fc activity measured by one stage clotting assay (OSA) was 20% lower than those obtained with chromogenic assay (CSA) in samples with FVIII levels higher than 20%, but this difference was lower than 10% when FVIII levels < 20%. Therefore, rFVIII-Fc recovery (R) always appeared lower when measured with OSA (Mean 2.38, range 1.33 - 5.7) than with CSA (mean 2.82, ranges 1.35 - 5.5) (p < 0.0001). No correlation was found between this recovery and age, weight, injected doses or VWF Ag levels. Mean T1/2 measured with rFVIII-Fc equaled 15 hours whatever the measurement method used (OSA or CSA), and was strongly correlated with vWFAg levels (R2 = 0.57). Using OSA, significantly lower recovery (1.86 vs. 2.49, p = 0.0002) and T1/2 values (11.75 vs. 15.13 hours, p = 0.0004) were measured in children (< 10 years, n = 19) compared to adults. Similar differences were evidenced with data obtained by CSA (recovery : 2.26 vs. 2.93, p = 0.0009 and T1/2 : 11.4 vs. 15.6 h, p = 0.004, n = 14 children < 10 years). PK parameters of FVIII-Fc were compared to those obtained with non EHL-FVIII (rFVIII or pdFVIII) in 47 patients (mean T1/2 equal to 10.0 hours; range 5.3 - 21.2), and half-lives of these two categories of products were well correlated (r2 = 0.57). However, the apparent benefit provided by FVIII-Fc was variable from one patient to another, with a mean T1/2 rFVIII-Fc / T1/2 FVIII ratio ranging from 0.6 to 2.4 (mean 1.4). Interestingly, the increase in T1/2 with FVIII-Fc was lower than 20% only in patients previously treated with BHK-derived rFVIII i.e. Helixate®/Kogenate®/ Kowaltry® (n=10). Whatever the FVIII injected (FVIII-Fc or other non EHL-FVIII), the T1/2 measured was also strongly correlated to vWF levels, which were significantly lower in patients for whom the mean T1/2 rFVIII Fc / T1/2 FVIII ratio was > 1.3 (mean 79% vs 116% in the others, p=0.017). Conclusion: This study is the first to report PK data obtained with rFVIII-Fc (Elocta®) in a large group of HA patients. Our results confirm the benefit of rFVIII-Fc in most HA patients, adults or children, but also emphasize the impact of vWF on half-life of rFVIII-Fc or conventional non EHL-FVIII. Indeed, the benefit of rFVIII-Fc clearly appears higher in patients with lower vWF levels, with a more significant prolongation of T1/2. Disclosures No relevant conflicts of interest to declare.

Bleeding Phenotype with Various Bay 94-9027 Dosing Regimens: Subanalyses from the Protect VIII Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1526-1526 ◽  
Author(s):  
Lisa N. Boggio ◽  
Walter Hong ◽  
Maria Wang ◽  
M. Elaine Eyster ◽  
Lisa A. Michaels
Keyword(s):  
Half Life ◽  
Hemophilia A ◽  
Phase 1 ◽  
P Value ◽  
Phase 2 ◽  
Dosing Regimen ◽  
On Demand ◽  
Dosing Regimens ◽  
Previously Treated ◽  
Dosing Intervals

Abstract Introduction: Factor VIII (FVIII) products with a longer half-life may allow for longer intervals between treatments for patients with hemophilia A and may facilitate prophylaxis tailored to an individual’s bleeding phenotype. BAY 94-9027, a PEGylated FVIII product, demonstrated an extended half-life in a phase 1 trial and was well tolerated and efficacious in a phase 2/3 study with dosing intervals up to every 7 days. In this subanalysis of the phase 2/3 trial, bleeding frequency calculated based on the BAY 94-9027 prophylactic dosing regimen during the study was compared with reported bleeding frequency in the 12 months before enrollment. Also, on-study annualized bleeding rates (ABRs) for joint, spontaneous, and trauma bleeds are presented by treatment group. Methods: PROTECT VIII was a multinational, partially randomized, open-label, 36-week study in previously treated patients aged 12–65 years with severe hemophilia A and no history of FVIII inhibitors. Patients received BAY 94-9027 for 36 weeks either on demand or prophylactically. Patients were assigned to 1 of 3 prophylaxis dosing regimens based on the number of bleeds observed during a 10-week run-in period, during which all patients in the prophylaxis arm were treated with 25 IU/kg BAY 94-9027 2x/week. Patients with ≤1 breakthrough bleed during the 10-week period were randomized 1:1 to BAY 94-9027 45–60 IU/kg every 5 days or 60 IU/kg every 7 days. Patients with ≥2 breakthrough bleeds received 30–40 IU/kg BAY 94-9027 2x/week. ABR and annualized joint bleeding rate (AJBR) for the 12 months before the study (collected retrospectively at screening) were compared with values calculated in patients previously treated with prophylaxis who used BAY 94-9027 prophylaxis during the study (weeks 0–36 for the combined prophylaxis groups [including the 10-week period]; weeks 10–36 for the 3 assigned prophylaxis dosing regimens). ABRs for joint, spontaneous, and trauma bleeds during the study were analyzed for the on-demand and combined prophylaxis groups (weeks 0–36) and in relation to patients’ BAY 94-9027 dosing regimen (weeks 10–36). Results: The intent-to-treat population comprised132 patients (prophylaxis, n=112; on demand, n=20). In patients previously treated with prophylaxis, median ABR and AJBR during BAY 94-9027 prophylaxis (weeks 0–36) were lower than corresponding prestudy values; ABR and AJBR during weeks 10–36 for every-5-day, every-7-day, and 2x/week BAY 94-9027 dosing were also lower than or comparable to prestudy values (Table). Median ABRs for joint, spontaneous, and trauma bleeds were lower for the combined prophylaxis groups (weeks 0–36) compared with the on-demand group (combined prophylaxis groups: 1.5, 1.4, and 0.0, respectively; on-demand group: 16.3, 14.3, and 9.1). In the prophylaxis arms (weeks 10–36), median ABRs for joint, spontaneous, and trauma bleeds were 2.1, 0.0, and 0.0 for 2x/week dosing; 1.9, 0.0, and 0.0 for every-5-day dosing; and 1.9, 1.9, and 0.0 for every-7-day dosing. Abstract 1526. Table. Bleeding Frequency During BAY 94-9027 Prophylaxis vs Prestudy Values Combined Prophylaxis, 2x/week, week 10–36 Every 5 Days, Every 7 Days, week 0–36(n=87)* Required† (n=9) Not Randomized‡ (n=6) week 10–36(n=34) week 10–36(n=37) ABR, median Prestudy 5 12 5.5 3 2 Study 2.82 8.7 0.75 1.48 2.88 P value 0.0015 0.2445 0.0766 0.0039 0.4981 AJBR, median Prestudy 2 9 3.5 2 2 Study 1.46 7.24 0 1.40 1.39 P value 0.0045 0.3484 0.0673 0.0131 0.4111 P values (paired Student’s t test) are nominal, as no multiplicity control was applied. *n=86 for AJBR. †Patients with ≥2 breakthrough bleeds in weeks 0–10. ‡Patients with ≤1 bleeds in weeks 0–10 who were not randomized (randomized arms were filled). Conclusions: BAY 94-9027 prophylaxis resulted in lower ABRs and AJBRs during the 36-week study period compared with prestudy values in patients previously treated with prophylaxis. Subgroup analyses based on prophylactic dosing regimens (including dosing intervals of up to every 7 days) showed that patients who were randomized based on bleeding phenotype during the 10-week run-in period achieved bleeding control that was better than or comparable to their prestudy levels, highlighting the value of individualized phenotype-based dosing with BAY 94-9027. In addition, prophylaxis with BAY 94-9027 resulted in reduced joint, spontaneous, and trauma bleeds compared with on-demand treatment. Disclosures Boggio: Bayer, Baxter, Novo Nordisk, CSL Behring, Grifols, and Pfizer: Consultancy. Hong:Bayer HealthCare: Employment. Wang:Bayer HealthCare Pharmaceuticals: Employment. Michaels:Bayer HealthCare Pharmaceuticals: Employment.

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.

Cellular Uptake of rFVIIIFc in Liver Is Primarily Contributed by Sinusoidal Endothelial Cells.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2219-2219
Author(s):  
Siyuan Tan ◽  
Kai Chen ◽  
Arjan van der Flier ◽  
Zhan Liu ◽  
David R. Light ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Factor Viii ◽  
Cellular Uptake ◽  
Kupffer Cells ◽  
Half Life ◽  
Hemophilia A ◽  
Liver Cells ◽  
Whole Body ◽  
Sinusoidal Endothelial Cells ◽  
The Impact

Abstract Abstract 2219 rFVIIIFc is a recombinant fusion protein consisting of human B-domain deleted factor VIII covalently linked to the Fc domain of IgG1. In hemophilia A patients, rFVIIIFc has been shown to display a ∼1.6-fold longer half-life than recombinant full length FVIII (Advate®) (Powell et al., 2012. Blood). This half-life extension can be attributed to a natural pathway mediated by the neonatal Fc receptor (FcRn) that re-circulates IgG molecules into the vascular system, as the long-lasting activity of rFVIIIFc is not observed in FcRn knockout mice. To identify the cell type that takes up and subsequently protects and recycles rFVIIIFc, we have recombinantly replaced the missing B-domain with a Halo tag in rFVIIIFc (rFVIIIFc-Halo) to allow visualization of the protein in the presence of fluorescently labeled Halo-ligand using confocal microscopy. Purified rFVIIIFc-Halo protein displayed similar specific activity and pharmacokinetic properties as rFVIIIFc in hemophilia A (HemA) mice, indicating that the addition of the Halo tag does not alter the functionality and the clearance mechanisms of rFVIIIFc. In quantitative whole body autoradiography studies (QWBA) in HemA mice with radiolabeled rFVIIIFc, we observed that 125I-rFVIIIFc is predominately distributed to the liver. Therefore, we selected primary liver cells isolated from HemA mice to study cellular uptake of rFVIIIFc. A co-culture of hepatocytes and non-parenchymal cells was isolated from HemA mice and prepared at a 1:1 ratio. Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) in this culture were identified by fluorescently labeled antibodies to CD31 and F4/80 respectively. Both cell types effectively took up the fluorescently labeled AcLDL, confirming that the isolated LSECs and KCs retained the capacity for functional endocytosis in vitro. It was found that LSECs, as opposed to Kupffer cells or hepatocytes, are predominantly responsible for the cellular uptake of rFVIIIFc, as the localization of rFVIIIFc-Halo is apparent only in LSECs within 5 minutes after exposing 10 nM of rFVIIIFc-Halo to primary co-culture freshly isolated from HemA mice. In contrast, even with longer exposure time (up to 1 hour) and higher protein concentration (up to 40 nM), the localization of rFVIIIFc-Halo in Kupffer cells and hepatocytes still remains undetectable. Analysis of recombinant Halo-tagged factor VIII (rFVIII-Halo) yielded similar results, suggesting that the Fc-fusion does not alter the cellular uptake pathway of FVIII, which is consistent with the notion that the interaction of Fc with FcRn occurs at the intracellular level. Therefore, interestingly, both rFVIII-Halo and rFVIIIFc-Halo are internalized by LSEC that are the same cells reported to express FVIII by in situ hybridization studies (Hollestelle et al. 2001 Thromb Haemost). This study, together with recent findings that somatic cells in the liver are primarily responsible for rFVIIIFc recycling (Abstract by van der Flier et al), highlights the critical role of LSECs in the clearance of rFVIIIFc and suggests that rFVIIIFc is primarily recycled by FcRn in LSECs. The impact of VWF on the cellular uptake and recycling of the rFVIIIFc-VWF complex in liver cells may also be assessed utilizing this system. Disclosures: Tan: BiogenIdec: Employment. Chen:BiogenIdec: Employment. van der Flier:BiogenIdec: Employment. Liu:BiogenIdec: Employment. Light:biogenidec: Employment. Jiang:biogenidec: Employment.

The Pharmacokinetics Of Turoctocog Alfa Are Consistent Over Different Concentrations and Production Lots

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4783-4783 ◽  
Author(s):  
Víctor Jiménez-Yuste ◽  
Sandra Lejniece ◽  
Robert Klamroth ◽  
Trine Saugstrup ◽  
Judi Moss
Keyword(s):  
Half Life ◽  
Research Funding ◽  
Fixed Effects ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Pooled Data ◽  
One Stage ◽  
Chromogenic Assay ◽  
The One ◽  
Pharmacokinetic Difference

Introduction Turoctocog alfa is a B domain truncated human recombinant FVIII for treatment of patients with hemophilia A. The production yields a highly homogenous product with the same tyrosine sulphation as human FVIII. In order to confirm the consistency of turoctocog alfa pharmacokinetics (PK) over different production lots and vial strengths, a clinical trial was performed in 15 patients with severe hemophilia A. Aim To compare the PK of 3 lots of 2000 IU/vial and 1 lot of 3000 IU/vial of turoctocog alfa after i.v. administration of 50 IU/kg in patients with severe haemophilia A. Methods This was a multi-centre, open-label trial investigating the PK of 4 lots of turoctocog alfa (3 lots of 2000 IU/vial; Lots A, B and C, and 1 lot of 3000 IU/vial; Lot D) in patients with severe hemophilia A (FVIII<1%). The trial was performed as a two-period, incomplete block, cross-over trial, in which each patient was allocated at random to a predefined sequence of 2 different lots of turoctocog alfa. The FVIII activity was assessed using both the one-stage clot and chromogenic assays. Both the primary endpoint, normalized AUC (AUC*(planned dose/actual dose)), and the secondary PK endpoints were analyzed by ANCOVA on the log transformed values, with lot, visit and patient as fixed effects. Each of the three 2000 IU/vial lots was compared and tested against the 2 other 2000 IU/vial lots. If not significantly different on a 5% level, the 3 lots were pooled together and tested against the 3000 IU/vial lot. Results Fifteen patients with a mean age of 38.6 years (ranging from 21 to 60 years) were included from 3 hemophilia centres in 3 different countries. Three adverse events (AEs) were reported in the trial by 2 separate patients; all AEs were judged to be unlikely related to the trial product. There was no development of inhibitors. There was no pharmacokinetic difference observed between Lots A, B, C (2000 IU/vials) and there was no pharmacokinetic difference observed between the pooled data from lot A, B and C (2000 IU/vial) and lot D (3000 IU/vial) based on normalized AUC, half-life, incremental recovery and clearance. The estimated mean values (with 90% CI) for the PK parameters based on the chromogenic assay are presented in Table 1. The results were similar for the one-stage clot assay and the chromogenic assay. Conclusions No pharmacokinetic differences were observed between the three 2000 IU/vial lots (Lot A, Lot B and Lot C), nor were there pharmacokinetic differences between Lot D (3000 IU/vial) and pooled data from Lots A, B and C, based on normalized AUC, half-life, incremental recovery and clearance. There were no safety concerns and no inhibitor development in the trial. Disclosures: Jiménez-Yuste: Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Klamroth:Novo Nordisk, CSL Behring, Bayer, Baxter, Pfizer: Honoraria, Research Funding. Saugstrup:Novo Nordisk: Employment. Moss:Novo Nordisk: Employment.

Prevalence of Discrepancy Between the Results of One-Stage and Chromogenic Factor VIII:C Assays in Iranian Patients with Mild / Moderate Hemophilia A

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4982-4982 ◽  
Author(s):  
Minoo Ahmadinejad ◽  
Fatemeh Vossough ◽  
Kataioon Karimi ◽  
Mohammad Reza Tabatabaei ◽  
Sanaz Homayoun ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Assessment Tools ◽  
Lower Activity ◽  
Bleeding Tendency ◽  
Severe Hemophilia ◽  
One Stage ◽  
Chromogenic Assay ◽  
Iranian Patients

Abstract Background: Factor VIII activity (FVIII:C) level is important in the diagnosis and classification of the severity of hemophilia A and can be measured by three methods (one- stage clotting based, two- stage clotting based and chromogenic). About one third of mild / moderate hemophilia A patients show considerable discrepancy in the results of FVIII:C assayed by the above mentioned methods. This group of patients are called "discrepant hemophilia A". Aims: To determine the prevalence of discrepancy in the results of FVIII:C assays by one- stage and chromogenic methods in Iranian patients with non-severe hemophilia A and the importance of this discrepancy in change of classification of disease severity. We also studied the relationship between the bleeding tendency of these patients with the level of FVIII:C for correct prediction of clinical behavior of the disease. Methods: FVIII:C level was measured using one- stage (FVIII:C1) and chromogenic (FVIII:CR) assays in 78 individuals with mild, moderate or carrier for hemophilia A. Exclusion criteria in our study was considered: receiving FVIII concentrate within 10 days before sampling or having normal results with both methods. Discrepancy was defined as a two- fold or greater difference between the results of two assays. aPTT and mixed-aPTT assays were also performed in all cases. The severity of bleeding symptoms was evaluated using three bleeding assessment tools (BATs): ISTH/SSC BAT, Condensed MCMDM-1VWD bleeding questionary and Vicenza bleeding questionary for the diagnosis of type 1 von willebrand disease. Results: In our study the FVIII:C level was normal with both one-stage and chromogenic methods in 5 patients so they were removed from the data. In the remaining 73 cases, assay discrepancy observed in 45 (62%) patients [43 cases with the lower activity in chromogenic assay (standard discrepancy) and two with the lower activity in the one- stage assay (reverse discrepancy)] ( see the Table and Flow-chart below). Classification of hemophilia A severity changed in 25 (34%) patients (20 patients changed from mild to moderate, 4 cases from mild to normal and 1 patient from normal to mild) based on the results of chromogenic assay. FVIII:C was normal in one patient with one- stage assay but chromogenic assay revealed mild deficiency. As a screening test aPTT did not prolong in 13 (17.8%) of our patients. The relation of ISTH bleeding phenotype with the results of FVIII:C assay by both methods were statistically meaningful; but not about "Vicenza bleeding questionary" and "Condensed MCMDM-1VWD" one. Conclusions: Regarding to the high prevalence of assay discrepancy in Iranian patients with non- severe hemophilia A (62%) and changing the classification of the severity of disease in 34% of cases by chromogenic assay, it is recommended that measurement of FVIII:C by both methods should be mandatory in reference coagulation labs in Iran for definitive exclusion of mild hemophilia A, however it is still not clear that which method is completely compatible with the clinical phenotype. Moreover, due to presence of a meaningful relation between ISTH BAT and FVIII:C levels, use of this BAT in hemophilia patients can help to improve the diagnosis accuracy. Figure Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prophylaxis Dose Adjustment in Hemophilia a Using a New Version of Population Pharmacokinetics Estimation Model Based on Bayesian Procedure

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5014-5014
Author(s):  
José María Sánchez-Raga ◽  
Maria Margalida Santandreu Estelrich ◽  
Bernat Galmés Sureda ◽  
Antonio Palomero Massanet ◽  
Guiomar Puget ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Trough Level ◽  
Demographic Data ◽  
Case Series ◽  
Time Profile ◽  
Estimation Model ◽  
Treatment Frequency ◽  
Blood Samples ◽  
The Impact

Abstract INTRODUCTION Prophylaxis with factor VIII (FVIII) is considered the gold standard for managing hemophilia A (HA) patients without inhibitors to prevent bleedings and to preserve normal musculoskeletal function. Classically, the prophylaxis with a standard half-life FVIII is 20 to 40 IU/kg administered every other day. In practice this "one-size-fits-all" way of dosing does not work in many patients due to the interindividual variability on the concentration-time profile of FVIII, body weight, age, blood group and level of Von Willebrand factor. Pharmacokinetic (PK)-guided regimens have been proposed as an effective way to optimize prophylaxis efficacy. Different online PK tools have been developed to estimate patients' PK with only 2 blood samples. The integration of PK and clinical data can help physicians to adjust dosing. Since 2014 we have been using an online tool to perform PK estimation in patients using the FVIII product Advate® (myPKFiT®, www.mypkfit.com; Baxter Healthcare Corporation; Haemophilia 2014, 20 (Suppl.2):15). In June 2018 a new version has been launch, the version 3.0. This v3.0 includes a dose calculation update based on the ability to modify an individual dose or trough level of an individual prophylaxis regimen providing an accurate adjustment of prophylaxis dosing in comparison with version 2.0 (v2.0). This report describes the impact of the PK estimation in the infusion frequency and factor consumption, comparing both versions, in a cohort of people with HA. METHODS This is an observational case series from a single hemophilia treatment Spanish center. The inclusion criteria were: patients receiving prophylaxis with octocog alfa who accepted to participate in the PK study. Two blood samples have been collected for the estimation of FVIII PK (3-4 hours and 24-28 hours after administration of their usual dose of FVIII) in real world practice. We measured FVIII using one-stage assay. The FVIII trough levels were adjusted between 1% and 3% according to patients characteristics. Demographic data, PK parameters, infusion frequency, dosage and consumption after PK adjustment of prophylaxis using the v2.0 and v3.0 tool were analyzed. RESULTS Eleven patients were evaluated (7 severe, 3 moderate, 1 mild HA) aged 2-43 years (median 14 years). There were no differences in PK parameters between v2.0 and v3.0 as the applied algorithm for both versions is the same. PK results are shown in the Panel A of the table below. The elected trough level was between 1-3% depending of the physical activity and joint health of every individual patient. Prophylaxis regimen was modified in 6/11 patients after PK analysis with both versions of the App: 2 pediatric patients increased their FVIII dose and 3 adults increased their treatment frequency. We have only observed differences in 3 patients comparing the two versions: Patient 1 started a new infusion regimen (every 48h to 48-48-72h) with a mild increase in consumption, and patient 2 and 5 maintained the regimen every 48h with slight reductions in consumption. Results are shown in the Panel B of the table below. CONCLUSIONS Both versions of myPKFit™ are a helpful tool to adjust FVIII dosing regimens. This latest version allows to individualize even more the treatment regimen and to achieve a more efficient consumption. Prospective evaluation of the use of PK‐tailored prophylaxis in routine care and its impact on patient outcomes is needed. Table. Table. Disclosures No relevant conflicts of interest to declare.

scholarly journals Real Life Experience in Clinical Practice with Recombinant Coagulation FVIII-Fc Fusion Protein

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4929-4929
Author(s):  
Teresa Álvarez Roman ◽  
Elena Monzón Manzano ◽  
Ihosvany Fernandez-Bello ◽  
Mónica Martín ◽  
María Isabel Rivas Pollmar ◽  
...  
Keyword(s):  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Trough Level ◽  
Real Life ◽  
University Hospital ◽  
Severe Hemophilia ◽  
Median Dose ◽  
La Paz ◽  
Before And After

Introduction: Efmoroctocog alfa (Elocta®) is a recombinant coagulation FVIII-Fc (rFVIIIFc), a fully recombinant fusion protein produced in human embryonic kidney cells, with an extended half-life used for the treatment and prevention of bleeding in patients with severe hemophilia A. Using rFVIIIFc for the treatment of severe hemophilia A patients received the approval of reimbursement in Spain at the end of 2016. Therefore, there are no many comparative data published about real life use of rFVIIIFc. Objective: This work aims to describe characteristics of the treatment of severe hemophilia A patients with rFVIIIFc and to compare its results with those previously obtained employing other FVIII products. Methods: This was an open-label non-interventional retrospective study reviewing patient characteristics and treatment outcomes before and after the use of rFVIIIFc. The La Paz University Hospital Ethics Committee approved the experimental protocol. Patients with severe hemophilia A without inhibitors being treated with rFVIIIFc since at least six months before study approval by Ethics Committee were included. The following data were collected for patients included in the study: dose (IU/kg) and prophylaxis treatment regimen, number of spontaneous and traumatic bleedings, annual bleeding rate (ABR) and FVIII trough level. The statistical analysis on the variables listed above comparing before and after rFVIIIFc usage was performed by the Biostatistics Unit of La Paz University Hospital with the statistical package SPSS v.18.0 (SPSS Inc., Chicago, IL, USA). Results: Twenty two severe hemophilia A patients (median age: 20 years old, ranging from 6 to 63 years) on prophylaxis with rFVIIIFc were considered to be included in this study, but two were excluded due to lack of data. Median follow-up period was 14 months (ranging from 6 to 28 months). Nineteen severe hemophilia A patients have been previously treated with rFVIII (two of them with other extended half-life product) and one with plasma-derived FVIII. Eight of the ten severe hemophilia A patients who presented an ABR greater than 0 with previous treatments reduced their ABR when treated with rFVIIIFc (Table 1). Among those patients with an ABR=0 with previously used FVIII products, only one increased to an ABR=1 when treated with Elocta® due to a traumatic bleeding. Table 1 shows ABR across all patients before and after rFVIIIFc. There was no difference in dose per injection between other FVIII products and rFVIIIFc (median dose for patients treated with other FVIII products: 46.0 IU/kg, ranging from 26 to 65 IU/kg; median dose for patients treated with rFVIIIFc: 46.5 IU/kg, ranging from 26 to 65 IU/kg). Nevertheless, a reduction was observed in administration frequency. Among the twelve patients who received treatment with other FVIII products every 48 hours, eleven came to receive rFVIIIFc 3 times a week and the one previously receiving a plasma-derived FVIII, to twice a week. Five of the patients receiving treatment 3 times a week reduced its frequency to twice per week. Three patients maintained the same schedule of administration. To note, one of the two patients receiving another prolonged half-life product maintained the schedule of treatment and the other reduced its frequency from every 48 hours to 3 times a week. FVIII trough level in plasma (% of FVIII), expressed as median (25th-75th percentile), was 1.1 (0.1-4.0) for rFVIIIFc treatment and 0.2 (0.0-1.9) for other FVIII products (p=0.06). Conclusions: 85% of the severe hemophilia A patients from our cohort reduced the weekly dose administration after beginning treatment with rFVIIIFc. Most of the patients increased plasma trough level of FVIII with rFVIIIFc. 45% of patients reduced and 40% kept their ABR=0 when they changed rFVIIIFc. These data suggest that treatment with rFVIIIFc gives a higher protection to severe hemophilia A patients. However, further research with larger sample size is required to investigate this. This work was supported by SOBI. NB holds a tenure track grant from FIS-FONDOS FEDER (CP14/00024). Disclosures Álvarez Roman: Takeda: Research Funding; Amgen: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau. Fernandez-Bello:Novartis, Pfizer, ROCHE, Stago: Speakers Bureau. Martín:SOBI: Research Funding; Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau. Rivas Pollmar:Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau; SOBI: Research Funding. García Barcenilla:Bayer, Pfizer, Takeda, Novartis: Speakers Bureau; SOBI: Research Funding. Canales:SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Sandoz: Honoraria. Butta:Roche, Pfizer: Speakers Bureau; Novartis: Consultancy. Jimenez-Yuste:Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Shire: Consultancy, Honoraria, Other: reimbursement for attending symposia/congresses , Research Funding, Speakers Bureau.

scholarly journals Phase 1 Repeat Dosing with BIVV001: The First Investigational Factor VIII Product to Break through the Von Willebrand Factor-Imposed Half-Life Ceiling

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 625-625 ◽  
Author(s):  
Toshko Lissitchkov ◽  
Kara Rice ◽  
Suresh Katragadda ◽  
Annemieke Willemze ◽  
Craig Benson ◽  
...  
Keyword(s):  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Phase 1 ◽  
Geometric Mean ◽  
Activity Levels ◽  
Severe Hemophilia ◽  
Fviii Activity ◽  
Equity Ownership ◽  
Von Willebrand

Introduction The use of factor VIII (FVIII) replacement products enables comprehensive management (prophylaxis, acute bleed control, and perioperative hemostasis) of patients with severe hemophilia A. Prophylaxis with standard half-life FVIII replacement therapies requires frequent administration, and low FVIII activity levels between infusions lead to an increased risk of bleeds. FVIII replacement products that achieve optimal bleed protection with once-weekly dosing intervals remain an unmet need for people living with severe hemophilia A. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel FVIII therapy composed of single-chain FVIII, the Fc domain of human immunoglobulin G1, the FVIII-binding D′D3 domain of von Willebrand factor (VWF), and 2 XTEN polypeptides. BIVV001 is designed to be a next-generation FVIII therapy that circulates independently of endogenous VWF, thereby breaking the VWF-imposed half-life ceiling. Single-dose BIVV001 was well tolerated and provided sustained FVIII activity in a first-in-human trial (Konkle et al, Blood, 2018). Here, we report final data for an open-label Phase 1 trial to assess the safety, tolerability, and pharmacokinetics (PK) of repeat dosing with BIVV001 in subjects with severe hemophilia A (&lt;1 IU/dL [&lt;1%] endogenous FVIII) (EudraCT No: 2018-001535-51). Methods Eligible subjects were 18-65 years of age, had severe hemophilia A, and ≥150 exposure days to prior FVIII products. After screening and washout, subjects received 4 once-weekly doses of BIVV001 (Days 1, 8, 15, and 22) at either 50 IU/kg (Cohort 1) or 65 IU/kg (Cohort 2). The safety observation period extended for 28 days after the last dose of BIVV001. Primary endpoints were the occurrence of adverse events and clinically significant abnormalities in laboratory tests, including inhibitor development. Secondary endpoints were PK parameters derived from FVIII activity evaluated using a one-stage activated partial thromboplastin time clotting assay. PK blood samples were collected immediately before BIVV001 infusion on Days 1, 8, 15, and 22 and at multiple times after dosing on Days 1 and 22. Results All subjects enrolled in Cohort 1 (n=10) and Cohort 2 (n=14) completed the study. Mean (range) age of subjects was 35 (25-55) years for Cohort 1 and 41 (24-58) years for Cohort 2. BIVV001 was well tolerated. No inhibitor development to FVIII was detected, and there were no events of hypersensitivity or anaphylaxis reported. Baseline-corrected PK data were available for 9 subjects in Cohort 1 and all subjects in Cohort 2. Consistent with the single-dose study, the geometric mean (range) half-life for 50 IU/kg and 65 IU/kg BIVV001 was 41.3 (34.2-50.1) hours and 37.3 (28.9-43.8) hours, respectively. After 4 weekly doses of BIVV001 (Day 22), geometric mean (range) area under the activity-time curve from hour 0 over the dosing interval (AUC0-tau) and maximum concentration at steady state (Cmaxss) of BIVV001 were 8290 (5810-10,300) hr × IU/dL and 131 (96-191) IU/dL for Cohort 1 and 11,200 (7040-15,800) hr × IU/dL and 171 (118-211) IU/dL for Cohort 2, respectively. Mean (standard deviation) FVIII activity immediately prior to the final dose of BIVV001 (Ctrough) was 9.9 (2.8) IU/dL in Cohort 1 and 11.7 (5.5) IU/dL in Cohort 2. The mean (range) Day 22-Day 1 accumulation index was 1.07 (1.03-1.11) for Cohort 1 and 1.05 (1.02-1.08) for Cohort 2. At 5 and 7 days after the final BIVV001 infusion, mean steady-state FVIII activity was 22% and 10% for Cohort 1 and 27% and 12% for Cohort 2, respectively (Figure). Geometric mean (range) incremental recovery after the first dose of BIVV001 was 2.3 (1.6-2.8) IU/dL per IU/kg for Cohort 1 and 2.4 (1.6-3.3) IU/dL per IU/kg for Cohort 2. Conclusions Four weekly infusions of 50 IU/kg or 65 IU/kg BIVV001 were well tolerated with no identified safety concerns. FVIII activity levels were sustained and nonaccumulating between doses. By breaking through the VWF-imposed half-life ceiling, BIVV001 prophylaxis may lead to more optimal, extended protection against bleeds for patients with severe hemophilia A than standard FVIII therapies. These results support the continued development of BIVV001 in a Phase 3 clinical trial program. Disclosures Lissitchkov: Roche: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Sanofi: Equity Ownership, Research Funding; Bayer: Consultancy, Equity Ownership, Honoraria, Other: Principal investigator for clinical trials, Research Funding; Sobi: Consultancy, Equity Ownership, Honoraria; Shire: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Octapharma: Equity Ownership, Research Funding. Rice:Sanofi: Employment. Katragadda:Sanofi: Employment. Willemze:Sanofi: Employment. Benson:Sanofi: Employment. Knobe:Sanofi: Employment.

Gene Therapy for Hemophilia: a review on clinical benefit, limitations and remaining issues

Blood ◽  
2021 ◽  
Author(s):  
Frank W.G. Leebeek ◽  
Wolfgang Miesbach
Keyword(s):  
Gene Therapy ◽  
Clinical Benefit ◽  
Hemophilia A ◽  
Phase 1 ◽  
Successful Outcome ◽  
Severe Hemophilia ◽  
The Past ◽  
Therapy Studies ◽  
The Impact ◽  
Made In

In the past decade enormous progress has been made in the development of gene therapy for hemophilia A and B. After the first encouraging results of intravenously administered AAV-based liver-directed gene therapy in patients with severe hemophilia B were reported in 2011, many gene therapy studies have been initiated. Most of these studies, using AAV vectors with various gene constructs, showed sufficient FVIII and FIX expression in patients to significantly reduce the number of bleeds and the need for prophylaxis in the fast majority of the severe hemophilia patients. This resulted in great clinical benefit for nearly all patients. In this review we will summarize the most recent findings of reported and ongoing gene therapy trials. We will highlight the successful outcome of trials with focus on the results of recently reported phase 1 trials and preliminary results of phase 2b/3 trials for hemophilia A and B. These new reports also reveal the impact of side effects and drawbacks associated with gene therapy. We will therefore also discuss the limitations and remaining issues of the current gene therapy approaches. These issues have to be resolved before gene therapy will be widely available for the hemophilia patient population.

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