Spontaneous Annualized Bleeding Rate Research Articles

The Real-World Data of Emicizumab in Previously Untreated and Minimally Treated Patients with Hemophilia a Infants from China

Introduction Emicizumab (EMI) is safe and efficient in pediatric patients with hemophilia A (HA). However, real-world data regarding immune response, pharmacokinetics (PK) and pharmacodynamics (PD) during EMI for previously untreated (PUP) and minimally treated (MTP) patients with HA infants(<3y) are limited in China. This study investigated the immune response and PK/PD of EMI in PUP and MTP with HA infants in China. Methods We performed a retrospective analysis of pediatric HA patients to collect data on PUPs and MTPs at our Comprehensive Hemophilia Care Center. Data included patients' baseline characteristics, therapy details, bleeding episode of pre- and post-EMI, and adverse events. Immune response included anti-emicizumab antibodies (ADAs) and factor VIII (FVIII) inhibitors. Laboratory analyses included FVIII-like activity and EMI concentration measurements. Results Sixteen PUPs and MTPs with HA had received EMI prophylaxis for a median (range) duration of 21.8 (4.9-47.0) months by July 2024. The median age at the beginning of EMI was 11.8 (5.8-33.3) months. At the initiation of EMI, all patients were inhibitor-negative. While on EMI, EMI showed effectively prevented bleeding even: the median annualized bleeding rate (ABR) of 0.6 (0.0-1.9), annualized joint bleeding rate (AJBR) of 0.0 (0.0-0.3), and annualized spontaneous bleeding rate (ASBR) of 0.0 (0.0-1.59). Seven(43.8%) patients reached zero-bleeding rate (ZBR). No drug-related serious adverse events were observed. In the loading phase, patients with median age of 10.8 (5.8-32.9) months and body mass index (BMI) of 17.8 (15.6-21.6) received a median EMI loading dose of 3.0 (2.4-3.5) mg/kg. Their median EMI concentration was 65.9 (36.2-79.9) μg/mL and FVIII-like activity was 27.0 (13.5-35.4) IU/dL. Even though the mdian EMI 4-weekly maintenance dosage [4.8 (4.0-5.6)mg/kg] was below the internationally recommended dosage (6mg/kg), patients reached EMI concentration of 50.2 (36.0-76.8) μg/mL, and FVIII-like activity of 14.9 (10.4-30.4) IU/dL. EMI concentration was correlated with FVIII-like activity (rs=0.858，p＜0.001). Four (25%) patients received a total of 9 administrations of factor-based therapy. During the long-term follow-up period, the median number of exposure days (EDs) was only 0 (0-3) days. No patients tested positive for ADAs or FVIII inhibitors. Conclusion EMI has demonstrated favorable tolerability and efficacy in PUPs and MTPs with HA in infants. Using EMI at substandard doses can still achieve relatively high maintenance concentrations. Furthermore, the concentration of EMI correlates well with their FVIII-like activity. No patients developed ADAs or FVIII inhibitors.

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.

The use of emicizumab in children with hemophilia A without inhibitors in the real-world clinical setting

In our country, the use of emicizumab in children with hemophilia A without inhibitors (HA) in the real-world clinical setting is limited and is available only as few individual case reports. Our aim was to evaluate the effectiveness and safety of the prophylactic use of emicizumab in children with severe HA in the real-world clinical setting. We conducted a retrospective analysis of medical records of children with HA who had received emicizumab at 9 centers based in the Russian Federation. We assessed the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (ASBR), annualized joint bleeding rate (AJBR), annualized bleeding rate for bleeding episodes that required additional treatment with FVIII concentrate (ABRRT) and the number of hospital admissions for bleeding both before and after the treatment with emicizumab, as well as the occurrence and severity of adverse events during the therapy. Ethics committee approval was not required for this study because it involved the use of aggregated retrospective data from routine clinical practice that were fully anonymized. Two emicizumab administration regimens were compared with regard to their effectiveness. Before the treatment with emicizumab, ABR was 5.38 (95% confidence interval (CI) 3.90–7.64), ASBR – 4.16 (95% CI 2.99–5.94), AJBR – 2.7 (95% CI 1.87–4.03), and ABRRT – 4.8 (95% CI 3.37–7.08). After the initiation of the treatment with emicizumab, the bleeding rate plummeted: ABR decreased by 93.9% (95% CI 88.8–96.7), ASBR – by 96.9% (95% CI 93.1–98.6), AJBR – by 96.1% (95% CI 90.4–98.4%) and ABRRT – by 95.1% (95% CI 90.0–97.6). During the treatment with emicizumab, the rate of bleeding episodes that required hospital admission decreased from 1.58 (95% CI 0.98–2.68) to 0.04 (0.01–0.10), which amounted to 97.6% (95% CI 91.1–99.4). The median follow-up time for the patients treated with emicizumab was 15.5 months (range 9–29 months). When comparing the annualized bleeding rates in the groups of the patients who were preventively treated with emicizumab at doses of 3 mg/kg (administered once every 2 weeks) and 1.5 mg/kg (once per week), we didn't find any statistically significant differences. In the real-world clinical setting, the use of emicizumab in the children with HA led to a significant reduction in all bleeding episodes (by more than 90%), regardless of the administration regimen.

Prophylaxis with recombinant von Willebrand factor in patients with type 3 von Willebrand disease: Results of a post hoc analysis from a phase 3 trial.

To describe efficacy/safety of recombinant von Willebrand factor (rVWF) prophylaxis in patients with type 3 von Willebrand disease (VWD). This post hoc analysis of a phase 3 open-label trial provides a more detailed analysis of adults with type 3 VWD, categorized based on prior treatment at screening: "Prior On-Demand (OD)" (OD VWF; ≥3 documented spontaneous bleeding events [BEs] requiring VWF in previous 12 months) or "Switch" (plasma-derived [pd] VWF prophylaxis for ≥12 months). Annualized bleeding rates (ABRs) were evaluated during 12 months of rVWF prophylaxis versus historical data from medical records. In the Prior OD group (n = 10), mean spontaneous ABR (sABR) for treated BEs was reduced by 91.6% (ratio, 0.08; 95% CI, 0.02-0.45) versus mean historical sABR. In the Switch group (n = 8), mean sABR for treated BEs was reduced by 47% (ratio, 0.53; 95% CI, 0.08-3.62). One non-serious adverse event (AE) was considered possibly related to rVWF. No treatment-related, fatal, or life-threatening serious AEs were reported, and no patient developed VWF inhibitors. rVWF prophylaxis reduced sABR in type 3 VWD patients previously treated with OD VWF therapy, and maintained a similar level of hemostatic control in those switching from pdVWF prophylaxis to rVWF prophylaxis.

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

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

Real-world experience of emicizumab prophylaxis in young children with hemophilia A: retrospective data from China.

As a new non-factor therapy for hemophilia A (HA), real-world study of emicizumab is still scarce. This study aimed to investigate the real-world use of emicizumab in Chinese boys with HA. Patients with moderate or severe HA were enrolled at Beijing Children's Hospital. They take emicizumab weekly (3 mg/kg) for a month and then went into a maintenance period with a different dosing regimen. After obtaining platelet-poor plasma at end of the loading period and during the maintenance period, coagulation ability and FVIII inhibitor were determined using human and bovine chromogenic Bethesda assay. Patients' bleeding rates were calculated through patients' records from 24 weeks before to at least 6 months after the switch (to emicizumab). In total, 13 pediatric patients with HA (severe: moderate = 11:2) were enrolled in this study. The patients' age was 3.51 (0.73-6.65) years. Eight had FVIII inhibitors at enrollment and one of them developed FVIII inhibitors again during the switch. The coagulation level of the maintenance period was 19.6 (13.5-32.8) IU/dL (N = 10). The median dose of each emicizumab injection was 2.7 (1.3-3.8) mg/kg and the monthly consumption of emicizumab was 5.2 (3.2-6.8) mg/kg/month. After switching to emicizumab, reduced annualized bleeding rate (ABR) [0.5 (0-4) vs. 4 (0-18), P < 0.01], annualized joint bleeding rate (AJBR) [0 (0-1.1) vs. 1.0 (0-12), P < 0.01], and annualized spontaneous bleeding rate (ASBR) [0 (0-1) vs. 2.0 (0-18), P < 0.01] were observed. In patients with or without FVIII inhibitor, similar ABR [0.33 (0-4) vs. 0.5 (0-3), P = 0.78], AJBR [0 (0-1.1) vs. 0 (0-0.5), P = 0.63], and ASBR [0 (0-1) vs. 0 (0-1.5), P = 0.73] were also noticed. Five inhibitor-positive patients (at enrollment) all had their inhibitor titer reduced. In addition, all target joints vanished after switching to emicizumab. Emicizumab could reduce bleeds in pediatric patients with/without FVIII inhibitors and eliminate target joints.

Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors

AbstractDespite current therapies, there remains an unmet need for treatment for patients with hemophilia. The main parts of two phase 2 trials established clinical proof-of-concept for once-daily, subcutaneous concizumab prophylaxis in patients with hemophilia A/B with inhibitors (HAwI/HBwI; explorer4) and severe hemophilia A without inhibitors (HA; explorer5). Here, we present results from extension parts of these trials, included to evaluate longer term safety and efficacy. Both trials included main (≥24 weeks) and extension (52-102 weeks) parts, with patients receiving concizumab 0.15 mg/kg with potential dose escalation to concizumab 0.20 or 0.25 mg/kg if they experienced ≥3 treated spontaneous bleeding episodes within 12 weeks. Endpoints included annualized bleeding rate (ABR), adverse events (AEs), and occurrence of antidrug antibodies. Thromboembolic events were AEs of special interest. Thirty-six patients with HA, 15 with HAwI, and 10 with HBwI were exposed to concizumab. Estimated ABRs during the main + extension parts at last dose level were 4.8 (95% confidence interval [CI], 3.2-7.2) and 6.4 (95% CI, 4.1-9.9) in explorer4 and explorer5, respectively (spontaneous ABRs were 1.8 [95% CI, 1.2-2.6] and 2.1 [95% CI, 1.3-3.3]). Most AEs were mild, with no deaths, events leading to withdrawal, or thromboembolic events. Anti-drug antibodies developed in 25% of patients and were low titer and transient, with no observed clinical effect in most cases. Results of the main + extension parts of these trials were consistent with results of the main parts. Ongoing phase 3 trials will further evaluate concizumab as a once-daily, subcutaneous treatment across hemophilia subtypes. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297.

Recombinant single‐chain factor VIII in severe hemophilia: Long‐term safety and efficacy in previously treated patients in the AFFINITY extension study

BackgroundrVIII‐SingleChain is a recombinant single‐chain factor VIII used to treat people with hemophilia A. ObjectivesThe aim of this extension study was to investigate the long‐term safety and efficacy of rVIII‐SingleChain prophylaxis in ≥200 previously treated patients (PTPs) with hemophilia A with ≥100 exposure days (EDs). MethodsIn total, 222 patients were enrolled, of which 204 rolled over from prior rVIII‐SingleChain studies. The median age was 21 years (range, 2–65 years), including 155 patients ≥12 years and 67 patients <12 years. Patients continued with their previously assigned dose and regimen, or switched at the investigator’s discretion. Patients were treated for a mean duration of 31 months (range, 1–47 months), the mean ED was 342 (standard deviation, 135.5), and 212 (95.5%) patients achieved >100 EDs. When the study ended, most patients were on either a prophylaxis regimen of 34.9 (17–62) IU/kg, 3×/week (N = 88; 39.6%), or 37.2 (13–65) IU/kg, 2×/week regimen (N = 72; 32.4%). ResultsHemostatic efficacy was rated excellent or good in 87.1% of assessed bleeds. The median (range) annualized bleeding rate was 1.21 (0.0–42.6), and the annualized spontaneous bleeding rate (AsBR) was 0.32 (0.0–33.0) for prophylaxis regimens. Median AsBR was similar for patients treated 3×/week and 2×/week (0.31 and 0.30, respectively). Surgical hemostatic efficacy was rated excellent or good in 100% of surgeries. No inhibitors, anaphylactic reactions, or thromboembolic events were reported in PTPs. ConclusionThese results confirm the safety and efficacy of rVIII‐SingleChain as a long‐term prophylaxis treatment modality for PTPs with severe hemophilia A.

Fitusiran, an Investigational siRNA Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: First Results from a Phase 3 Study to Evaluate Efficacy and Safety in People with Hemophilia a or B without Inhibitors (ATLAS-A/B)

Fitusiran, an Investigational siRNA Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: First Results from a Phase 3 Study to Evaluate Efficacy and Safety in People with Hemophilia a or B without Inhibitors (ATLAS-A/B)

Efficacy and Safety of Fitusiran Prophylaxis, an siRNA Therapeutic, in a Multicenter Phase 3 Study (ATLAS-INH) in People with Hemophilia A or B, with Inhibitors (PwHI)

IntroductionHemophilia A and B are rare bleeding disorders characterized by ineffective clot formation due to impaired thrombin generation as a result of deficiency of FVIII or FIX, respectively. Fitusiran is a subcutaneously (SC) administered investigational siRNA therapeutic targeting antithrombin to restore thrombin generation and rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. Here, we present the safety and efficacy of fitusiran prophylaxis for PwHI in a phase 3 study (ATLAS-INH; NCT03417102).MethodsThe ATLAS-INH study is a randomized, open-label Phase 3 study designed to evaluate the efficacy and safety of fitusiran in PwHI. Eligible males ≥12 years receiving on-demand treatment with bypassing agents (BPA) were randomized in a 2:1 ratio to receive once monthly 80 mg SC fitusiran prophylaxis or continue with on-demand BPA. The primary endpoint is annualized bleeding rate (ABR) in PwHI on fitusiran prophylaxis compared to those on BPA on-demand in the efficacy period. The secondary endpoints include spontaneous ABR, joint ABR, and quality of life (QoL) measured by Haem-A-QoL.Results57 subjects were randomized into the study. Mean (range) age of the study participants at screening was 28.4 (13-63) yrs. Statistical significance was achieved for primary and all secondary endpoints with significant reduction in ABRs of treated bleeds: all, spontaneous and joint bleeds for fitusiran vs on-demand BPA arm (Table 1). A total of 25 patients in fitusiran arm (65.8%) had zero treated bleeding events. Efficacy of fitusiran prophylaxis treatment was seen in both hemophilia A and hemophilia B patients with inhibitors. Statistical significance was also achieved for improvement in physical health domain score, with a difference (95% CI) of -28.72 (-39.07 to -18.37, p-value <0.0001) as well as overall HRQoL and between fitusiran and on-demand BPA arms.Overall, 38 patients (92.7%) in the fitusiran arm and 11 patients (57.9%) in the on-demand BPA arm experienced at least 1 treatment emergent adverse event (TEAE). A total of 13 treatment emergent serious adverse events (TESAEs) were reported in 7 patients (17.1%) in the fitusiran arm and 8 TESAEs were reported in 5 patients (26.3%) in the on-demand BPA arm. All TESAEs were reported in 1 patient each; in the fitusiran prophylaxis arm these included events of device related infection, hematuria, spinal vascular disorder, subclavian vein thrombosis, thrombosis, acute cholecystitis, chronic cholecystitis and asymptomatic COVID-19. One patient (2.4%) in the fitusiran arm experienced TEAEs that resulted in study drug discontinuation (spinal vascular disorder and thrombosis). There were no fatal TEAEs reported.ConclusionsThis Phase 3 study demonstrated the efficacy of the 80 mg monthly subcutaneous prophylaxis dose of fitusiran in people with hemophilia A or B with inhibitors. Specifically, fitusiran significantly reduced bleeding with a median ABR of zero and significant proportion of people with zero bleeds, resulting in a meaningful improvement in health-related quality of life. Reported TESAEs were generally consistent with what is anticipated in an adult and adolescent population with severe hemophilia A or B with inhibitors, or with the previously identified risks of fitusiran. A revised fitusiran dosing regimen with reduced dose and dose frequency is currently being evaluated in ongoing clinical studies. [Display omitted] DisclosuresYoung: Genentech/Roche, Grifols, and Takeda: Research Funding; Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy. Kavakli: Roche: Consultancy, Other: Clinical Trial Support; Novo Nordisk A/S: Consultancy, Other: Clinical Trial Support; Takeda: Consultancy, Other: Clinical Trial Support. Poloskey: Sanofi: Current Employment, Current equity holder in publicly-traded company. Qui: Sanofi: Current Employment, Current equity holder in publicly-traded company. Kichou: Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson: Sanofi: Current Employment, Current equity holder in publicly-traded company; WEST advisory committee member: Membership on an entity's Board of Directors or advisory committees. Mei: Sanofi: Current Employment, Current equity holder in publicly-traded company. Rangarajan: Sanofi: Other: Advisory Board; Pfizer: Other: Advisory Board; Reliance Life Sciences: Consultancy; Takeda: Other: Advisory Board, Conference Support, Speakers Bureau.

Clinical benefits of a Bayesian model for plasma-derived factor VIII/VWF after one year of pharmacokinetic-guided prophylaxis in severe/moderate hemophilia A patients

IntroductionIndividual pharmacokinetic (PK) profiling in hemophilia A (HA) helps to individualize prophylaxis using population PK models (popPK). A specific popPK model for plasma-derived factor VIII containing von-Willebrand Factor (pdFVIII/VWF) was developed. AimTo compare standard versus PK-driven prophylaxis, using a generic or a specific popPK model for pdFVIII/VWF. Materials and methodsA prospective study conducted in HA patients in prophylaxis with pdFVIII/VWF (Fanhdi®) comparing three one-year study periods: (1) standard prophylaxis, (2) PK-guided prophylaxis using a generic pdFVIII popPK model which described FVIII activity irrespective of FVIII concentrate, and (3) PK-guided prophylaxis with specific pdFVIII/VWF popPK model. PK parameters analyzed were half-life, trough levels (TL) at 24, 48 and 72 h, and time to reach FVIII levels of 1, 2, 5% (T5%). Clinical outcomes were dose/kg, FVIII consumption, annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), spontaneous and traumatic bleeds. ResultsOf the 30 analyzed patients, 28 had severe HA and the median age was 31.2. Fifteen patient's prophylaxis doses were PK-adjusted. After the generic PK-guided prophylaxis period, younger patients showed more joint bleeds, a shorter half-life, and lower TL48, TL72 and T5%. Using the specific pdFVIII/VWF popPK model compared with standard prophylaxis, a lower spontaneous AJBR was observed in the entire cohort and in patients aged >15 years. Additionally, lower spontaneous ABR was reported in patients aged ≤15 years comparing specific and generic models. ConclusionsPK-guided prophylaxis with a specific pdFVIII/VWF popPK model allowed treatment individualization and improved bleeding control in routine clinical practice, especially in younger patients with short pdFVIII/VWF half-lives.

BAY 94-9027 Provides Safe and Effective Long-Term Prophylaxis in Pediatric Patients: Results from the PROTECT VIII Kids Extension Study

BAY 94-9027 Provides Safe and Effective Long-Term Prophylaxis in Pediatric Patients: Results from the PROTECT VIII Kids Extension Study

Interim Analysis of the Extension Study with rVIII-SingleChain in Previously Untreated Patients (PUPs) with Severe Hemophilia A (CSL627-3001)

Interim Analysis of the Extension Study with rVIII-SingleChain in Previously Untreated Patients (PUPs) with Severe Hemophilia A (CSL627-3001)

Inhibitor Development with Simoctocog Alfa in Previously Untreated Patients with Severe Haemophilia a: Final Results of the Nuprotect Study

Introduction FVIII inhibitor development is the greatest challenge when treating previously untreated patients (PUPs) with hemophilia A (HA). The SIPPET study reported a cumulative inhibitor incidence of 44.5% (28.4% high-titre) in PUPs treated with recombinant FVIII (rFVIII) products produced in hamster cell lines and 26.8% (18.6% high-titre) with plasma-derived FVIII products containing von Willebrand factor (pdFVIII/VWF). Simoctocog alfa (Nuwiq®) is a 4th generation rFVIII produced in a human cell line without chemical modification or protein fusion. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in PUPs with severe HA. A prespecified interim analysis was published with data up to 20 and 50 EDs (Haemophilia 2018; 24:211) and here we report the final results. Methods NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. True PUPs (no prior FVIII treatment) with severe HA of any age and ethnicity were to be enrolled and treated for 100 exposure days (EDs) or a maximum of 5 years with simoctocog alfa for prophylaxis, on-demand treatment, treatment of breakthrough bleeding episodes (BEs) and surgical prophylaxis. Type of treatment and dose were determined by the investigator. Inhibitor screening (modified Bethesda assay) was performed at screening, every 3-4 EDs until ED20, then every 10-12 EDs or at least every 3 months, at completion, and if inhibitor development was suspected. Inhibitor levels of ≥0.6 to &amp;lt;5 Bethesda units [BU]/mL were defined as low-titer and ≥5 BU/mL as high-titer. Cumulative inhibitor incidence (primary endpoint) and 95% confidence intervals (CIs) were calculated (Kaplan-Meier). Efficacy endpoints (inhibitor-free periods) included the annualized bleeding rate (ABR) during prophylaxis and efficacy in treating BEs/surgical prophylaxis (4-point objective scales: excellent, good [successful]; moderate or none). Adverse events (AEs) were monitored throughout the study. Results Of 108 subjects consented, 105 PUPs, median age of 12 months (range 0-146) at ED1 were evaluable for inhibitor development. They were treated for a median of 101 EDs (range 1-1164), with 96 patients treated for ≥100 EDs (or until inhibitor development, including 5 patients with 97-99 EDs). The majority of patients with available genetic data had null F8 gene mutations (90/102 [88.2%]) and 13 (12.0%) had a family history of inhibitors. Cumulative inhibitor incidence was 17.6% (95% CI: 10.0%, 25.3%) for high-titre inhibitors and 27.9% (95% CI: 19.1%, 36.7%) for all inhibitors (Figure 1). No PUPs with non-null F8 mutations developed inhibitors. In 50 PUPs on continuous prophylaxis for ≥6 months, the mean (SD) ABR was 0.54 (1.07) [median 0] for spontaneous BEs and 3.61 (3.82) [median 2.53] for all BEs. The treatment of BEs was successful in 92.9% (747/804) of rated BEs in 85 patients with treated BEs and 91.9% of BEs were controlled with 1 or 2 infusions. Surgical prophylaxis was successful for 94.7% (18/19) of rated procedures and moderate for 5.3% (1/19). Excluding inhibitors, only one (0.9%) patient had an AE classified as serious by the investigator (hospitalization due to a mild rash that resolved with anti-histamine treatment). Conclusions Simoctocog alfa had a similar inhibitor incidence in PUPs with severe HA as pdFVIII/VWF products in SIPPET. No inhibitors occurred in PUPs with non-null F8 mutations. Simoctocog alfa had a median spontaneous ABR of 0 during prophylaxis and was successful in the treatment of 92.9% of BEs and in 94.7% of surgical procedures. These results complement results in previously treated patients (PTPs) and support the use of simoctocog alfa in the prevention and treatment of BEs in PUPs and PTPs. References Liesner R, et al. Haemophilia 2018; 24: 211-20. Disclosures Liesner: Octapharma, Bayer, Takeda, Novo Nordisk, CSL Behring, Roche: Research Funding; Octapharma, SOBI, Novo Nordisk: Speakers Bureau; Octapharma, Bayer, Takeda: Consultancy. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored).

Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP

Aims: Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals, and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients.Materials and methods: A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated hemophilia B patients aged ≥12 years (FIX ≤2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A z-test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated.Results: Seven articles investigating six rFIX products were identified. Median ABR, AsBR, and AjBR ranged from 0–3.0, 0–1.0, and 0–1.1 (means = 0.8–4.26, 0.13–2.6, and 0.34–2.85), respectively. rIX-FP achieved the lowest median and mean values in all three parameters. Z-tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products.Limitations: The low number of appropriate trials available for comparison limits the quantity of data available for comparison, and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field.Conclusion: This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably vs other rFIX products for prophylaxis in hemophilia B.

Extended Interval Prophylaxis with Bay 94-9027 for > 4 Years Leads to Median Spontaneous Annualized Bleeding Rates < 1 in the Protect VIII Extension

Introduction: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial. This analysis provides an updated assessment of the frequency of spontaneous bleeds with BAY 94-9027 prophylaxis during the PROTECT FVIII trial and its extension of more than 4 years.Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days (ED). Prophylaxis patients received BAY 94-9027 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous or joint bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice weekly (2×W). Following completion of the main PROTECT VIII trial, patients could enter an extension, continuing BAY 94-9027 prophylaxis on either their regimen or switch regimens at the beginning or at any time during the extension. Prophylaxis patients who switched regimen at any time later than 7 days after the beginning of the extension period, were analyzed together in a variable frequency group. Annualized bleeding rates (ABRs) of spontaneous and trauma bleeds were calculated.Results: The intent-to-treat population in the PROTECT VIII study extension included 121 subjects (prophylaxis, n = 107; on demand, n = 14) of the 134 previously treated with BAY 94-9027 in the main study. At data cut-off (31 January 2018), patients in the prophylaxis arms had spent a median (range) of 3.9 (0.8; 5.4) years on-study (main and extension studies combined; a median of 3.2 years were in the extension), with 223 (23; 563) ED. Median dose of BAY 94-9027 prophylaxis during the extension study was 47.8 IU/kg/infusion, with total FVIII consumption of 3488 IU/kg/year. The overall adherence was 100%. At data cut-off or last visit, 34, 45 and 28 patients were in the 2xW, E5D and E7D treatment arms, respectively. During the extension period, median spontaneous ABR (Q1; Q3) was 0.7 (0.0; 2.9) in patients receiving BAY 94-9027 prophylaxis; 2×W (n = 23, 0.8 [0.0; 3.1]), E5D (n = 33, 0.7 [0.0; 2.9]), E7D (n = 23, 0.2 [0.0; 0.8]), or at a variable frequency (n = 28, 1.8 [0.7; 4.3]). This was consistent with median spontaneous ABRs (Q1; Q3) in the main study of 0.0 (0.0; 4.0), 0.0 (0.0; 4.0) and 1.9 (0.0; 6.3) for patients receiving BAY 94-9027 infusions 2×W (n = 24), E5D (n = 43), or E7D (n = 43), respectively; and with spontaneous ABRs for the last 12 months of the extension study of 1.5 (0.0; 2.0), 1.0 (0.0; 3.0) and 0.0 (0.0; 0.0) for these treatment groups (1.0 [1.0; 2.12] in the variable group). Rates of trauma bleeding were consistent across the study periods, with a median ABR of 0.0 in each prophylaxis group in the main study (0.0 [0.0; 2.0] for all prophylaxis patients), 0.3 (0.0; 1.3) for all prophylaxis patients in the extension and 0.0 (0.0; 1.0) for all prophylaxis patients in the last 12 months of the extension.Conclusions: Most patients were treated every 5 or 7 days with BAY 94-9027. Median spontaneous ABR remained < 1 with prophylaxis for > 4 years in all treatment groups (2×W, E5D and E7D). DisclosuresAhuja:Bayer: Honoraria; Bioverativ: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Tseneklidou-Stoeter:Bayer: Employment.

Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B

AbstractGene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay, and all 10 were enrolled. A single dose of 5 × 1012 or 2 × 1013 genome copies of AMT-060/kilogram was administered to 5 participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8% to 4.6% (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts, and 8 of 9 participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n = 1) and higher-dose (n = 2) cohorts were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids. This trial was registered at www.clinicaltrials.gov as #NCT02396342; EudraCT #2013-005579-42.

Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIFc) in Adults/Adolescents with Severe Hemophilia a

Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIFc) in Adults/Adolescents with Severe Hemophilia a

Clinical Outcomes in Adults/Adolescents with Hemophilia B Treated Long Term with Recombinant Factor IX Fc Fusion Protein (rFIXFc) Prophylaxis: Interim Results of the B-Yond Extension Study

Clinical Outcomes in Adults/Adolescents with Hemophilia B Treated Long Term with Recombinant Factor IX Fc Fusion Protein (rFIXFc) Prophylaxis: Interim Results of the B-Yond Extension Study

Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Children with Severe Hemophilia a

Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Children with Severe Hemophilia a