scholarly journals Real-World Data of the Hemostatic Efficacy of Recombinant Human Factor VIIa Eptacog Beta for Acute Bleeding Events in Patients with Hemophilia a and B with Inhibitors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4246-4246
Author(s):  
Glaivy Batsuli ◽  
Duc Quang Tran ◽  
Guy Young ◽  
Robert F. Sidonio
Keyword(s):  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
Factor Viia ◽  
Hemophilia B ◽  
Bleeding Events ◽  
Real World Data ◽  
Acute Bleeding ◽  
Bleeding Management ◽  
Hemostatic Efficacy

Abstract Introduction: Activated prothrombin complex concentrate (FEIBA, Takeda) and recombinant factor VIIa (rFVIIa, Novoseven, NovoNordisk) remain the primary bypassing agents (BPA) available for bleeding management in patients with hemophilia and inhibitors. Eptacog beta [rFVIIa-B, Coagulation factor VIIa (recombinant)-jncw, Sevenfact, HEMA Biologics & LFB] is a recombinant human FVIIa approved by the FDA in 2020 for the treatment of acute bleeding events in adult and adolescent patients ≥12 years old with hemophilia A or B with inhibitors. rFVIIa-B demonstrated hemostatic efficacy of 86% in a phase 3, randomized cross-over study of 465 mild/moderate bleeding events in 27 patients with hemophilia A and B with inhibitors. The purpose of this study is to report real-world data on the hemostatic efficacy of rFVIIa-B for acute bleeding management in patients with hemophilia A and B with inhibitors. Methods: This is a retrospective chart-review of individuals ≥12 years of age with severe hemophilia A (factor VIII <1%) or hemophilia B (factor IX <1%) with an active inhibitor from 3 U.S. hemophilia treatment centers who utilized rFVIIa-B for acute bleed management. Results: Seven bleeds were treated among the 3 patients identified. Patient characteristics and bleeding events are summarized in Table 1. The 3 patients were 12, 13, and 31 years of age. Two patients had hemophilia A and 1 patient had hemophilia B. The 2 patients with hemophilia A were on emicizumab prophylaxis per standard dosing regimens for bleeding prevention. The individual patient with hemophilia B had a history of anaphylaxis at inhibitor development and received on-demand BPA for acute bleeding events. All 7 bleeds consisted of hemarthroses with the knee being the primary site in 57% of the bleeds. Five of the 7 bleeds (71%) received a severe bleeding dose of 210-225 microgram per kilogram (mcg/kg) for the initial rFVIIa-B dose followed by 70-75 mcg/kg for subsequent doses. Final dosing regimens were dependent on available vial sizes. rFVIIa-B resulted in complete resolution of all bleeds (100%) at a median of 4 doses (range 1-8 doses) and a median of 24 hours (range 3-48 hours). There were no failures in bleeding resolution following treatment. No adverse events with infusions were reported including infusion-related reactions, hypersensitivity reactions, thrombosis, or thrombotic microangiopathy. Conclusions: Administration of rFVIIa-B in the real-world setting appears to demonstrate hemostatic efficacy in a cohort of pediatric and adult patients with hemophilia A and B with inhibitors and may serve as an alternative human rFVIIa therapy for the management of acute bleeds in this population. Further post-marketing studies are warranted to expand the indication to younger children (<12 years of age) and to continue to monitor drug efficacy and adverse events in a larger population of patients over time including individuals on non-factor therapies such as emicizumab. Figure 1 Figure 1. Disclosures Batsuli: Bio Product Laboratory: Honoraria; Kedrion: Honoraria. Tran: HEMA Biologics: Honoraria. Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Sidonio: Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Catalyst: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Biomarin: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Genentech: Consultancy, Research Funding.

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 Characterization of a Novel Human Factor VIIa Chimera with Increased Tissue Factor-Independent Activity for Emergency Hemostasis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3623-3623
Author(s):  
Ammon Fager ◽  
Maureane Hoffman ◽  
Dougald Monroe
Keyword(s):  
Tissue Factor ◽  
Research Funding ◽  
Protein C ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Factor Viia ◽  
Hek293 Cells ◽  
Cell Protein ◽  
Acute Bleeding ◽  
Hemostatic Efficacy

While prophylactic treatment with emicizumab has shown remarkable efficacy in patients with hemophilia A, the treatment options for traumatic, perioperative, and breakthrough bleeding in hemophilia A or B patients with inhibitors remain extremely limited. Recombinant Factor VIIa (rFVIIa) is routinely used to promote hemostasis in hemophilia patients with inhibitors and is recommended as first line therapy for acute bleeding, especially for patients on emicizumab. In addition, rFVIIa has extensive off-label use for hemostasis in cardiovascular surgery, trauma, and intracranial hemorrhage. The hemostatic efficacy of rFVIIa depends on its ability to bind activated platelets and promote thrombin generation by activating Factor X (FX) in a tissue factor (TF)-independent manner. However, the use of rFVIIa requires frequent high doses at significant cost, and is limited by an inconsistent response. Therefore, there is a critical need for new strategies to treat acute bleeding in hemophilia patients with inhibitors and others requiring emergency hemostasis. We have previously shown that human platelets express endothelial cell protein C receptor which contributes to the platelet binding and activity of rFVIIa. Based on this work, we designed a novel FVIIa chimera (PC-FVIIa) with the potential for increased hemostatic efficacy and an enhanced safety profile compared to rFVIIa. The purpose of the current study was to characterize the in vitro activity of this chimera. A cDNA construct encoding the Gla and EGF1 domains of human Protein C along with the EGF2 and catalytic domains of human FVIIa was synthesized and cloned into HEK293 cells. Stable transfectants were selected and PC-FVIIa was purified from the media. Protein electrophoresis of eluates confirmed bands consistent with the expected molecular weight. Similar to rFVIIa, we found that autoactivation of PC-FVIIa readily occurs in the presence of calcium and phospholipid (15% PS/41% PC/44% PE). Autoactivation is rapidly accelerated by the addition of Factor Xa (FXa) and significantly impaired in the absence of either calcium or phospholipid. There was no significant difference between activated PC-FVIIa and rFVIIa in their ability to cleave a synthetic FVIIa substrate. As the Gla and EGF1 domains of rFVIIa are primarily responsible for binding TF, we hypothesized that PC-FVIIa would have little to no affinity for TF. Indeed, we found that the interaction between PC-FVIIa and TF is too weak to be measured in an assay designed to detect weak TF binding. We therefore determined the TF-independent activity of PC-FVIIa using FXa and thrombin generation assays. For some experiments, phospholipid vesicles were incubated with rFVIIa or PC-FVIIa. Plasma levels of FX were added and FXa generation was assessed using a chromogenic substrate. In these assays, the rate of FX activation by PC-FVIIa was significantly higher than that of rFVIIa (Figure 1). To determine the ability of PC-FVIIa to promote thrombin generation, we performed a modified calibrated automated thrombography assay in the absence of TF. Hemophilia A plasma was incubated with PC-FVIIa or rFVIIa in the presence of phospholipid. Subsequent thrombin generation was assessed by monitoring cleavage of a fluorogenic substrate. No appreciable thrombin generation was seen in plasma alone. Adding rFVIIa resulted in a shorter lag time than PC-FVIIa. However, PC-FVIIa led to significantly higher peak thrombin concentration and endogenous thrombin potential compared to rFVIIa. Finally, we used a prothrombinase detection system to determine the activity of PC-FVIIa on the surface of platelets activated with thrombin plus a collagen receptor agonist to generate highly procoagulant platelets. Once again, the rate of thrombin generation was significantly higher with PC-FVIIa as compared to rFVIIa, consistent with a higher rate of FX activation on the platelet surface. Taken together, these data suggest that the PC-FVIIa chimera has the potential for increased hemostatic efficacy compared to rFVIIa. Additional studies will characterize the in vivo activity of PC-FVIIa. However, the lack of affinity for TF represents a potential advantage for PC-FVIIa since long-term exposure to high levels of rFVIIa can lead to thrombosis in TF-rich tissues. As such, PC-FVIIa warrants further study as a potential therapeutic agent with unique characteristics compared to rFVIIa. Disclosures Fager: Otello Medical Inc.: Research Funding. Hoffman:Novo Nordisk A/S: Honoraria, Research Funding. Monroe:Novo Nordisk: Honoraria, Research Funding.

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1126-1126
Author(s):  
Karen L. Zimowski ◽  
Glaivy M. Batsuli ◽  
Paulette Bryant ◽  
Jenny McDaniel ◽  
Kelly Tickle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Bleeding ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Acute Bleeding ◽  
Fviii Activity ◽  
Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: 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; Bioverativ: 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, Research Funding; Grifols: 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; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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 Prospective Controlled Monitoring of Hemlibra Prophylaxis Initiation in a Large Cohort of Hemophilia a Patients- Real World Data

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2397-2397
Author(s):  
Assaf Arie Barg ◽  
Tami Livnat ◽  
Tami Brutman-Barazani ◽  
Nurit Rosenberg ◽  
Ivan Budnik ◽  
...  
Keyword(s):  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
Previous History ◽  
Peak Height ◽  
Real World Data ◽  
World Data ◽  
Young Infants ◽  
Bleeding Episodes ◽  
Supplemental Therapy

Background: Hemlibra is a bispecific antibody that bridges factor IXa and factor X to restore hemostasis in patients with Hemophilia A (HA). It has proven efficacy and safety in multicenter trials. However, real world data is currently lacking. Ancillary tests' results for monitoring Hemlibra's hemostatic effect are scarce. Aim: To evaluate laboratory monitoring and any clinical correlations to hemostasis in patients with HA who initiate prophylactic treatment with Hemlibra, per standard protocol. Methods: Any severe HA patient with or without inhibitors treated by Hemlibra and followed by our National Hemophilia Center was eligible for the study, as approved by our institutional review board. The first two subcutaneous loading injections (3 mg/kg body weight given once weekly for 4 weeks) were administered in the clinic, as was the first post-loading maintenance dose (1.5 mg/kg given once weekly) injection. The patients were instructed to contact and consult the center about any trauma, bleeding or other adverse events. Bleeding episodes as well as any surgical intervention were documented. Blood samples were obtained before initiation of therapy, during the loading period (week 2), and following the initiation of maintenance therapy (week 5). Platelet-poor plasma (PPP) was obtained and activated partial thromboplastin time (aPTT), FVIII activity and inhibitor Bethesda units (BU) assay were performed. Hemlibra levels were evaluated as previously described.1 Thrombin generation (TG) was measured in PPP and thrombin peak height and endogenous thrombin potential (ETP) were calculated.2 Results: Forty patients with HA, median age 10 years (range 6 month- 76 years) were enrolled. The group consisted of 25 children and 15 adults, of whom 18 patients had FVIII inhibitors (median 16, range 1-900BU) and 22 were without inhibitors, including 9 patients with previous history of inhibitor. Patients were clinically followed for a median of 18 weeks (range 9-76 weeks). During follow-up only one patient experienced spontaneous bleeding episodes. Hemarthroses (mainly target joints) occurred in 4/40 patients (1 child only) and post traumatic bleeds were documented in 8 patients. However, 17/40 experienced trauma that did not cause any bleeding. For 32/40 patients, Hemlibra prophylaxis was sufficient to maintain hemostasis without additional supplemental therapy. Five minor surgeries were safely performed in 4 children (2/5 without supplemental therapy), yet another procedure (circumcision of a 3-months-old baby) was complicated by major bleeding. Laboratory analyses, presented as median (interquartile range), disclosed statistically significant increase of Hemlibra plasma levels from 19 (15-22) µg/ml to 50 (42-57) µg/ml between week 2 and week 5, respectively (Fig 1A). The extended aPTT values measured before treatment of 85(61-127) sec were normalized at week 2 [28 (26-30) sec] with additional significant shortening at week 5 [23 (22-25) sec; Fig 1B]. Both ETP and peak height significantly increased from baseline 43 (0-374) nM×min and 14 (6-22) nM to 700 (202-1043) nM×min and 47 (12-76) nM after 2 weeks and further to 981 (476-1396) nM×min and 72 (35-100) nM after 5 weeks; however, TG did not reach the levels observed in normal controls [ETP 1594 (1505-1722) nM×min and peak height 221 (199-273) nM]; Fig 1C,D. No differences were found between adults and children or between inhibitor and non- inhibitor patients yet notably, initial aPTT was significantly prolonged among patients with inhibitors as compared to non- inhibitor patients and the same difference persisted at week 2 and disappeared at week 5. No differences were noted between patients experiencing any bleeding or non- bleeders, probably as most bleeding episodes were trauma related. Positive correlations were found between aPTT, Hemlibra levels and TG parameters. Notably lower TG was observed in very young infants, thus interpretation of laboratory results in this age required caution. Conclusion: This study confirms the safety and efficacy of Hemlibra prophylaxis in patients with HA, including young infants. Laboratory analyses prove that Hemlibra loading, results in higher drug levels and correlates with aPTT shortening and improved TG parameters. While aPTT normalizes during Hemlibra loading, TG is still lower than the normal range observed in controls and may be a more sensitive ancillary test to predict patients' hemostasis. Disclosures Kenet: Roche: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Opko Biologics: Consultancy, Honoraria, Research Funding; CSL: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; BPL: Research Funding.

scholarly journals The Role of Antithrombin Lowering in Patients with Hemophilia: Hemostatic Control Pre- and Post-Fitusiran Dosing Interruption

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2477-2477 ◽  
Author(s):  
Margaret V. Ragni ◽  
Pencho Georgiev ◽  
Michael Desmond Creagh ◽  
Toshko Jelev Lissitchkov ◽  
Steve K. Austin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Thrombin Generation ◽  
Time Course ◽  
Hemophilia A ◽  
Hemophilia B ◽  
Phase 2 ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Clinical Hold

Abstract Introduction Hemophilia A and hemophilia B are rare bleeding disorders characterized by insufficient thrombin generation due to deficiencies in factors VIII or IX, respectively. Standard treatment for hemophilia is currently based on replacement of the deficient factor with factor concentrate. This, unfortunately, subjects the patient to the risk of developing neutralizing antibodies, or inhibitors, against replacement factor VIII or IX. Individuals with inhibitors become refractory to standard replacement therapy, a serious complication for as many as one-third of patients with severe hemophilia A and a lower proportion of patients with hemophilia B. Fitusiran is a once-monthly subcutaneously administered investigational RNA interference therapeutic that targets antithrombin (AT) to improve thrombin generation (TG) and promote hemostasis in patients with hemophilia A or hemophilia B with or without inhibitors. In September 2017, fitusiran dosing in the Phase 2 open-label extension (OLE) study was temporarily suspended to investigate a case of fatal cerebral venous sinus thrombosis. Following this investigation, fitusiran dosing resumed in December 2017 with protocol amendments for bleed management dosing and safety monitoring. During the temporary dosing suspension, AT levels, TG, bleeding events, and frequency of factor replacement and bypassing agents were assessed. Methods Before the dosing suspension, 33 patients (hemophilia A=27, hemophilia B=6) were enrolled, of whom 28 patients continued treatment over 20 months in the Phase 2 OLE study, with a median of 11 months on study. As of June 2018, data collected monthly during the clinical hold included AT levels, TG, and description and management of treated bleeding events before and during the clinical hold, which were used to estimate annualized bleeding rates (ABRs) and bleeding rates per month. Results AT activity in patients previously receiving fitusiran demonstrated a progressive increase during the interruption of fitusiran dosing. Median %AT increased to >60% after a 5-month period compared with the last data point before dosing interruption. These data confirm our previous findings that discontinuation of fitusiran results in gradual recovery of AT activity over time. Subjects also demonstrated a concomitant steady decrease in TG during the interruption of fitusiran dosing, which occurred over a similar time course to that of AT recovery. Consistent with both the increase in AT activity and decrease in TG, preliminary analysis shows the median overall ABR increased from 1.43 events/year before the dosing interruption to 6.07 events/year during the dosing interruption. Conclusions During a period of fitusiran dosing suspension, recovery of AT activity was accompanied by a decrease in TG and an increase in bleeding events. These observations provide support for the therapeutic hypothesis that AT activity lowering by fitusiran leads to an increase in TG and improved hemostasis. Phase 3 studies of fitusiran are ongoing. Disclosures Ragni: Bioverativ: Consultancy, Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding. Georgiev:Alnylam: Consultancy. Lissitchkov:Novo Nordisk: Other: Investigator fees as a participant of the clinical trial. Austin:Pfizer: Research Funding. Chowdary:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Freeline: Consultancy; Bayer: Honoraria; Baxalta (Shire): Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum AB (Sobi): Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foster:Sanofi Genzyme: Employment. Yu:Sanofi Genzyme: Employment. Benson:Sanofi Genzyme: Employment. Madigan:Alnylam Pharmaceuticals Inc: Employment. Nguyen:Alnylam Pharmaceuticals Inc: Employment. Ali:Sanofi Genzyme: Employment. Kadam:Sanofi Genzyme: Employment. Jain:Sanofi Genzyme: Employment. Pasi:Octapharma: Honoraria; Catalyst Bio: Honoraria; Bayer: Speakers Bureau; Shire: Speakers Bureau; NovoNordisk: Speakers Bureau; Sobi: Honoraria; Apcintex: Honoraria; Biomarin: Honoraria, Research Funding; Pfizer: Speakers Bureau; Alnylam: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding.

scholarly journals A Novel Methodology for Building Longitudinal, Patient-Centric Real World Datasets in Hemophilia A

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 594-594
Author(s):  
Mark W Skinner ◽  
Gillian Hanson ◽  
Tao Xu ◽  
Richard Ofori-Asenso ◽  
Richard H. Ko ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Stock Options ◽  
Research Funding ◽  
Hemophilia A ◽  
Advisory Board ◽  
Real World Data ◽  
Advisory Committees ◽  
Patient Reported ◽  
Privately Held

Abstract Background: There are limited real-world data (RWD) available on the unmet needs of people with mild or moderate hemophilia A (PwHA). This population accounts for 40-52% of all PwHA, including nearly all women with hemophilia A (HA), and is under-represented in scientific literature (Michele, et al. Haemophilia 2014; Benson, et al. Blood Transfus 2018; Peyvandi, et al. Haemophilia 2019). Available claims data from payer databases are confined to billing codes, and lack key information on outcomes and disease characterization (e.g. severity, treatment response.) (Tyree, et al. Am J Med Qual 2006). Registry datasets can require resource-intensive data entry and potentially miss key information about care received at outside facilities, at home, or after patients switch providers (Gliklich, et al. Registries for Evaluating Patient Outcomes: A User's Guide. 2014). To address these data gaps, we developed a novel, patient-centered approach to create a longitudinal healthcare database from individuals with mild and moderate HA in the United States. This study assessed the feasibility of this approach, which integrates medical record data collected during routine clinical care along with patient-reported outcomes (PROs) to provide needed insights into this under-represented population. Methods: Recruitment began in June 2020 via a broad strategy of social media outreach, healthcare provider partnerships, and patient advocacy groups. Eligibility was confined to mild or moderate PwHA, confirmed via physician report within provider notes in combination with baseline factor VIII levels (&gt;5-50% mild, 1-5% moderate.) This study received research ethics board approval and abides by the guiding principles of the Declaration of Helsinki. PwHA enrolled via an online record management platform, PicnicHealth. After signing authorization forms for collection of their electronic health records (EHR) and informed consent to share their de-identified data for research, participants were prompted to enter information on their care providers. Records were gathered from all providers, across any facility, retrospectively as records were available. (Figure 1) All records obtained were made available to the participants via a medical timeline. Records were translated to text via optical character recognition with human review. Data elements from structured text as well as disease-specific elements from narrative text were captured using natural language processing and supervised machine learning. All elements, including visit metadata, conditions, measurements, drugs, and procedures were mapped to standardized medical ontologies and reviewed by a team of nurses. (Table 1) Quality control was assessed via inter-abstractor agreement on outputs with physician review. Patient-reported bleed, treatment, and pain data were collected via online questionnaire for a subset of PwHA, with participants prompted to enter data every 2 weeks. Abstracted EHR data was linked to PRO responses in a de-identified dataset. Cohort and abstraction characteristics were summarized descriptively. Results: From June 1, 2020 to June 30, 2021, 104 PwHA met eligibility criteria for enrollment (65 [62.5%] mild; 39 [37.5%] moderate). Participants saw providers across 34 states in the US, 22.1% (23/104) were female, and 20.6% (14/68) of those with known race/ethnicity status were from minority groups. Records were gathered from a median of six care sites and 16 providers per participant. A median of 50 (IQR [21-93]) clinical documents from 11 years were processed for each PwHA. (Table 2) Inter-abstractor agreement to assess abstraction quality averaged 95.9% for condition, 99.5% for drug name, and 95.4% for drug start date. As of June 2021, the average PRO response rate was 90.3% (150/166 of all requests) and continues prospectively. Conclusions: The patient-centric data collection methods implemented in this study provide a novel approach to build longitudinal real-world data sets. Technology-enabled data abstraction showed consistent high quality when processing the heterogeneous clinical records across disparate providers and care sites, and direct engagement with patients complements potential gaps in the clinical record. Additionally, this approach provides needed data on groups under-represented in RWD and traditional PwHA cohorts, including those with mild and moderate disease and women with HA. Figure 1 Figure 1. Disclosures Skinner: ICER: Membership on an entity's Board of Directors or advisory committees; Spark (DMC): Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Honoraria; Pfizer (DMC): Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; uniQure: Research Funding; Takeda: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Freeline: Research Funding; BioMarin: Honoraria, Research Funding; IPA Ltd.: Current holder of individual stocks in a privately-held company; National Hemophilia Foundation: Consultancy; Institute for Policy Advancement Ltd: Current Employment; WFH USA: Membership on an entity's Board of Directors or advisory committees; BCBS MAP: Membership on an entity's Board of Directors or advisory committees. Hanson: PicnicHealth: Current Employment, Current holder of stock options in a privately-held company. Xu: F. Hoffmann-La Roche AG: Current Employment. Ofori-Asenso: F. Hoffmann-La Roche Ltd: Current Employment. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cibelli: PicnicHealth: Current Employment. Nissen: Novartis: Consultancy; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. Witkop: Roche Advisory Panel: Consultancy; National Hemophilia Foundation: Current Employment. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Shapiro: Novartis: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Octapharma: Research Funding; Pfizer: Research Funding; OPKO: Research Funding; Prometric BioTherapeutics: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Takeda: Research Funding; Kedrion Biopharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; BioMarin: Research Funding; Agios: Research Funding.

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.

Bleeding Events and Safety Outcomes in Patients with Hemophilia a with Inhibitors: A Prospective, Multicenter, Non-Interventional Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3800-3800 ◽  
Author(s):  
Johnny Mahlangu ◽  
Johannes Oldenburg ◽  
Michael U Callaghan ◽  
Midori Shima ◽  
Elena Santagostino ◽  
...  
Keyword(s):  
Research Funding ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Interventional Study ◽  
Bleeding Events ◽  
Legal Guardian ◽  
Phase 3 ◽  
Advisory Committees ◽  
Safety Outcomes ◽  
Bypassing Agents

Abstract Introduction: Coagulation factor VIII (FVIII) deficiency in hemophilia A (HA) patients (pts) results in spontaneous bleeding events, secondary arthropathy and diminished quality of life (QoL). FVIII replacement agents, the current standard of care, may require several infusions to treat bleeding events and infusions 2-3 times a week are needed for prevention of bleeding events due to relatively short half-lives. A major challenge of current therapies is development of anti-FVIII alloantibodies (inhibitors), which occur in 15-30% of HA pts, diminish effectiveness of FVIII replacement and are associated with significant morbidity and reduced QoL. Options for pts with inhibitors are limited. Bypassing agents to prevent/treat bleeding events, and immune tolerance induction to eliminate inhibitors, require frequent dosing, are not available in all countries, and have suboptimal efficacy. Thus, a high unmet need exists for safe, more effective and less burdensome options for pts with inhibitors. Emicizumab (ACE910), a bispecific monoclonal antibody in development for the management of HA, binds to FIXa and FX to mimic FVIII cofactor function and may be able to address current treatment needs. Real world data (RWD) collected from HA pts are considered of high importance for the emicizumab clinical development program, providing the possibility of intra-patient comparison for those who may be subsequently eligible to participate in a pivotal emicizumab Phase 3 study (NCT02622321). This non-interventional study (NIS) aims to prospectively collect detailed, high-quality data on bleeding events and safety outcomes in HA pts treated according to local routine clinical practice. In the first cohort (Cohort A), data from adult/adolescents with inhibitors were collected. Methods: This prospective NIS (NCT02476942) was approved by local Ethics review groups, and all pts and/or legal guardians signed informed consent/assent prior to study entry. In Cohort A, eligible pts were ≥12 years old and had congenital HA of any severity; documented history of high-titer FVIII inhibitors (≥5 Bethesda Units/mL); documented treatment with bypassing agents for ≥6 months; and, ≥6 or ≥2 bleeds in the last 6 months on episodic or prophylactic treatment, respectively. Primary objective was to characterize the number of bleeding events over time. Bleeding/bypassing agent data were collected through a bleed and medication questionnaire (BMQ) developed by the Sponsor, as no standard questionnaire is available. BMQ was completed by the pt/legal guardian via an electronic handheld device. Demographic data and medical history were collected from pts' medical records on an electronic Case Report Form. Throughout the study, investigators recorded adverse events (AEs), concomitant medication, and routine laboratory assessment data. At least monthly interactions of pts/legal guardian with a professional from their treatment center were requested to confirm self-reported bleed/medication information. Results: 103 HA pts with inhibitors (75 on episodic and 28 on prophylactic regimens with bypassing agents) from 33 centers and 12 countries were enrolled in Cohort A. As of 7/21/16, 54 pts had rolled over to the emicizumab Phase 3 study in adults/adolescents with inhibitors. The following Cohort A data will be presented: pt demographics/characteristics; global distribution of pts by country; summary of hemophilia medical history, concomitant medications and surgeries; pts' self-reported information on bleeding events and treatment (all, and by episodic and prophylactic treatment), including bleeding rates, types and locations, reason for coagulation product use, product type used, dose; and, safety. Conclusion: The NIS will provide high quality documentation of bleeding events and safety outcomes in adult/adolescent HA pts with inhibitors treated with bypassing agents according to local clinical practice. For those participating in the ongoing Phase 3 emicizumab study, these data will provide the opportunity to perform robust intra-patient comparisons of prospectively collected bleeding event/medication data before and during emicizumab treatment. This is the first report of prospective RWD being collected for use as a valid historical control for a pivotal Phase 3 study in HA pts with inhibitors, and a novel and unique approach to bolster data reported in the clinical development of emicizumab. Disclosures Mahlangu: Bayer: Research Funding, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Amgen: Speakers Bureau; Biotest: Speakers Bureau; Baxalta: Consultancy. Callaghan:Grifols: Honoraria; Bayer: Honoraria; Baxalta: Honoraria, Research Funding; Roche: Honoraria, Research Funding; CSL Behring: Honoraria; Biogen: Honoraria. Shima:F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sysmex Corporation: Patents & Royalties, Research Funding. Santagostino:Bayer: Consultancy; Grifols: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Octapharma: Consultancy; CSL Behring: Consultancy; Baxalta: Consultancy; Pfizer: Consultancy; Biogen Idec: Consultancy; Sobi: Consultancy; Roche: Consultancy. Lehle:Roche: Employment. Uguen:Roche: Employment. Hirst:F. Hoffmann La-Roche Ltd: Employment; AstraZeneca: Other: Previous employment . Recht:Novo Nordisk: Consultancy, Research Funding; Biogen Idec: Research Funding; Baxalta: Research Funding; Kedrion: Consultancy. Kruse-Jarres:Pfizer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria; Bayer: Consultancy, Honoraria.

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