Annualized Bleeding Rate Research Articles

Durability of Bleeding Protection and Factor IX Activity Levels Are Demonstrated in Individuals with and without Adeno-Associated Virus Serotype 5 Neutralizing Antibodies (Titers

Introduction: Pre-existing adeno-associated virus (AAV) neutralizing antibodies (NAbs) have limited the efficacy of AAV-based gene therapy in prior clinical applications, including in hemophilia. A unique aspect of the Phase 3 HOPE-B clinical trial (NCT03569891) assessing etranacogene dezaparvovec gene therapy, an AAV serotype 5 vector expressing Padua factor IX (FIX), was the enrollment of participants regardless of their baseline AAV5 NAb status. The HOPE-B clinical trial met its primary efficacy endpoint, providing hemostatic protection superior to standard of care FIX prophylaxis over 52 weeks of follow-up after stable FIX Padua expression (defined as Months 7-18). Aim: Assess efficacy and safety of etranacogene dezaparvovec in HOPE-B participants with (NAb+) and without (NAb-) pre-existing AAV5 NAbs over 18 and 24 months of follow-up. Methods: Adult male participants with severe or moderately severe hemophilia B (FIX ≤2%), NAb+ or NAb-, were treated in the Phase 3, open-label, single-arm, HOPE-B trial with a single intravenous infusion of etranacogene dezaparvovec (2x1013 gc/kg), following a ≥6-month lead-in period receiving FIX prophylaxis. FIX activity, annualized bleed rate (ABR), and use of infused replacement FIX concentrates were assessed regularly during the lead-in and the first 12 months after receiving etranacogene dezaparvovec, then every 6 months during the long-term follow-up (Years 2-5). Adverse events were recorded continuously. Although not an exclusion criterion, AAV5 NAbs were assessed on the day of intravenous dosing (baseline), using a custom-developed, cell-based in vitro AAV5 transduction inhibition assay (sensitivity 10 ng/mL antibody, titer 1:7, intra and inter-run coefficient of variation [CV] <30%). Results: Of the 54 participants who received etranacogene dezaparvovec, at baseline 33 participants were NAb- and 21 were NAb+. The median (Q1-Q3) titer among NAb+ participants was 56.9 (23.3-198.9) and 20/21 (95%) NAb+ participants had titers of <1:700. One participant with a markedly high NAb titer of 3212 prior to vector dosing and one participant who only received a partial dose (due to an infusion-related reaction; NAb titer: 198.9), did not express FIX Padua and did not discontinue FIX prophylaxis. All other participants (52/54) discontinued FIX prophylaxis. At 18- and 24-months post-dose, no clinically meaningful correlation between an individual's baseline AAV5 NAb titer and FIX activity levels was identified, up to a NAb titer of <1:700 (24-month Pearson coefficient: -0.29; Spearman coefficient: -0.25; R2: 0.086). Sustained FIX activity levels (median [min-max]) were demonstrated at 18 months post-dose in NAb+ <1:700 (32.0% [10.3-57.9]) and NAb- (35.0% [4.5-122.9]) participants and at 24 months post-dose in NAb+ <1:700 (33.5% [9.1-88.3]) and the NAb- (35.4% [4.7-99.2]) participants (Table 1). At both 18- and 24-months post-dose, NAb+ <1:700 and NAb- participants demonstrated a low ABR (Table 2). The ABR achieved by the NAb+ <1:700 and NAb- subgroups at 18 months was 1.30 and 0.93, and at 24 months was 1.65 and 0.80, respectively. These ABRs were significantly improved compared with the respective ABRs of 4.29 (p=0.0005 and p=0.0065 at 18 and 24 months, respectively) and 3.80 (p<0.0001 at 18 and 24 months) observed during the ≥6-month lead-in period of continuous FIX prophylaxis. The safety profile of etranacogene dezaparvovec was similar between NAb subgroups. At 24 months, corticosteroid-treated transaminase elevations occurred in 6/33 NAb- (18.2%) and 3/21 NAb+ (14.3%) participants. Infusion-related reactions occurred in 2/33 NAb- (6.1%) and 5/21 NAb+ (23.8%) participants. There was no statistically significant association between infusion-related reactions and NAb status (p=0.0956). Conclusions: Throughout 24 months of follow-up, AAV5 NAb- and NAb+ (<700 titer) HOPE-B participants receiving etranacogene dezaparvovec demonstrated significant reductions in ABR, freedom from continuous FIX prophylaxis and a comparable and acceptable safety profile, regardless of NAb status. FIX activity levels were stable, with no association between baseline NAb status (up to titer <1:700) and the long-term durability of FIX expression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes of Emicizumab in Hemophilia A with or without FVIII Inhibitors from the Canadian Hemophilia Bleeding Disorder Registry

Background: Hemophilia A is a bleeding disorder characterized by deficiency or absence of blood coagulation factor (F)VIII, which leads to lifelong bleeding tendency. The Canadian Bleeding Disorders Registry (CBDR) is a clinical database designed to assist clinicians in Canadian hemophilia treatment centers with the management of people with bleeding disorders and gain a better understanding of their incidence and prevalence, their treatment patterns, outcomes, and safety. Emicizumab is a bispecific monoclonal antibody that bridges activated FIX and FX to substitute for missing activated FVIII in people with hemophilia A (PwHA), thereby restoring hemostasis. Emicizumab was approved by Health Canada for the treatment of PwHA with FVIII inhibitors in 2018, and for PwHA without FVIII inhibitors in 2019. In this non-interventional, secondary data use cohort study, we use data routinely collected by the CBDR to evaluate the effectiveness, safety, and treatment patterns of emicizumab in Canada. The study includes patients treated according to routine clinical practice; therefore, it reflects patterns of care and outcomes in the real world, outside of the experimental setting. Methods: We retrieved de-identified data from the CBDR database of all registered PwHA who had received emicizumab at least once prior to December 31, 2021. Baseline demographic characteristics, including sex, body mass index, FVIII inhibitor status, emicizumab regimen, and immune tolerance induction (ITI) while receiving emicizumab were stratified by disease severity (defined by the level of endogenous FVIII activity) and age. Real-world efficacy outcomes were measured by the proportion of patients with zero traumatic, spontaneous, or joint bleeds as well as annualized bleeding rates (ABR) for any treated bleed. ABRs were calculated as (total number of bleeds/duration of follow-up [days])*365.25. Efficacy outcomes also included patients’ Hemophilia Joint Health Score (HJHS), Patient Reported Outcomes Burdens and Experiences (PROBE), and EQ-5D index and visual analog scale (VAS) scores. We performed a complete data analysis, without imputation. Intra-patient comparisons of bleeding were performed for all patients This study was approved by the research ethics board of McMaster University and other participating centers, and abides by the guiding principles of the Declaration of Helsinki. Results: In total, 146 PwHA received emicizumab at least once up to December 2021 in the CBDR database. The median (Q1, Q3) age at initiation of emicizumab was 13.9 (6.7, 28.7) years; 58.9% (n=86) of PwHA were ≤18 years (Table 1). Overall, 132 PwHA had severe disease, 10 had moderate disease, and 4 had mild disease. In total, 40.4% (n=59) of PwHA had current FVIII inhibitors, 15.1% (n=22) had a history of FVIII inhibitors, and 44.5% (n=65) had no history of inhibitors; 4.1% (n=6, all with severe HA) received ITI while on emicizumab. Three adverse events were reported during 2021, including two allergic reactions and one case of large hematoma at the operative site following removal of a port-a-cath. No thromboembolisms or thrombotic microangiopathies were reported. Over a median follow-up of 389.0 days, 76.7% (n=112) of PwHA had no recorded bleeds (Table 2). For the 34 patients with recorded bleeds on emicizumab, median (Q1, Q3) ABR was 1.0 (0.5, 2.0); 13 of the 34 had joint bleeds, 18 had traumatic bleeds, and 19 had spontaneous bleeds. An intra-patient comparison in all PwHA (n=146) showed a decrease in mean (95% confidence interval [CI]) ABR from 2.38 (1.77-3.22) pre-emicizumab (2018, prior to first dose) to 0.36 (0.24-0.53) post-emicizumab (rate ratio [RR] 0.15, p<0.0001). In PwHA with bleeds before or after initiation of emicizumab (n=97), mean (95% CI) ABR decreased from 5.31 (3.79-7.45) pre-emicizumab to 0.87 (0.58-1.32) post-emicizumab (RR 0.16, p<0.0001). Conclusions: This analysis describes the baseline characteristics, bleed outcomes, and safety of Canadian PwHA treated with emicizumab before December 31, 2021. The majority had severe disease and current or historical FVIII inhibitors. The data show 76.7% had no recorded bleeds and there was a substantial decrease in bleeds post-emicizumab. The CBDR allows for a longitudinal follow-up of the Canadian hemophilia A population, which can inform healthcare practitioners and regulatory authorities of the real-world safety and effectiveness outcomes of treatments. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Prophylaxis with a Plasma-Derived Von Willebrand Factor/ Factor VIII Concentrate in Previously Treated Patients with Von Willebrand Disease

Introduction: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in von Willebrand disease (VWD) patients with a history of severe and frequent bleeds, regardless of age or VWD type. Data on the efficacy and safety of prophylaxis with a human plasma-derived VWF/factor VIII concentrate (pdVWF/FVIII; wilate®) that contains the two factors in a physiological 1:1 activity ratio have been collected previously from 19 VWD patients in four prospective, multicenter phase 2 and 3 trials. In these patients, bleeding rates were significantly reduced compared with previous treatment. Aims: To investigate the efficacy and safety of regular prophylaxis with a pdVWF/FVIII concentratein previously treated patients with VWD. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled patients of any gender with VWD type 1 (VWF:RCo <30 IU/dL), type 2 (except 2N) or type 3, who were at least 6 years old. Prior to entering the WIL-31 study, all patients had received on-demand treatment with pdVWF/FVIII during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 bleeding episodes (BEs), excluding menstrual bleeds, with at least 2 of these BEs treated with a VWF-containing product, were eligible to enter WIL-31. Patients in WIL-31 received regular pdVWF/FVIIIprophylaxis, 2-3 times per week at a dose of 20-40 IU/kg, for 12 months. The primary endpoint of the study was to demonstrate that prophylaxis with pdVWF/FVIII lowered the mean total annualized bleeding rate (ABR) compared with that during 6 months of on-demand treatment by more than 50%. Secondary outcomes included spontaneous ABR and treatment-emergent adverse events. Results: Thirty-three patients were included in the modified full analysis set, with a median (range) age of 18 years (7-61). Fourteen (42.4%) patients were female, 9 (27.3%) patients were <12 years old. Six (18.2%) patients had severe Type 1 VWD, 7 (21.2%) had type 2, and 20 (60.6%) patients had type 3 VWD. Mean (median, range) total ABR in the on-demand run-in period and during pdVWF/FVIII prophylaxis was 33.4 (24.5, 11-115) and 5.2 (1.9, 0-35.8), respectively (Figure 1), meeting the primary endpoint of a ≥50% reduction in mean ABR. Mean (median, range) spontaneous ABR in the on-demand run-in period and during pdVWF/FVIII prophylaxis was 24.4 (18.7, 5-93) and 3.2 (1.0, 0-24.6), respectively. Of the 33 patients, 10 (30.3%) and 15 (45.5%) patients had zero total or spontaneous BEs during the study period, respectively. A total of 173 BEs occurred, the majority of which (146 BEs; 84.4%) were classified as minor. Of the 173 BEs, 121 (69.9%) were treated with pdVWF/FVIII. The overall efficacy of treatment was assessed as "excellent” or "good” for 120 (99.2%) BEs and "moderate” for 1 (0.8%) BE. Five serious adverse events were reported, none of which were assessed as related to the study treatment. Two patients had adverse events assessed as probably or possibly related to the study treatment by the investigator, and both patients discontinued from the study. One patient developed mild chest tightness (3 events), the other had hypersensitivity reactions of moderate severity (2 events). No thrombotic events occurred. Conclusions: Prophylaxis with a pdVWF/FVIII containing VWF and FVIII in a 1:1 activity ratio was effective in pediatric and adult patients with VWD of all types. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim Subgroup Analysis of the Effectiveness and Safety of Damoctocog Alfa Pegol Prophylaxis in Previously Treated Patients with Hemophilia A Treated Every 5 or Every 7 Days: Results from the Real-World Observational HEM-POWR Study

Background: Extended half-life (EHL) FVIII products have been developed to reduce the burden of frequent intravenous infusions for people with hemophilia A (HA). Damoctocog alfa pegol is an EHL PEGylated B-domain-deleted recombinant FVIII concentrate approved for use in previously treated patients (PTPs) aged ≥12 years with HA. The recommended initial prophylactic dosing regimen in the USA is twice weekly, which may be adjusted to every 5 days (E5D) and can then be individually tailored to less or more frequent dosing based on bleeding episodes (FDA 2018). The safety and efficacy of extended dosing intervals were demonstrated in the pivotal PROTECT VIII studies (Reding et al, Haemophilia 2021). Real-world safety and effectiveness of damoctocog alfa pegol administered with any dosing regimen has been reported in the previously presented interim analyses of the HEM-POWR study (Reding et al., ISTH 2021, 2022). However, separate analyses of E5D or every-7-day (E7D) prophylaxis regimens in the real-world have not yet been reported. Objective: Post hoc analysis to explore the safety and effectiveness of extended dosing with damoctocog alfa pegol in PTPs receiving prophylactic treatment in the ongoing real-world HEM-POWR study. Methods: HEM-POWR (NCT03932201) is a prospective, multinational, observational open-label Phase IV cohort study of damoctocog alfa pegol in PTPs with mild, moderate, and severe HA. Patients in this subgroup analysis received prophylactic damoctocog alfa pegol E5D or E7D. The primary endpoint was annualized bleeding rate (ABR), and secondary endpoints included measures of joint health and safety. Safety analyses were primarily performed on treatment-emergent adverse events (TEAEs) in the safety analysis set population. Effectiveness analyses were primarily performed on the full analysis set (FAS). Data were captured from patient diaries and physician records, and ethical approval was obtained for all sites. Results: At data cut-off (31 August 2021), a total of 162 patients were enrolled in the study. In this subgroup analysis, 21 patients in the FAS received prophylactic treatment E5D (n=14) or E7D (n=7). The majority of patients had severe HA (n=12/14, 85.7% E5D; n=5/7, 71.4% E7D). Prior to initial visit, all patients received FVIII replacement therapy; some of these patients received prior damoctocog alfa pegol prophylactic treatment (n=7/14, 50.0% E5D; n=5/7, 71.4% E7D). The proportion of patients with no affected joints increased over time in both E5D and E7D subgroups (Figure 1). In the E5D subgroup at follow-up 1 (n=10), 40.0% of patients had no affected joints. In the E7D subgroup, all patients reported no affected joints at the first follow-up (n=5). Median (mean, SD) total ABR was 0.0 (1.0, 1.6) for the E5D subgroup and 0.0 (0.8, 1.5) for the E7D subgroup. The median (mean, SD) difference in ABR between observation period and prior to initiation of damoctocog alfa pegol in the E5D and E7D subgroups is reported in Table 1. No development of FVIII inhibitors, TEAEs, or deaths were reported. Conclusions: Damoctocog alfa pegol continues to show a favorable effectiveness and safety profile in PTPs with mild, moderate, or severe hemophilia in a real-world clinical setting with extended prophylactic dosing intervals. Improvements in joint health and ABR were demonstrated with both E5D and E7D prophylaxis regimens. The option of extended dosing intervals allows for further PK-guided treatment individualization for selected patients, based on bleeding phenotype and lifestyle, without compromising treatment efficacy. References Bayer. Damoctocog alfa pegol (Jivi®). Prescribing Information. Last updated August 2018. Available at: https://www.fda.gov. Accessed: July 2022. Reding MT, Pabinger I, Holme PA, et al. Haemophilia. 2021;27:e347-e356. Reding M, Alvarez Román M, Sanabria M, et al. [abstract presented at ISTH 2021]. Res Pract Thromb Haemost. 2021;5(Suppl 2). Reding M, Alvarez Román M, Sanabria M, et al. [abstract presented at ISTH 2022]. https://abstracts.isth.org/abstract/annualised-bleeding-rate-and-joint-health-second-interim-analysis-of-the-real-world-hem-powr-study-evaluating-the-effectiveness-of-damoctocog-alfa-pegol-in-patients-with-haemophilia-a/. Accessed July 19, 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Personalization of Clotting Factor VIII Replacement Therapy Based on Population Pharmacokinetics in Adult Patients with Severe Hemophilia a Who Frequently Switch Factor VIII Concentrates

Interindividual pharmacokinetic differences in clotting factor VIII (FVIII) metabolism impede the dosing regimen optimization in patients with hemophilia A. The population pharmacokinetic (PK) analysis enables the estimation of FVIII pharmacokinetics in individual patients which is used to personalize dosing regimens. Therefore, we conducted a prospective study on adult patients with severe hemophilia A who received different FVIII concentrates for tertiary prophylaxis and whose dosage of FVIII was adjusted based on individual PK results. We aimed to compare the number of bleeding episodes and FVIII consumption before and after dosing adjustment. The study, conducted for 18 months for each participant, was divided into 3 phases: (1) pre-PK: assessments before FVIII dosing adjustment, (2) dosing adjustment based on the PK analysis of FVIII, and (3) assessments after FVIII dosing adjustment. All patients gave informed consent before enrolment, and all procedures were carried out according to the Declaration of Helsinki. During the study patients frequently changed FVIII concentrates (each patient used 3-5 different products) which reflects the standard of care in adult patients with hemophilia in Poland. During phase 1 of the study, over 5-13 months [median: 11.0 months, mean(standard deviation - SD): 10.8(1.9) months], patients recorded FVIII consumption and bleedings using electronic diaries (myPKFiT® licensed for octocog alfa). In phase 2 of the study, a PK analysis (clearance, half-time, time to reach the 1 IU/dl concentration) was performed: following the 72-hour washout period, blood samples were collected, and patients received the infusion of octocog alfa with the mean dose (SD) of 51.1(1.7) IU/kg. Two more blood samples were collected 3-4 h and 24-36 h after the infusion. Plasma FVIII activity was measured with a one-stage clotting assay, and the FVIII inhibitor with the Nijmegen modification of the standard Bethesda method. The myPKFiT® was used to obtain individualized FVIII dosing regimens based on PK analysis results. The dosing adjustment was offered to patients who experienced breakthrough bleeds during phase 1 or in whom the pre-PK treatment did not secure FVIII trough level of >1 IU/dl. In case of favorable PK results and no breakthrough bleeds during phase 1, a less intensive regimen was implemented. In phase 3 of the study (which lasted for 5-13 months, median: 7.7 months, mean(SD): 7.6(1.6) months), patients continued treatment with locally available FVIII concentrates and used electronic diaries to record FVIII consumption and bleedings. All bleeding rates were annualized (annualized bleeding rates - ABR). The final analysis set included 22 male patients, aged 23-68 years. The clearance of octocog alpha ranged from 0.014 to 0.051 dL/h/kg [mean(SD), 0.030±0.010 dL/h/kg; coefficient of variation (CV)=33%], half-life - from 9.1 to 27.9 h (14.6(4.3) h, CV=29%), and time to reach 1 IU/dl - from 51 to 179 h [91(29) h, CV=32%]. Three individuals were categorized as slow metabolizers (clearance of 0.014, 0.018, and 0.019 dL/h/kg), and 2 as fast metabolizers (clearance of 0.048 and 0.051 dL/kg/h). FVIII inhibitor was undetectable (<0.5 BU/ml) in all patients. After the PK analysis, 21 of 22 patients met the criteria of FVIII dosing adjustment. Four patients did not agree to change the regimen. Seventeen patients modified it according to the PK results (10 of them had FVIII trough levels of >1 IU/dl and 7 of them of <1 IU/dl in phase 1 of the study). Changing the dosing regimen in the 17 patients resulted in ABR reduction compared to the pre-PK phase: a decrease of 3.1-fold in total ABR (p=0.045 for dependent samples t-test); 3.2-fold in spontaneous ABR (p=0.046); and 3.1-fold in injury-related ABR (p=0.072). The consumption of FVIII due to bleeds had decreased by 77% (p=0.034). In conclusion, personalizing the FVIII replacement therapy based on population PK models helps to lower bleeding risk and drug consumption in patients with severe hemophilia A. Presented results suggest that prophylaxis regimen based on PK analysis carried out with octocog alfa and myPKFiT® application is clinically effective also with the use of other FVIII concentrates.

Protocol and Primary Analysis of Lome: A Randomized Trial of Low- Versus Intermediate-Dose Immune Tolerance Induction with Recombinant Factor VIII (Omfiloctocog alfa, SCT800) in China

Background: Although the cohort and registry data support low-dose (LD; 50 IU/kg once every other day) and intermediate-dose (MD; 100 IU/kg daily) immune tolerance induction (ITI) are almost equally effective in inducing tolerance in people with severe hemophilia A, with inhibitors (PwHI)1-3, there has been no prospective randomized trials, especially in China. Here, we present the protocol and results of the primary analysis in LOME (ChiCTR2200056603). Methods LOME is a multicenter, prospective, randomized comparison of LD and MD ITI, in severe hemophilia A (HA) patients (FVIII level < 1%) with peak historical inhibitor ≥ 5 and < 200 Bethesda Unite (BU/ml). In the first year of recruitment (Part A), patients with age ≤ 8 years at time of randomized will be included. In the second year of recruitment (Part B), patients with age ≤ 12 years at time of randomized will be included. Patients have received ITI therapy before randomization will be excluded. Subjects were randomized 1:1 to LD or MD ITI with the first domestic recombinant factor VIII (rFVIII) (Omfiloctocog alfa, SCT800) approved in China. Factor III (FVIII) inhibitor screening, ITI monitoring and dose tapering will be based on the consensus from United Kingdom Hemophilia Center Doctors' Organization (UKHCDO)4. If (a) there is an upward trend in titer over 3-6 months period; or (b) fall in chromogenic Bethesda titer of less than 20% in 6 months period after initial peak inhibitor titer; or (c) titer ≥ 200BU/ml during ITI therapy; or (d) spontaneous bleeding > 1 monthly over 3-6 months period, modify the regimen as below: In the LD arm, increase to 100IU/kg daily;In the MD arm, rituximab 375 mg/m2 weekly × 4 weeks (maximum 600 mg) and prednisone 2 mg/kg daily × 1 month (maximum 60 mg, tapering over 3 months) would be added. Once the patient had achieved Success, taper dose as below: In the LD arm, the FVIII dose would be reduced slowly to 25IU/kg three times a week for continuing prophylaxis;In the MD arm, the FVIII dose would be reduced slowly to LD ITI, then same as LD arm. The primary endpoints are ITI outcomes (Success: negative inhibitor titer and FVIII recovery ≥ 66% of expected) and the time taken to ITI Success, in PwHI with LD ITI compared to those with MD ITI. Key secondary endpoints include annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) for any bleeds and treated bleeds; joint and bone health assessed by Hemophilia Joint Health Score 2.0 (HJHS 2.0) and ultrasound; quality of life measured by the Canadian Hemophilia Outcomes-Kids Life Assessment Tool 2.0 (CHO-KLAT 2.0) and numbers of days out of school; average consumption cost (per kg body weight) was calculated based on the intermediate number of treatment doses consumed to achieve Success. This included the cost of rFVIII and rituximab for ITI, prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) for treatment of breakthrough bleed, and intravenous immunoglobulin (IVIG) for infection prevention in patients receiving immunosuppressants. Safety was also a secondary endpoint. Results: Ten subjects were randomized into the study with median follow-up time of 1.64 [range (minimum, maximum), 0.23, 3.91] months in LD arm, and 2.66 (0.26,3.91) months in MD arm. Baseline includes age at time of randomized, age of inhibitor detection, exposure days before inhibitor detection, initial inhibitor titer, inhibitor titer at start of ITI and so on, between two arms are summarized in Table 1. Twenty percent (1/5) in MD arm achieved Success after 7 weeks of treatment and still maintained until the latest follow-up. No one achieved Success in LD arm. The bleeds between the treatment arms are summarized in Table 2. Nearly 2-fold difference in mean ABR and AJBR for treated bleeds, between treatment arms, and 3- to 4-fold in ABR and AJBR for any bleeds. Conclusions: It is planned to enroll 40 patients in Part A and 60 patients in Part B, who will be followed for up to 2 years. The study is ongoing and, currently, 10/40 (25%, in Part A) PwHI from 4 HTCs have been included. LOME study is the first, multicenter, prospective, randomized trial of LD vs MD ITI with domestic rFVIII (Omfiloctocog alfa, SCT800) in Chinese PwHI. This study is likely to contribute with the choice of optimal ITI regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Performance of the Comprehensive Assessment Tool for Challenges in Hemophilia (CATCH) 2.0

Introduction: The Comprehensive Assessment Tool for Challenges in Hemophilia (CATCH) was developed in 2018 to capture various outcomes that were important to children and adult persons with hemophilia (PwH) and their caregivers. It contains concepts related to quality of life, lifestyle restrictions, and physical activity, and was intended to be used in clinical trial and clinical practice settings across therapies, with adult and pediatric PwH A or B (with or without inhibitors) and caregivers of PwH. In this study, the abbreviated CATCH 2.0 was developed and validated to capture a selected set of outcomes that are most important to PwH and their caregivers. Methods: This was a psychometric validation study using data from a prospective multi-center single arm trial (that included children and adult PwH with mild to moderate hemophilia A), a US-based psychometric study (that included children and adult PwH A or B), and a nationwide survey of adult PwH A. Item-level analyses assisted in the identification of potential questions for deletion, followed by exploratory factor analysis - which examined relationships between the measured survey items and their domains. Reliability (internal consistency and test-retest), validity (construct, convergent, criterion and known-groups), responsiveness to change, and thresholds for meaningful change for each domain were evaluated. Results: Data from 126 children, 232 adults, and 118 caregivers were analyzed across the 3 studies. This included data from 396 (83%) PwH A and 80 (17%) PwH B, of which 68 (14%) had severe disease and 408 (86%) had mild or moderate hemophilia, and 115 (24%) had active inhibitors. In general, the CATCH 2.0 demonstrated acceptable psychometric properties. Internal consistency reliability for all domains (alpha > 0.87) and test-retest reliability (intraclass correlation coefficient >0.70) were acceptable for 6 of 8 domains. Medium to large correlations (correlation coefficient 0.3 to 0.6) were reported between associated measures (EQ-5D, WPAI, and pain rating) and the majority of CATCH domains. Known-groups validity for most domains (based on categorizations of severity and inhibitor status) was good. Treatment Burden was the only domain which demonstrated any responsiveness over time. Most correlations with annualized bleed rate (ABR) were not significant. Since anchor-based methods using ABR were not feasible (due to poor correlation), thresholds for clinically meaningful change were estimated using a distribution-based approach (standard error of measurement ranged from 6.7 to 16.5). Table 1 contains a list of the domains included in each of the 3 versions. Each version is expected to take < 10 minutes to complete. Conclusions: The CATCH 2.0, an abbreviated version of the original CATCH, captures important outcomes for PwH A and B, along with their caregivers. CATCH 2.0 has an excellent factor structure and its psychometric properties demonstrated acceptable performance, particularly for reliability, convergent validity, and known-groups validity. Support for responsiveness in mild/moderate populations however, was limited. Results highlight the need for more longitudinal data in heterogeneous groups of PwH to further refine the performance of this tool. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pharmacokinetics, Efficacy and Safety Evaluation of FRSW107 in Previously Treated Hemophilia a Patients: A Multicentre, Open-Label, Non-Randomized Phase III Study

Background: FRSW 107, a novel homodimer recombinant factor VIII (rFVIII) Fc fusion protein, is the first domestic extended half-life (EHL) rFVIII under development in China，and is currently at stage of Biologics License Application (BLA) in NMPA for the prophylaxis and treatment of bleeding episodes in adolescent and adult (≥12 yr) with hemophilia A (HA). Aims: This phase III (NCT04456387, CTR20201212), open-label, non-randomized, multicenter trial aimed to evaluate the pharmacokinetics (PK), safety, and clinical efficacy of FRSW 107 for prophylaxis and treatment of bleeding in previously treated HA patients ≥12 yr. Methods: Eligible patients included male severe HA (FVIII:C< 1%) ≥12 yr, previous treatment with FVIII concentrates for ≥150 exposure days (EDs), and absence of FVIII inhibitors (＜0.6 Bethesda Units/mL). A total of 119 patients received FRSW 107 for prophylaxis treatment (n=83) or on-demand treatment (n=36). The patients in the prophylaxis group were administered one dose of 50 IU/kg of FRSW 107 every three days for at least 50 EDs for a minimum period of 6 months, and the primary efficacy endpoint was annualized bleeding rate (ABR). The patients in the on-demand treatment group received 30 to 50 IU/kg of FRSW 107 over 6 months, according to the severity and location of the bleeding, and the primary efficacy endpoint was hemostatic effect (excellent, good). The single-dose and repeat dose PK parameters of 15 patients in the prophylaxis group were analyzed at ED1 and ED35, respectively. Results: In the prophylaxis group, the mean and median annualized bleeding rate (ABR) were 1.61±3.74 and 0.00 (IQR, 0.00-2.02), decreased by 95.01% versus the baseline 32.24±23.98 and 26.00 (IQR, 16.00-46.00), and 56 (67.5%) patients had no bleeds during the trial. Detailed ABR data for prophylaxis group was included in the table below. In the on-demand treatment group, hemostatic efficacy was rated as "excellent” or "good” for 98.9% of bleeds. 97.9% of 721 reported bleeds were treated with ≤2 injections. No FVIII inhibitors have been reported in this study. Drug-related adverse events (AEs) occurred in 10.1% of the patients. No SAE was judged to be related to FRSW107 treatment. No thromboembolic events were reported, and there are no unexpected safety concerns. The terminal half-life of FRSW 107 ranged between 20 to 22 hours. The incremental recovery (IR) was approximately 2.14 (IU/dL)/(IU/kg). The PK parameters and profiles remained consistent between ED1 and the repeated dosing at ED35. Conclusions: The data indicate that FRSW 107 was safe and effective for prophylaxis and treatment of bleeding episodes in previously treated adolescent and adult HA patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fitusiran Prophylaxis Improves Health-Related Quality of Life in People with Hemophilia a or B, with or without Inhibitors: Results of ATLAS-PPX Study

Background: Fitusiran is a prophylactic investigational therapeutic comprised of synthetic small interfering ribonucleic acid (siRNA) that targets antithrombin to enhance thrombin generation and rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. In previous Phase 3 trials, once-monthly fitusiran prophylaxis significantly improved HRQoL in PwHA/B, with or without inhibitors versus episodic/on-demand treatment Objective: We present health-related quality of life (HRQoL) results from the phase 3 ATLAS-PPX study (NCT03549871) comparing fitusiran prophylaxis versus prior prophylaxis with clotting factor concentrates (CFC) or bypass agents (BPA) in PwHA/B with or without inhibitors. Methods: This multicenter, multinational, open-label, Phase 3 study recruited male patients aged ≥12 years with severe hemophilia A or B, with or without inhibitors. Participants continued factor/BPA prophylaxis (6 months between month -6 and Day 0) before switching to once-monthly 80 mg SC fitusiran prophylaxis (7 months between Day 1 and month 7). Aside from annualized bleeding rates (ABR), the study assessed HRQoL at Month -6, Day 1 (baseline) and Month 7, during factor/BPA prophylaxis and during treatment with fitusiran using the following questionnaires: Hemophilia Quality of Life Questionnaire (Haem-A-QoL & Haemo-QoL; lower scores = improved HRQoL), Hemophilia Activity List (HAL & PedHal; range 0-100, higher scores = improved HRQoL), EuroQoL-5 Dimension 5-Level (EQ-5D-5L; index score ranges 0-1, higher scores = improved HRQoL), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and the Hemophilia Joint Health Score (HJHS). Results: A total of 80 participants were enrolled and 65 were evaluable for efficacy analyses (inhibitor/non-inhibitor, n=19/46; hemophilia A/hemophilia B, n=50/15). At enrollment (Month -6), the mean (SD) age was 24.8 (11.2) years, transformed Haem-A-QoL physical health and total scores were 32.87 (23.68) and 31.63 (18.54) respectively, EQ-5D-5L index score was 0.83 (0.13), HAL total score was 79.11 (20.29) and TSQM-9 baseline score for effectiveness, convenience and satisfaction were 66.76 (18.06), 61.29 (17.97) and 69.35 (15.91), respectively. Fitusiran achieved the study primary endpoint and significantly reduced the frequency of bleeding episodes; observed median (IQR) ABR for treated bleeds was 0.0 (0.0; 2.3) in the fitusiran efficacy period and 4.35 (2.2; 10.9) in the factor /BPA prophylaxis period. The least squares (LS) mean difference between change from Month -6 to baseline (Day 1) and change from Month -6 to Month 7 in Haem-A-QoL scores demonstrated significant improvement in transformed total score with fitusiran treatment vs factor/BPA prophylaxis (-4.55 [95% CI: -7.56, -1.54]) and nominal improvement in physical health score in favor of fitusiran (-3.60 [95%-CI: -10.52, 3.33]). In addition to showing a good functional ability to perform activities of daily living, patients rated an even better physical ability over the two periods of assessment of the study as evidenced by changes in HAL scores: mean (SD) changes in total score were 3.05 (20.04) and 2.45 (19.42) for fitusiran and factor/BPA prophylaxis, respectively. Similar to the results from disease specific questionnaire, fitusiran also demonstrated nominal improvements in the EQ-5D-5L index score versus factor/BPA prophylaxis, with mean (SD) changes from Month -6 to Month 7/ Day 1of 0.04 (0.13) versus 0.0 (0.13). Overall results of the mean (SD) TSQM-9 score consistently favored fitusiran prophylaxis versus factor/BPA prophylaxis in all three domains of effectiveness, convenience, and global satisfaction (Table 1). Conclusions: Associated with a marked ABR reduction, PwHA/B with or without inhibitors on fitusiran prophylaxis consistently improved all HRQoL endpoints, demonstrating added value in PwHA/B beyond the improvement in bleeding phenotype. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Matching Adjusted Indirect Comparisons of Personalized Prophylaxis with Simoctocog Alfa Versus Efmoroctocog Alfa, Damoctocog Alfa Pegol and Rurioctocog Alfa Pegol in Patients with Hemophilia a

Introduction: Prophylactic factor VIII (FVIII) therapy is the gold standard to prevent bleeding in patients with severe hemophilia A and should be individualized to patient needs. Although several FVIII products are available, the lack of head-to-head studies makes it difficult to compare their efficacy. The objective of this analysis was to indirectly compare the efficacy of personalized prophylaxis with simoctocog alfa (Nuwiq®) with three comparator FVIII products - efmoroctocog alfa (Eloctate®), damoctocog alfa pegol (Jivi®) and rurioctocog alfa pegol (Adynovate®) - among adults with severe hemophilia A. Methods: Matching adjusted indirect comparison (MAIC) methodology was used to estimate relative treatment effects during personalized prophylaxis after matching study populations with respect to clinically important baseline characteristics. Individual patient data (IPD) from 65 patients on personalized prophylaxis with simoctocog alfa in the NuPreviq study were compared with aggregated data for efmoroctocog alfa from 117 patients in the personalized prophylaxis arm of the A-LONG study, 110 patients treated with damoctocog alfa pegol in the PROTECT VIII study, and patients treated with rurioctocog alfa pegol in the FVIII target trough level 1-3% arm (57 patients) or the 8-12% arm (58 patients) from the PROPEL study. Following feasibility assessments for all proposed analyses, outcomes and matching variables were determined. Patients in the NuPreviq study who would have not met the inclusion criteria for the comparator studies were excluded from the analyses. Baseline age and body weight were used to re-weight the simoctocog alfa IPD such that the weighted summary statistics for simoctocog alfa matched those reported for efmoroctocog alfa; baseline age and body mass index were used for the comparison with damoctocog alfa pegol; and baseline age for the comparison with rurioctocog alfa pegol. Unanchored indirect treatment comparisons were then performed for each outcome using the weighted data for simoctocog alfa. Results: One patient from the NuPreviq study was excluded from the comparison with damoctocog alfa pegol based on baseline age, and 10 patients from the comparison with rurioctocog alfa pegol based on body weight. After matching the populations based on baseline characteristics, the effective sample sizes (ESS) for simoctocog alfa were 44, 40, 27, and 40 for the MAIC analyses with efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol 1-3% and 8-12%, respectively (Table 1). The percentage of patients with zero bleeds was significantly higher with simoctocog alfa for three of the analyses (Figure 1, Table 1): simoctocog alfa (75%) vs efmoroctocog alfa (45%); simoctocog alfa (76.8%) vs damoctocog alfa pegol (38.2%); and simoctocog alfa (78.4%) vs rurioctocog alfa pegol 1-3% (42.1%). The percentage of patients with zero spontaneous bleeds was significantly higher for simoctocog alfa vs rurioctocog alfa pegol 1-3%; these data were not available for efmoroctocog alfa or damoctocog alfa pegol. The total annualized bleeding rates (ABRs) were generally lower with simoctocog alfa vs the comparators, but the difference only reached statistical significance vs damoctocog alfa pegol (Table 1). Spontaneous and joint ABRs were lower with simoctocog alfa vs rurioctocog alfa pegol 1-3%, but the differences were not statistically significant; these data were not available for efmoroctocog alfa or damoctocog alfa pegol. The mean weekly dose was significantly higher in patients treated with simoctocog alfa compared with comparator products: simoctocog alfa vs efmoroctocog alfa (101 vs 85 IU/kg), vs damoctocog alfa pegol (97 vs 70 IU/kg) and vs rurioctocog alfa pegol 1-3% (99 vs 74 IU/kg) (Table 1). Patients treated with simoctocog alfa required a significantly lower average weekly dose than those treated with rurioctocog alfa pegol 8-12% (99 vs 143 IU/kg). Dosing of all products was consistent with the respective prescribing information. Conclusions: The results of these indirect treatment comparisons indicate that pharmacokinetics-adjusted, individualized treatment with simoctocog alfa can lead to decreased ABRs and significantly increased zero bleed rates compared with extended half-life concentrates, albeit at a higher weekly dose. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Emicizumab Switch: Real-World Data of 251 Pediatric Patients from the Pednet Registry

Background: Despite the rapid uptake of emicizumab in the pediatric hemophilia A (HA) population, real-world data on emicizumab safety and efficacy outcomes are limited to the HAVEN-2 trial (N = 85) and single center cohort studies. Aim: To report on bleeding and safety in children and adolescents with HA receiving emicizumab prophylaxis in a large prospective multicenter cohort study. Methods: Data were extracted from the ongoing PedNet Registry (Clin.gov.trial-NCT02979119; date of extraction: Jan 2022). Patients were included if they had a diagnosis of congenital hemophilia A with a baseline factor FVIII up to 25% and were < 18 years old at start of emicizumab. Patients were required to have maintenance therapy of emicizumab and bleeding data available for a minimum of 4 weeks. Patients with concomitant coagulopathies were excluded (N = 2). Bleeding data were compared during emicizumab to bleeding data before emicizumab up to a maximum of two years prior to the start of emicizumab. Patient characteristics were summarized as numbers (%) and median with IQR (P25-P75). Mean annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were estimated and compared between prophylactic regimens by negative binomial regression modelling. Results: 251 patients were included from 30 hemophilia treatment centers, see Table 1 for patient characteristics. The median age at start of emicizumab therapy was 6.1 years (IQR: 2.1 - 12.0). Median follow-up time before emicizumab was 1.51 years and during emicizumab was 1.23 years with a total of 361 patient years reported on emicizumab therapy. Most patients (94%) had severe HA and 76% of the patients were younger than 12 years at start of emicizumab therapy. Approximately one third (37%) of the patients had an inhibitor at start of emicizumab with a median peak titer of 128 BU/ml (IQR: 34 - 600). The ABR and AJBR significantly improved during emicizumab therapy in patients with and without inhibitors, see Figure 1. In patients without inhibitors the mean ABR reduced from 2.8 prior to emicizumab to 1.1 during emicizumab (p < 0.001), while the AJBR reduced from 0.8 to 0.3 (p < 0.001). Similar results were seen in patients with inhibitors. The mean ABR reduced from 5.5 to 1.1 (p<0.001), while the AJBR reduced from 2.3 to 0.3 (p<0.001). In this cohort, two serious adverse events and six adverse events were reported during emicizumab therapy in eight patients (3% of total cohort). Serious adverse events included one death unrelated to emicizumab therapy (retroperitoneal bleed in a baby treated with LMWH for CVL thrombosis) and one patient developed anti-drug antibodies without breakthrough bleeding, who continued emicizumab therapy. Non serious adverse events were all related to local injection site reaction in six patients. No TMA or thrombotic events were observed. Conclusions: This large cohort study with prospectively collected data showed improved bleeding control compared to previous therapy and a favorable safety profile during emicizumab treatment in pediatric patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adults with Severe or Moderately Severe Hemophilia B Receiving Etranacogene Dezaparvovec in the HOPE-B Phase 3 Clinical Trial Continue to Experience a Stable Increase in Mean Factor IX Activity Levels and Durable Hemostatic Protection after 24 Months’ Follow-up

Introduction: Etranacogene dezaparvovec (formerly AMT-061), an investigational gene therapy for hemophilia B, is an adeno-associated virus serotype 5 (AAV5) vector, containing a codon-optimized, highly active factor IX (FIX) Padua R338L transgene under the control of a liver-specific promoter. The Phase 3 HOPE-B clinical trial (NCT03569891) of etranacogene dezaparvovec met its primary efficacy endpoint, providing hemostatic protection superior to standard of care FIX prophylaxis over 52 weeks of follow-up after stable FIX Padua expression (defined as Months 7-18). However, the potential for liver-directed AAV to sustain long-term clotting factor expression remains unknown, with most human experience derived from early phase clinical trials. Aim: Efficacy and safety data is provided from the pivotal Phase 3 HOPE-B clinical trial over a period of 24 months of gene expression. Methods: In this open-label, single-arm study, adult male participants with severe or moderately severe hemophilia B (FIX≤2%), with or without pre-existing AAV5 neutralizing antibodies (NAbs), were infused with a single dose of etranacogene dezaparvovec (2x1013 gc/kg), following a ≥6-month lead-in period receiving FIX prophylaxis. FIX activity, annualized bleed rate (ABR), and FIX infusions were assessed frequently during the lead-in and first 12 months after receiving etranacogene dezaparvovec, then every 6 months during the long-term follow-up (Years 2-5). Adverse events (AEs) were recorded continuously. Results: Of the 54 participants who received etranacogene dezaparvovec, 53 participants received the full dose and 52 completed 24 months of follow-up. At 464 days (~15 months) following infusion, one 75-year-old participant died from cardiogenic shock, preceded by a urinary tract infection, which was considered unrelated to treatment. Of the 54 participants, 52 (96.3%) discontinued and remained free of continuous FIX prophylaxis from Day 21 to Month 24, including 20 participants with baseline AAV5 NAb titers up to 1:700. One participant with a markedly higher AAV5 NAbs titer (1:3212) and one participant who received only a partial vector dose (due to an infusion-related reaction) did not express FIX Padua or discontinue FIX prophylaxis. Compared with the ≥6-month lead-in period (mean ABR 4.18), mean ABR for all bleeds during Months 7-24 post-treatment was significantly reduced by 64% (mean ABR 1.51; p=0.0002), sustaining the same bleed reduction that satisfied the primary endpoint of the trial during Months 7-18. The mean ABR for all other bleed types was also substantially reduced (Figure 1). The mean FIX activity level of participants was 39.0 IU/dL (standard deviation [SD]: ±18.7; min-max: 8.2-97.1) at Month 6 (n=51) and sustained at 36.7 IU/dL (±19.0; 4.7-99.2) at Month 24 post-treatment (n=50; Figure 2). There was an overall 96% reduction in mean unadjusted annualized FIX consumption from the lead-in period (257,339 IU/year/participant) to Months 19-24 (9751 IU/year/participant; p<0.0001). During the 24 months post-dose, all participants experienced at least one treatment-emergent AE (TEAE); of the 557 events, 424 (76%) were mild, 115 (21%) were moderate, and 18 (3%) were severe. A total of 38 participants (70.4%) experienced 93 treatment-related TEAEs, with only one occurring during Months 18-24. There was an increase in alanine transaminase (with or without increased aspartate transaminase) in eleven participants (20.4%). Nine participants (16.7%) received supportive care with reactive corticosteroids for a mean duration of 79.8 days (SD: 26.6; range: 51-130 days). There were no serious AEs related to treatment; a serious AE of hepatocellular carcinoma was determined by independent molecular genomic and integration analysis to be unrelated to treatment. Conclusions: Demonstrating durability of disease correction with acceptable safety is the next major hurdle for gene therapy in people with hemophilia B. After 24 months’ follow-up, single-dose etranacogene dezaparvovec resulted in stable FIX Padua expression in participants with AAV NAb undetected or <1:700 titer; reduction in ABR remained durable and superior to FIX prophylaxis. This outcome was achieved with limited early reactive corticosteroid exposure in a minority of participants, allowing all participants who discontinued prophylaxis to remain off prophylaxis at Month 24. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Esplorhem Study Design and Progress: Evaluation of Spanish Experience of Using Florio® Heamo, Digital Medical Device for Treatment Monitoring in Hemophilia Patients

Background: The use of electronic diaries (eDiaries) has been implemented as a promising strategy to improve the follow-up of diseases such as hemophilia, both for clinicians and for the patients themselves. In particular, standard treatment of hemophilia patients is mainly based on infusion of factor concentrates and is performed at home by patients or caregivers. This practice involves a thorough recording of infusions, bleedings, and other adverse events, which is usually carried out on paper and is deficient in most cases, making it very difficult to follow up and optimize patient treatment. Florio® HAEMO is a cell phone application (app) designed for hemophilia patients, where they can record bleeding and infusion details and share them with their physician in real time. The implementation of this app in the clinical routine of hemophilia patients promises to improve patient follow-up, enabling treatment at home in a more controlled and autonomous manner. Methods: eSPLORHEM (Evaluation of Spanish experience of using florio HAEMO ediary) is a bispective, observational and multicenter study designed to evaluate the national experience on the use of florio HAEMO for treatment monitoring in hemophilia patients. Hemophilia A and B patients with factor levels <5%, with no other hemostasis problems and who are not participating in a phase 1-3 clinical trial will be included. The effect of the use of the app on adherence to treatment and the annual bleeding rate will be evaluated. Adherence to treatment will be calculated based on the prescribed treatment and concentrates collected at the pharmacy by the patient and ABR will be calculated by the number of bleedings for one year. Quality of life survey data will also be collected through the EQ-5D-5L questionnaire and at the end of the study a survey will be conducted with both patients and clinicians to assess the degree of satisfaction with the use of florio HAEMO. The quality of the documentation recorded in the app will be assessed by comparing the drug stock that the patient picks up at the pharmacy against the number of infusions and the stock recorded. Results: To date, a total of 12 Spanish centers have confirmed their participation and it is estimated that a total of approximately 100 patients will be included. The protocol was approved by the competent authorities in January 2022 and is being implemented in all collaborating centers. The recruitment phase will be open until the end of August 2022, including a retrospective phase since May 2020 in order to include the experience of patients who have already started using the app. The follow-up period will end in August 2023, so that patients will complete a minimum follow-up period of 12 months. Final analysis report is expected to be available in November 2023. Conclusion: The results of this study will provide objective evidence of the effect of the use of florio HAEMO, through clinical parameters such as treatment adherence and ABR, as well as the degree of patient and clinician satisfaction. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AOZORA Study: Interim Analysis of Joint Health in Children with Hemophilia A, without FVIII Inhibitors, 3 Years after Initiating Emicizumab

Background: Progressive joint damage is a common complication of hemophilia A (HA), a condition characterized by excessive bleeding due to missing or inactive coagulation factor (F) VIII. The risk of joint damage in people with HA (PwHA) can be mitigated by prophylaxis. Emicizumab, a bispecific monoclonal antibody that bridges activated FIX and FX to substitute for activated FVIII, is a prophylactic treatment for PwHA, with proven efficacy and a favorable safety profile. However, data on long-term joint health in PwHA receiving emicizumab are sparse. Methods: AOZORA is an ongoing multicenter, open-label, Phase IV study designed to evaluate the long-term safety and effects on joint health of emicizumab over 6 years in pediatric PwHA without FVIII inhibitors (JapicCTI-194701). Eligible participants were aged <12 years old, weighing >3 kg, and diagnosed with severe congenital HA. They entered AOZORA as emicizumab-naïve or following the Phase III HOHOEMI study (Shima et al. Haemophilia 2019) and are receiving emicizumab at an approved dosing regimen. The primary endpoints include evaluation of adverse events (AEs), and joint health and function assessment using magnetic resonance imaging (MRI) and the Hemophilia Joint Health Score (HJHS) version 2.1. MRI evaluation uses the International Prophylaxis Study Group (IPSG) MRI scale; a positive IPSG score indicates pathological changes in the knee and/or ankle joints. Exploratory endpoints include: annualized bleed rates (ABRs) for treated bleeds and treated joint bleeds; activities and activity-related treated bleeds. Full details are in the protocol manuscript (Shima et al. BMJ Open 2022). The AOZORA study has been approved by the Institutional Review Boards of Nara Medical University and the St Marianna University Group. Written informed consent from the legal representative and, where possible, assent from participants ≥3 years old has been obtained. Results: A total of 30 participants have enrolled in AOZORA. This pre-defined interim analysis presents 3-year joint evaluation results of the 10 participants who continued from HOHOEMI. Data cut-off was the last day of Week 145 for each participant. The participants were a median (range) of 5.9 (1.5-10.7) years old and included two under 2 years of age at enrollment (Table 1). No participant had FVIII inhibitors upon entry into HOHOEMI. All participants were previously treated with FVIII prophylaxis. One participant had a target joint. All participants had ≥1 AE during the 3 years of observation (HOHOEMI and AOZORA), including four serious AEs in three participants: post-traumatic pain; soft tissue hemorrhage; and skull fracture and epidural hematoma in the same participant. Only one AE, an injection-site reaction, was related to emicizumab. No thrombotic events or thrombotic microangiopathies were observed. There were no osteochondral changes seen at this interim analysis. Five participants (50%) had no MRI findings at Week 1, which was maintained through Week 145. Five participants (50%) had positive IPSG scores in 13 joints at Week 1: six knee joints and six ankle joints, all with mild effusion/hemarthrosis, and one ankle joint with both mild synovial hypertrophy and mild hemosiderin (Table 2). At Week 145, three (30%) of these five participants' joint health showed improvement as they had no MRI findings in any joint, including the ankle joint with synovial hypertrophy and hemosiderin at Week 1. Two participants (20%) still had positive IPSG scores in three joints: one knee joint and two ankle joints, all with mild effusion/hemarthrosis. In five participants (50%), HJHS was zero between Week 1 and Week 145. Of the four participants with an HJHS of ≥1 at Week 1, three had a score of zero from Week 97 onwards. The participant with synovial hypertrophy and hemosiderin of the ankle joint had an HJHS of zero throughout. Calculated mean ABRs for treated bleeds and treated joint bleeds while receiving emicizumab were 0.6 (95% confidence interval [CI]: 0.0-4.8) and 0.1 (0.0-4.0), respectively. Data on activities will be provided in future analyses. Conclusions: This interim analysis is limited by the small number of participants and relatively short observation period. Nonetheless, these results demonstrate 3-year safety and maintenance or improvement of joint health in 10 children with HA who enrolled in AOZORA following HOHOEMI. Data on all participants will be reported in due course. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Serpinpc in Persons with Severe Hemophilia (PwH): Updated Results from a Multi-Center, Multi-Part, First-in-Human Study

Introduction SerpinPC is a recombinant serine protease inhibitor (SERPIN), whose specificity and kinetics aim to rebalance hemostasis for PwH. SerpinPC is designed to increase the amount of thrombin at sites of tissue damage by reducing the activity level of circulating activated protein C (APC) and thereby prolong the activity of prothrombinase. The normal levels and activity of the zymogen precursor protein C are likely maintained due to SerpinPC's specificity for the active form. Methods AP-0101 is an ongoing first in human open label multicenter study utilizing an adaptive design to investigate the safety, tolerability and pharmacokinetics of subcutaneous doses of SerpinPC in male participants with severe hemophilia A or B (HemA, HemB). Reduction in the annualized bleeding rates (ABRs) was also assessed. AP-0101 consists of 5 parts: Part 1 was a Single Ascending Dose Study completed in 15 healthy male subjects and in 12 male PwH (Part 1b: 0.1 to 1.2 mg/kg, 4 cohorts). All 12 PwH in Part 1b chose to participate in Part 2. Part 2 enrolled 23 male PwH (19 HemA and 4 HemB) who were not on replacement factor prophylaxis to receive SerpinPC at 0.3, 0.6 or 1.2 mg/kg, administered as a subcutaneous injection every 4 weeks over a 24-week period (6 total doses). In Part 3, subjects who completed Part 2 receive a flat dose of 60mg of SerpinPC every 4 weeks for 48 weeks. Part 4 is a further extension in which subjects who completed Part 3 receive 1.2mg/kg of SerpinPC every 2 weeks for 24 weeks. Part 5 is an additional extension in which subjects who complete Part 4 receive 1.2mg/kg of SerpinPC every 2 weeks for a further 52 weeks. ResultsUpdated results from Part 3 and 4 - with an estimated follow-up of 48 and 24 weeks respectively - are expected for presentation at the meeting. In Part 2, one subject with a history of a skin disorder discontinued treatment due to an injection site reaction. No other treatment-related adverse events were observed. There was no reported sustained elevation in D-dimer throughout the 24-week study. Two subjects had anti-drug antibodies and remained on treatment without apparent impact on ABRs. In the highest dose cohort, SerpinPC reduced the self-reported 'all bleeds ABR' by 88% during the pre-specified assessment period as compared with the 'all bleeds ABR' prospectively measured during the pre-exposure observation period. The self-reported spontaneous joint bleeds ABR was reduced by 94%. ABR reductions appeared to be similar between the HemA and HemB subgroups. Conclusions The results from Parts 1 and 2 suggest that SerpinPC was well-tolerated in subjects. Reduction in ABR in Part 2 provides preliminary evidence of activity for SerpinPC as a prophylactic agent in preventing bleeding in PwH. The effects of length of treatment and exposure will be further examined in Parts 3-5. More clinical trials are planned to evaluate the benefit and risk profile of SerpinPC in PwH.

Emicizumab Prophylaxis for the Treatment of Infants with Severe Hemophilia A without Factor VIII Inhibitors: Results from the Interim Analysis of the HAVEN 7 Study

Background: Currently, many infants with severe hemophilia A (HA) do not receive prophylaxis until at least one year of age, due to the challenges of factor (F)VIII administration. Emicizumab enables initiation of prophylaxis from HA diagnosis via subcutaneous administration, and may mitigate the risk of spontaneous and traumatic bleeding, including intracranial hemorrhages. Aims: This interim analysis of HAVEN 7 (NCT04431726) aims to evaluate the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of emicizumab in infants with severe HA without FVIII inhibitors. Methods: HAVEN 7 is a Phase IIIb, multi-center, open-label study of emicizumab in infants ≤12 months with severe HA without FVIII inhibitors. Informed consent from parents/legally authorized representatives and ethics approval have been obtained. Participants receive subcutaneous emicizumab 3mg/kg weekly for 4 weeks, then 3mg/kg every 2 weeks for 52 weeks; at Week 53, participants can continue with this regimen or switch to 1.5mg/kg weekly or 6mg/kg every 4 weeks for the 7-year long-term follow-up period. Efficacy endpoints include the number of treated bleeds; all bleeds; treated spontaneous bleeds; and treated joint bleeds. Annualized bleed rates (ABR) are estimated using a negative binomial regression model. Safety endpoints include adverse events (AEs); thromboembolic events (TEs) and thrombotic microangiopathies (TMAs); and immunogenicity (incidence of anti-drug [emicizumab] antibodies [ADAs]). PK and PD endpoints include plasma trough emicizumab concentration; FIX and FX antigen concentrations; and effect of emicizumab on activated partial thromboplastin time (aPTT), thrombin generation (TG) and FVIII-like activity (measured using a chromogenic assay with human factors). Results: At the interim analysis cut-off date (March 31, 2022), 54 participants (55.6% [n=30] ≥3-≤12 months old; 44.4% [n=24] <3 months) had ≥1 dose of emicizumab; all were male, with a median (range) age of 4.5 (0-11) months. Of these, 30 (55.6%) were minimally treated (≤5 exposure days with hemophilia-related treatments [i.e., FVIII, plasma, cryoprecipitate or whole blood products]) prior to the study, and 24 (44.4%) were previously untreated. Median (range) emicizumab treatment duration was 42.1 (1-60) weeks. Overall, 77 bleeds were reported in 31 participants (57.4%): 88.3% traumatic; 5.2% procedural/surgical; 6.5% spontaneous (Table 1). One participant experienced 12 bleeds (all traumatic; none joint or muscle; none treated). In total, 14 treated bleeds, all traumatic, were reported in 12 participants (22.2%). No intracranial hemorrhage occurred and no participant experienced >2 treated bleeds. Mean model-based ABR (95% confidence interval [CI]) for treated bleeds was 0.4 (0.23-0.65); it was 1.9 (95% CI: 1.35-2.68) and 0.1 (95% CI: 0.01-0.22) for all bleeds and treated joint bleeds, respectively (Table 1). Zero treated bleeds were reported in 77.8% of participants (n=42), while 42.6% of participants (n=23) had no bleeds at all. Fifty participants (92.6%) had ≥1 AE and nine (16.7%) had ≥1 emicizumab-related AE (all injection-site reactions). No AE leading to treatment withdrawal/modification/interruption occurred (Table 2). Eight participants reported 12 serious AEs (SAEs); none was considered emicizumab related. There were no deaths, TEs or TMAs at the time of this interim analysis. PK data were evaluable in 52 participants. Mean trough concentrations of emicizumab increased with loading doses, with concentrations of 63.2µg/mL (95% CI: 59.5-66.8) at Week 5; steady-state concentrations were maintained at 60-65µg/mL thereafter. Emicizumab concentrations were higher than those observed with the same dosing regimen in older people with HA in the HAVEN 1-4 studies (46.7 ± 14.9µg/mL). None of the 48 participants evaluable for immunogenicity analysis tested positive for ADAs. Mean FVIII-like activity increased during loading to 21U/dL and was sustained thereafter. TG peak height increased during loading and continued to increase to reach 100nM from Week 17 onwards. aPTT was normalized by Week 3 (first data point post-baseline) in most participants. Mean FIX and FX concentrations were unaffected by emicizumab. Conclusions: The results of this interim analysis indicate the efficacy and confirm the safety of emicizumab in infants with severe HA without FVIII inhibitors. PK and PD activities were sustained. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mim8 Clinical Development Program: An Overview of the Frontier Studies

Background Mim8 is a bispecific antibody, mimicking activated factor VIII (FVIIIa), currently in clinical development as a treatment for patients with hemophilia A (PwHA), independent of inhibitor status. Preclinical data demonstrate that Mim8 is highly potent with an efficacious hemostatic effect. The FRONTIER program aims to expedite Mim8 development, recruiting participants from >30 countries including women, previously untreated patients (PUPs), and patients with mild/moderate disease severity. FRONTIER 1 (NCT04204408; EudraCT:2019-000465-20), a phase 1/2 study of Mim8 in healthy participants and PwHA, provided proof of concept that Mim8 enables clinically relevant levels of thrombin generation with no safety concerns, and no occurrences of anti-Mim8 antibodies. The study also used biomarker bridging (in vitro and ex vivo) to benchmark against emicizumab. The outcomes from FRONTIER 1 support the further development of Mim8 in the ongoing phase 3 studies (FRONTIER 2 and 3). Methods & Study Design To allow for rapid clinical development, the observational run-in phases of both phase 3 studies were initiated prior to FRONTIER 1 completion (Figure 1A) and are running in parallel. FRONTIER 2 (NCT05053139; EudraCT:2020-001048-24) is an ongoing, open-label, randomized control study investigating the efficacy and safety of Mim8 dosed once-weekly (QW) and once-monthly (QM) in adult and adolescent PwHA (≥12 years of age). The study aims to recruit ~250 PwHA. The primary endpoint is the annualized bleeding rate. Prior to their first Mim8 dose, patients currently on FVIII or bypassing agent prophylaxis will remain on this treatment for ≥26-week observational run-in period (Figure 1B). Patients currently treated on demand with ≥5 bleeds in the 26 weeks prior to screening can join the main phase of the trial without a run-in period. Participants receiving emicizumab must discontinue use and switch to factor prophylaxis when entering the run-in period. Exclusion criteria include planned major surgery, ongoing/planned immune tolerance induction (ITI), and previous or current thromboembolic diseases/events. FRONTIER 3 (NCT05306418; EudraCT:2020-003467-26) is an ongoing, open-label, uncontrolled study investigating the safety of Mim8 in pediatric PwHA (aged 1-11 years). It is targeting recruitment of 70 children with HA with or without inhibitors, who will receive subcutaneous doses of Mim8 QW for 26 weeks. Thereafter, participants can choose between QW and QM prophylaxis regimen for the next 26 weeks (Figure 1B). The primary endpoint is the number of treatment-emergent adverse events during the 52-week treatment period. Key inclusion criteria for FRONTIER 3 include: previously treated patients prescribed FVIII, or by-passing agents, and PUPs with severe HA. Key exclusion criteria are the same as FRONTIER 2. ITI would need to be discontinued prior to joining the trial. To collect further data on the safety and efficacy of Mim8, FRONTIER 1-3 study participants will be invited to join the long-term, open-label extension FRONTIER 4 study. Additionally, plasma samples will be collected from participants with the aim of future exploratory analysis of further biomarkers. Conclusions The FRONTIER studies are a comprehensive clinical development program designed to evaluate Mim8 in PwHA, with or without inhibitors. The FRONTIER 2 and FRONTIER 3 studies initiated recruitment prior to the completion of FRONTIER 1 to accelerate the development of a novel alternative to current HA treatments. Moreover, Mim8 is being investigated in a broad patient population across many different countries and the inclusion criteria were designed to allow for the incorporation of female patients, PUPs, all disease severities, and all ages. This aims to ensure that the study population is as comparable to and representative as possible of the real-world population of PwHA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Vector Analysis of Multicentric Lymphoma in a Severe Hemophilia Α Dog after AAV Gene Therapy

Background Adeno-associated viral (AAV) vector gene therapy for severe hemophilia A (HA) is approaching a clinical reality with multiple successful clinical trials. Despite this success, questions remain about the long-term safety of AAV vectors, especially regarding genomic integration and resulting oncogenesis. Studies of neonatal mice have demonstrated AAV integrations that drive hepatocellular carcinoma formation (Donsante et al. Science, 2007). Studies in HA canine models have also demonstrated AAV integrations and clonal expansion of hepatocytes with integrated vector genomes, but no evidence of tumor formation (Nguyen et al. Nat Biotechnol, 2021). Additionally, three tumors have been reported in AAV gene therapy recipients with HA or hemophilia B in clinical trials, without evidence of vector integrations driving oncogenesis. Though overall reassuring, these data highlight that the field needs to remain vigilant about the possibility of AAV integrations driving cancer development. Thus, the assessment of tumors in gene therapy recipients remains important for the AAV field. Aims To determine the role of AAV vector in the development of multicentric lymphoma in a severe HA dog that received liver-directed gene therapy. Methods Vector genome copy numbers in relevant tissues were determined by real-time PCR with primers situated in the 3'-end of the promoter and the 5'- end of the transgene. The vector copy number was calculated by comparing the analyte amplification signal against a standard curve of the plasmid DNA. Results A privately owned mixed-breed dog (PC9) with a history of recurrent spontaneous bleeding events presented with canine factor VIII (cFVIII) levels <1% normal, consistent with severe HA. At 9-months of age, he received liver-directed AAV8 gene therapy with a high-expressing canine factor FVIII (cFVIII-ΔF/V3) variant transgene at a dose of 6 x 1012 vg/kg via intravenous administration. Following gene therapy, his cFVIII levels increased to 2-3% normal and remained stable through duration of follow-up. His annualized bleeding rate decreased from 8 pre-gene therapy to 0 post-gene therapy. At 3.5 years after vector administration, PC9 was diagnosed with a widely disseminated cancer and euthanized due to complications of the disease. At autopsy, he was diagnosed with multicentric lymphoma involving peripheral and visceral lymph nodes, spleen, liver, and lungs. The average age of lymphoma diagnosis in dogs is between 6-9 years of age (Edwards et al. Vet Comp Oncol, 2003), so the development of cancer at an early age in a gene therapy recipient warranted additional study. Vector copy number analysis showed that the liver had the highest levels of AAV vector genomes, as expected. Liver samples showed a heterogenous distribution of vector genomes, consistent with previous studies of AAV8 transduction (Bell et al. Hum Gene Ther, 2011). Splenic samples also had a high level of AAV vector genomes, which again is consistent with known targeting of AAV8. Importantly, the lymph nodes had no detectable AAV vector genomes present, suggesting that vector integration could not contribute to lymphoma development. cFVIII levels remained stable before and after diagnosis of lymphoma, supporting lack of vector integration in the malignant cells. Conclusions AAV gene therapy resulted in a 100% reduction in the annualized bleeding rate in this pet dog with severe HA. Furthermore, the multicentric lymphoma that developed 3.5 years after liver-directed gene therapy is unlikely related to the AAV vector. We are unable to rule out other factors that may have contributed, including environmental influences or genetic predispositions for lymphoma. These results support the ongoing efforts to treat HA with AAV-based gene therapy and reinforce the safety profile of AAV vectors outside of a laboratory environment.

AAV8 Gene Therapy for Hemophilia A Patients from China

Background Treatments of hemophilia A patients by adeno-associated virus (AAV) based delivery of coagulation factors VIII (FVIII) have shown great promise, with multiple clinical trials be conducted currently. However, to ensure enough expression level of FVIII, the dosages of AAV capsids are relatively high (up to 6E13vg/kg) in these trials. High dosages of AAV capsid carry the potential risk of toxicity, raise the possibilities of host immune response and increase the economic burden for patients. Besides, the sustainability of efficacy is also a challenge. Current gene therapies showed that the level of FVIII gradually decreased over time. Hence, it is necessary to explore a gene therapy with high expression level of FVIII and sustained efficacy. GS001, an rAAV8 vector expressing B domain deleted FVIII was developed. In the preclinical study, high level of FVIII activity (FVIII:C) (155 IU/dl) was achieved when the hemophilia A mice received a single infusion of GS001 at a dose of 1.1E11 vg/kg. Toxicity studies in monkeys showed good tolerance at the dose of 2E13 vg/kg. Based on these preclinical data, GS001 was investigated in clinical trial for hemophilia A gene therapy. The purpose is to evaluate the safety and efficacy of GS001 in Chinese hemophilia A patients and obtain clinical data for further study. Method We enrolled Chinese hemophilia A patients (> 18 years) whose baseline FVIII:C was < 1 IU/dl without FVIII inhibitor. All subjects had low titer of neutralizing antibodies (Nab) (≤1:5) against the vector capsid. Eligible participants received a single intravenously infusion of GS001 with a dose of 2E12vg/kg after one week of prophylactic prednisone treatment or prednisone and tacrolimus treatment. The primary endpoint was safety including treatment-related adverse events (AEs), change of alanine aminotransferase (ALT) and antibodies against the vector capsid. Enrollment is now ongoing. This study was registered at ClinicalTrials.gov, NCT04728841. Results Six patients were enrolled. The first three patients (patients 1 to 3) were infused with GS001 after one week of prophylactic prednisone treatment. The mean follow-up time were 397±52 days. FVIII:C level reached the peak around seven weeks post infusion. After that, the FVIII:C decreased with the elevation of ALT, and the decrease trend was improved after treatment with tacrolimus. Patients 4 to 6 were infused with GS001 after one week of prophylactic prednisone and tacrolimus treatment. The mean follow-up time were 49±8 days. The FVIII:C level quickly reached peak level in the first week compared to the first three participants. No rising trend of ALT was found. The mean annual bleeding rates (ABR) and the factor VIII usage for all the six participants decreased dramatically after GS001 infusion. There were totally 55 AEs, with 54 AEs were grade 1(54 AE) and only one was grade 2 which was not related to GS001. Twenty-two (40%) AEs were possibly related to the immunosuppressant therapy, only 12.7% of the AEs (7/55) was possibly related to GS001. No severe adverse events have been observed. None of the six participants had developed a FVIII inhibitor. Conlcusions This pilot study demonstrated the safety and tolerance of GS001. Vector derived FVIII:C level was sufficient to prevent bleeding events and minimize the need for replacement therapy. Prophylaxis treatment of tacrolimus combined with prednisone could be an effective immunosuppressive regimen against the vector capsid in gene therapy for hemophilia A patients. These findings support further studies.

Usefulness of Emicizumab Associated with Immune Tolerance Induction in Patient with Hemophilia a and Inhibitors: Experience in Cuenca-Ecuador

Background: Referring to the World Federation of Hemophilia (WFH) 2020 Annual Global Survey Report published in October 2021: In Ecuador, with a population of 17,643,060 inhabitants, there are 1,708 cases of hemophilia, 99 cases of Von Willebrand disease, and 7 cases of other coagulation disorders. Within the hemophilia A group, 21 patients have active inhibitors, and there is a record of 2 new cases of inhibitors in relation to the previous notification. Emicizumab is a bispecific, humanized monoclonal antibody that binds activated FIX and factor X (FX) resulting in the generation of activated FX (FXa) which then catalyzes the formation of thrombin from prothrombin. Based on the HAVEN 1-4 clinical trials, the FDA and EMA approved the use of Emicizumab as prophylaxis in Hemophilia A (with and without inhibitors) in both adults/adolescents (>12 years) and pediatrics (<12 years). In both the primary analyzes and long-term follow-up, emicizumab produced statistically and clinically significant reductions in annual bleeding rates compared with Factor VIII prophylaxis (in patients without inhibitors); and with bypassing agents (in patients with inhibitors). These trials excluded patients in immune tolerance (ITI). Keywords: emicizumab, immune tolerance, hemophilia. Objectives: -Assess the usefulness of Emicizumab in immune tolerance in terms of bleeding control, osteoarticular health and functional activity Materials and Methods: 1) The evaluation was carried out in a 9-year-old patient (boy) with severe Hemophilia A and high titer inhibitors who, prior to the start of ITI, had predictive factors of high risk and poor prognosis (historical peak 234 UB, 5 years since inhibitor screening) with 4-8 joint bleeds per year. The ITI scheme used was with plasmatic Factor VIII 100 IU/Kg 3 times a week with management with bypass agents on demand (ITI duration: 3 years) and inclusion of emicizumab 2 years after starting the strategy 2) The analysis was determined based on periodic clinical evaluations, osteoarticular status was assessed through the Hemophilia Joint Health Score 2.1 (HJHS), Disease Activity Score (DAS28); and functional activity through Functional Independence Score in Hemophilia (FISH), and Health Assessment Questionnaire (HAQ). An analysis was made prior to the start of immune tolerance and after reaching immunological tolerance. Results: 1) This strategy contributed to better control of joint bleeding, and therefore to the inhibitor eradication process. 2) Improved the evolutionary course of his osteoarticular state: - Prior to ITI: DAS28: 4.26 (moderate activity), HJHS 33. Target joints: left knee and ankle. - After immunological tolerance: DAS28: 1.87 (clinical remission), HJHS 12. 3) Favorable progression of his functional status, despite slight limitation of his left knee in flexion (sequel to recurrent episodes of hemarthrosis): - Prior to the start of ITI: FISH 14, HAQ: 1.50 (severely affected functional capacity), functional scale IV (use of a wheelchair). - After immunological tolerance: FISH 27, HAQ: 1.00, functional scale II (able to carry out activities of daily living with slight difficulty). Conclusions: 1) Larger-scale studies and accumulated evidence are needed that allow us to establish the usefulness of Emicizumab in ITI and therefore corroborate these results. 2) We must establish the best clinical application profile and the economic impact of these therapies; especially in health systems like ours, in which accessibility to drugs is complex and optimization of resources is the norm. Bibliography: 1. Alvarez Roman M: Guías Españolas para el manejo de la hemophilia. 2022, 1-190. 2. Callaghan M, Negrier C, Paz-Priel I, Chang T, Chebon S y col: Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. 2021;137(16):2231-2242 3. Carcao M, Escurriola C, Santagostina E, Oldenburg J, Liesner R y col: The changing face of immune tolerance induction 3. Hematology Am Soc Hematol Educ Program. 2021, Dec 10;2021(1):219-225. 4. Young G: Management of children with hemophilia A: How emicizumab has changed the landscape. Journal of Thrombosis and Haemostasis. 2021 Jul;19(7):1629-1637 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal