Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B.

BACKGROUND: Fidanacogene elaparvovec, an adeno-associated virus (AAV) gene-therapy vector for hemophilia B containing a high-activity human factor IX variant (FIX-R338L/FIX-Padua), was associated with sustained factor IX activity in a phase 1-2a study. METHODS: We conducted a phase 3 open-label study of fidanacogene elaparvovec at a dose of 5×1011 vector genome copies per kilogram of body weight. Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were eligible for screening if they had received at least 6 months of therapy with prophylactic factor IX concentrate. The primary end point, tested for noninferiority, was the annualized bleeding rate (treated and untreated bleeding episodes) from week 12 to month 15 after treatment with fidanacogene elaparvovec as compared with the prophylaxis lead-in period. Superiority, additional efficacy end points, and safety were also assessed. RESULTS: Of 316 men who underwent screening for the lead-in study, 204 (64.6%) were not eligible; 188 (59.5%) of those were ineligible owing to the presence of anti-AAV neutralizing antibodies. Of the 45 participants who received fidanacogene elaparvovec, 44 completed at least 15 months of follow-up. The annualized rate of bleeding for all bleeding episodes decreased by 71%, from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after gene therapy, a treatment difference of -3.15 episodes (95% CI, -5.46 to -0.83; P = 0.008). This result shows the noninferiority and superiority of fidanacogene elaparvovec to prophylaxis. At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0) by one-stage SynthASil assay. A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, development of factor IX inhibitors, or malignant conditions were observed. CONCLUSIONS: Fidanacogene elaparvovec was superior to prophylaxis for the treatment of participants with hemophilia B, leading to reduced bleeding and stable factor IX expression. (Funded by Pfizer; BENEGENE-2 ClinicalTrials.gov number, NCT03861273.).

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

ABSTRACT: Fitusiran, 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.

Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b open-label trial.

ABSTRACT: Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30-0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors.

Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. METHODS: This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102. FINDINGS: Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. INTERPRETATION: Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. FUNDING: Sanofi.

Plasma-derived human factor X concentrate for the treatment of patients with hereditary factor X deficiency.

INTRODUCTION: Hereditary factor X (FX) deficiency (HFXD) is an autosomal recessive rare bleeding disorder that leads to defects in the FX protein. Depending on the degree of deficiency, patients may be at risk of life-threatening bleeding episodes. Historical treatments for FX deficiency include prothrombin complex concentrates, which can increase the risk of thrombosis, and fresh frozen plasma, which can cause volume overload and transfusion reactions. Plasma-derived FX (pdFX), a single-factor, high-purity, high-potency human FX treatment, was approved in 2015 in the United States and in 2016 in Europe for on-demand treatment and prophylaxis of bleeding episodes and perioperative management of patients with HFXD. METHODS: Five studies that examined the use of pdFX in patients with mild (plasma FX activity [FX:C] ≥5 IU/dL), moderate (FX:C ≥1 and <5 IU/dL), or severe (FX:C < 1 IU/dL) HFXD were reviewed: TEN01, TEN02 and TEN03 were prospective, open-label, multicentre, nonrandomised studies, and TEN05 and TEN06 were multicentre retrospective studies. RESULTS: When used as an on-demand treatment, pdFX was judged by investigators to be successful in treating 41/42 (97.6%), 2/3 (66.6%) and 79/79 (100%) bleeds in TEN01, TEN02 and TEN05, respectively. When used prophylactically, pdFX was judged 'excellent' for the prevention of bleeds in nine (100%) and eight (100%) patients in TEN02 and TEN05, respectively. Perioperative treatment and pharmacokinetics were also assessed. pdFX was safe and well tolerated. CONCLUSIONS: Together, these studies support the use of pdFX for on-demand treatment of bleeding, routine prophylaxis, and perioperative management of bleeding in patients with HFXD.

Accuracy and clinical role of digital templating for total knee arthroplasty performed on haemophilic knees.

INTRODUCTION: In total knee arthroplasty (TKA), choosing the correct implant size is important. There is lack of data on accuracy of templating on haemophilic knees. Our aim was to test the accuracy of 2D digital templating for TKA on haemophilic arthropathy (HA) of knee. MATERIALS AND METHODS: TKAs performed on HA between January 2011 and January 2022 were screened. Osteoarthritis (OA) group was created as control group by a one-to-one matching regarding type of implant used. Intra- and interobserver correlations were measured in HA, then correlation between templated and implanted sizes was investigated in four assessments (femur AP, femur lateral, tibia AP, tibia lateral), then compared with OA group. Fifty-eight knees in each group included. RESULTS: Regarding intraobserver correlation in HA, there was excellent correlation for femur AP [.93 (.73-.98)], femur lateral [.98 (.91-.99)], and tibia AP (1.0) templating. Regarding interobserver correlation in HA, excellent correlation was observed for femur lateral [.93 (.74-.98)] and tibia AP templating [.90 (.65-.97)]. Regarding correlation of templated and applied sizes in HA; tibia AP, tibia lateral and femur lateral templating showed good correlation [.81 (.70-.89), .86 (.77-.91), .79 (.67-.87) while femur AP templating showed moderate correlation [.67 (.50-.79)]. Comparing HA and OA, there was no difference in correlation levels regarding femur AP, femur lateral, tibia AP and tibia lateral templating (p = .056, p = .781, p = .761, p = .083, respectively). CONCLUSION: Although 2D digital templating shows comparable correlation in HA and OA, clinical applicability of templating on HA appears to be limited in its current state.

Morphological analysis of patellofemoral joint in haemophilic arthropathy: A case-control study.

INTRODUCTION: Knees affected by haemophilic arthropathy exhibit distinct differences in both bone morphology and soft tissue behaviour. This study aims to analyse the morphological characteristics of the distal femur and patellofemoral joint in patients with haemophilia in comparison to normal healthy population. MATERIAL AND METHODS: Study was conducted as pair-matched case-control study with 43 individuals in both the haemophilia group and the control group. Patellar luxation, patellar tilt (PT), length of the patella in both axis (pAP, pML), depth and angle of trochlear sulcus (SD, SA), lateral trochlear inclination (LTI), medial and lateral femoral facet length (mFL, LFL), intercondylar depth (ID), transepicondylar axis (TEA) and lateral condyle length (LCL) were assessed on knee MRI. Correlation between Pettersson score and measured variables were also analysed. RESULTS: PT was medial sided in 10 (23.2%) cases in haemophilic group. Mean values of pAP, pML, PT were significantly lower in haemophilia group (p < .001, p: .007, p = .001 respectively). There were no significant changes in SA (p = .628), SD (p = .340), LTI (p = .685), LFL (p = .241) and MFC-LFC (p = .770) whilst mFL was significantly longer in haemophilia group (p = .009). ID (p < .001), TEA (p = .007) and LCL (p = .001) were all shorter in haemophilia group. Pettersson score was inversely correlated with pAP, pML, ID, TEA, LCL, pML/SA and ID/LCL. CONCLUSION: Morphological changes in haemophilic arthropathy involve a smaller and medially-tilted patella, narrowed lateral condyle and transepicondylar axis, combined with reduced intercondylar depth. These alterations must keep in mind especially in pre- and intraoperative assessments for arthroplasty procedures.

Recombinant porcine factor VIII in patients with congenital haemophilia A with inhibitors undergoing surgery: Phase 3, single-arm, open-label study.

INTRODUCTION: Recombinant porcine factor VIII (rpFVIII; susoctocog alfa) is predicted to provide functional FVIII activity in patients with congenital haemophilia A with inhibitors (CHAWI). AIMS: To evaluate the efficacy and safety of rpFVIII in patients with CHAWI undergoing invasive procedures. METHODS: This phase 3, multicentre, single-arm, open-label study (NCT02895945) enrolled males aged 12-75 years with severe/moderately severe CHAWI who required surgical/invasive procedures. Patients received a loading dose of rpFVIII 1-2 h before surgery. The primary outcome was the proportion of all procedures with a 'good' or 'excellent' response (treatment success) on the global haemostatic efficacy assessment score. RESULTS: Of the eight dosed patients, five completed the study. Six of seven surgeries (85.7%; 95% confidence interval, 42.1-99.6) achieved treatment success; five were rated 'excellent', one was rated 'good'. Seven surgery-related bleeding episodes occurred in three patients during the study, with none requiring additional surgical intervention. Overall, six of eight patients experienced 17 treatment-emergent adverse events. Three patients developed de novo inhibitors to rpFVIII. Five patients reported anamnestic reactions, three to both human (h) FVIII (i.e., alloantibodies to exogenous FVIII detected with anti-hFVIII assays) and rpFVIII, and two to hFVIII only. Four serious adverse events were considered related to rpFVIII (three anti-rpFVIII antibody positive; one anamnestic reaction to hFVIII and rpFVIII). CONCLUSION: Good haemostasis was achieved with rpFVIII during the immediate perioperative period. The study was terminated early because the study sponsor and health authorities determined that the risk of anamnestic reactions outweighs the benefits in this study population.

Management of haemophilia A with inhibitors: A regional cross-talk.

INTRODUCTION: The development of inhibitors with factor VIII (FVIII) replacement therapy is one of the most common and challenging complications of haemophilia A (HA) treatment, jeopardising treatment efficacy and predisposing patients to high risks of morbidity and mortality. The management of patients with inhibitors is particularly challenging in countries where resources are limited. AIM: To provide a comprehensive summary of the management of HA with inhibitors while focusing on differences in practice between Western and non-Western countries and how resource scarcity can impact HA management, leading to suboptimal outcomes in patients with inhibitors. METHODS: Summary of key evidence and regional expert opinion. RESULTS: We address, particularly, the diagnosis of and testing for inhibitors, as well as the epidemiology of inhibitors, including incidence, prevalence and disease burden. Secondly, we provide an overview of the current treatment landscape in HA with inhibitors regarding the eradication of inhibitors with immune tolerance induction and the treatment and prevention of bleeding with bypassing agents, non-factor replacement agents and other experimental therapies. This is complemented with insights from the authors around the applicability of, and challenges associated with, such therapies in their settings of practice. CONCLUSIONS: We conclude by proposing some key steps towards bridging the gaps in the management of HA with inhibitors in resource-limited countries, including: (1) the collection of quality data that can inform healthcare reforms and policies; (2) improving disease knowledge among healthcare practitioners and patients with the aim of standardising disease management across centres and (3) working towards promoting equal access to HA care and therapies for everyone.

The value of ultrasonography in detecting early arthropathic changes and contribution to the clinical approach in patients of hemophilia.

PURPOSE\AIM: Hemophilia affects the blood clotting process, is a genetic disease characterized by recurrent bleeding. The hemophilia early arthropathy detection with ultrasound (HEAD-US) procedure and scoring method were designed for the detection of early changes in affected joints of patients. In this article, it was aimed to detect early arthropathic changes in the joints of hemophilia patients with the HEAD US scoring system and to investigate its clinical contribution. It was aimed to investigate the effectiveness of HEAD-US scoring in showing early joint damage in subclinical hemophilia cases and its contribution to treatment. METHODS: The present study included 50 hemophilia patients who were admitted to Departments of Pediatric and Adult Hematology for routine follow-up. During routine follow-up controls, patients were scored by physical examination and HJHS 2.1 and by ultrasonography and HEAD US. Statistical tests were used to analyze joint health status and the results of US examination in the patient group. RESULTS: A total of 294 joints (elbow n = 100, knee n = 94, ankle n = 100) were evaluated by ultrasonography. The mean HJHS and HEAD-US scores of the patients were 14.94 ± 15.18 and 15.6 ± 12.6, respectively. CONCLUSIONS: HEAD-US is accepted to be more sensitive than HJHS in detecting early signs of arthropathy. Detection of early abnormalities by ultrasonography will enable the development of individualized treatment protocols and to the prevention of arthropathy development.

Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results.

Results from the main parts (24 weeks) of 2 concizumab phase 2 trials are presented: explorer4 in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI) and explorer5 in HA. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level), with secondary objectives being safety and immunogenicity (assessed as number of adverse events [AEs] and antidrug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if ≥3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic (PK/PD) parameters were assessed. Thirty-six HA, 9 HAwI, and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15 of 17; 88.2%) did not escalate the dose; all patients chose to continue to the extension phase of the trials. Clinical proof of concept for prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs HA: 3.0 (95% confidence interval [CI], 1.7; 5.3) and 5.9 (95% CI, 4.2; 8.5) vs 7.0 (95% CI, 4.6; 10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin fragment 1+2, and d-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very low to medium titer) ADA+ tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297.

Prophylaxis in children with haemophilia in an evolving treatment landscape.

INTRODUCTION: For children with haemophilia, early initiation of prophylaxis is crucial to prevent life-threatening bleeds and maintain joint health throughout life. Options for prophylaxis have recently increased from replacement therapy with standard or extended half-life coagulation factor products to include other haemostasis products, such as the non-replacement therapy emicizumab. AIM: To review key factors that determine the choice of prophylaxis in young children. METHODS: Key clinical questions on the implementation of prophylaxis for haemophilia in children were identified and PubMed was searched for evidence supporting guidance on the implementation of prophylaxis. RESULTS: The results of the literature search and the practical experience of the authors were used to build consensus on when to start prophylaxis, the pros and cons of the products available to guide the choice of product, and practical aspects of starting prophylaxis to guide the choice of regimen. CONCLUSIONS: In this era of increasing therapeutic choices, available information about the range of treatment options must be considered when initiating prophylaxis in young children. Parents or care givers must be sufficiently informed to allow informed shared decision making. Although plentiful data and clinical experience have been gathered on prophylaxis with clotting factor replacement therapy, its use in young children brings practical challenges, such as the need for intravenous administration. In contrast, our relatively brief experience and limited data with subcutaneously administered non-replacement therapy (i.e., emicizumab) in this patient group imply that starting emicizumab prophylaxis in young children requires careful consideration, despite the more convenient route of administration.

Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial.

INTRODUCTION: Turoctocog alfa is a recombinant, B domain-truncated factor VIII (FVIII) approved for patients with haemophilia A. AIM: To evaluate the safety and efficacy of turoctocog alfa in previously untreated patients (PUPs) with severe haemophilia A. METHODS: Guardian 4 was a multicentre, multinational, non-randomized, open-label phase 3 trial comprising a main and extension phase. The former concluded once ≥ 50 patients had received treatment for ≥ 50 exposure days (EDs) or developed inhibitors. Patients received turoctocog alfa intravenously for prevention and treatment of bleeds. The primary endpoint was the incidence rate of FVIII inhibitors (≥0.6 Bethesda Units) reported during the first 50 EDs. RESULTS: Of the 58 patients who completed the main phase, 25 (43.1%) patients developed inhibitors (detected within 6-24 [mean: 14.2] EDs from treatment start). High-risk mutations were identified in 60% of patients who developed inhibitors in the main phase and were a significant predictor of inhibitor development (P = .003). Of the 21 patients who started immune tolerance induction therapy, 85.7% completed treatment with a negative inhibitor test (note that data on the last 3 patients completing ITI are based on information collated from sites prior to the final database lock). Haemostatic response (including missing values as failure) was rated as 'excellent' or 'good' for 86.1% of bleeds occurring during prophylaxis. The estimated mean annualized bleeding rate for patients on prophylaxis was 4.26 bleeds/patient/year (95% CI: 3.34 - 5.44). CONCLUSIONS: Turoctocog alfa was effective at preventing and stopping bleeds and was well tolerated. Inhibitor development was within the expected range for this PUP population.

Evaluation of Bleeding Phenotype of Inherited Factor VII Deficiency in Children With a Bleeding Assessment Tool and Global Assays.

INTRODUCTION: Inherited factor VII (FVII) deficiency is the most common of the rare bleeding disorders and shows a heterogenous distribution of bleeding phenotypes independent of factor activity level. The bleeding score (BS) evaluates the phenotype of patients with rare bleeding disorders. Thromboelastography (TEG) and thrombin generation assays (TGAs) are 2 methods to evaluate global hemostasis, and controversially both tests are useful for identifying different bleeding tendency phenotypes. The purpose of this study was to investigate the use of the BS and global assays (TEG and TGAs) to predict the bleeding phenotype of inherited FVII deficiency. MATERIALS AND METHODS: A total of 27 patients with FVII deficiency were evaluated with the BS and global hemostasis assays. RESULTS: The BS was compatible with disease severity according to the FVII activity level (P<0.05) but the BS and bleeding grade of patients did not show a statistically significant correlation with factor activity level (P>0.05). No significant correlation was observed between the factor activity level and any TEG parameter (P>0.05). The factor activity level was negatively correlated with the lag time of the TGA on the contrary positively correlated with the peak thrombin time of the TGA (P<0.05). CONCLUSIONS: The global assays do not successfully predict the bleeding phenotype. The BS is a more suitable tool than conventional and global assays for predicting the bleeding phenotype.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data.

INTRODUCTION: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential. AIM: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy. METHODS: Free TFPI predictions were generated using an estimated concizumab-free TFPI exposure-response (Emax ) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 µg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations. RESULTS: The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re-established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab-free TFPI and concizumab-TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once-daily dosing would minimize within-patient concizumab PK variability. CONCLUSION: Concizumab phase 2 trials will target an exposure ≥100 ng/mL, with a once-daily regimen.

The burden of bleeds and other clinical determinants on caregivers of children with haemophilia (the BBC Study).

INTRODUCTION: Treatment burden for the people with haemophilia has been documented, as has the burden of caring for a child with a common chronic disease such as asthma or diabetes. However, there remains a paucity of data about caregiver burden in haemophilia. AIMS: The aim of this study was to evaluate the impact of bleeding on caregivers of children with haemophilia. Caregiver burden was stratified by the clinical status of their child. METHODS: A multinational, non-interventional study of caregivers of children with severe or moderate haemophilia, using the HEMOCABquestionnaire to evaluate caregiver burden. RESULTS: A total of 144 caregivers from seven EU countries participated in the study. Differences in caregiver burden were identified based on the clinical situation of the child. Greater burden was seen in caregivers of children who experienced joint bleeding in the preceding 12 months, or had target joints or reduced range of motion in most domains of the HEMOCAB. Caring for a child with a current inhibitor also caused significantly higher burden for caregivers when compared to caring for a child with tolerized inhibitor or without inhibitor. Caregivers of children with chronic pain reported significantly higher burden in all domains of the HEMOCAB except for "interaction with the father." CONCLUSION: Caregiver burden can be affected by the child's haemophilia status, particularly if joint health is impacted (eg bleeds, decreased mobility) or if the child suffers from chronic pain which was moderately correlated with joint bleeds.

The impact of psychosocial determinants on caregivers' burden of children with haemophilia (results of the BBC study).

INTRODUCTION: Caring for a child with haemophilia is burdensome and impacting on caregivers' emotional and financial status. This paper assesses the impact of psychosocial determinants on caregivers' burden across European countries. METHODS: This non-interventional study enrolled caregiver/child dyads at haemophilia treatment centres (HTCs) using the "HEMOphilia associated CAregiver Burden scale" (HEMOCAB). Socio-demographic characteristics and clinical data were collected. RESULTS: A total of 144 dyads from Germany (n = 19), Italy (n = 19), Netherlands (n = 19), Turkey (n = 20), Sweden (n = 21), UK (n = 21) and Poland (n = 25) participated. Caregivers' mean age was 39.84 ± 7 (range 24-57); 81.3% were mothers, married (80.4%), living with a partner (86.6%), had a college/university degree (66.5%) and worked (74.2%). Around two thirds of caregivers (66.2%) reported that haemophilia affected their life; 26.8% reported an economic impact; 57.6% reported their child cannot do certain things because of his condition. Caregivers lost an average of 8.35 ± 14.5 days due to haemophilia. The highest burden was reported in the HEMOCAB domains "Perception of Child" (37.9 ± 24.7), "Emotional Stress" (37.4 ± 22.6) and "Medical Management" (33.1 ± 22.8). Significantly, higher burden was found in caregivers who reported that haemophilia "affects their life" (P < 0.0001), "has an economic impact" (P < 0.0001), "their child cannot do certain things" (P < 0.0001), "they spent ≥5 h/mo infusing" (P < 0.003) and "they needed ≥3 h/mo to reach the HTC" (P < 0.0001). CONCLUSION: This "snapshot" analysis of burden related to caring for a child with haemophilia across Europe revealed the greatest burdens are economic, including days lost from work, and things that a child cannot do, impacting on both child and caregiver.

Efficacy and safety of a new human fibrinogen concentrate in patients with congenital fibrinogen deficiency: an interim analysis of a Phase III trial.

BACKGROUND: Fibrinogen concentrate is the preferred choice for fibrinogen replacement in congenital fibrinogen deficiency. This study investigated hemostatic efficacy of a new plasma-derived, double virus-inactivated (using two dedicated virus inactivation/elimination steps) human fibrinogen concentrate for on-demand treatment of bleeding episodes (BEs) and surgical prophylaxis. STUDY DESIGN AND METHODS: In this planned interim analysis of a prospective, multinational Phase III study (NCT02267226), 13 patients with afibrinogenemia (≥12 years) received fibrinogen concentrate (FIBRYGA, Octapharma AG). Hemostatic efficacy was assessed by investigators and an independent data monitoring and endpoint adjudication committee (IDMEAC) using objective four-point criteria and by thromboelastometry maximum clot firmness (MCF). RESULTS: Fibrinogen concentrate was used on-demand to treat 23 BEs in 11 patients, with 21 (91.3%) requiring a single infusion only. Treatment success was 95.7% (90% confidence interval [CI], 0.81-1.00; assessment missing for one BE) by investigators and 100% (90% CI, 0.88-1.00) by IDMEAC. Mean MCF increased significantly from 0.0 to 6.5 mm (95% CI, 5.65-7.40; p < 0.0001) at 1 hour postinfusion of a median (range) dose of 58.8 (33.9-101.7) mg/kg per BE. Four patients received fibrinogen concentrate as surgical prophylaxis, with intraoperative and postoperative treatment success rated 100% (90% CI, 0.50-1.00) by investigators and IDMEAC (median [range] dose per surgery 93.5 [34.1-225.4] mg/kg). No additional hemostatic interventions were required. No deaths, thromboses, or seroconversions were reported. CONCLUSION: These data showed that the new fibrinogen concentrate was efficacious for on-demand treatment of acute bleeding and surgical prophylaxis in congenital afibrinogenemia patients.

Long-term safety and efficacy of turoctocog alfa in prophylaxis and treatment of bleeding episodes in severe haemophilia A: Final results from the guardian 2 extension trial.

INTRODUCTION: Turoctocog alfa is a recombinant factor VIII (FVIII) molecule, approved for treatment and prophylaxis of bleeding in patients with haemophilia A. In the guardian 1 (adolescents/adults) and guardian 3 (children) phase 3 trials, turoctocog alfa demonstrated a favourable efficacy and safety profile. Guardian 1 or 3 completers could enrol in the guardian 2 extension. Final guardian 2 results are reported here. AIM: Investigate long-term safety and efficacy of turoctocog alfa administered for prophylaxis and treatment of bleeds. METHODS: In this phase 3b open-label trial, previously treated males of all ages with severe haemophilia A received prophylaxis regimens of turoctocog alfa or on-demand treatment of bleeds. The primary safety endpoint was frequency of FVIII inhibitor development. Efficacy endpoints included annualized bleeding rate (ABR) during prophylaxis, haemostatic response in treatment of bleeds and number of injections required to treat bleeds. RESULTS: Overall, 213 patients were dosed with turoctocog alfa; 207 patients received prophylaxis; 19 received on-demand treatment. No FVIII inhibitors (≥0.6 BU) were reported. For all patients on prophylaxis, overall median ABR was 1.37 bleeds/y; success rate for treatment of bleeds was 90.2%; and 88.2% of bleeds were controlled with 1-2 injections of turoctocog alfa. For the on-demand regimen, overall median ABR was 30.44 bleeds/y; success rate for treatment of bleeds was 96.7%; and 94.9% of bleeds were controlled with 1-2 injections of turoctocog alfa. CONCLUSION: Extended use of turoctocog alfa is safe and effective for prevention and treatment of bleeding episodes in previously treated patients with haemophilia A across all ages.