Direct comparison of two extended-half-life recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A

AbstractThe pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.

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BUDGET IMPACT OF AN EXTENDED HALF LIFE RECOMBINANT FVIII THERAPY FOR A HYPOTHETICAL POPULATION OF SEVERE HEMOPHILIA A PATIENTS IN AN INSURED POPULATION IN THE UNITED STATES

Value in Health ◽

10.1016/j.jval.2016.03.1039 ◽

2016 ◽

Vol 19 (3) ◽

pp. A243

Author(s):

M. Bron ◽

Y. Xiong ◽

J. Booth ◽

P.H. Glover ◽

J. Epstein

Keyword(s):

United States ◽

Half Life ◽

Budget Impact ◽

Hemophilia A ◽

The United States ◽

Severe Hemophilia ◽

Recombinant Fviii

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Cost-Effectiveness Model of Recombinant FVIII Versus Emicizumab Treatment of Patients With Severe Hemophilia A Without Inhibitors

Blood ◽

10.1182/blood-2019-124421 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2102-2102 ◽

Cited By ~ 1

Author(s):

Shawn X. Sun ◽

Yanyu Wu ◽

Michael McDermott ◽

Marjolijn van Keep

Keyword(s):

Cost Effectiveness ◽

Half Life ◽

Hemophilia A ◽

Pooled Analysis ◽

Health State ◽

Severe Hemophilia ◽

Health States ◽

On Demand ◽

Factor Therapy ◽

Recombinant Fviii

Introduction: The standard of care for patients with hemophilia A without inhibitors is factor VIII (FVIII) replacement therapy. The availability of non-factor therapy such as emicizumab (Hemlibra®; Genentech, Inc., South San Francisco, CA, USA) is changing the treatment landscape. A model was developed from the perspective of the US healthcare system to compare the cost-effectiveness of recombinant FVIII (rFVIII) products (standard half-life [SHL] and extended half-life [EHL]) versus non-factor therapy emicizumab in the treatment of patients with severe hemophilia A without inhibitors. Methods: The Markovian model used in this analysis included 5 mutually exclusive hemophilia A-related health states: with/without target joints (TJs), with/without arthropathy, and death. Health states changed or remained constant, depending on bleeds and recovery probability. Transition to the health state "death" was derived from mortality rates in the general US population according to age. Each health state was associated with costs and utilities that were summed over time. Estimated total costs and treatment effectiveness as measured by quality-adjusted life years (QALYs; a measure of health outcome that incorporates the impact on both quantity and quality of life) for each health state were then used to calculate incremental cost-effectiveness ratios for pairwise comparisons of treatments (prophylaxis or on-demand for a pooled analysis of 6 rFVIII products [SHL and EHL] vs emicizumab prophylaxis; Table 1) over a life-time horizon. Patient data used in the model were based on a systematic literature review and clinical trial results, and network meta-analysis. Model parameters included patient baseline characteristics, change in body weight by age, prior prophylaxis or on-demand treatment, annualized bleeding rate (ABR), probability of developing or resolving TJs or arthropathy, mortality, number infusions per bleed, medical check-ups, and hospitalization. Based on these data, patients in the model were assumed to be male and 33 years of age at baseline; 72.0% had TJs and 58.4% had arthropathy. Probability of developing TJs per joint bleed was estimated to be 0.9% (prophylaxis and on-demand treatment). Probability of developing arthropathy per joint bleed was estimated to be 2.2% for patients who received prior on-demand treatment and patients who received prior prophylaxis were assumed to have no risk of developing arthropathy. The model assumed life-long adherence to the same prophylactic hemophilia treatment. Drug cost was based on 2018 average sales price and dosing was on label. The model did not include treatment-specific adverse events or inhibitor development. Results: Prophylaxis with rFVIII (SHL and EHL) was estimated to be less costly and more effective (total $13,656,238; QALYs 17.61) versus non-factor prophylaxis with emicizumab (total $16,447,843; QALYs 17.58) over an estimated 70-year lifespan of a patient with severe hemophilia A, which suggests rFVIII prophylaxis is an economically preferable strategy. Total cost consists of costs directly related to prophylactic treatment (rFVIII $12,850,894 vs emicizumab $15,555,379) and costs associated with healthcare resources (rFVIII $805,344 vs emicizumab $892,464). rFVIII prophylaxis was also estimated to be less costly and more effective (total $13,656,238; QALYs 17.61) versus on-demand rFVIII treatment (total $13,823,123; QALYs 12.29). Conclusions: In this pooled analysis of select SHL and EHL rFVIII products, the results suggest that rFVIII prophylaxis is a cost-effective long-term intervention for patients with severe hemophilia A without inhibitors compared with non-factor prophylaxis with emicizumab and on-demand rFVIII treatment. Disclosures Sun: Shire US Inc., a Takeda company: Employment, Other: a Takeda stock owner. Wu:Shire US Inc., a Takeda company: Employment, Other: a Takeda stockowner. McDermott:BresMed Health Solutions Ltd.: Employment. van Keep:BresMed Health Solutions Ltd.: Employment.

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Efficacy and Safety Results from a Phase 3b, Open-Label, Multicenter, Continuation Study of Rurioctocog Alfa Pegol for Prophylaxis in Previously Treated Patients with Severe Hemophilia A

Blood ◽

10.1182/blood-2018-99-110190 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2483-2483 ◽

Cited By ~ 1

Author(s):

Eric S. Mullins ◽

Barbara A Konkle ◽

Catherine E. McGuinn ◽

Werner Engl ◽

Srilatha D. Tangada

Keyword(s):

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Open Label ◽

Advisory Committees ◽

Previously Treated Patients ◽

Previously Treated ◽

Equity Ownership ◽

Recombinant Fviii

Abstract Background: Patients with severe hemophilia A experience substantial morbidity and mortality due to frequent spontaneous and traumatic bleeding episodes, especially in joints. Prophylaxis with standard half-life factor VIII (FVIII) is the standard of care to prevent bleeds. Extended half-life products benefit patients by reducing the number of infusions without impacting the treatment efficacy. Methods: This phase 3b, prospective, open-label, multicenter, continuation study (NCT# 01945593) investigated the safety and efficacy of a PEGylated recombinant FVIII with an extended half-life, rurioctocog alfa pegol (SHP660, BAX 855, ADYNOVATE®, Shire, Lexington, MA, USA), for prophylaxis and treatment of bleeding in patients with severe hemophilia A (FVIII <1%). Eligible children and adults were ≤75 years of age and had either completed a previous rurioctocog alfa pegol study (NCT# 01599819, 01736475, 02210091, 02615691, 01913405, or 02585960) and were willing to immediately transition to the continuation study, or were naïve to rurioctocog alfa pegol but had received treatment with plasma-derived or recombinant FVIII for ≥150 (in patients ≥6 years of age) or ≥50 (in patients <6 years of age) exposure days. Patients received prophylactic rurioctocog alfa pegol at least twice weekly, either at a fixed dose (FD; 45 ± 5 IU/kg in patients ≥12 years of age; 50 ± 10 IU/kg in those <12 years of age; dose adjustment ≤80 ± 5 IU/kg allowed) or with pharmacokinetically (PK)-tailored dosing (≤80 ± 5 IU/kg) to maintain FVIII trough levels ≥3%. The co-primary endpoints assessed were the incidence of FVIII inhibitory antibody development (as measured by ≥0.6 BU in the Nijmegen modification of the Bethesda assay) and the spontaneous annualized bleed rate (ABR). Secondary endpoints included overall hemostatic efficacy ratings and occurrence of adverse events (AEs). Results: The study began in October 2013 and completed in March 2018. Overall, 216 patients receiving prophylaxis were eligible and included in the safety/full analysis dataset (≥1 dose received). Of these, 215 were male, the mean (SD) age at enrollment was 22.8 (15.7) years, the mean (SD) number of documented previous rurioctocog alfa pegol exposure days was 57.0 (39.6), the total ABR over 3-6 months prior to enrollment in the continuation study (including patients naïve to rurioctocog alfa pegol or receiving on-demand or prophylactic treatment with rurioctocog alfa pegol) was mean (SD) 4.7 (12.6), median (range) 0.0 (0-69). Most patients (206; 95.4%) had participated in a previous rurioctocog alfa pegol study. Overall, 215 patients received ≥1 dose in the FD regimen and 25 received ≥1 dose in the PK regimen. These patients received a mean (SD) of 1.72 (0.29) and 2.11 (0.61) prophylactic infusions per week, respectively, with a mean (SD) dose per infusion of 51.15 (8.11) IU/kg and 52.14 (17.03) IU/kg, respectively. None of the patients developed a confirmed FVIII inhibitor in this study and only 1 treatment-related allergic or hypersensitivity reaction (a nonserious mild AE) was reported. Nonserious AEs assessed by the investigators to be related to treatment occurred in 11/216 (5.1%) patients. Serious AEs (SAEs) occurred in 33 (15.3%) patients; there were no SAEs assessed by the investigators to be related to treatment. Descriptive statistics on spontaneous, joint, and total ABR by prophylactic regimen are shown in the Table. The overall total ABR in all patients was mean (SD) 2.5 (3.1), median (range) 1.6 (0.0-19.5). Overall hemostatic efficacy was rated as good or excellent in 88.5% of all bleeds and 89.4% of all bleeds were treated with 1 or 2 infusions. Conclusions: These results show that in previously treated patients with severe hemophilia A, rurioctocog alfa pegol prophylaxis in FD- and PK-tailored regimens was well tolerated and effective. None of the patients developed FVIII inhibitory antibodies, and a decrease in mean total ABR was reported in these patients compared with baseline. Disclosures Mullins: Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konkle:Genentech: Consultancy; CSL Behring: Consultancy; Gilead: Consultancy; Pfizer: Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy; Bioverativ: Research Funding; Shire: Research Funding; Sangamo: Research Funding. McGuinn:CSL Behring: Consultancy; BioMarin: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark: Consultancy, Research Funding; Genentech: Consultancy; Shire: Research Funding; Pfizer: Research Funding. Engl:Shire: Employment, Equity Ownership. Tangada:Shire: Employment, Equity Ownership.

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Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Blood ◽

10.1182/blood-2021-155156 ◽

2021 ◽

Vol 138 (Supplement 2) ◽

pp. LBA-5-LBA-5

Author(s):

Lynn Malec ◽

An Van Damme ◽

Anthony Chan ◽

Mariya Spasova ◽

Nisha Jain ◽

...

Keyword(s):

Half Life ◽

Stock Options ◽

Research Funding ◽

Hemophilia A ◽

High Titer ◽

High Dose ◽

Severe Hemophilia ◽

First Time ◽

Inhibitor Titer ◽

Privately Held

Abstract Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR >66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

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

Blood ◽

10.1182/blood.v122.21.4783.4783 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4783-4783 ◽

Cited By ~ 1

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.

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Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽

10.1182/blood.v128.22.3778.3778 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3778-3778

Author(s):

Amy L. Dunn ◽

Alexis A. Thompson ◽

Werner Engl ◽

Marlies Sharkhawy ◽

Brigitt E. Abbuehl

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Pediatric Patients ◽

Hemophilia A ◽

Point Estimate ◽

Severe Hemophilia ◽

Advisory Committees ◽

The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

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Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A

Blood ◽

10.1182/blood-2015-03-630897 ◽

2015 ◽

Vol 126 (9) ◽

pp. 1078-1085 ◽

Cited By ~ 126

Author(s):

Barbara A. Konkle ◽

Oleksandra Stasyshyn ◽

Pratima Chowdary ◽

David H. Bevan ◽

Tim Mant ◽

...

Keyword(s):

Adverse Events ◽

Half Life ◽

Hemophilia A ◽

Full Length ◽

Severe Hemophilia ◽

Bleeding Events ◽

On Demand ◽

Key Points ◽

Prevention And Treatment ◽

Inhibitory Antibodies

Key Points BAX 855, a pegylated full-length rFVIII with extended half-life, was highly effective in the prevention and treatment of bleeding events. No subjects receiving BAX 855 developed FVIII inhibitory antibodies nor experienced unexpected adverse events.

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

Blood ◽

10.1182/blood-2019-127878 ◽

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.

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