Real-World Age-Stratified FVIII Consumption and Bleed Outcomes Before and After Switching to Rurioctocog Alfa Pegol in a Retrospective, Observational Study Using US Specialty Pharmacy Data

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2411-2411
Author(s):  
Maureen Watt ◽  
Scott Milligan
Keyword(s):  
Clinical Trial ◽  
Real World ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Patient Data ◽  
Severe Hemophilia ◽  
Before And After ◽  
Pharmacy Data

Introduction: The safety and efficacy of rurioctocog alfa pegol (BAX 855, SHP-660, TAK-660; Adynovate®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in patients with severe hemophilia A has been reported previously (Konkle BA et al., Blood 2015, 126:1078-85; Brand B et al., Haemophilia 2016, 22:e251-8; Mullins ES et al., Haemophilia 2017, 23:238-46); however, research describing patient experience with extended half-life (EHL) recombinant factor VIII (FVIII) products outside clinical trials is limited. The objective of this study was to assess real-world utilization of TAK-660 in patients with hemophilia A and describe their clinical profiles before and after switching to TAK-660. Factor consumption and bleed outcomes stratified by age (<18 and ≥18 years) are reported herein. Methods: This was a retrospective, observational database study of patient data from US specialty pharmacies. Pharmacy data sources included patient records, prescriptions, and patient-reported bleed logs. Informed consent was obtained for all analyzed patient data. Eligible patients with hemophilia A were treated with prophylactic TAK-660 with on-label dosing from November 2015 to September 2018, and had received ≥90 days of FVIII (standard half-life [SHL] or EHL) therapy before switching to TAK-660. Main exclusion criteria were participation in a TAK-660 clinical trial before/during this study, only on-demand treatment before switching to TAK-660, or presence of active FVIII inhibitor requiring treatment and/or use of immune tolerance induction during the study period. Assessments included prior hemophilia therapy, FVIII administration frequency and consumption, and annualized bleeding rate (ABR) before and after switching to TAK-660. Results: Data was collected from 82 patients (of 61 providers in 44 practices across 25 states in the United States): 44% of the patients (36/82) were <18 years old; 56% (46/82) were ≥18 years old (none were ≥60 years old); 83% (68/82) had severe hemophilia A; and 88% (72/82) had received prior SHL-FVIII treatment. The SHL antihemophilic factor (recombinant) (Advate®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) was used by 67% (55/82) of patients overall, of whom 47% (26/55) were <18 years old and 53% (29/55) were ≥18 years old. Compared with any prior FVIII therapy, switching to TAK-660 increased FVIII dose per administration in patients <18 and ≥18 years old (+39.5% and +22.9%, respectively), while their weekly administration frequency decreased (-21.4% and -28.1%, respectively; Table 1). Weekly FVIII consumption increased in patients aged <18 years (+11.2%) and decreased in those aged ≥18 years (-12.8%). FVIII administration frequency and consumption by prior SHL- or EHL-FVIII are reported in Table 1. ABR data before and after switching were available in 47 of 82 patients. Compared with any prior FVIII therapy, mean ABR decreased in patients aged <18 years (-39.5%; 2.8 to 1.7) and ≥18 years (-50.3%; 3.4 to 1.7) with TAK-660 treatment (Table 2). Changes in mean ABR by prior FVIII therapy and disease severity are reported in Table 2. The small number of patients who received prior EHL FVIII was a limiting factor in the comparison of patients who received prior SHL- and EHL-FVIII therapy. Conclusions: In patients with hemophilia A previously treated with SHL- or EHL-FVIII products, switching to TAK-660 prophylaxis resulted in a significant decrease in ABR of 40-50% in both age groups analyzed. The adult population (ie, ≥18 years old) showed a tendency for reduced weekly FVIII consumption. These findings from real-world data are in agreement with TAK-660 clinical trial results. The observed differences in FVIII consumption between patients <18 and ≥18 years old may have been in part a result of age-related changes in bleeding patters, growth, and other factors. Disclosures Watt: Shire International GmbH, a Takeda company: Employment, Other: a Takeda stock owner. Milligan:Sanofi: Research Funding; Merck: Research Funding; Gilead: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Trio Health: Employment; Viiv: Research Funding.

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 Real-World Data on the Use of rFIXFc in Subjects With Hemophilia B for Up to 3.7 Years Demonstrates Improved Bleed Control and Adherence With Reduced Treatment Burden

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2493-2493 ◽  
Author(s):  
Amy Shapiro ◽  
Ateefa Chaudhury ◽  
Nisha Jain ◽  
Elisa Tsao ◽  
Chris Barnowski ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
The United States ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Real World Data ◽  
Advisory Committees ◽  
Dosing Interval ◽  
Before And After

Abstract Introduction: Recombinant factor IX Fc fusion protein (rFIXFc) was the first extended half-life FIX product approved in the United States to treat children and adults with hemophilia B. Long-term data from clinical trials have demonstrated the safety and efficacy of rFIXFc as well as an extended dosing interval (once weekly or every 10‒14 days based on individual needs); however, real-world data are limited (Wang et al. Haemophilia, 2018; Buckley et al. AMCP NEXUS, 2015). We therefore performed a retrospective chart review to further understand the clinical experience and outcomes associated with real-world treatment of hemophilia B with rFIXFc. Methods: This retrospective chart review is being conducted at 6 sites across different regions of the United States and aims to include 70 patient charts. Data entry for 43 patient charts has been completed to date (cutoff: June 29, 2018). Data collection is ongoing. Inclusion criteria were diagnosis of hemophilia B and receipt of rFIXFc for ≥6 months. Subjects with other coagulation disorders or any record of positive FIX inhibitor titers were excluded. De-identified subject-level data were transcribed onto anonymous electronic case report forms. Endpoints included changes in FIX therapy dosing interval, factor consumption, bleed control, and patient adherence before and after rFIXFc initiation. Descriptive statistics were used to summarize the results. Results: For the 43 charts available for analysis, the duration of follow-up receiving rFIXFc ranged from 0.5 to 3.7 years. Of these, 58% of subjects (25/43) were >18 years of age, 77% (33/43) were of white race, and 51% (22/43) had severe hemophilia B (Table 1). The most common genotype was missense, occurring in 63% of subjects (27/43). Among subjects with comorbidity, 37% reported hemophilic arthropathy (16/43) and 28% had hepatitis C (12/43). All 22 subjects with severe hemophilia B were treated with rFIXFc prophylactically compared with 9/15 moderate and 3/6 mild cases. From the data collected thus far, 94% of prophylaxis subjects were on a dosing interval of weekly or longer (every 7 days, n=20; every 10 days, n=3; and every 14 days, n=9). The total weekly dose before and after switching to rFIXFc prophylaxis were available for 20 subjects. Of the 12 adults (9 severe, 2 moderate, and 1 mild), the median weekly factor consumption decreased from 111 IU/kg to 52.5 IU/kg. A similar pattern was observed for subjects who were 12-18 years of age (n=4). For subjects <12 years of age (n=4), 2 had reduced weekly consumption after switching to rFIXFc, whereas 2 (on plasma-derived product pre-rFIXFc) had an increase in weekly consumption. The annualized bleeding rates (ABRs), annualized spontaneous bleeding rates (AsBRs), and annualized joint bleeding rates (AjBRs) were available for 17 subjects treated with prophylaxis regimens pre- and post-rFIXFc (Table 2). Of these subjects, 11 had severe, 5 had moderate, and 1 had mild hemophilia B. Among 11 subjects with severe hemophilia B, median (interquartile range) ABRs decreased from 8.2 (4.4‒11.5) to 2.3 (0.6‒10.2), AsBR from 1.2 (0‒9.7) to 0.3 (0‒8.7), and AjBR from 2.3 (1.4‒8.2) to 0.7 (0‒6.9) before and after rFIXFc treatment. Subjects with moderate disease had a similar pattern (Table 2). The most common reason for switching to rFIXFc was to reduce the burden associated with therapy (21/43, 49%). No rationale for switching was documented in 40% (17/43) of subjects, and 7% (3/43) switched due to lack of efficacy with previous treatment. The other reasons, including difficult venous access, lack of adherence, and failure to reach desired trough were mentioned by <5% of subjects. No subject reported adherence issues while on rFIXFc. Conclusions: This real-world study of rFIXFc demonstrates improved bleed control, reduced overall consumption, and reduced frequency of injection for subjects with moderate and severe hemophilia B. The data also show that rFIXFc provides an opportunity to tailor dosing and improve adherence. These results echo the findings of the pivotal trials and add to the pool of evidence supporting rFIXFc in the treatment of hemophilia B. These data also reflect the use of rFIXFc for mild hemophilia patients in the real-world setting. Disclosures Shapiro: Kedrion Biopharma: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; BioMarin: Research Funding; Bio Products Laboratory: Consultancy; Octapharma: Research Funding; OPKO: Research Funding; Sangamo Biosciences: Consultancy; Daiichi Sankyo: Research Funding. Chaudhury:Bioverativ, a Sanofi Company: Consultancy, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees. Jain:Bioverativ: Employment. Tsao:Bioverativ: Employment. Barnowski:Bioverativ, a Sanofi Company: Employment. Feng:Bioverativ: Employment. Quon:Shire: Speakers Bureau; Genetech: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Bayer: Consultancy; Octapharma: Consultancy; Bioverativ, a Sanofi Company: Speakers Bureau.

scholarly journals Adoption of Prophylaxis in the United States in the Era of Extended Half-Life Factor Concentrates

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2467-2467
Author(s):  
Lynn M. Malec ◽  
Gilbert C. White ◽  
Stacy E. Croteau ◽  
Dunlei Cheng ◽  
Margaret V. Ragni
Keyword(s):  
United States ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Number Of Patients

Abstract Background: Use of prophylaxis is the evidence-based strategy to prevent joint bleeds and reduce arthropathy for patients with severe hemophilia however, prophylaxis has not been universally adopted in the United States. Amongst patients with severe hemophilia enrolled in the ATHNdataset, the largest database of patients with disorders of hemostasis and thrombosis in the United States, as of 2015, 37% of patients with hemophilia A, and 45% of patients with hemophilia B do not receive prophylaxis. With the approval of extended half-life (EHL) factor products, patients and providers have options for less treatment-intense and burdensome prophylaxis. With the changing landscape of available hemophilia products, we aimed to quantify the number of patients treated at U.S. HTCs on prophylaxis utilizing the ATHNdataset with the objective determining the impact of EHL products on the proportion of patients with severe hemophilia receiving prophylaxis and to characterize use of prophylaxis according to age, race and ethnicity, geographic region, and payer. Methods: The ATHNdataset, a HIPAA compliant limited dataset sponsored by the American Thrombosis and Hemostasis Network (ATHN), was accessed as of June 30, 2018. The proportion of subjects with severe hemophilia on prophylaxis were compared to those on demand by age cohort. The proportion of subjects on prophylaxis was analyzed by race, ethnicity, insurance status, and hemophilia treatment center region. For each group receiving prophylaxis, the product (EHL versus standard half-life (SHL)), dose and frequency of treatment was analyzed. Results: ATHNdataset included 6,160 severe hemophilia patients using factor replacements, 5,234 individuals with hemophilia A and 926 individuals with hemophilia B. Overall, 76.0% (n=4,864) of patients with severe hemophilia are on prophylaxis whereas 24.0% (n=1426) are on demand; this included a total of 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B on prophylaxis. Treatment type (prophylaxis or not) had significant associations with age (p-value <0.001), ethnicity (p<0.001), race (p=0.005), hemophilia treatment center (HTC) region (p<0.001), and hemophilia type (p=0.015) (Table 1). Prophylaxis was not significantly correlated with payer (p=0.847) with a similar number of patients with Medicare/Medicaid or private insurance receiving prophylaxis. Among patients on prophylaxis, 30.8% (n=1,462) are prescribed EHL products including 27.4% of patients with hemophilia A and 50.4% with hemophilia B. In terms of dosing frequency (n=758), 73.8% of hemophilia A patients on prophylaxis receive EHL two times per week while 73.7% (n=1,906) receive SHL every other day (Table 2). Of hemophilia B patients using EHL products, 63.3% of patients receive prophylaxis once weekly, 12.7% every 10 days, and 15.0% every 2 weeks (Table 2). Discussion: The ATHNdataset highlights increased use of prophylaxis over the past 3 years in the U.S. with 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B currently receiving prophylactic therapy as compared to 63% and 55% of patients, respectively, in 2015. Further, the majority (83.7%) of patients are beginning prophylaxis according to the World Federation of Haemophilia recommendation to initiate prophylaxis by three years of age. There has been an uptake of the use of EHL factor products including a majority of patients (50.4%) with severe hemophilia B. Although not captured in the ATHNdataset, a plausible reason for the increased uptake of EHL in the hemophilia B population includes the data that 91% of patients are able to dose between weekly or less frequently. As the hemophilia treatment landscape continues to evolve, it is important to continue to understand the adoption of these new products into practice and to examine their real-world impact. Disclosures Malec: Shire: Consultancy; Bioverativ: Consultancy; Bayer: Consultancy; Bioverativ: Research Funding. White:Biomarin: Other: DSMB; Bioverativ: Other: DSMB; Bayer: Other: GRAC; Shire: Other: Physician Leadership Group; Novo Nordisk: Consultancy; Asklepios: Other: Scientific Advisory Board; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Croteau:Biomarin: Consultancy; Bioveritiv: Consultancy; Catalyst Biosciences: Consultancy; CSL-Behring: Consultancy; Genetech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Ragni:Sangamo: Research Funding; CSL Behring: Research Funding; Bioverativ: Consultancy, Research Funding; SPARK: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Shire: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
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 &lt;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 &gt;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

scholarly journals Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2409-2409
Author(s):  
Tiffany Lin Lucas ◽  
Shveta Gupta ◽  
Joanna A. Davis ◽  
Fernando F. Corrales-Medina
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Haemophilia A ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Increased Risk ◽  
Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

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.

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 ◽  
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.

scholarly journals Real World Use of Extended Half-Life Products and the Impact on Bleeding Events and Joint Health in the United States

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1195-1195 ◽  
Author(s):  
Lynn M. Malec ◽  
Char M Witmer ◽  
Julie Jaffray ◽  
Peter A. Kouides ◽  
Kristina M. Haley ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
Advisory Board ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
On Demand ◽  
Joint Health

Abstract Background : The hemophilia treatment landscape has evolved substantially in the last several years with the approval of extended half-life (EHL) products which reduce the burden of prophylaxis. Data reported from the American Thrombosis and Hemostasis Network (ATHN) as of June 2017 indicate that 21% of patients with moderate or severe hemophilia A, and 42% of patients with moderate or severe hemophilia B, receive prophylaxis utilizing an EHL. As new treatments become available and are adopted into practice, it is important to recognize the need for evaluation of efficacy, safety, and economic impact of their use outside of the clinical trial setting. We aimed to characterize the real world impact of EHL products by collecting detailed information on bleeding rates, joint health and quality of life amongst patients cared for at ATHN-affiliated Hemophilia Treatment Centers. We hypothesized that use of EHL products were utilized in at least 30% of patients and would lead to decreased ABRs and improved joint health. To date 67 of a planned 135 subjects have been enrolled, constituting this interim analysis. Methods:Subjects were recruited from seven U.S. Hemophilia Treatment Centers. Subjects with severe hemophilia A or B ≤ 30 years of age on prophylaxis or demand therapy were eligible for enrollment. Subjects excluded from study were those with a recent joint bleed (within the last 2 weeks) or those unwilling to complete all elements of the study. Data were collected during a one-time encounter concurrent with an appointment for clinical evaluation, including demographic information, treatment regimen, product type, frequency, location and severity of all bleeds, Hemophilia Joint Health Scores (HJHS), and Quality of life (QoL). Bleeding rates in subjects receiving prophylaxis were compared with those receiving on demand therapy by type treatment, EHL vs standard half-life (SHL), and by hemophilia type. Severity of bleeding events (mild, moderate, or severe) and HJHS were compared by prophylaxis groups. Results: A total of 67 patients were enrolled and eligible for analysis. This included 58 subjects with severe hemophilia A, and 9 subjects with severe hemophilia B. The mean age of the cohort was 15 years (median 12 years, IQR 8 - 21 years). For these patients whose race information was known, 89.1% were Caucasian, 3.3% African-American, 3.3% Asian, and 4.7% were of mixed or 'other' race. Eleven out of 61 (18.0%) subjects with known ethnicity were Hispanic. Among 59 patients whose treatment type were available, the majority were on prophylaxis (n=53; 89.8%) as compared to on demand therapy (n=6; 10.2%). The average annualized bleeding rate (ABR) was 2.8 amongst all individuals. As expected, the ABR was substantially lower in those receiving prophylaxis (ABR=1.0) as compared to on demand therapy (ABR=18.6) (p<0.001). Additionally, HJHS in those receiving prophylaxis was lower (mean HJHS= 3.9), meaning less evidence of joint damage, than in those receiving demand therapy (mean HJHS= 8.8) (p=0.162). For patients with severe hemophilia A, the ABR was lower in those individuals receiving EHL (ABR= 0.5) versus SHL (ABR= 1.5), although this did not reach statistical significance (p=0.136). All subjects with severe hemophilia B enrolled to date receive EHL products (n=9) therefore no comparison of ABR could be made between EHL and SHL products; the ABR in this group was 0.9. In patients with severe hemophilia A, there was a higher HJHS for those receiving EHL (mean HJHS= 7.0) versus those receiving SHL (mean HJHS = 2.1) (p=0.053). For patients with severe hemophilia B, all of whom received EHL, the mean HJHS was lower than in the hemophilia A cohort (mean HJHS=1.2). Conclusions: We report real-world bleeding events and joint health in patients with severe hemophilia A and B utilizing EHL and SHL products across a wide U.S. geographic distribution. As anticipated, there is substantial bleed reduction with prophylaxis versus on demand therapy. In our severe hemophilia A cohort, the ABR for patients receiving EHL products was similar to ABRs reported in clinical trials, suggesting clinical trial data may be reflective of real world use. Patients with severe hemophilia A receiving EHL for prophylaxis had a lower ABR than those receiving SHL, although the early impact is not reflected in the HJHS score. Longer follow-up will be necessary to determine the impact of EHL on HJHS. Disclosures Malec: Bioverativ: Research Funding; Bayer: Consultancy; Bioverativ: Consultancy; Shire: Consultancy. Jaffray:Octapharma: Consultancy; Bayer: Consultancy; CSL Behring: Consultancy, Research Funding. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Sidonio:Octapharma: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board; Kedrion: Research Funding; Biomarin: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board. Abshire:CSL: Consultancy; Shire: Consultancy; Novo Nordisk: Other: DSMB. White:Asklepios: Other: Scientific Advisory Board; Novo Nordisk: Consultancy; Shire: Other: Physician Leadership Group; Bayer: Other: GRAC; Bioverativ: Other: DSMB; Biomarin: Other: DSMB; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Ragni:CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Bioverativ: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

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.

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