Mean Annualized Bleeding Rate Research Articles

Bleeding phenotype according to factor level in 825 children with nonsevere hemophilia: data from the PedNet cohort

BackgroundInformation on bleeding phenotype in nonsevere hemophilia may be used to determine target factor levels for prophylaxis or gene therapy in severe hemophilia. ObjectivesTo assess the association between endogenous factor level and bleeding phenotype in children with nonsevere (factor [F]VIII/FIX activity 1%-25%) hemophilia A (HA) and B without prophylaxis. MethodsData on annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and onset of bleeding were extracted from the international PedNet cohort including children born since 2000. Mean ABR and AJBR were modeled and compared according to FVIII/FIX endogenous activity (1%-2%, 3%-5%, 6%-10%, 11%-15%, 16%-20%, and 21%-25%) using negative binomial regression. Onset of bleeding was analyzed using Kaplan–Meier survival curves. ResultsEight hundred twenty-five children (40% with moderate hemophilia; 87% with HA) with median follow-up of 7.4 years/child were included. The median age at onset of bleeding and median bleeding rates changed with increasing endogenous activity. From endogenous FVIII 1% to 2% to 21% to 25%, the age at onset of bleeding changed from a median of 1.4 to 14.2 years, ABR from 1.6 to 0.1/y, and AJBR from 0.5 to 0.0/y. From endogenous FIX 1% to 2% to 16% to 25%, the onset of bleeding changed from a median of 1.7 to 6.1 years, ABR from 0.5 to 0.1/y, and AJBR from 0.1 to 0.0/y. The negative correlation between AJBR and factor level was most strongly pronounced up to a factor level of 6% in HA and hemophilia B. ConclusionEndogenous factor activity of >5% was identified as a threshold to significantly lower joint bleeding rate, while FVIII levels >15% and FIX levels >10% were sufficient to achieve the goal of 0 bleeds in this pediatric cohort.

Comparative Effectiveness of Valoctocogene Roxaparvovec and Prophylactic FactorVIII Replacement in Severe HemophiliaA.

A prospective, non-interventional study (270-902) followed 294 adults with severe hemophiliaA (SHA) receiving prophylactic factorVIII (FVIII). From these participants, 112 rolled over into a single-arm, multicenter, phase3 trial (GENEr8-1; NCT03370913) that evaluated efficacy and safety of valoctocogene roxaparvovec, a gene therapy that provides endogenous FVIII in individuals with SHA. Participants from 270-902 who did not roll over provide an opportunity for a contemporaneous external control. Therefore, the comparative effectiveness of valoctocogene roxaparvovec vs FVIII prophylaxis was evaluated using propensity scoring (PS). This posthoc analysis compared 112 participants from GENEr8-1 (treated cohort) to 73 participants in 270-902 who did not enroll in GENEr8-1 (control cohort). The primary analysis used standardized mortality ratio weighting to re-weight baseline characteristics of the control cohort to better match the treated cohort. Mean annualized bleeding rates (ABR) for treated and all bleeds were compared between cohorts along with the proportion of participants with zero bleeds (treated and all bleeds). Sensitivity and scenario analyses were also conducted. PS adjustments reduced differences in baseline characteristics between cohorts. Mean treated (4.40 vs 0.85; P < 0.001) and all (5.01 vs 1.54; P < 0.001) ABR were significantly lower, and the proportions of participants with zero treated bleeds (82.1% vs 32.9%; P < 0.001) and all bleeds (58.0% vs 28.5%; P < 0.001) were significantly higher in GENEr8-1. PS-adjusted analyses were consistent with prior intra-individual comparisons. Compared with participants receiving prophylactic FVIII, the participants receiving valoctocogene roxaparvovec experienced lower ABR, and a higher proportion had zero bleeds. ClinicalTrials.gov identifier, NCT03370913.

Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A

BackgroundValoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection. ObjectivesTo present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial. MethodsGENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate, annualized FVIII utilization, FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Safety was assessed by adverse events (AEs). ResultsAt week 156, 131 of 134 participants remained in the study; overall, 17 of 134 resumed prophylaxis. Mean annualized bleeding rate for treated bleeds decreased from 4.8 (SD, 6.5) bleeds/y at baseline to 0.8 (SD, 2.3; P < .0001) bleeds/y after prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/y during year 3. Annualized FVIII utilization decreased 96.8% from baseline after prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2 and 3 than between years 1 and 2. At the end of year 3, clinically meaningful improvements in the Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score were observed (mean change from baseline, 6.6; 95% CI, 4.24-8.87; P < .0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment. ConclusionHemostatic efficacy was maintained, and safety remained unchanged from previous years.

Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial

AbstractFitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871.

Experience with Emicizumab Among People with Hemophilia A in the Canadian Hemophilia Bleeding Disorders Registry

Background: The use of emicizumab as prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes in congenital hemophilia A (HA) was approved by Health Canada for the treatment of people living with HA (PwHA) with FVIII inhibitors in 2018, and without inhibitors in 2019. Here we present the results of a non-interventional, cohort study, using data routinely collected by the Canadian Bleeding Disorders Registry (CBDR) to evaluate treatment patterns of emicizumab in Canada and the associated safety and effectiveness outcomes, including quality of life. Methods: De-identified data were extracted from the CBDR database for all registered PwHA who had received emicizumab at least once prior to December 31, 2022. Baseline demographic characteristics were stratified by disease severity (defined by the level of endogenous FVIII activity) and age. Effectiveness 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. Intra-patient comparisons of bleeding were performed for all patients and for those with at least six months follow-up in both pre- and post-emicizumab periods as a sensitivity analysis. Effectiveness 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. 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, 533 PwHA received at least one dose of emicizumab (PwHA E) in the CBDR database. Overall, 498 (93.4%) PwHA E had severe disease, 28 (5.3%) had moderate disease, and 7 (1.3%) had mild disease. At start of emicizumab exposure, 220 (41.3%) PwHA E were &amp;lt;18 years old; 78 (14.6%) PwHA E had current FVIII inhibitors, 82 (15.4%) had a history of FVIII inhibitors, and 373 (70%) had no history of inhibitors ( Table 1). A total of 13 adverse events were reported in the entire observation period, including one event of thrombosis (occurring in one person with COVID-19), seven allergic reactions, two FVIII Inhibitor development, two neurological events (headache; and headache, nausea, and vomiting) and one case of large hematoma developed at operative site following removal of port-a-cath. Moreover, nine COVID-19 cases were reported as adverse events. Over a median (first quartile, third quartile) follow-up time of 249 (136, 395) days, 388 (72.8%) PwHA E had no recorded bleeds. Out of 145 PwHA E with recorded bleeds, 106 had joint bleeds, 87 had traumatic bleeds, 69 had spontaneous bleeds and 46 had other bleeds (Table 2). An intra-patient comparison in all PwHA E (n=533) showed a decrease in mean (95% confidence interval [CI]) annualized bleeding rate (ABR) from 1.22 (1.06, 1.42), pre-emicizumab (2018, prior to first dose) to 0.50 (0.41, 0.60) post-emicizumab (rate ratio (95% CI) 0.41 (0.33, 0.50), p-value &amp;lt;0.001). The Intra-patient comparison in PwHA E without current inhibitor (n=455) showed a decrease in mean ABR (95% CI) from 1.02 (0.87, 1.19) to 0.54 (0.44, 0.66) (rate ratio (95% CI) 0.53 (0.43, 0.65), p-value &amp;lt;0.001). The Intra-patient comparison in PwHA E with current inhibitor (n=78) showed a decrease in mean ABR (95% CI) from 5.03 (3.30, 7.66) to 0.41 (0.26, 0.65) (rate ratio (95% CI) 0.08 (0.04, 0.15), p-value &amp;lt;0.001). Conclusions: This analysis describes the baseline characteristics, safety and effectiveness outcomes of Canadian PwHA treated with emicizumab before December 31, 2022. A total of 387 new patients were included in this analysis compared to the previous one (data cut: December 31, 2021, n=146). The data shows that 72.8% PwHA E had no recorded bleeds since they started emicizumab and that there was a substantial decrease in bleeds post-emicizumab in both PwHA with and without current FVIII inhibitor. The safety profile of emicizumab was consistent with previous reports. The CBDR allows for a longitudinal follow-up of the Canadian hemophilia A population, which can inform healthcare practitioners and regulatory authorities of the safety and efficacy outcomes of treatments in routine clinical practice.

Adult Patients with Hemophilia B and with a History of Chronic HCV/HBV Infection Receiving Liver-Directed Gene Therapy Demonstrated Long-Term Bleeding Protection and Sustained FIX Activity: Efficacy and Safety Results from the HOPE-B Trial 3 Years after Administration of a Single Dose of Etranacogene Dezaparvovec

Introduction: Liver-targeted recombinant adeno-associated virus (rAAV) gene therapy for hemophilia B has recently become a real-world therapeutic option for an adult population burdened with prevalent co-morbid chronic hepatitis C virus (HCV) and hepatitis B virus (HBV). The pivotal phase 3 HOPE-B trial (NCT03489291) evaluated the efficacy and safety of etranacogene dezaparvovec (CSL222, formerly AMT-061), an AAV5 vector, containing a codon-optimized, highly active factor IX (FIX) Padua R338L transgene under the control of the liver-specific promoter LP-1. Here we evaluate the efficacy and safety of etranacogene dezaparvovec in the subset of HOPE-B participants with a history of chronic HCV and/or HBV. Methods: Adult male participants with hemophilia B (FIX ≤2%), were infused with a single dose of etranacogene dezaparvovec (2x10 13 gc/kg), following a ≥6-month lead-in period receiving their usual FIX prophylaxis. Relevant exclusion criteria included baseline liver chemistries &amp;gt; 2X the upper limit of normal (ULN); active HCV (HCV RNA detectable), HBV (HBV DNA detectable or HBV sAg reactive) or uncontrolled HIV infection; or advanced liver fibrosis (FibroScan™ score of ≥9 kPa). Regular liver ultrasound screening, serum chemistries, and alphafetoprotein (AFP) were collected along with FIX expression and bleeding data. During the first months post-treatment, alanine aminotransferase (ALT) increase to 2X the subject's baseline or &amp;gt;ULN was treated with a per-protocol tapering course of oral corticosteroids. Results: Among 54 HOPE-B trial participants, 31 (57.4%) had history of co-morbid chronic HCV, without active disease and with undetectable HCV RNA. Of these 31 subjects, 7 had a history of chronic HBV infection without active disease (HBV DNA undetectable; HBV sAg neg). Two subjects were HCV/HIV co-infected (HIV DNA neg; CD4+ T-cell count &amp;gt;200). Two subjects were HBV+ (HBV env AB reactive, HBV sAg non-reactive, HBV DNA undetectable)/HCV-/HIV-. The mean age in the HCV+ and/or HBV+ subgroup (HCBV n=33) was 50.0 years (range 31-75). All HCBV participants had central lab (CL) ALT &amp;lt;ULN (ULN=41 U/L) on the day of dosing except one subject who had a CL ALT of 48 U/L. The mean screening fibroscan (liver elastography) score for this subgroup was 5.2 kPa (range 2.8-8.0). In HCBV participants 16/33 (48.5%) had pre-existing AAV5 neutralizing antibodies (NAb), with titers ranging from 8.5-3232; all NAb+ HCBV patients had titer ≤678 except one participant who had a titer of 3212 and never demonstrated FIX expression; as a result his prophylactic FIX infusions were never discontinued and his efficacy outcomes reflect exogenous FIX therapy. One HCBV participant returned to continuous routine prophylaxis 30 months post treatment. In the HOPE-B trial 11/54 (20.4%) of participants had 12 adverse events of ALT elevation of 2X above baseline or &amp;gt;ULN within 12 weeks after etranacogene dezaparvovec treatment, which triggered immunosuppressive therapy with corticosteroids in 9/54 (16.7%) participants. In the HCBV subgroup, 5/33 (15.2%) participants had ALT elevations of which 4/33 (12.1%) participants received corticosteroids. As reported previously (Schmidt M, et al. Blood Advances. 2023), one HCBV subject maintained normal AFP levels however per-protocol screening ultrasound at one year after gene therapy this participant developed a hepatocellular carcinoma (HCC); molecular characterization demonstrated the HCC was not related to etranacogene dezaparvovec treatment. Factor IX expression was stably increased above baseline throughout 36 months after the single CSL222 infusion. History of chronic HCBV did not impact FIX expression (Table 1). After excluding the subject with the pre-existing AAV5 NAb titer 3212 whose continued prophylaxis use confounds analysis, the mean annualized bleeding rate (ABR) decreased after gene therapy compared to lead-in standard of care FIX prophylaxis. HCBV participants demonstrated an ABR rate ratio of 0.31 (95% CI 0.13, 0.72) indicating 69% reduction in all bleeding, sustained from months 7-36 following etranacogene dezaparvovec treatment. Conclusions: The majority of HOPE-B trial participants were adults with a history of chronic HCV and/or HBV infection without active viral disease or evident pre-existing liver fibrosis. Safety and efficacy are observed in the HCBV participants.

Efficacy of Regular Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate in Reducing Nose Bleeds in Children and Adults with Von Willebrand Disease

Background: The use of a von Willebrand factor (VWF) concentrate for long-term prophylaxis is recommended for individuals with von Willebrand disease (VWD) who have a history of frequent and severe bleeds, regardless of their age or the type of VWD. Bleeding from the nose (epistaxis) is one of the most common types of bleeding in VWD patients. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (wilate ®) in adults and children with VWD of all types. The primary endpoint was met, showing a decrease of 84% in the mean total annualized bleeding rate (ABR) compared with prior on-demand treatment. Aims: To investigate the efficacy of regular prophylaxis with a pdVWF/FVIII concentrate in reducing nose bleeds in people with VWD, compared with previous on-demand treatment. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years with VWD type 1 (VWF:RCo &amp;lt;30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a VWF-containing product during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 bleeding episodes, excluding menstrual bleeds, of which ≥2 were treated with a VWF-containing product, were eligible to enter WIL-31. Patients in WIL-31 received regular prophylaxis with pdVWF/FVIII 2-3 times per week at a dose of 20-40 IU/kg for 12 months. In this post-hoc analysis, nose bleeds during WIL-29/-31 were described, and the mean ABRs were compared. Results: The study population included 33 patients with a median (range) age of 18 (7-61) years; 9 (27.3%) patients were 6-11 years old, 6 (18.2%) were 12-16 years old, and 18 (54.5%) were ≥17 years old. All VWD types were represented: type 1 (n=6), type 2 (n=5); and type 3 (n=22). There were 173 breakthrough bleeds in total during WIL-31, of which nose bleeds were the most common (89/173; 51.4%). Nose bleeds occurred in 16 of 33 patients during prophylaxis vs 26 of 33 during on-demand treatment. Of the 89 nose bleeds, 17 were traumatic, 69 spontaneous, and 3 due to allergic reaction (not product related). The mean number of spontaneous nose bleeds per patient during prophylaxis was 2.1, 2.3, 1.2, and 2.2, for the overall population, and the 6-11, 12-16, and ≥17 years age groups, respectively. Eight nose bleeds (9.0%) were major (all in the same patient). The mean nose ABR was reduced by 76% during prophylaxis vs on-demand treatment. The reduction was consistent across age groups (74-77%, Figure 1) but not across VWD types, with mean nose ABR reductions of 48, 89, and 80% for VWD type 1, type 2, and type 3 patients, respectively. During prophylaxis, a higher number of VWD type 3 patients, compared with type 1 and type 2 patients, experienced nose bleeds (12 vs 3 vs 1). The mean duration of nose bleeds decreased during prophylaxis vs on-demand for 12-17 years old, ≥17 years old, type 2 and type 3 VWD patients, but increased for 6-11 years old and severe type 1 patients. No relationship was observed between the number of nose bleeds and patient age (R 2=0.082). The majority (80.9%; 72/89) of nose bleeds were treated with pdVWF/FVIII with 86.1% (62/72) requiring only a single infusion; two required concomitant treatment with tranexamic acid. All treated nose bleeds were rated as “successfully treated”. Conclusion: The data indicate thatprophylaxis with pdVWF/FVIII was effective at reducing nose bleeds in patients with VWD type 2 and 3, and across all age groups.

Efficacy and Safety of the Anti-Tissue Factor Pathway Inhibitor Marstacimab in Participants with Severe Hemophilia without Inhibitors: Results from the Phase 3 Basis Trial

Background:Marstacimab (PF-06741086) is a monoclonal antibody targeted to the tissue factor pathway inhibitor protein to improve hemostasis via the extrinsic pathway of blood coagulation. Previous phase 1/2 studies demonstrated the efficacy and safety of long-term administration of marstacimab up to 450 mg weekly for reducing bleeding episodes in adults with severe hemophilia A (HA) or hemophilia B (HB), with or without inhibitors, compared with on-demand (OD) therapy. We evaluated the efficacy and safety of marstacimab in participants with severe HA or moderately severe to severe HB without inhibitors compared with previous factor replacement therapy. Methods: BASIS (NCT03938792) is an open-label, multicenter, pivotal phase 3 study that enrolled male participants aged ≥12 to ˂75 y with severe HA (factor [F] VIII ˂1%) or moderately severe to severe (FIX ≤2%) HB, with or without inhibitors. Following screening, participants entered a 6-month observational phase (OP) and were categorized by factor replacement treatment: (1) OD or (2) routine prophylaxis (RP). Participants who completed the OP crossed over to 12-month active treatment phase (ATP) and received a single subcutaneous loading dose of 300 mg followed by once weekly 150 mg marstacimab. Primary endpoints were annualized bleeding rate (ABR) for treated bleeds and safety outcomes. Secondary endpoints included incidence of various types of breakthrough bleeds and health-related quality of life (HRQoL) measures. Participants who completed the ATP were eligible to enroll in the long-term extension (LTE) study. Informed consent/ethics committee approvals were obtained. Results for participants without inhibitors are presented. Results: Participants (N=128; 108 adults, 20 adolescents) with HA or HB without inhibitors entered the OP (OD: HA n=29, HB n=8; RP: n=72, HB n=19); of these, 116 entered the ATP. The median age was 30 [range, 13-66] y, most participants were White (50.8%) or Asian (47.7%) and predominately from Europe and India (51.6%). At baseline, 89 participants (69.5%; OD: n=36; RP: n=53) had ≥1 target joint. Mean (range) duration of marstacimab treatment was 12.1 (11.5-13.1) months for OD and 11.6 (0.9-12.8) months for RP. Eighty-eight participants entered the LTE (OD: HA n=22, HB n=7; RP: HA n=45; HB n=13). Data were not available by the cutoff date for 1 RP participant and was not included in the LTE safety analysis set. The mean (range) treatment duration in the LTE was 8.0 (1.2-14.5) months for OD and 6.5 (1.1-16.1) months for RP. In the phase 3 study, the OD group reported 12 (36.4%) adverse events (AEs) during ATP vs 9 (24.3%) in OP whereas the RP group reported 62 (74.7%) AEs in ATP vs 20 (22.0%) in OP. Both groups reported more treatment-related AEs during ATP ( Table 1). ADAs developed in 23/112 participants (20.5% incidence), of which titers were low and resolved in 22 participants by end of study. One RP participant discontinued due to a non-treatment-related SAE, and no deaths or thromboembolic events were recorded in the phase 3 study or the LTE. Mean (95% CI) ABR for treated bleeds was reduced for OD (91.6% [88.1-94.1%]) and RP (35.2% [5.6-55.6%]) participants over the 12-month ATP and marstacimab demonstrated superiority vs OD (P&amp;lt;0.001) and non-inferiority and superiority vs RP (P=0.0376) therapy. Marstacimab was also associated with significant reductions in ABR across all breakthrough bleed categories vs OD, and numerical reductions vs RP (non-inferiority). Overall, mean ABR declined over the first 6 months of ATP, which continued to Month 12 (data not shown). Bleed rates for an additional 16 months of follow-up in the LTE were consistent with those observed during the first 12 months of treatment in the phase 3 study ( Table 2). The ABR reductions observed with marstacimab during ATP were consistent across hemophilia types and age groups for OD and were generally consistent across hemophilia types and age groups for RP, with all point estimates for a difference &amp;lt;2.5 (non-inferiority margin for the ABR of treated bleeds). HRQoL parameters demonstrated non-significant improvements vs OD therapy and non-inferiority vs RP therapy. Conclusion: Compared with previous OD or RP therapy, once weekly subcutaneous marstacimab was safe and effective for reducing bleeding events in participants with severe HA or moderately severe to severe HB without inhibitors beyond 12 months in the phase 3 study and up to an additional 16 months in the LTE study.

Emicizumab Efficacy in Severe Hemophilia (A): Experience in Ecuador

Introduction: In Ecuador, there are 1708 cases of hemophilia in a population of 17,643,060 habitants; according to the World Federation of Hemophilia (WFH) Annual Global Survey Report 2020 released in October 2021. Eleven patients use emicizumab in Ecuador (ten patients under ministerial authorization, and one patient through private insurance); being the first administered in June 2021. Objectives: To describe the demographic characteristics of patients receiving emicizumab in Ecuador. To determine efficacy and response with emicizumab: based on annual bleeding rate (ABR), performance status assessment, activity, and participation. Methods: Population: Pediatric Severe Hemophilia A (PwHA) patients (&amp;lt;12 years) and adults/adolescents (&amp;gt;12 years), both from the public and private health sector. Study design: Retrospective, multicentric study, with a case-report research design. The sources of information were the medical records of the patients. Efficacy variables: ABR was calculated by: (number of bleeds/number of days times 365.25). Body structure and function was assessed with the Hemophilia Joint Health Score 2.1 (HJHS). Activity and participation were assessed with the Functional Independence Score in Hemophilia (FISH). Statistic analysis: Shapiro-Wilk test to know the distribution of the sample, t-Test paired tests (parametric), Wilcoxon statistic (non-parametric); Descriptive statistics: relative frequencies, measures of central tendency and dispersion, column graphs. Analysis and results: Ten patients with an average (Q1,Q3) age of 11.5 years (7.15) were registered. The youngest patient was one year old and the oldest, fifty years old. 90% (n:9) had hemophilia A with high-response inhibitors. Prior to starting emicizumab: 20% (n:2) presented Central Nervous System bleeding, 30% (n:3) had muscle bleeding, and 10% (n:1) developed catheter-associated infection. The mean ABR was 10 pre-emicizumab events, and 0.3 post-emicizumab events (p=0.002), with follow-ups at 22 months (n: 2), 17 months (n:2), 3 months (n:2 ), 4 months (n: 3), 5 months (n: 1). The mean HJHS (±SD, n) was 20.9 (± 20,096, 10) pre-emicizumab, and 9.7 (± 16.52, 10) (p=0.003) The mean by FISH (±SD, n) was 16.2 (± 8.59, 10) pre-emicizumab, and from 22.6 (± 11.62, 10) with the use of emicizumab. The use of the t-Test for paired samples determined that there are statistically significant differences between the pre-emicizumab and post-emicizumab groups for the variables ABR, HJHS and FISH (95% confidence level). Conclusion: The use of Emicizumab allowed better control of joint bleeding; and it contributed favorably in the evolutionary course of both the functional state and the activity. It is essential to corroborate these results with a longer follow-up and a larger sample size. Bibliography: 1. Alvarez Roman M: Spanish guidelines for the management of 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. Blood. 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 in haemophilia A with the advent of emicizumab. Haemophilia. 2019;25:676-684. 4. Ellsworth P, Ma A: Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates?. Hematology Am Soc Hematol Educ Program. 2021, Dec 10;2021(1):219-225. 5. 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

Post-Immune Tolerance Induction Prophylactic FVIII Infusions May Not be Necessary for Tolerized Hemophilia a Patients on Emicizumab

Background: Hemophilia A is a hereditary bleeding disorder characterized by low factor VIII (FVIII) activity. Patients with severe bleeding phenotypes are at risk for significant bleeding-related morbidity and mortality including the development of hemophilic arthropathy. In recent years, prophylaxis with emicizumab, a bispecific monoclonal antibody, has supplanted prophylactic FVIII infusions due to its ease of self-administration, long half-life, and low annual bleeding rate (ABR), independent of tolerization status to alloantibodies against FVIII (inhibitors). However, it is unclear if emicizumab FVIII-mimic activity is sufficient to achieve hemostasis in moderate-severe bleeds, and therefore, FVIII replacement may still be necessary. Despite its well-established benefits, the use of emicizumab in previously untreated patients (PUPs), and patients with under 20 exposures to FVIII is still not well understood due to a lack of long-term experience and understanding of its impact on the pathophysiology of FVIII inhibitors. Further investigation is also needed regarding the risk of inhibitor recurrence in patients with previous inhibitors and the concomitant use of emicizumab. At our institution, patients on emicizumab with a history of inhibitors do not continue post-immune tolerance induction prophylactic FVIII infusions. We also initiate emicizumab before 20 exposures to FVIII, and sometimes before immune tolerance induction (ITI). We explored our patient population to understand inhibitor incidence and recurrence amidst emicizumab prophylaxis. Methods: We performed a single center retrospective analysis of patients served by the Hemophilia Center of Western Pennsylvania. We identified patients with Hemophilia A on emicizumab prophylaxis. Relevant data was collected including demographics, inhibitor status at time of transition to emicizumab and in the available follow-up period, bleeding events after transition, and number of FVIII exposures before and after transition. Inhibitor recurrence was defined as laboratory evidence of inhibitor using chromogenic Bethesda assay and/or unexplained breakthrough bleeding events despite on-demand FVIII infusions. Results: Data was reviewed for 36 patients on emicizumab prophylaxis. Three patients were lost to follow-up. Median age was 15.3 years (range 1.2 - 82). Median follow-up time on emicizumab was 3.5 years (range 0.5 - 5). Two patients had &amp;lt; 20 FVIII exposures prior to emicizumab, and one of those had an inhibitor before emicizumab. In total, 15 patients (45%) were diagnosed with an inhibitor prior to emicizumab. Of these, 8 patients (53%) were tolerized prior to emicizumab, and 7 patients (47%) were not tolerized prior to emicizumab. Median peak inhibitor titer was 4.2 Bethesda units (range 0.7 - 281 Bethesda units). After transition to emicizumab, no tolerized patients for which inhibitor status was tested during the follow-up period had inhibitor recurrence, and 1 non-tolerized patient's inhibitor became undetectable after 4 years of emicizumab therapy (the same patient who had developed an inhibitor with &amp;lt; 20 FVIII exposures prior to emicizumab). Mean ABR was 0.33 events/year for tolerized patients (median 0, range 0 - 3); 0.17 events/year for non-tolerized patients (median 0, range 0 - 1); and 0.60 events/year for patients with no history of inhibitor (median 0, range 0 - 4). Mean number of FVIII exposures per year was 0.09 for tolerized patients (median 0, range 0 - 1); 0.07 for non-tolerized patients (median 0, range 0 - 1); and 1.2 for patients with no history of inhibitor (median 0, range 0 - 20). Conclusion: In our small cohort, no patient who was tolerized prior to emicizumab had recurrence of clinical or laboratory evidence of inhibitor while on emicizumab therapy, despite infrequent exposure to FVIII infusion. We did not have enough power to determine whether patients with &amp;lt; 20 FVIII exposures before emicizumab developed inhibitors, though one such patient had inhibitor resolution on emicizumab without ITI. Consistent with other works, overall ABRs in all patients on emicizumab therapy were low. These findings add to other studies on the safety of emicizumab and its impact on the natural history of FVIII inhibitors. Our study also suggests that continuing post-ITI prophylactic FVIII infusions in tolerized patients on emicizumab may not be necessary. Larger-scale studies are required to substantiate our findings.

Stable Therapeutic Transgenic FIX Levels for More Than 10 Years in Subjects with Severe Hemophilia B Who Received scAAV2/8-LP1-Hfixco Adeno-Associated Virus Gene Therapy

Background: Previously, we reported data from a first-in-human, dose-escalation, Phase 1 gene therapy trial demonstrating a dose-dependent increase in transgenic factor IX (FIX) expression in 10 adults with severe hemophilia B (FIX activity ≤1%). This was achieved following a single intravenous infusion of a self-complementary adeno-associated virus (scAAV) vector containing the wild-type FIX gene (codon-optimized), under the control of a synthetic liver-specific promoter and pseudotyped AAV8 capsid (scAAV2/8-LP1-hFIXco; ClinicalTrials.gov:NCT00979238). We now report durable efficacy and long-term safety over at least 10 years of follow-up in these participants. Methods: FIX activity, annualized bleeding rate (ABR), use of FIX concentrates, safety (specifically transaminitis and oncogenesis), and FIX expression kinetics were evaluated in the 10 participants following a bolus infusion of scAAV2/8-LP1-hFIXco at a dose of 2x10 11vg/kg (N=2), 6x10 11vg/kg (N=2), or 2x10 12vg/kg (N=6), between 2010 and 2012. Results: As of December 31, 2022, the median follow-up was 10.7 years (range 4-12 years). A total of 11 treatment-related adverse events occurred in 10 participants, including transient elevation of liver transaminases within 3 months of vector infusion in 4 of 6 patients treated with the high vector dose, without any recurrence. Two new serious adverse events were reported: (1) non-mucinous lung adenocarcinoma in situ, identified incidentally following a bullectomy for spontaneous pneumothorax 5 years after gene therapy in a 48-year-old participant considered not related to gene therapy following molecular studies, and (2) adenocarcinoma of the prostate in a 72-year-old participant 12 years after gene therapy. Tissue evaluation of the latter case is ongoing. No FIX inhibitors, thrombosis, persistent transaminitis or deaths were observed. Transgenic FIX expression has remained stable, with mean (±SD) FIX activity (one-stage) for the three dose cohorts of 1.7±0.9, 2.3±0.9 and 4.9±2.2 IU/dL, respectively (Figure 1). The mean and median ABR over the 10-year period following gene therapy of all 10 participants were 1.95 and 1.6 compared to 16.5 and 14, respectively, before gene therapy. This represents an 8.5-fold reduction in bleeding events (Wilcoxon signed rank test p=0.002). In the 6 high-dose participants, the ABR was 21-fold lower (mean=1.16, median 1, paired t-test, p&amp;lt;0.008). Mean and median FIX concentrate usage before gene therapy in the 10 participants were 2869 and 2526 IU/kg dropping to 945 and 274 IU/kg, respectively, over a 10-year period after gene therapy (p=0.0003). All participants developed a persistent, high-titer polyclonal anti-AAV8 capsid-specific antibody response after administration of scAAV2/8-LP1-hFIXco. Conclusion: Expression of transgenic FIX has remained stable over a period of 10 years following systemic administration of scAAV2/8-LP1-hFIXco resulting in sustained clinical benefit, with substantial reduction in ABR and FIX concentrate use.

Long-Term Bleeding Protection, Sustained FIX Activity, Reduction of FIX Consumption and Safety of Hemophilia B Gene Therapy: Results from the HOPE-B Trial 3 Years after Administration of a Single Dose of Etranacogene Dezaparvovec in Adult Patients with Severe or Moderately Severe Hemophilia B

Introduction: Etranacogene dezaparvovec (formerly AMT-061) is the first approved gene therapy for hemophilia B in the US and Europe. It 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 the liver-specific promoter LP-1. The pivotal phase 3 HOPE-B clinical trial (NCT03569891) of etranacogene dezaparvovec demonstrated superiority of bleeding protection compared to standard of care FIX prophylaxis up to 24 months post-treatment; long-term follow-up from Year 2 post-administration onward is currently ongoing. Aim: To report long-term efficacy and safety data of etranacogene dezaparvovec from the HOPE-B trial over a period of 3 years post-treatment. Methods: In this pivotal phase 3 open-label, single-arm trial, adult male participants with severe or moderately severe hemophilia B (FIX ≤2%), with or without preexisting AAV5 neutralizing antibodies (NAbs), were infused with a single dose (2×10 13 gc/kg) of etranacogene dezaparvovec, following a ≥6-month lead-in period of receiving their usual FIX prophylaxis. Efficacy (bleeding rates, aPTT-based FIX activity levels, FIX consumption) and safety data (adverse events [AEs]) during Years 1, 2, and 3 post-treatment with etranacogene dezaparvovec are reported. Results: Of 54 participants who received etranacogene dezaparvovec, 52 completed 36 months of follow-up. Mean annualized bleeding rate (ABR) for all bleeds during Months 7-36 post-treatment was significantly reduced by 64% (mean ABR 1.52) compared with the ≥6-month lead-in period (mean ABR 4.17; P=0.0004). Total number of bleeds (all types) were 136 during the ≥6-month lead-in period and decreased to 55 during Year 1, 48 during Year 2, and 37 during Year 3 post-treatment. Median [range] bleeds per participant decreased from 2.0 [0-10] during the lead-in period and remained stable to 0.0 [0-4] during Year 1, 0.0 [0-10] during Year 2, and 0.0 [0-8] during Year 3. Superior bleeding protection was in line with the level of transgene-derived endogenous FIX expression. The mean±SD (median; range) endogenous FIX activity level (ie. in the absence of exogenous FIX exposure) of participants was 41.5 IU/dL ±21.7 (39.9; 5.9-113, n=50) at Year 1, 36.7 IU/dL ±19.0 (33.9; 4.7-99.2, n=50) at Year 2, and sustained at 38.6 IU/dL ±17.8 (36.0; 4.8-80.3, n=48) at Year 3 post-treatment. Pharmacodynamic profile was not significantly different in participants with AA5 NAb undetected or titer ≤1:678. At 3 years post-treatment, 51 (94%) remained free of continuous FIX prophylaxis. One participant who lacked efficacy (highest AAV5 NAbs titer of 1:3212) and 1 who received a 10% partial dose of treatment did not discontinue prophylaxis; 1 participant eventually had his FIX levels declined to 2-5% range; his bleeding phenotype returned, and he resumed prophylaxis per protocol at month 30 post-treatment. During Year 2 and Year 3 post-treatment, 37 (70%) and 39 (75%) participants received no FIX infusion, respectively. Overall mean annualized FIX consumption decreased by 96% over 3 years post-treatment compared to the ≥6-month lead-in period (-246,763 IU/kg/participant, including those receiving FIX prophylaxis post-treatment; P&amp;lt;0.0001). During the 3 years post-dose, all participants experienced at least 1 treatment-emergent AE (TEAE); of 709 events, 541 (76%) were mild, 137 (19%) were moderate, and 31 (4%) were severe. There were no serious AEs related to treatment [a serious AE of hepatocellular carcinoma (HCC) and a death were reported previously before Year 2 and determined to be unrelated to treatment]. A total of 38/54 (70%) participants experienced 96 treatment-related TEAEs, of which 95% occurred before 6 months post-treatment. The most common AE was an increase in alanine transaminase (ALT), for which 9 (16.7%) participants received supportive care with reactive corticosteroids for a mean duration of 81.4 days (SD: 28.6; range: 51-130 days). No new deaths, no new HCC, and no late treatment-related ALT elevations or thromboembolic events were reported. Conclusion: Long-term follow-up during the HOPE-B trial has shown that a single-dose of etranacogene dezaparvovec resulted in long-term endogenous FIX Padua expression and superior bleeding protection compared to FIX prophylaxis in participants without or with AAV NAb titer ≤1:678, with a favorable safety profile over 3 years post-administration.

Phase 3 Trial of Concizumab in Hemophilia with Inhibitors

BackgroundConcizumab is an anti–tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors.MethodsWe conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed.ResultsOf 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time.ConclusionsAmong patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.)

Clinical Profile and Bleeding Outcome of Pediatric Rare Bleeding Disorders: The Royal Hospital’s Experience, Oman

Introduction: Rare Bleeding Disorders (RBDs), a group of inherited coagulation factor deficiencies, are more common in areas with a high rate of consanguineous marriages. Data on the frequency and outcome of RBDs among children in Oman are limited. Aim: This study evaluated the clinical profile and bleeding outcomes of paediatric RBDs at the Royal Hospital, the largest referring centre in Oman, from 2010 to 2020. Methods: This retrospective descriptive cohort study includes all Omani children, less than 13 years of age, diagnosed with RBDs, and followed at the Royal Hospital. The patient’s data was retrieved from the electronic chart system. Results: Forty-one patients (24 males and 17 females) were included. Based on factor level at diagnosis, 34(83%) patients have factor VII deficiency, four (9.7%) patients have factor XIII deficiency, one (2.4%) patient has fibrinogen deficiency, and one patient (2.4%) has factor X deficiency. Four (9.4%) patients required blood transfusion for active bleeding, 15(36.6%) patients were treated on demand with tranexamic acid, and 3(7.3%) patients were on regular prophylaxis with tranexamic acid. The mean period of follow-up was 3.15 years. The majority (87.8%) of patients had no active bleeding, and only two (4.9%) patients developed severe bleeding. The mean annual bleeding rate outcome was 0.2, 0.5, and 7 for patients with FVII, FXIII, and FX, respectively. Conclusions: Omani children with rare bleeding disorders are commonly diagnosed incidentally. They usually do not require active treatment because their bleeding outcome is favourable.

Budget impact of prophylactic treatment of rVIII-SingleChain in moderate and severe hemophilia A in Italy

IntroductionrVIII-SingleChain, a recombinant factor VIII (rFVIII), has demonstrated safety and efficacy in patients with hemophilia A in clinical trials and real-world evidence. This analysis aimed to estimate the potential budget impact of increasing the usage of rVIII-SingleChain for the prophylactic treatment of hemophilia A over 3 years in Italy.MethodsPatients with moderate and severe hemophilia A receiving prophylaxis were included in the analysis. Epidemiological data were obtained from published literature. Mean product consumption and mean annual bleeding rate for rVIII-SingleChain, rFVIIIFc, octocog alfa and BAY 81-8973 were based on pooled real-world data from Italy, Germany and US. A budget impact model has been developed in order to compare two scenarios: a base-case scenario where current rVIII-SingleChain shares are kept constant over 3 years and an alternative scenario where rVIII-SingleChain shares increase by taking from other rFVIII products. Analysis 1 was based on the current Italian list prices and Analysis 2 considered current regional acquisition prices for both scenarios.ResultsAnnually, adult patients treated with rVIII-SingleChain prophylaxis are expected to consume 324,589 units per patient, resulting in annual costs of €240,196 per patient. In Analysis 1, comparing the base case (constant market share of 9% rVIII-SingleChain over time) with the alternative scenario (higher rVIII-SingleChain market share and increasing from 15% in the first year to 25% in the third year), the total expenditure for prophylaxis using rFVIII products is expected to decrease by €1.4 million in Year 1, by €3.1 million in Year 2 and by €5.4 million in Year 3. In Analysis 2 based on regional prices, the results remained consistent.Discussion/ConclusionThis analysis suggests that increasing utilization of rVIII-SingleChain in hemophilia A patients may lead to cost savings as a result of reduced consumption with uncompromised efficacy in bleed protection.

Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A

BackgroundEfanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor–imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear.MethodsWe conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health.ResultsIn group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P=0.03), and joint health (P=0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected.ConclusionsIn patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.)

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

Durability of Factor IX Activity and Bleeding Rate in People with Severe or Moderately Severe Hemophilia B after 5 Years of Follow-up in the Phase 1/2 Study of AMT-060, and after 3 Years of Follow-up in the Phase 2b and 2 Years of Follow-up in the Phase 3 Studies of Etranacogene Dezaparvovec (AMT-061)

Introduction: Gene therapy for people with hemophilia B appears to have a durable response, with data presented over 5 years (Samelson-Jones. Blood 2021; 138_suppl 1: 3975) and 8 years (Nathwani. Blood 2018; 132_suppl 1: 491) post-administration. Here we review the durability of AMT-060 and etranacogene dezaparvovec (formerly AMT-061) investigational gene therapies for hemophilia B, defined by sustained factor IX (FIX) activity levels and hemostatic protection. AMT-060 was developed as a precursor to etranacogene dezaparvovec. Both gene therapies are almost identical, comprising an adeno-associated virus serotype 5 (AAV5) vector containing a FIX transgene under the control of a liver-specific promoter; the transgene encodes wild-type FIX in AMT-060 and the highly active Padua variant of FIX in etranacogene dezaparvovec, differing by only one amino acid. Therefore, durability of response is expected to be similar for AMT-060 and etranacogene dezaparvovec. Aim: Outline the observed durability of AMT-060 and etranacogene dezaparvovec in people with severe or moderately severe hemophilia B. Methods: Three clinical trials are ongoing in adults with severe or moderately severe hemophilia B. Data have been captured over 5 years in the Phase 1/2 study assessing AMT-060 (N=10; Cohort 1: n=5, 5x1012 gc/kg ; Cohort 2: n=5, 2x1013 gc/kg; NCT02396342), 3 years in the Phase 2b study assessing etranacogene dezaparvovec (N=3, 2x1013 gc/kg; NCT03489291) and 2 years in the Phase 3 HOPE-B study assessing etranacogene dezaparvovec (N=54, 2x1013 gc/kg; NCT03569891). Study designs have been reported previously. All three studies assessed FIX activity levels and bleeding events. Results: In the Phase 1/2 AMT-060 study, FIX activity levels remained stable in both cohorts 5 years after dosing. Mean FIX activity was 4.4% for Cohort 1 at 52 weeks and 6.9% for Cohort 2 at 26 weeks; mean FIX activity after 5 years was 5.2% and 7.4%, for Cohorts 1 and 2, respectively. Greater FIX activity levels were achieved with etranacogene dezaparvovec. After 3 and 2 years of follow-up in the Phase 2b and 3 studies, respectively, mean FIX activity levels remained in the near-normal range (Table). In the Phase 2b study, mean FIX activity was 23.4% at Week 3 (n=3); this increased to 36.9% at Year 3 (n=2). A sustained mean FIX activity level was seen in the Phase 3 study: 38.95% at Month 6 (n=51) and 36.66% at Year 2 (n=50). This was observed in both the full analysis set (n=54) and in the modified intent-to-treat population (n=52) that excluded two non-responders (one with the highest AAV5 neutralizing antibody titer of 3212; one that received only a partial dose; Table). With regards to hemostatic protection, in Year 1 post-AMT-060 administration, the mean annualized bleeding rate (ABR) was 7.30 in Cohort 1, and this decreased to 6.40 at Year 5. In Cohort 2, mean ABR decreased from 1.58 in Year 1 to 0.20 in Year 5. The etranacogene dezaparvovec studies showed a similar low bleeding rate. In the Phase 2b study, no bleeding episodes occurred between 2.5-3 years of follow-up. Overall, the ABR over 3 years was 0.22. Two bleeding episodes (one very mild, spontaneous bleed; one traumatic) occurred in one participant within 18 months of dosing; the participant received FIX product replacement therapy (1700 IU) after each bleed. In the Phase 3 study, ABR (all bleeds) achieved at Months 7-18 post-administration was 1.51 (reduced from 4.18 at baseline); this was maintained through to 2 years in the full analysis set (n=54; Table). A similar trend was seen when assessing the modified intent-to-treat population (n=52), with a reduction in ABR from 4.00 at baseline to 0.95 after 2 years of follow-up. Reductions in ABR for spontaneous, joint, and traumatic bleeds were also maintained through 2 years of follow-up. No new safety signals have been identified after 5 years of follow-up for AMT-060 and up to 3 years of follow-up for etranacogene dezaparvovec. Conclusions: Gene therapy for hemophilia B appears to have a durable response. Across the Phase 1/2 study of AMT-060 and the Phase 2b and Phase 3 studies of etranacogene dezaparvovec, FIX activity levels are sustained throughout the observation period. Reductions in bleeding events also remained stable across the course of the three studies. Similar durable responses have been observed in published literature for hemophilia B gene therapies. 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

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