Prophylaxis In Haemophilia Research Articles

Emicizumab initiation and bleeding outcomes in people with hemophilia A with and without inhibitors: A single‐center report

BackgroundEmicizumab, a bispecific antibody factor VIII mimetic, is approved for prophylaxis in hemophilia, and has different risks and side effects compared to factor VIII products. ObjectiveTo better understand the early impact of emicizumab on our patients at the University of Colorado Hemophilia and Thrombosis Center (UCHTC), we evaluated adverse reactions, factor prophylaxis overlap, and bleeding rates after starting emicizumab through a quality improvement project. Patients/MethodsA retrospective chart review and structured phone interview were conducted from June to September 2019 for all patients who had started emicizumab at the UCHTC. Data about emicizumab dosing, reactions, bleeding events, and bleeding treatment were collected in 68 children and adults (aged 0.55‐79.8 years, on emicizumab a median 213 days; range, 51‐1229 days) with hemophilia A (35.3% with past or current inhibitor). ResultsAdverse reactions were primarily skin reactions, with no anaphylactic reactions or thrombosis. Bleeding events, defined as pain or swelling treated with factor or supportive measures, demonstrated wide variability, with 25 of 68 experiencing zero bleeds and 5 of 68 experiencing >8 bleeds per year. The most prevalent bleed type was traumatic musculoskeletal bleeding. Bleeding events occurred more often in the first 10 weeks after starting emicizumab, but no time period was without bleeding events. The majority of patients were prescribed every‐week or every‐2‐week dosing, but some had alternative dosing frequency. ConclusionsReal‐world emicizumab use in our center was characterized by variations in prescribing practices and bleeding outcomes and lack of severe adverse reactions.

Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses

BackgroundThe anti‐tissue factor plasma inhibitor monoclonal antibody concizumab is under clinical investigation for subcutaneous prophylaxis of hemophilia A/B (HA/HB) with or without inhibitors. Breakthrough bleeds while on concizumab prophylaxis may be treated with bypassing agents (recombinant activated factor VIIa [rFVIIa] and activated prothrombin complex concentrate [APCC]), or with factor VIII (FVIII) or factor IX (FIX). ObjectivesTo evaluate the effect of combining concizumab with rFVIIa, APCC, rFVIII, and rFIX on thrombin generation (TG) potential. MethodsPooled HA plasma was spiked in vitro with concizumab alone or together with rFVIIa, APCC, or rFVIII. rFVIIa, APCC, and rFVIII were added ex vivo to plasma from HA patients receiving concizumab prophylaxis. Pooled HB plasma was spiked with concizumab alone or together with rFIX. TG potential was measured after initiation with tissue factor. ResultsConcizumab increased thrombin peak in a concentration‐dependent manner. Adding rFVIIa, APCC, rFVIII, or rFIX caused a further increase in thrombin peak. The effects of concizumab and rFVIIa, APCC, rFVIII, or rFIX were mainly additive, with no or up to maximally ~25% extra effect caused by drug‐‐drug interaction. No strong synergistic effects were observed upon combining concizumab with rFVIIa, APCC, rFVIII, or rFIX. The thrombin peak obtained with 0.5 IU/ml rFVIII or rFIX in the presence of concizumab was on occasion slightly higher, but mostly comparable to the thrombin peak with 1 IU/ml rFVIII or rFIX in the absence of concizumab. ConclusionrFVIIa, APCC, rFVIII, and rFIX enhanced plasma TG potential in the presence of concizumab. Dose levels of concomitant use should be adjusted accordingly to balance potential safety concerns while maintaining the necessary hemostatic effect. Please see the video in the Supplementary Material for an animated summary of the data presented.

Bleeding outcomes and factor utilization after switching to an extended half-life product for prophylaxis in haemophilia A in Austria

To prevent bleeding in severe haemophilia A [SHA, defined as factor VIII (FVIII) activity < 1%] regular prophylactic FVIII replacement therapy is required, and the benefits of factor products with extended half-life (EHL) over traditional standard half-life (SHL) are still being debated. We performed a multi-centre, retrospective cohort study of persons with SHA in Austria aiming to compare clinical outcomes and factor utilization in patients with SHA, who switched from prophylaxis with SHL to an EHL. Data were collected from haemophilia-specific patient diaries and medical records. Twenty male persons with SHA (median age: 32.5 years) were included. The most common reason for switching to the EHL was a high bleeding rate with SHL. Switch to rFVIII-Fc resulted in a significantly decreased annualized bleeding rate (ABR; median difference (IQR): − 0.3 (− 4.5–0); Wilcoxon signed-rank test for matched pairs: Z = − 2.7, p = 0.008) and number of prophylactic infusions per week (− 0.75 (− 1.0–0.0); Z = − 2.7, p = 0.007). Factor utilization was comparable to prior prophylaxis with SHL (0.0 (− 15.8–24.8) IU/kg/week; Z = − 0.4, p = 0.691). In summary, switch to EHL (rFVIII-Fc) was associated with an improved clinical outcome, reflected by ABR reduction, and less frequent infusions, without significantly higher factor usage.

Converting factor and nonfactor usage into a single metric to facilitate benchmarking the resources consumed for haemophilia care across jurisdictions and over time.

The World Federation of Hemophilia started measuring factor utilization at the country level as IU/capita (International Units of factor concentrates used per country population) in 2001 for its Annual Global Survey. IU/capita have been used to benchmark a country's usage over time and for advocacy. The introduction of a common metric usage spanning across standard half-life (SHL), and extended half-life (EHL) clotting factor concentrates (CFCs) and emicizumab would be a valuable simplification for national healthcare policymaking and industrial production planning. Develop and examine a method of converting IU of SHL or EHL, and milligrams of emicizumab into a single metric. We developed conversion factors from manufacturer's recommended dose for prophylaxis with SHL, EHL, and emicizumab as reported on the licensing information for the United States and Europe. We validate the accuracy of these conversion factors against real-world usage data. The prescribing information in the United States and Europe is marginally different. The SHL/EHL conversion factors are higher when calculated based on the prescribing information than on real-world studies, which are considered more representative of clinical practice. The best estimate of the SHL/EHL conversion factors for FVIII and FIX were 1.04 and 1.87. The conversion factor for emicizumab to SHL is 70IU/mg. We have generated robust estimates of conversion factors for currently used treatment options for prophylaxis in haemophilia. Usage of a single, harmonized metric will facilitate benchmarking across different countries or longitudinally irrespective of the case-mix of treatment options.

Emicizumab prophylaxis: Prospective longitudinal real-world follow-up and monitoring.

Real-world data on prophylaxis of severe haemophilia A (HA) patients treated by emicizumab are scarce. To study the efficacy and safety of longitudinal emicizumab prophylaxis and assess laboratory monitoring correlations in a large patient cohort. HA patients with and without FVIII inhibitors, initiating emicizumab prophylaxis, were prospectively enrolled. Bleeding, adverse events and surgeries were documented. FVIII inhibitors, emicizumab levels and thrombin generation (TG) were sequentially measured. A total of 107 patients, including 58 children (whose median (IQR) age was 6 (1-11) years) with severe HA, composed the study cohort. Twenty-nine per cent (31/107) of our HA patients had FVIII inhibitors. Patients were followed for a median of 67weeks (up to 144weeks). Fifty-three patients, whose median follow-up was 53weeks, experienced zero bleeds. Most bleeds (94%) among children were trauma-related, whereas 61% of adults sustained spontaneous joint bleeds. Four patients experienced major bleeds, with a fatal outcome in one infant, who also presented with central venous line thrombosis. No other serious adverse events were encountered. Seven patients have decided to stop emicizumab treatment for various reasons. Emicizumab plasma levels increased after emicizumab prophylaxis initiation, and values were maintained during follow-up, in all but one patient, suspected of anti-drug antibodies. A significant reduction of FVIII inhibitor levels was noted among inhibitor patients. TG was increased and sustained yet could not prognosticate bleeding risk. Emicizumab prophylaxis was mostly well tolerated, although 50% of patients experienced breakthrough bleeds. Routine TG monitoring is not obligatory, and further studies are warranted in selected patient populations.

Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies

AbstractProphylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.

Safety, pharmacokinetics, and pharmacodynamics of a next‐generation subcutaneously administered coagulation factor IX variant, dalcinonacog alfa, in previously treated hemophilia B patients

BackgroundDalcinonacog alfa (DalcA), a next‐generation, recombinant human factor IX (FIX) variant, was developed using a rational design approach for increased procoagulant activity and longer duration of action to be administered subcutaneously (SC) for prophylaxis of hemophilia B bleeding episodes. ObjectivesTo investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DalcA. MethodsThis multicenter, phase 1/2a study (NCT03186677) was conducted in 11 males aged 12 to 65 years with severe hemophilia B. In cohort 1, subjects received intravenous (IV) 75 IU/kg BeneFIX and DalcA. Cohorts 2 and 3 had DalcA IV 75 IU/kg and SC 75 IU/kg or 150 IU/kg. Cohort 4 was omitted. Cohort 5 received daily SC 150 IU/kg DalcA for 6 days and cohort 6 received IV 75 IU/kg and daily SC 150 IU/kg DalcA for 9 days. Blood sampling was performed for chemistry, hematology, PK, PD, and anti‐drug antibody measurement. Subjects were monitored for safety endpoints for 30 days postdosing. ResultsDalcA demonstrated a 24‐fold greater potency over BeneFIX and longer mean residence time (33.8 h). SC bioavailability 8.2% to 20.3%, beta half‐life 53.9 to 106.9 h and Tmax 24 to 48 h. A median 15.7% FIX activity level (interquartile range, 14.9%‐16.6%) was reached after 6 daily doses. Neutralizing antibodies to ISU304, but not wild‐type FIX, occurred in two cousins. ConclusionsThe data demonstrated that DalcA achieved protective FIX activity levels between 11% and 18%, corresponding to a reduced chance of spontaneous bleeds. Based on the results, a phase 2b trial to assess the safety and efficacy of 28 daily SC doses of DalcA was performed.

Predicted coagulation potential using an in vitro simulated model of emicizumab prophylaxis and immune tolerance induction therapy in hemophilia A patients with inhibitor.

Emicizumab reduces bleeding in hemophilia A patients with inhibitor (HA-inh). A combination of immune tolerance induction therapy (ITI) and emicizumab prophylaxis may provide additional benefits, but coagulation potential during this treatment remains unknown. We assessed coagulation potentials in simulated ITI models in vitro using modified-clot waveform analysis. Factor (F)VIII-deficient plasma preincubated with anti-A2 and anti-C2 monoclonal antibodies was reacted with emicizumab (50µg/mL) (emicizumab-HA-plasma), then spiking bypassing agents (BPAs): activated prothrombin complex concentrates (aPCC 1.3IU/mL; 50IU/kg), recombinant factor (rF)VIIa (2.2µg/mL; 90µg/kg), and FVIIa/FX (1.5µg/mL; 60µg/kg), and/or FVIII (100, 200IU/dL). Coagulation potentials in emicizumab-HA-plasma (10 BU/mL) remained within the normal range when BPA and FVIII were both present. In emicizumab-HA-plasma (1 BU/mL) with BPA and FVIII (200IU/dL), they were near or beyond the normal range, but those with a half concentration of rFVIIa based on the half-life in blood were within the normal range. In samples without inhibitor, coagulation potentials with combined BPA and FVIII were far beyond the normal range but with FVIII (100IU/dL) and rFVIIa at half concentration they remained within the normal range. These results may provide information on the feasibility of concurrent ITI under emicizumab prophylaxis.

Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: Real-world data.

Emicizumab (Hemlibra™) is approved for prophylaxis of Haemophilia A (HA) patients with and without inhibitors. However, real-world data on emicizumab use in the elderly HA patients with concomitant cardiovascular risk factors are lacking. To evaluate the safety and efficacy of emicizumab in a real-world cohort of elderly HA patients. A prospective longitudinal observational study on HA patients over 50years old treated, followed and monitored during emicizumab prophylaxis was conducted. We documented any bleeding or adverse events and collected plasma samples for emicizumab levels, aPTT and thrombin generation (TG). Seventeen HA patients (2 with inhibitor), whose median age was 62.4years (range: 51.5-77.1) composed the cohort, including 9/17 with multiple cardiovascular risk factors (high risk group). Seven patients had chronic HIV infection. The median follow-up of our cohort was 400days (range 89-805, IQR 211-479days). The median annualized bleeding rate (ABR) significantly decreased for all patients. Among patients who displayed significant bleeding tendencies, emicizumab steady state levels as well as TG were lower as compared with the group. The ABR of four patients concomitantly treated by antiplatelet agents was significantly higher compared with the rest of the cohort. Neither thrombosis nor thrombotic microangiopathy (TMA) was encountered. Emicizumab prophylaxis for HA patients older than 50years including those with cardiovascular risk factors was well tolerated. As lower emicizumab and TG levels were observed among bleeding patients, we suggest that monitoring laboratory assays could be of value within this age group.

Safety first: Tracking adverse events associated with new therapies for people with hemophilia

Safety first: Tracking adverse events associated with new therapies for people with hemophilia

Emicizumab in severe hemophilia A

Emicizumab is a recombinant, humanized, bispecific, asymmetric monoclonal antibody that bridges activated factor IX and factor X (FX) and leads to activation of FX, thus mimicking the hemostatic function of activated factor VIII (FVIIIa). The clinical trial program showed that emicizumab prophylaxis maintains low bleed rates and is well tolerated by patients with hemophilia A of all ages with and without factor VIII (FVIII) inhibitors. Emicizumab prophylaxis in severe hemophilia A patients with high titer inhibitor against FVIII was launched in Poland in 2020. As of April 2021, 42 patients were receiving emicizumab in Poland, not including clinical trials. The aim of this paper was to review the most recent data on the role of emicizumab in the management of patients with severe hemophilia A.

Safety and effectiveness of Rixubis in patients with hemophilia B: a real-world, prospective, postmarketing surveillance study in South Korea.

BackgroundRixubis (recombinant factor IX, nonacog gamma) is indicated for the control and prevention of bleeding episodes, perioperative management, and routine prophylaxis in hemophilia B patients. This real-world, postmarketing surveillance study aimed to evaluate the safety and effectiveness of Rixubis in adult and pediatric hemophilia B patients in South Korea.MethodsThis prospective, observational, multicenter study (clinicaltrials.gov identifier NCT029 22231) was conducted in hemophilia B patients between April 2015 and April 2019, who were observed for up to 6 months after the initiation of Rixubis treatment. Safety was evaluated based on the number and severity of adverse events (AEs) and serious AEs (SAEs). Hemostatic effectiveness was assessed by physicians and patients by using a four-point scale and rated as excellent, good, fair, or no response based on treatment type.ResultsIn all, 58 patients were enrolled from four centers by seven physicians during the study period. The safety and effectiveness analysis sets included 57 and 54 patients, respectively. Overall, 11 AEs were reported in eight patients (14.0%), of which three were SAEs and occurred in three patients (5.3%). All 11 AEs were reported as unexpected and mild in severity, with no anaphylactic reaction, and 10 AEs (90.9%) resolved. The majority of AEs (10) were unrelated to Rixubis. Of the 142 hemostatic effectiveness assessments, 123 (86.6%) were reported as good or excellent.ConclusionRixubis demonstrated an acceptable safety and effectiveness profile in the treatment of bleeding, perioperative management, and prophylaxis in hemophilia B patients in a real-world setting in South Korea.

The potential role of emicizumab prophylaxis in severe von Willebrand disease

BackgroundSevere von Willebrand disease (VWD) may be associated with chronic joint damage and may require prophylactic therapy. Emicizumab is a humanized bispecific antibody, which mimics the function of coagulation factor VIII (FVIII), and it has been approved for prophylaxis in hemophilia A. MethodsThis is the first study assessing the potential future role of emicizumab as an alternative prophylactic treatment in patients with severe VWD, based upon a thrombin generation (TG) ex vivo analysis. We report 51 weeks of successful off label emicizumab prophylaxis in a child with severe VWD and recurrent hemarthroses and progressive arthropathy despite adherence to previous prophylaxis with replacement therapy. Results and conclusionsOur work demonstrated that ex vivo spiking with emicizumab increased TG in plasma from patients with type 3 VWD. Similar TG results were observed in our treated patient, whose therapy was well tolerated without any adverse events. Both in vitro and ex vivo TG data support sufficient hemostasis without exceeding the range seen in healthy volunteers. Further collaborative studies on the efficacy and safety of emicizumab prophylaxis in severe VWD is warranted.

Choosing the frequency of follow-up in longitudinal studies: Is more necessarily better?

Background Follow-up frequency is an important design parameter in longitudinal studies. We quantified the impact of reducing follow-up frequency on the precision of estimated regression parameters, and investigated the impact of incorrectly assuming an exchangeable correlation structure on estimates of the loss of precision resulting from reduced follow-up. Methods We estimated the loss in precision on deleting every second observation from three longitudinal cohorts: patients with Childhood Systemic Lupus Erythematosus (cSLE), the Canadian Haemophilia Prophylaxis Study (CHPS), and patients with Juvenile Dermatomyositis (JDM). We compared these results with those from a theoretical formula assuming an exchangeable correlation structure. Results The increase in sample size needed to compensate for halving follow-up frequency was 9%, 6% and 28% for the cSLE, CHPS and JDM cohorts respectively. Under the assumption of an exchangeable correlation, the estimated increases in sample size were 22%, 11% and 10% respectively. Conclusions Reducing follow-up frequency can result in minimal loss of information, as seen in the CHPS cohort. While using a theoretical formula based on an exchangeable correlation structure is convenient, it can be inaccurate when the true correlation structure is not exchangeable.

PRO40 Cost-Consequence Analysis of Emicizumab Prophylaxis for Severe Hemophilia a Patients without Inhibitors

PRO40 Cost-Consequence Analysis of Emicizumab Prophylaxis for Severe Hemophilia a Patients without Inhibitors

PRO4 Matching-Adjusted Indirect Comparisons of Annualized Bleeding RATE and Treatment Utilization between Extended Half-Life Recombinant Factor VIII Products, Bay 94-9027 and Turoctocog ALFA Pegol, for Prophylaxis of Severe Haemophilia a

PRO4 Matching-Adjusted Indirect Comparisons of Annualized Bleeding RATE and Treatment Utilization between Extended Half-Life Recombinant Factor VIII Products, Bay 94-9027 and Turoctocog ALFA Pegol, for Prophylaxis of Severe Haemophilia a

PRO53 Economic IMPACT of Emicizumab Prophylaxis for Hemophilia a with and without Inhibitors

PRO53 Economic IMPACT of Emicizumab Prophylaxis for Hemophilia a with and without Inhibitors

The Influence of Personalized 2-Year Physiotherapy on Musculoskeletal Health and Quality of Life in Severe Hemophilia Patients with Inhibitor - Interim Analysis after 1 Year of the Program

Development of factor VIII (FVIII) inhibitor is a serious complication of factor replacement therapy observed in about 15-30% of severe hemophilia A (HA) patients. Inhibitors interfere with the treatment by neutralizing intravenously injected FVIII. Although bleeding rate is not increased in severe HA patients who developed the inhibitor, the inhibitors reduce the efficacy of factor replacement therapy during bleeding episodes and in consequence accelerate the progression of hemophilic arthropathy. In Poland, prophylaxis in hemophilia with inhibitors has been introduced in 2016, and therefore many HA patients with inhibitor still suffer from particularly severe arthropathy, and have a reduced quality of life. The aim of the study was to evaluate the musculoskeletal health and quality of life in patients with severe hemophilia A with inhibitor before initiation of personalized physiotherapy and after 2 years of the personalized physiotherapeutic program. The study was performed in 24 persons with severe HA with inhibitor (mean age 42.1 years, median age 42 years) receiving prophylaxis regimen with aPCC 85 ± 15 IU/kg 3 times a week. At the beginning of the project, the patients were examined by hematologist and physiotherapist. Joint condition was evaluated using the Hemophilia Joint Health Score (HJHS) and magnetic resonance imaging of the most affected joint. Quality of life was evaluated using EQ-5D scale (EuroQoL). aPCC dosing schedule in context of rehabilitation program was adjusted by the hematologist. Each patient was enrolled to a personalized exercise program developed based on age, general condition, stage of arthropathy, date of the last bleeding episode, and a history of physiotherapy. The program consisted of weekly 60 to 90 minutes rehabilitation sessions at home, and participated in four 5-day rehabilitation camps with 5 hours of rehabilitation sessions a day organized in Poznan after 6, 12, 18 and 24 months of the program. All patients were examined by hematologist, and the rehabilitation was provided only to the patients on regular prophylaxis with aPCC provided that a dose of aPCC was always administered 1 hour before the initiation of rehabilitation session. HJHS varied among the participants, with mean value at baseline 34.2 (median 36.5). Baseline mean EQ-5D score was 54.2 (median 60). Evaluation at month 12 was performed in 18 participants (2 patients withdrawn from the program, and 4 patients could not participate in the evaluation due to COVID-19 pandemics). The results obtained at month 12 show a significant improving the quality of life and musculoskeletal health of patients with HA after combined prophylaxis and personalized rehabilitation. Mean HJHS decreased from 34.2 to 30.4 points (median from 36.5 to 31 points). An average 3.8 point decrease confirms positive effects of long-term aPCC prophylaxis with personalized, regular rehabilitation. Increase in mean EQ-5D score from 54.2 to 70.1 (median from 60 to 72) show enhancing patients' mood resulted from the improved health status and regained capability to conduct more normal lifestyle. After the first year of the project we can conclude that regular prophylaxis with aPCC and personalized, once-a-week rehabilitation program positively influence joint status and quality of life of adult HA patients with inhibitor complicated with significant arthropathy. Regular rehabilitation may slow down the progression of arthropathy due to the choice of the exercise program appropriate for each patient. These positive effects justify the continuation of the project in patients with hemophilia A with inhibitor. Figure Disclosures No relevant conflicts of interest to declare.

The Potential Role of Emicizuamb Prophylaxis in Severe Von Willebrand Disease

Severe Von Willebrand's disease (VWD) may be associated with chronic joint damage and may require prophylactic therapy. In severe VWD, factor VIII (FVIII) levels are low due to rapid clearness. Emicizumab is a humanized bispecific antibody which mimics the function of coagulation factor VIII (FVIII). It has been approved for prophylaxis in hemophilia A. This is the first study assessing the potential role of emicizumab as an alternative prophylactic treatment in a cohort of patients with severe VWD. We present a TG model evaluating patients' hemostasis following ex vivo spiking of their plasma samples with emicizumab. We also report 24 weeks of successful emicizumab prophylaxis in a child with severe VWD and repeated hemarthroses. A cohort of twenty-four VWD patients were included in the study. Fifty-four percent of our patients were males and the cohort consisted of 14 children (≤18 years) and 10 adults. The majority of patients (96%) were of Caucasian origin. Hemarthrosis was encountered in most type 3 VWD patients, whereas none of the type 2 VWD patients had any joint bleeds. Prophylactic treatment was administered in the majority of type 3 VWD patients, whereas type 2 VWD patients largely required only intermittent on demand therapy applied for bleeding episodes or any surgical interventions. Thrombin generation analysis was carried out blindly in plasma obtained from thirteen type 3 VWD patients and eleven type 2 VWD patients. Seventeen healthy volunteers served as a control group. In plasma from type 3 VWD patients, TG was substantially lower than in plasma from type 2 VWD patients, with ETP of 765 nM×min (596-962) vs. 1954 nM×min (1483-2008) (P = 0•001) and peak height of 47 nM (36-65) vs. 262 nM (142-318) (P = 0•002) In order to examine the potential use of emicizumab as an alternative treatment option for type 3 VWD patients, an ex vivo spiking analysis comparing the effect of Haemate P and emicizumab on TG was performed. An improvement in peak height was demonstrated following spiking with both Haemate P concentrations (P = 0•001 for both) and with the higher emicizumab concentration (P = 0•011). Notably, whereas spiking with both Haemate P concentrations increased peak height to near-normal level, spiking with higher emicizumab concentration increased it to a lesser extent (the median was still lower than in normal controls (P = 0•005). Following the decision to treat our impetus patient with emicizumab prophylaxis, TG analyses were performed in the patient's plasma before and during emicizumab loading and maintenance (Figure 3). As expected, patient's initial TG was extremely low and improved following the first administration of emicizumab loading dose (at week 2 after therapy initiation), at which time emicizumab level was 21 µg/mL. Further significant improvement of TG was noted following loading period completion while emicizumab level was 62 µg/mL. Our patient has been treated with emicizumab for more than six months altogether and did not encounter any joint bleeds since the commencement of therapy. During this period, a single dose of Haemate P was administered following tooth exfoliation. Our study contributes towards a better understanding of TG as a surrogate marker of VWD patients' hemostasis. Our data suggests that some severe VWD patients could be safely and efficiently treated with emicizumab. The successful prophylaxis of our patient and our ex vivo laboratory findings should set the ground for further collaborative multicenter studies to examine the efficacy and safety of emicizumab prophylaxis in type 3 VWD patients. Disclosures Barg: roshe: Honoraria, Speakers Bureau. Kenet:PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The use of Emicizumab in sever Von Willebrand disease

Real-World Experience Using Emicizumab Prophylaxis for Hemophilia a: Single-Center Experience

INTRODUCTION: Emicizumab is a recombinant humanized bispecific antibody that mimics Factor VIII by bridging Factor IXa and X. It is an important breakthrough in the therapeutic armamentarium for Hemophilia A. Recently concluded Phase III HAVEN trials demonstrated that prophylaxis with emicizumab is superior to recombinant Factor VIII (rFVIII). Patients with Hemophilia A with inhibitors had a 79% reduction in the Annualized Bleeding Rate (ABR) while on emicizumab prophylaxis vs other bypassing agents. Patients without inhibitors had a 68% reduction in ABR on emicizumab vs rFVIII prophylaxis. However, there is limited data on its use in the post-marketing era. METHODS: We report our experience with emicizumab in children and adults with Hemophilia A with and without inhibitors at a single Hemophilia Treatment Center. This Northwell IRB approved retrospective analysis (Jan 2017 - Jun 2020) included data from 12 months prior to starting emicizumab prophylaxis RESULTS: A total of 38 patients on emicizumab prophylaxis were included. 35 patients (92.1%) had severe and 3 (7.9%) had moderate Hemophilia A. 11 patients (28.9%) had a FVIII inhibitor. The mean age was 16.4 yrs with 18 patients (47%) below the age of 12 (age limit used in HAVEN trials). 54.1% of patients were Caucasian, 18.9% were Asian and 16.2% were African American. Thirty patients (78.9%) were on prophylaxis with either rFVIII (71.5%) or FEIBA (21.4%) before starting emicizumab. All 38 patients were started on emicizumab with a loading dose of 3 mg/kg once weekly for 4 weeks followed by a maintenance dose of 1.5 mg/kg weekly. The ABR decreased by 52% for inhibitor patients (3.6 events before and 1.7 events after starting emicizumab). Similarly, there was a dramatic 70.6% reduction for non-inhibitor patients (1.5 events before and 0.44 events after starting emicizumab). Patients on emicizumab prophylaxis experienced 35 bleeding events over 24 months. Nine out of these 35 events occurred in one patient alone with a high titer FVIII inhibitor. 56.5% of these events were joint bleeds, 26.1% (muscle bleeds), 13% (soft tissue bleeds) and 4.4% were mucocutaneous bleeds. Barring 2 events, all episodes (93.9%) were managed outpatient. A majority of these bleeds (72.1%) in inhibitor patients were treated with recombinant Factor VIIa (rVIIa, 16-24 doses for documented hemarthroses) and 3.4% were treated with FEIBA after nonresponse to rVIIa (9-15 doses) due to delayed treatment. Remaining non -inhibitor patients were treated with rFVIII (2-5 doses) with a good response. 52 % of these bleeds were trauma-related. Five surgeries were conducted in the inhibitor patients while on emicizumab prophylaxis and none experienced perioperative bleeding. RVIIa was used as a bypassing agent for 2 of these surgeries - a hemispherectomy and a port removal. No bypassing agent was used for the remaining 3 port removals. Five surgeries (1 total knee arthroplasty and 4 port removals) were performed in patients without a FVIII inhibitor. Recombinant Factor VIII was used as the replacement agent and the patient with knee arthroplasty experienced post-operative bleeding. There were no thrombotic episodes or deaths and all but one continued on emicizumab. The patient post knee arthroplasty discontinued emicizumab after recurrent bleeds into the replaced joint despite aggressive replacement with rFVIII and absence of an inhibitor. DISCUSSION: We report a real-world experience on the use of emicizumab prophylaxis for Hemophilia A with and without inhibitors in children and adults with 78.9% of our cohort below the age of 21 years. Our study demonstrated a similar decrease in ABR for non-inhibitor patients comparable to the HAVEN clinical trials. However, our inhibitor patients experienced a lower bleed reduction rate on emicizumab and all patients still experienced a considerable number of trauma-related bleeds (likely due to increased participation of inhibitor patients in sports). Two patients with traumatic muscle/joint bleeds were treated with aPCC due to non-response to rVIIa suggesting the need for early treatment of suspected bleeds on emicizumab. No thrombotic events or thrombotic microangiopathy was observed in our patient cohort. Our data suggest the need for ongoing patient education for early bleed recognition on emicizumab prophylaxis, prompt treatment of breakthrough bleeds and pre-sports prophylaxis with FVIII or bypassing agents. Disclosures Acharya: BPL: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Membership on an entity's Board of Directors or advisory committees; Bayer Pharma Inc.: Research Funding.