Median Annualized Bleeding Rate Research Articles

Evaluation of Safety and Efficacy of Emicizumab Prophylaxis in Egyptian Pediatric Patients with Hemophilia A: Single Center Cross Sectional Study.

Hemophilia A (HA) is an X-linked hereditary bleeding disorder caused by deficiency of coagulation factor VIII activity. Emicizumab is a bispecific monoclonal antibody that replaces the function of activated FVIII and prevents bleeds in patients with hemophilia A. Emicizumab is expected to reduce the risk of severe bleeds in those patients with their subsequent complications. However, data about its safety and efficacy in patients with hemophilia A is limited. We aimed to evaluate safety and efficacy of Emicizumab prophylaxis in Egyptian pediatric patients with HA. A prospective cohort study was conducted on 88 HA patient who received prophylaxis with Emicizumab. Breakthrough bleeding episodes as well as annualized bleeding rate(ABR) were reported for all patients before and after Emicizumab prophylaxis. All adverse events during prophylaxis were reported to evaluate the safety of Emicizumab. Joint bleeds were present in 94 % of the patients. 58% of them had one target joint, 36.4% had more than one target joint while 5.6% had no target joints. 17% of patients were positive for FVIII inhibitors. The median annualized joint bleeding rate (AJBR) was reduced remarkably after Emicizumab prophylaxis (36 before versus zero after Emicizumab. Also, the median ABR was 48 before Emicizumab versus zero after Emicizumab. Eight patients developed mild breakthrough bleeding episodes. The most common adverse events were local reaction at the injection sites, headache, arthralgia, fever and diarrhea. Emicizumab prophylaxis was associated with significantly lower rate of bleeding events in patients with HA with and without inhibitors. The majority of patients had zero bleeds with Emicizumab prophylaxis.

Real-world usage and effectiveness of recombinant factor VIII/factor IX Fc in hemophilia A/B: final data from the 24-month, prospective, noninterventional PREVENT study in Germany

BackgroundReal-world experience with efmoroctocog alfa (a recombinant factor [F]VIII Fc fusion protein [rFVIIIFc]) and eftrenonacog alfa (a recombinant factor IX Fc fusion protein [rFIXFc]) is needed to bridge evidence gaps. ObjectivesTo describe rFVIIIFc/rFIXFc usage and effectiveness over a 24-month prospective period. MethodsPREVENT (NCT03055611), a noninterventional study across 25 German hemophilia treatment centers, enrolled previously treated persons with hemophilia A and B (all ages/severities) on individualized rFVIIIFc/rFIXFc prophylaxis before/at enrollment. Primary endpoints included annualized bleeding rate (ABR), injection frequency (IF), and factor consumption (FC). Additionally, up to 12 months of retrospective FVIII/FIX data were collected. Physician and patient satisfaction, and safety outcomes were also assessed. ResultsOverall, 150 patients received ≥1 rFVIIIFc dose and 47 patients received ≥1 rFIXFc dose, with median prospective follow-up of 20.6 and 21.0 months, respectively. rFVIIIFc/rFIXFc demonstrated low median ABR (0.5/1.7), annualized IF (121.8/52.2 injections/y), and FC (4611.7/2423.9 IU/kg) in line with product labels. Compared with previous FVIII/FIX, there was a 56.0% reduction in ABR for rFVIIIFc (rate ratio, 0.44; 95% CI, 0.31-0.64), with no change for rFIXFc (rate ratio, 0.93; 95% CI, 0.66-1.31); rFVIIIFc/rFIXFc reduced annualized IF (rFVIIIFc, mean difference, −31.7; 95% CI, −40.3 to −23.1; rFIXFc, mean difference, −37.3; 95% CI, −46.9 to −27.8), while FC remained stable (rFVIIIFc, +374.1; 95% CI, +46.8 to +701.3; rFIXFc, +503.9; 95% CI, +95.4 to +912.4). Most physicians and patients were satisfied or highly satisfied with rFVIIIFc/rFIXFc. rFVIIIFc/rFIXFc were well tolerated, with no inhibitor development or treatment-related serious adverse events. ConclusionReal-world PREVENT data complement phase 3 trials and show that individualized rFVIIIFc/rFIXFc prophylaxis provided stable bleed protection with low IF and maintained FC. Compared with previous FVIII, ABR was considerably reduced with rFVIIIFc, with stable annualized FC. For rFIXFc, bleed protection was maintained vs previous FIX while reducing annualized IF.

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.

Adult People with Hemophilia A Have Low Annualized Bleeding Rate, However the Arthropathy Remains a Burden: A Retrospective Cohort Study.

Congenital Hemophilia A is a complex disease to treat, especially in places without access to hemophilia treatment centers (HTCs). The primary aim of this study was to analyze the outcomes of a cohort of adult people with congenital hemophilia A in an HTC localized in the Bajio region of Mexico. Observational retrospective study of a cohort of 82 adult people with congenital hemophilia A treated in a tertiary-level hospital in the Bajio region of Mexico, between June 2022 and June 2023. The median age of the patients was 29.5years, 60.9% with severe hemophilia A, 53.6% were under some factor VIII prophylaxis regimen, and 52.4% had home therapy. The median annualized bleeding rate (ABR) was one bleed/year (IQR 0-3 bleeds/year) including a median of zero joint bleeds/year (IQR 0-3 bleeds/year). The presence of high-response inhibitors was detected in 8.5%, with an overall incidence of inhibitors of 14.6% of the cohort. Univariate analysis showed that inhibitors (OR 21.10; CI 95% 1.20-370.3; P = 0.03) and clinical arthropathy (OR 6.14; CI 95% 2.13-17.68; P = 0.001) were significantly higher in severe hemophilia. Clinically significant arthropathy was found in 71.9% of patients. Ultrasonography of the target joints showed that mainly cartilage degeneration was affected. Blood transfusion-associated viral infections were detected in 10.9% of patients. In our HTC, current treatment with hemostatic agents allows adequate control of ABR with acceptable inhibitor rates. However, we still have joint damage in most patients, which is partly explained by the fact that prophylaxis was introduced only in recent years.

Effectiveness of emicizumab in preventing bleeding events in severe and moderate hemophilia A: A single-center experience in Bangladesh.

Emicizumab is a monoclonal antibody that bridges activated factor IX (FIX) and factor X (FX) to replace the function of missing activated factor VIII (FVIII) in hemophilia A patients irrespective of FVIII inhibitor status. This study assessed the effectiveness of emicizumab in preventing bleeding episodes in patients with hemophilia A. This observational study included patients with moderate to severe hemophilia A who were undergoing episodic FVIII replacement therapy. The primary endpoint was the difference in annualized bleeding rates (ABR) and the secondary endpoint was the difference in Hemophilia Joint Health Score (HJHS) before and after emicizumab prophylaxis. A total of 30 male hemophilia patients were included, the mean age was 16.7 (SD: ±8.1) years, and most of them had moderate hemophilia A [63.3%]. Before prophylaxis, the median ABR was 48 (interquartile range [IQR]: 35-60), and 93.3% of patients had ABR greater than eight, whereas after prophylaxis the median ABR decreased significantly (median [IQR]: 0 [0.0-0.4], p<0.001), and 56.7% had zero bleeds. ABR was not significantly different in patient with and without FVIII inhibitors. The HJHS scores significantly improved after prophylaxis (10 vs. 2.5, p<0.001). The bleeding events were reduced significantly (23 vs. 0.0, p<0.001), and zero new target joints were reported after prophylaxis. Most of the patients [93.3%] did not face any serious adverse events after prophylaxis. Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events among participants with hemophilia A, regardless of inhibitor status.

Regular prophylaxis with activated prothrombin complex concentrates in pediatric hemophilia.

Regular prophylaxis with activated prothrombin complex concentrates (aPCCs) is effective in adult patients with hemophilia with inhibitors; however, data in children are scarce. This was a single-center retrospective study at Saitama Children's Medical Center. Patients with severe and moderate hemophilia with inhibitors aged <15 years at the start of aPCCs prophylaxis were included. Medical records were retrospectively reviewed. We treated nine pediatric patients with hemophilia with inhibitors (median age, 1.9 years; age range, 1.3-12.9 years; inhibitor titers before treatment with aPCCs, 5.9-69 BU/mL) using prophylactic aPCCs (doses, 50-100 U/kg; 2-3 times/week). The median prophylactic period was 13 months (range: 5-31 months). The median annualized bleeding rate (ABR) during prophylactic treatment with aPCCs was 2 (range, 0-17). In four patients, ABR was reduced by 19%-100% with prophylactic aPCCs compared to on-demand aPCCs. An adverse effect of treatment was that a patient with hemophilia B developed nephrotic syndrome 34 months after starting regular prophylaxis with aPCCs. Regular prophylactic aPCCs reduced the ABR even in younger children with hemophilia A and B. Serious adverse events include nephrotic syndrome, which requires caution.

Safety and Efficacy of Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Previously Untreated Patients with Hemophilia B.

Introduction Recombinant fusion protein linking coagulation factor IX (FIX) with albumin (rIX-FP) has been shown to be an effective, well-tolerated treatment for patients with severe hemophilia B who had previously received factor replacement therapy. This study investigated the safety and efficacy of rIX-FP in previously untreated patients (PUPs). Methods Patients with moderately severe/severe hemophilia B (≤2% FIX) previously untreated with FIX replacement products received rIX-FP (25-75 IU/kg) prophylaxis weekly or on-demand treatment over ≥50 exposure days (EDs). Primary outcomes were the number of patients who developed FIX inhibitors and mean incremental recovery (IR) following a 50 IU/kg dose of rIX-FP. Secondary outcomes included incidence of adverse events (AEs) and annualized bleeding rates (ABRs). Results In total, 12 PUPs with a median age of 0 years (range, 0-11 years) were treated with rIX-FP for a median of 50 EDs (6/12 prophylaxis; 6/12 on-demand then prophylaxis). Overall, 11/12 patients did not develop FIX inhibitors; one 11-year-old patient developed an inhibitor against FIX after 8 EDs and was ultimately withdrawn. Mean (standard deviation) IR was 1.2 (0.4, n = 8) (IU/dL)/(IU/kg). Of the 137 treatment-emergent AEs recorded, five were attributed to rIX-FP. On the prophylaxis regimen, median ABR was 1.0 (range, 0-3.9, n = 12). No thromboembolic events or deaths occurred during the study. Conclusion This study provides data to support the safety and efficacy of rIX-FP in PUPs requiring on-demand or prophylactic treatment for moderately severe/severe hemophilia B, consistent with results in previously treated patients. Overall, 1/12 patients developed an inhibitor against FIX.

Real-world data on the use of emicizumab in patients with haemophilia A with and without inhibitors in Singapore.

Emicizumab is a bispecific monoclonal antibody that mimics the function of factor VIII by binding to factor IXa and factor X to achieve haemostasis in haemophilia A. The long half-life and subcutaneous mode of administration makes emicizumab a compelling treatment option for bleeding prophylaxis. There is still limited real-world data on its use and management considerations, especially during surgical procedures. The objective of the study is to describe the real-world experience of emicizumab in a cohort of adult and paediatric haemophilia A patients in Singapore, including its use in the periprocedural setting. This was an observational study conducted at the 2 main haemophilia treatment centres in Singapore. All haemophilia A patients who commenced treatment with emicizumab before 1 July 2022 were recruited. A total of 18 patients with haemophilia A were included in this study. Ten (55.6%) patients had active inhibitors. The median annual bleeding rate for all patients before emicizumab use was 4.5 events (interquartile range [IQR] 2.8-8.3) compared with 0 events (IQR 0-0) after emicizumab was commenced (P=0). There were no adverse events of venous or arterial thrombosis, thrombotic microangiopathy, or death. A total of 6 procedures in 5 patients were performed during the study period with no major bleeding complications. Emicizumab effectively protects against bleeding in haemophilia A patients with and without inhibitors, including in children less than 12 years old. More studies are required to address clinical nuances, such as periprocedural management and the role of immune tolerance in patients with inhibitors on emicizumab.

Sequential Use of Monthly Low Dose Emicizumab and Factor VIII Concentrate Prophylaxis Among Patients with Hemophilia a: A Case Series Report

Introduction: The effectiveness of monthly low dose emicizumab of 1.0 to 2.0 mg/kg has been reported among patients with and without inhibitor. However, their trough level of emicizumab was rather low ranging from 5.9 to 11.9 mg/mL and breakthrough bleeding episodes often occurred at the 4 th week after administering emicizumab. Moreover, non-exposure to factor VIII is one concern among patients receiving emicizumab prophylaxis. Therefore, the study aimed to evaluate the effectiveness of sequential use of monthly low dose emicizumab and factor VIII concentrate prophylaxis among patients with hemophilia A. Methods: Patients with hemophilia A without inhibitor were recruited. Sequential use of monthly low dose emicizumab in the first week and factor VIII concentrate in the 4 th week was provided. Patients were closely monitored concerning the number and sites of bleeding episode, cause of bleeding from spontaneous or trauma-related conditions and the amount of additional factor VIII concentrate to treat breakthrough bleeding episodes. Also, the comparison of quality of life, hemophilia joint health score (HJHS), hemophilia early arthropathy detection by ultrasound (HEAD-US) and ultrasonography of bilateral elbows, knees and ankles before and after prophylaxis was conducted. Results: Five male patients (4 adults, 1 boy) with hemophilia A (severe 2, moderate 3) without inhibitor were enrolled in the study with the mean (SD) age of 26.8 (15.5) years. They encompassed low bleeding risk circumstances including avoidance of contact sports and high velocity activities. Four adults initially received episodic treatment and subsequent low dose prophylaxis at 15-20 units/kg twice weekly but breakthrough bleeding episodes frequently occurred. The only boy also received low dose prophylaxis at 14 units/kg once weekly at the age of 5.9 years and increased to twice weekly one month later due to frequent spontaneous bleeding at the right knee. However, the difficulty in venous access created constraint in achieving adequate prophylaxis. Therefore, all patients were switched to receive the whole vial of emicizumab at the monthly low dose ranging from 1.14 to 1.25 mg/kg without 4-loading doses for 2 years and sequential use of median (IQR) monthly low dose emicizumab of 1.50 (1.31, 1.65) mg/kg in the first week and factor VIII concentrate 15 units/kg twice weekly in the 4 th week in the third year. The duration of follow-up in the third year was 6 months. The results revealed the median (interquartile range, IQR) trough level of plasma emicizumab concentration at the 4 th weeks before factor VIII administration determined by a modified one stage factor VIII assay using emicizumab calibrator was maintained at 8.5 (6.2,10.8) µg/mL. The median (IQR) APTT of all patients at 6-month prophylaxis of 25.7 sec (25.3, 26.0) was shortened compared with a baseline of 66.9 sec (54.3, 105.1) demonstrating the presence of emicizumab and the likely absence of anti-emicizumab antibodies. Also, no inhibitor to factor VIII clotting activity was detected among all patients before and after prophylaxis. Their median (IQR) annual bleeding rate significantly decreased from baseline of 30.0 (13, 36.5) to 5.0 (3, 12.5) in the first year, 1.0 (0.5, 8.5) in the second year and 1 (0, 3) in the third year of prophylaxis with p-values of 0.043. Impressively, zero annual bleeding rate in the third year of the current study was found among 2 patients while 2 patients exhibited one episode of trauma-related bleeding at the ankle and one patient had frequent epistaxis from high PM 2.5 in his hometown. Ultimately, all patients achieved annual spontaneous joint bleeding rate ≤1 episode during a 6-month period of sequential use of emicizumab and factor concentrate prophylaxis. In addition, quality of life, HJHS, HEAD-US and ultrasonography study were improved in all studied patients. Factor VIII concentrate was helpful in preventing bleeding especially at the 4 th week after administering emicizumab and providing other biological activities beyond hemostasis related to bone remodeling, dysregulated macrophage polarization and inflammatory processes among studied patients. Conclusion: The sequential use of monthly low dose emicizumab and factor VIII concentrate prophylaxis showed effectiveness with annual spontaneous joint bleeding rate ≤1 episode among all studied patients. The musculoskeletal system and quality of life were also improved.

Emicizumab Prophylaxis for the Treatment of Chinese Hemophilia A Patients in the Real World: A Multi-Center Retrospective Analysis

Background The real-world experiences of Hemophilia A (HA) patients receiving emicizumab prophylaxis in China are insufficient due to the high cost and later approval of emicizumab. In this study, we retrospectively analyzed Chinese HA patients with or without factor VIII (FVIII) inhibitors receiving emicizumab prophylaxis with the aim to investigate the efficacy and safety of emicizumab as well as the current status and effect of different doses of emicizumab in a real-world setting. Methods HA patients with or without FVIII inhibitors receiving emicizumab prophylaxis between June 2019 and June 2023 in China were included in the study. Data of HA patients including children and adults were retrospectively gathered from 27 hospitals all over the country. For each patient, the anonymized data were collected and telephone follow-ups were conducted to make sure the intact information collected as much as possible. Low dose and higher dose of emicizumab were defined as monthly dose &amp;lt;3 mg/kg and monthly dose ≥3 mg/kg, respectively. All analyses were performed using SPSS software version 25.0 (IBM Corporation, Armonk, New York, USA). Intraindividual comparisons were performed by nonparametric paired tests. Results A total of 127 male patients (10.2% [n=13] ≥18 years old; 89.8% [n=114] &amp;lt;18 years old) were enrolled in our study (severe: moderate = 103:24). Of these, 42 (33.1%) had FVIII inhibitors at initiating emicizumab. The median (interquartile range [IQR]) duration of emicizumab treatment was 16.0 (9.0-30.0) months. The median (IQR) annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) after emicizumab were 0.5 (0-1.5) and 0 (0-0), respectively (calculated in patients treated with emicizumab &amp;gt;6 months). Among the 127 patients, 67 (52.8%) patients had no bleeds at all. No intracranial hemorrhage occurred after emicizumab. Adverse events were reported in 12 (9.4%) patients and 10 (83.3%) were injection-site reactions. There were no deaths, thromboembolic events, or thrombotic microangiopathies in our study. Two (8.0%) patients had treated epistaxis after emicizumab with low dose compared with 0 (0.0%) with higher dose ( P =0.037). Four (16.0%) patients had target joints after emicizumab with low dose compared with 1 (1.0%) with higher dose ( P =0.005) (Table 1). There were no significant differences between low dose and higher dose of emicizumab prophylaxis in ABR, AJBR, the proportion of zero bleeds, the proportion of adverse events, and so on. The median (IQR) ABR was 5.0 (2.0-14.0) with prior treatment compared with 0.5 (0-1.5) with emicizumab, an 90% reduction in ABR with P value &amp;lt;0.001 (Table 2).Also, the use of emicizumab was also associated with significant reduction in AJBR ( P &amp;lt;0.001), number of target joints ( P &amp;lt;0.001), number of intracerebral hemorrhages ( P &amp;lt;0.001), inhibitor titer ( P =0.016), and days away from school/work ( P &amp;lt;0.001). Conclusion In this multi-center study, we indicated the efficacy and safety of emicizumab and that low dose and higher dose of emicizumab had similar efficacy in Chinese HA patients without increasing adverse events.

The Effect of Concizumab Prophylaxis on Target Joints, Resolution and Joint Bleeds in Patients With Hemophilia A or B With or Without Inhibitors in Phase 3 Clinical Trials

Background: Concizumab is a recombinant anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody under development as a once-daily subcutaneous prophylactic treatment for hemophilia patients with and without inhibitors, and has the potential to be one of the first subcutaneous treatment options for hemophilia B. Recurring joint bleeds may cause hemophilic arthropathy and reduce the quality of life of patients with hemophilia (van Vulpen LFD et al. Haemophilia. 2018; 24 Suppl 6:44-49). Results on target joints, their resolution, and joint bleeds in patients with hemophilia (hemophilia A or B with inhibitors [HAwI or HBwI] or without inhibitors [HA or HB]) from the prospective, multicenter, open-label explorer7 (NCT04083781) and explorer8 (NCT04082429) phase 3 concizumab clinical trials at the 56-week cut-off are presented. Aims: To assess and communicate the effect of longer term (56 weeks) concizumab prophylaxis (PPX) on target joints, their resolution, and joint bleeds in patients with hemophilia A or B with or without inhibitors. Methods: After informed consent/ethics committee approval were obtained, patients in both explorer7 and explorer8 trials were exposed to no PPX (arm 1) or concizumab PPX (arms 2-4) based on their treatment regimen before the trial. After the main part of the trial, all patients (arms 1-4) could continue in the extension part of the trial receiving concizumab for up to 136 weeks. Upon treatment restart following a treatment pause due to thromboembolic events, patients received a 1.0 mg/kg concizumab loading dose on Day 1, followed by an initial 0.20 mg/kg daily dose starting on Day 2, with potential adjustment to 0.15 or 0.25 mg/kg based on measured plasma concizumab concentration after week 4. The data presented here are from the 56-week cut-off that was defined as when all patients had completed the visit after 56 weeks or permanently discontinued treatment. Annualized bleeding rate (ABR) of joint bleeds was evaluated for all patients. Target joints at baseline by age group and target joint resolutions during the trial were assessed separately for this abstract. Target joints were defined as 3 or more spontaneous bleeds into a single joint within a consecutive 6-month period, and target joints were deemed resolved when there have been ≤2 bleeding episodes in the joint during the previous 12 months of exposure (Blanchette VS et al. J Thromb Haemost. 2014;12(11):1935-1939). Results: A total of 144 patients with HA or HB and a total of 127 patients with HAwI or HBwI were exposed to concizumab PPX at the 56-week cut-off. Upon treatment restart, 144 patients with HA or HB and 112 patients with HAwI or HBwI were included in the studies and were allocated to the new concizumab PPX dosing regimen, of which the majority were adults (HA + HB: 105; HAwI + HBwI: 72), some were adolescents (12-17 years) (HA + HB: 36; HAwI + HBwI: 40), and a few were elderly/very elderly (65-84 years) (HA + HB: 3; HAwI + HBwI: 0). Patients who had at least one target joint at baseline (HA + HB: adults [45/108], adolescents [18/36]; HAwI + HBwI: adults [35/72], adolescents [20/40]) mostly reported target joints in the ankle, elbow, and knee, and a few in the hip and shoulder, as presented per age group in Table 1. Of these patients who were exposed to concizumab PPX for at least 12 months, 49 patients with HA or HB reported a total of 80 target joints at baseline, of which 69 (86.3%) were resolved at the 56-week cut-off, and 49 patients with HAwI or HBwI reported 85 target joints at baseline, of which 78 (91.8%) were resolved at the 56-week cut-off. Most target joints were resolved within 12 months after treatment start (median [25th; 75th percentile])( 12.0 months [12.0; 12.0]), both for patients with HA or HB and HAwI or HBwI. The median ABRs for treated spontaneous and traumatic target joint bleeding episodes were 0.0 for patients with HA or HB and HAwI or HBwI, and the median ABRs for treated spontaneous and traumatic joint bleeding episodes were 1.3 for patients with HA or HB and 0.0 for patients with HAwI or HBwI at the 56-week cut-off, as presented in Table 2. Conclusions: Once-daily, subcutaneous concizumab prophylaxis resolved 86.3% of target joints in patients with HA or HB, and 91.8% of target joints in patients with HAwI or HBwI, most patients within 12.0 months. The median ABRs for treated spontaneous and traumatic target joint bleeding episodes at 56 weeks for both patients with HA or HB and HAwI or HBwI were 0.0.

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.

Patients with moderate hemophilia A and B with a severe bleeding phenotype have an increased burden of disease

BackgroundPatients with moderate hemophilia express varying bleeding phenotypes. ObjectivesTo assess the burden of disease in patients with moderate hemophilia and a mild or severe phenotype incorporating the thrombin generation profile. MethodsThis sub-study of the 6th Hemophilia in the Netherlands study, analyzed data of adults with moderate hemophilia A or B. Patient characteristics and information on bleeding tendency, joint status, and quality of life were obtained from electronic patient files and self-reported questionnaires. A severe bleeding phenotype was defined as an annual bleeding rate ≥5, an annual joint bleeding rate ≥3, and/or the use of secondary/tertiary prophylaxis, and a mild phenotype vice versa. TG was measured with the Nijmegen Hemostasis Assay. ResultsThis study included 116 patients: 21% had a severe phenotype of whom 46% used prophylaxis. Patients with a severe phenotype treated on demand reported a higher median annual bleeding rate (7), annual joint bleeding rate (3), and more frequently an impaired joint (77%) than patients with a severe phenotype on prophylaxis (2; 0; 70%) or patients with a mild phenotype (0; 0; 47%). Furthermore, patients with a severe phenotype treated on demand experienced a more decreased quality of life. Despite similar factor activity levels, patients with a severe phenotype had a lower thrombin peak height and thrombin potential (0.7%; 0.06%) than patients with a mild phenotype (21.3%; 46.8%). ConclusionPatients with moderate hemophilia and a severe phenotype treated on demand displayed a high burden of disease as well as a low thrombin generation profile advocating them toward more intensive prophylactic treatment.

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.)

The immunogenicity, safety, and efficacy of N8-GP in previously untreated patients with severe hemophilia A: pathfinder6 end-of-trial results

BackgroundThe pathfinder6 (NCT02137850) international phase 3 trial examined immunogenicity, safety, and efficacy of the extended half-life factor VIII (FVIII) replacement product N8-GP (turoctocog alfa pegol; Esperoct) in previously untreated patients (PUPs) with hemophilia A. ObjectivesWe present end-of trial results for extended PUP N8-GP treatment for up to a median (range) 2.5 (0.0; 7.4) years. Patients/MethodsLonger-term N8-GP treatment in PUPs with hemophilia A was examined. The prophylaxis regimen was ∼60 IU/kg N8-GP i.v. twice weekly, or every 3 or 7 days. The primary endpoint was the incidence of FVIII inhibitors. ResultsOverall, 81 patients received N8-GP and were included in this analysis. The inhibitor incidence was 30.0% (15.7% high-titer [>5 BU]) for the extension phase. Patients had a median (range) 2.9 (0.1; 7.2) years of prophylaxis following the pre-prophylaxis period. During prophylaxis, the median annualized bleeding rate (ABR) (interquartile range) was 1.4 (0.6; 3.5), 13% of patients experienced no bleeding episodes, and 55.1% of patients experienced no spontaneous bleeds. The proportion of patients without any spontaneous bleeding episodes increased after the first year of prophylaxis. The hemostatic success rate in the treatment of bleeding episodes was 87.6%. No additional safety concerns were observed in patients with previously reported observation of temporarily decreased incremental recovery (IR). ConclusionLong-term end-of-trial PUP N8-GP prophylaxis data indicate that PUPs respond well to long-term N8-GP treatment. The inhibitor incidence was consistent with previous results. Median ABR during prophylaxis was 1.4. There were no lasting clinical impacts or safety concerns for patients with an observation of temporarily decreased IR.

Long-term outcomes of prophylaxis with a recombinant factor VIII Fc or recombinant factor IX Fc in patients with hemophilia previously treated on demand

BackgroundProphylactic factor replacement therapy is recommended over on-demand treatment for preserving long-term joint health in hemophilia. Extended half-life products, including efmoroctocog alfa/eftrenonacog alfa (recombinant factor VIII [FVIII]/FIX Fc fusion proteins; herein rFVIIIFc/rFIXFc), have the potential to reduce treatment burden with less frequent administration and improve bleed prevention. ObjectivesWe report post hoc data from patients with hemophilia A or B (HA/HB) who switched from prestudy on-demand FVIII/FIX to rFVIIIFc/rFIXFc prophylaxis at the start of A-LONG/B-LONG or start of/during ASPIRE/B-YOND phase 3 studies. MethodsPatients with ≥6 months rFVIIIFc/rFIXFc prophylaxis were enrolled. Treatment exposure, dosing, annualized bleeding rates, joint health, and health-related quality of life (HRQoL) outcomes were assessed. Results were also stratified by age. ResultsSixty-seven patients with HA and 50 with HB were analyzed; ≥60% were from regions outside Europe/North America, predominately those aged 12 to ‍25 years. No subjects returned to on-demand treatment postswitch.After switch to rFVIIIFc/rFIXFc prophylaxis, median annualized bleeding rates were reduced and sustained at low levels with stable factor usage across age groups (median treatment duration: 4.8/3.6 years). HRQoL outcomes improved for all ages; most pronounced changes were in the sports and leisure and physical health domains. After switch to rFVIIIFc prophylaxis, total modified Hemophilia Joint Health Score and joints with pain decreased in 64.6% and 29.2% of patients with HA. Insufficient data from patients with HB limited joint health evaluation of rFIXFc. ConclusionsFindings add to existing evidence and demonstrate the clinical and HRQoL benefits of switching patients from on-demand treatment to rFVIIIFc/rFIXFc prophylaxis.

Impact of timing of prophylaxis commencement, F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A.

The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA). To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL). Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively. The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N=15, median age 26 years) and 31.5 years in the secondary group (N=22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p<.001), EQ-5D-5L index (0.9647 vs. 0.904, p=.022), EQ VAS (87 vs. 75, p=.01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p=.02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively,with similar ABR and HJHS. Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.

Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial

Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors. This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete. Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported. In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia. Sanofi.

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.)

Plasma-derived factor VIIa and factor X mixture agent (MC710) prophylaxis in haemophilia B patients with inhibitors.

Haemophilia B patients with factor IX inhibitors have particularly unmet needs for conventional therapy. Phase II/III clinical trial, multicentre, open-label, prospective, self-controlled study was conducted to assess MC710 prophylaxis in haemophilia B patients with inhibitors. We enrolled haemophilia patients who had received episodic or prophylactic treatment with bypassing agents up to that time. The participants continued their conventional therapy for 24weeks and then MC710 was prophylactically infused intravenously every 2 or 3 days at 60 to 120μg as FVIIa per kilogram of body weight for 24weeks. The primary endpoint was the annual bleeding rate (ABR) requiring bypassing agents, which was compared intraindividually between the conventional therapy period and the MC710 prophylaxis period. A total of 11 male haemophilia B patients were enrolled. The median ABR ratio for each participant (the prophylaxis period ABR divided by the conventional therapy period ABR) was .33 (2.1/6.5), range from .00 to 3.77. ABR ratios for 9 of the 11 patients ranged from .00 to .60, and 3 of the 9 patients had zero bleeding events during the prophylaxis period. Meanwhile, ABR ratios for the remaining two patients were 2.53 and 3.77, respectively. Although a fibrinogen decrease recovered by the dose reduction was reported for only one participant as the sole adverse drug reaction in this study, no thrombotic events or other safety concerns were reported. MC710 prophylaxis is considered to be decrease the bleeding rate in haemophilia B patients with inhibitors without safety concerns.