Recombinant factor IX Fc for the treatment of hemophilia B.

Current hemophilia B treatment guidelines recommend routine prophylaxis with factor IX (FIX) replacement products, tailored to maintain plasma activity at levels that will prevent bleeds. However, plasma FIX activity may not be the primary determinant or best indicator of hemostatic efficacy due to its extravascular distribution. FIX replacement therapy has evolved to include extended half-life (EHL) products that provide effective bleed protection when administered at intervals of 7 days or longer. rFIXFc is a recombinant fusion protein with an extended circulation time. rFIXFc has a biodistribution profile consistent with distribution into extravascular space, where it may support hemostasis at sites of vessel injury independent of circulating plasma activity levels. The safety and efficacy of rFIXFc prophylaxis is well established in adults, adolescents and children including previously untreated patients with hemophilia B, with substantial evidence from clinical trials and real-world clinical practice. This review describes the pharmacokinetic characteristics of rFIXFc, summarizes available safety and efficacy data, and evaluates the use of rFIXFc in special populations. Current hemophilia B treatment challenges, including target FIX plasma levels, perioperative use, and management of patients with comorbidities, are discussed together with the potential role of EHL products in the future treatment landscape of hemophilia B.

Inhibitors in hemophilia: association with surgery plans and outcomes in a retrospective cohort study.

Background: The development of antibodies (inhibitors) to clotting factors compromises the management of hemophilia A and B, resulting in resistance to clotting factor replacement and, in many cases, the need for bypassing agents to achieve hemostasis. Objectives: To evaluate the association between the presence of inhibitors and achievement of perioperative hemostasis, development of complications, and presurgical plan deviations. Methods: We conducted a retrospective study using data from the Indiana Hemophilia and Thrombosis Center surgical database (1998-2019). Associations between perioperative outcomes and inhibitor status were assessed while controlling for patient and procedural characteristics. Results: A total of 1492 surgeries were performed in 539 persons with hemophilia, with 72 procedures performed in 20 patients with inhibitors (15 with hemophilia A; 5 with hemophilia B). High-responding inhibitors (>5 BU/mL) were present in 27 procedures, low-responding inhibitors (≤5 BU/mL) were present in in 13 procedures, and 32 procedures were performed in patients with historically persistent inhibitors. Adjusting for age, diagnosis, surgery setting, hemostatic agent, data collection period, and surgery type (major/minor), inhibitors were associated with a higher risk of inadequate perioperative hemostasis (33.4% vs 8.6%; adjusted relative risk [adjRR], 3.78; 95% CI, 1.89-7.56; P < .001). Reported complications include hemorrhage, fever, pain, thrombosis, and infections. Complications were not statistically different based on inhibitor status (31.7% vs 14.6%; adjRR, 1.25; 95% CI, 0.63-2.49; P = .526). Presurgical plan deviations (eg, hemostatic medication dose adjustments, procedure rescheduling, and changes in the length of postoperative hospitalization) occurred more frequently in surgeries involving inhibitors (70.8 vs 39.5%; adjRR, 1.47; 95% CI, 1.12-1.93; P = .005). Conclusion: Inhibitors are associated with higher risks of adverse perioperative outcomes. Strategies to address inhibitor development should be prioritized to avoid undesirable perioperative outcomes.

Plasminogen, human-tvmh for the treatment of children and adults with plasminogen deficiency type 1.

AIM: An open-label phase 2/3 study of plasminogen, human-tvmh administered intravenously in paediatric and adult subjects with type 1 plasminogen deficiency was conducted. Interim data was previously reported. The final data on 15 subjects who completed the study up to a maximum of 124 weeks are reported here. METHODS: The primary objectives were to evaluate efficacy of plasminogen replacement therapy on clinically evident or visible lesions during 48 weeks of dosing and to achieve an increase in trough plasminogen activity levels by at least an absolute 10% above baseline during 12 weeks of treatment. RESULTS: The primary efficacy endpoint was achieved, as 100% of subjects (n = 11) with visible and assessable non-visible lesions at baseline demonstrated ≥ 50% improvement after 48 weeks of study drug treatment with plasminogen, human-tvmh. All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12. Plasminogen, human-tvmh at a dose of 6.6 mg/kg administered every 2-5 days for 48 weeks and every 1-7 days for up to 124 weeks was well tolerated. CONCLUSION: This study provides additional evidence regarding the long-term safety and clinical utility of replacement therapy with human plasminogen for the treatment of children and adults with type 1 plasminogen deficiency. Plasminogen, human-tvmh received marketing approval on June 4, 2021. This trial was registered at www. CLINICALTRIALS: gov as #NCT02690714.

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

Background: Prophylactic 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. Objectives: We 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. Methods: Patients 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. Results: Sixty-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. Conclusions: Findings add to existing evidence and demonstrate the clinical and HRQoL benefits of switching patients from on-demand treatment to rFVIIIFc/rFIXFc prophylaxis.

Recombinant factor IX Fc for major surgery in hemophilia B: factor IX plasma activity levels and effective hemostasis.

Background: Major surgical procedures are associated with significant bleeding risk and infectious complications in patients with hemophilia, which may be minimized by factor replacement. Monitoring perioperative factor levels guides dosing to maintain adequate levels for hemostatic control. Objectives: We report prospectively collected post hoc surgical data in patients with hemophilia B who underwent major surgery with extended half-life recombinant factor IX Fc fusion protein (rFIXFc) in phase 3 studies (B-LONG/Kids B-LONG and B-YOND). Methods: Achieved FIX plasma levels were described for those who underwent major surgeries with ≥1 peak and/or predose FIX assessment available on the day of surgery (Day 0 [D0]) from the central laboratory. Dosing, injection frequency, adverse events, and hemostatic responses were assessed. Two representative cases were described further including blood loss, transfusions, and concomitant medication assessment. Results: Of 35 major surgeries, 17 (N = 16 subjects) with sufficient FIX measurements were included in this analysis; 13 of 17 surgeries were orthopedic. On D0, a median loading (preoperative) dose of 101.1 International Units (IU)/kg/injection achieved a median peak FIX of 103.3 IU/dL. Across postoperative Days 1 to 3, 4 to 6, and 7 to 14, the median predose levels were 75.1 IU/dL with 1 injection/d, 71.6 IU/dL with 0 to 1 injection/d, and 43.2 IU/dL with 0 to 1 injection/d, respectively. Hemostasis was rated excellent (14 of 16) or good (2 of 16) across surgeries. Both case studies (knee arthroscopy and ankle fusion) illustrate measured FIX levels with rFIXFc. Conclusion: The aggregate analysis and representative cases of major surgeries demonstrate that rFIXFc can achieve FIX levels for effective hemostasis during invasive high-risk procedures.

Intracellular tPA-PAI-1 interaction determines VLDL assembly in hepatocytes.

Apolipoprotein B (apoB)-lipoproteins initiate and promote atherosclerotic cardiovascular disease. Plasma tissue plasminogen activator (tPA) activity is negatively associated with atherogenic apoB-lipoprotein cholesterol levels in humans, but the mechanisms are unknown. We found that tPA, partially through the lysine-binding site on its Kringle 2 domain, binds to the N terminus of apoB, blocking the interaction between apoB and microsomal triglyceride transfer protein (MTP) in hepatocytes, thereby reducing very-low-density lipoprotein (VLDL) assembly and plasma apoB-lipoprotein cholesterol levels. Plasminogen activator inhibitor 1 (PAI-1) sequesters tPA away from apoB and increases VLDL assembly. Humans with PAI-1 deficiency have smaller VLDL particles and lower plasma levels of apoB-lipoprotein cholesterol. These results suggest a mechanism that fine-tunes VLDL assembly by intracellular interactions among tPA, PAI-1, and apoB in hepatocytes.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for ultra-rare inherited bleeding disorders.

BACKGROUND: Ultra-rare inherited bleeding disorders (BDs) present important challenges for generating a strong evidence foundation for optimal diagnosis and management. Without disorder-appropriate treatment, affected individuals potentially face life-threatening bleeding, delayed diagnosis, suboptimal management of invasive procedures, psychosocial distress, pain, and decreased quality-of-life. RESEARCH DESIGN AND METHODS: The National Hemophilia Foundation (NHF) and the American Thrombosis and Hemostasis Network identified the priorities of people with inherited BDs and their caregivers, through extensive inclusive community consultations, to inform a blueprint for future decades of research. Multidisciplinary expert Working Group (WG) 3 distilled highly feasible transformative ultra-rare inherited BD research opportunities from the community-identified priorities. RESULTS: WG3 identified three focus areas with the potential to advance the needs of all people with ultra-rare inherited BDs and scored the feasibility, impact, and risk of priority initiatives, including 13 in systems biology and mechanistic science; 2 in clinical research, data collection, and research infrastructure; and 5 in the regulatory process for novel therapeutics and required data collection. CONCLUSIONS: Centralization and expansion of expertise and resources, flexible innovative research and regulatory approaches, and inclusion of all people with ultra-rare inherited BDs and their health care professionals will be essential to capitalize on the opportunities outlined herein.

Living with an ultra-rare inherited bleeding disorder is challenging. Patients can feel alone and unsure of where to find support because their disorder is so rare. In this paper, a group of ultra-rare bleeding disorder experts, including doctors, researchers, regulators, patient advocates, and patients, identify the research that could best improve the lives of people with these disorders. They propose a national network of specialists who can help doctors, who may never have seen these disorders before, to find the right diagnosis faster. A centralized laboratory specialized in ultra-rare bleeding disorders could also improve diagnosis and do research studies. This would help us learn, for example, how symptoms change throughout a patient's life, how effective different treatments are, and what it is like for patients to live with these disorders. A second research priority is to better understand each individual disorder so that the best treatments can be chosen or developed. A pathway showing doctors which treatment options to try, in which order, would help them help their patients. The third research priority is to make it easier to study new treatments for ultra-rare bleeding disorders. This requires designing studies with very small numbers of participants, identifying meaningful outcomes to measure, and convincing pharmaceutical companies to invest in these studies. International agreement on these requirements would allow more patients to participate and benefit from the research. These top-priority research goals should greatly improve knowledge about, and diagnosis and treatment of, ultra-rare inherited bleeding disorders.

Prevalence of selected bleeding and thrombotic events in persons with hemophilia versus the general population: A scoping review.

Life expectancy for persons with hemophilia has increased over recent decades due to advances in treatment practice and patient care. Those with hemophilia are now more likely to be affected by conditions associated with aging, such as myocardial infarction, hemorrhagic/ischemic stroke, deep vein thrombosis, pulmonary embolism, and intracranial hemorrhage. Here, we describe the results of a literature search designed to summarize current data on the prevalence of the above selected bleeding and thrombotic events in persons with hemophilia vs the general population. A total of 912 articles published between 2005 and 2022 were identified in a search of BIOSIS Previews, Embase, and MEDLINE databases conducted in July 2022. Case studies, conference abstracts, review articles, studies focusing on hemophilia treatments or surgical outcomes, and studies examining patients with inhibitors only were excluded. After screening, 83 relevant publications were identified. The prevalence of bleeding events was consistently higher in hemophilia populations vs reference populations (hemorrhagic stroke, 1.4%-5.31% vs 0.2%-0.97%; intracranial hemorrhage, 1.1%-10.8% vs 0.04%-0.4%). Serious bleeding events showed a high rate of mortality with standardized mortality ratios for intracranial hemorrhage ranging from 3.5 to 14.88. Although 9 studies reported lower prevalence of arterial thrombosis (myocardial infarction/stroke) in hemophilia vs general populations, 5 studies reported higher or comparable prevalence in hemophilia. Prospective studies are therefore needed to understand the prevalence of bleeding and thrombotic events in hemophilia populations, particularly with the observed increases in life expectancy and availability of novel treatments.

Post hoc longitudinal assessment of the efficacy and safety of recombinant factor IX Fc fusion protein in hemophilia B.

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B.

Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study.

BACKGROUND: Clinical trial data are scarce for the use of prophylaxis in people with non-severe haemophilia A. The HAVEN 6 study aims to assess safety and efficacy of emicizumab prophylaxis in people with non-severe haemophilia A without factor VIII (FVIII) inhibitors. METHODS: HAVEN 6 is a multicentre, open-label, single-arm, phase 3 study taking place in 22 specialty clinics and hospitals in Europe, North America, and South Africa. Eligible participants were people of all ages weighing at least 3 kg with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII >5%-<40%) haemophilia A without FVIII inhibitors requiring prophylaxis as assessed by the treating physician. Participants received subcutaneous emicizumab 3 mg/kg of bodyweight once weekly for 4 weeks, followed by the participant's choice of maintenance dose: 1·5 mg/kg once weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. Safety was the primary objective of the study. Safety endpoints included adverse events, serious adverse events, and adverse events of special interest including thromboembolic events and thrombotic microangiopathies. The primary efficacy endpoint was the annualised bleed rate for treated bleeds. Analyses were done for participants who received at least one dose of emicizumab. This study is registered with ClinicalTrials.gov, number NCT04158648, and is active but not recruiting. FINDINGS: Between Feb 10, 2020, and Aug 31, 2021, we assigned 73 people to treatment. 72 participants received at least one dose of emicizumab (51 moderate [71%]; 21 mild [29%]; 69 male [96%]; three female [4%]; and 61 White [85%]). Median age was 23·5 years (IQR 12·0-36·0); median follow-up was 55·6 weeks (IQR 52·3-61·6) weeks. At baseline, 24 participants (33%) had target joints and 37 (51%) were receiving FVIII prophylaxis. 60 participants (83%) had at least one adverse event; the most common adverse events were headache (in 12 participants [17%]), injection-site reaction (12 [17%]), and arthralgia (11 [15%]). 15 (21%) had at least one emicizumab-related adverse event; no adverse events led to treatment withdrawal, modification, or interruption. Eight participants (11%) reported ten serious adverse events in total, none emicizumab-related. There were no deaths or thrombotic microangiopathies. One participant had grade 1 thrombosed haemorrhoids (classified as a thromboembolic event), unrelated to emicizumab. The annualised bleed rate was 0·9 (95% CI 0·55-1·52) for treated bleeds. 48 participants (67%) had no treated bleeds. All-bleed annualised bleed rates were 10·1 (95% CI 6·93-14·76) from 24 weeks pre-study and 2·3 (1·67-3·12) on-study after a median follow-up of 55·6 weeks. INTERPRETATION: These data show efficacy and a favourable safety profile of emicizumab in people with non-severe haemophilia A without FVIII inhibitors who warrant prophylaxis, confirming emicizumab as a valuable treatment option in this population. FUNDING: F Hoffmann-La Roche.

Therapeutic and technological advancements in haemophilia care: Quantum leaps forward.

INTRODUCTION: Recent technological innovations in haemophilia have advanced at an astounding pace, including gene therapy programmes and bioengineered molecules for prophylaxis, products that reduce treatment burden through half-life extension, unique mechanisms of action, and subcutaneous administration. Additional technological advancements have emerged that are anticipated to further transform haemophilia care. AIM: Review new and emerging haemophilia therapies, including replacement and bypassing products, digital applications, utilisation of big data, and personalised medicine. METHODS: Data were obtained from peer-reviewed presentations/publications, and ongoing studies in haemophilia, ultrasonography, and artificial intelligence (AI). RESULTS: Available treatments include new recombinant factors VIII (FVIII) and IX (FIX), extended half-life FVIII/IX products, a new FVIIa product for inhibitor patients, and a FVIIIa-mimetic. Several novel therapeutics are in clinical trials, including FVIIIa mimetics and inhibitors of naturally-occurring anticoagulants. Ongoing gene therapy trials suggest that a single vector infusion using an optimised construct can produce factor activity that reduces bleeding to near zero for years. Today, persons with haemophilia (PwH) approach a lifespan comparable to that of the general population, presenting treatment challenges for age-related co-morbidities. Technological innovations have broadened beyond therapeutics to include large database analyses utilising remote data collection with handheld devices, and to tailor AI applications. Current development efforts include patient-performed ultrasonography, algorithms for scan interpretation, and point-of-care haemostatic testing devices. CONCLUSIONS: We have entered a golden age for haemophilia treatment and care with wide-ranging advancements targeting improved quality of life (QoL). Future-focused efforts by clinical and patient communities may provide equitable access and care for people impacted by haemophilia worldwide.

Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors.

INTRODUCTION: Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS: Using a randomised crossover design, subjects received initial doses of 75 or 225 µg/kg eptacog beta followed by 75 µg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS: Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 µg/kg initial dose regimen (IDR) and 60% in the 225 µg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 µg/kg IDR and 98% for the 225 µg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION: Both 75 and 225 µg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.

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

Despite 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.

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

INTRODUCTION: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). AIM: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. METHODS: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

Utilization of a surgical database to provide care and assess perioperative treatment and outcomes in patients with bleeding disorders.

OBJECTIVES: To describe the Indiana Hemophilia and Thrombosis Center (IHTC) surgical database, its key components, and exploratory analyses of surgeries conducted between 1998 and 2019. METHODS: Surgical data across bleeding disorders collected retrospectively (1998-2006) and prospectively (2006-2019) were analyzed. Perioperative hemostasis, complications, and surgical plan deviations were compared by bleeding disorder diagnosis and data collection period. RESULTS: Within the 21-year period, 3246 procedures were conducted in 1413 patients with a diagnosis of von Willebrand disease (vWD), hemophilia A (HA), hemophilia B (HB), and other bleeding disorders. Majority of the procedures were minor (63.3%), and median number of surgeries per patient was 1 (range: 1-22). Adequate perioperative hemostasis was achieved in 90.9%, complications occurred in 13.6%, and surgical plan deviations occurred in 31.3% of procedures. Inadequate perioperative hemostasis and surgical plan deviations occurred more frequently in procedures involving HB compared with other bleeding disorders. Complications were not significantly different across bleeding disorders (p = .164). The prospective data collection period was associated with higher rates of hemostatic efficacy (92.4% vs. 88.3%; p < .001), complications (14.3% vs. 12.3%; p < .001), and plan deviations (34.2% vs. 25.1%; p < .001). CONCLUSION: The surgical database is an important resource in surgical management in patients with bleeding disorders. Further evaluation will facilitate use for the development of predictive models and principles of care.

Final Results of the Prospective ADVATE® Immune Tolerance Induction Registry (PAIR) Study with Plasma- and Albumin-Free Recombinant Factor VIII.

INTRODUCTION: Neutralizing antibodies to coagulation factor VIII (FVIII) remain a major complication associated with FVIII replacement therapy. AIM: To assess safety and efficacy of immune tolerance induction (ITI) therapy with ADVATE® (antihemophilic factor [recombinant] [rAHF]) in patients who participated in the Prospective ADVATE Immune Tolerance Induction Registry (PAIR) study. METHODS: The PAIR study was an international, multicenter, open-label, prospective, observational study in patients with hemophilia A and inhibitors, prescribed rAHF ITI therapy in clinical practice. The primary endpoint was adverse event (AE) reporting; the secondary endpoints included incidence of central venous access device-related complications and success rates of ITI therapy. Maintenance of immune tolerance was monitored for 12 months post-ITI therapy. RESULTS: Of 44 patients, 36 completed ITI therapy, including 31 completing the 12-month follow-up. Most patients received rAHF 90-130 IU/kg/day (59.1%) and a mean of 6.0 doses/week; the median duration of rAHF ITI therapy during the PAIR study was 600 days. Overall, 284 AEs were reported; 56 AEs were serious, of which none were considered rAHF-related. Of 228 nonserious AEs, 14 (in six patients) were deemed rAHF-related: increase of FVIII inhibitors titer due to anamnestic response, nausea, catheter site pain, pyrexia, urticaria, upper respiratory tract infection, arthralgia, and hemarthrosis. None were severe or led to ITI discontinuation. Eighteen patients experienced ≥1 central venous access device-related complication, and 21 of 36 completers achieved a negative inhibitor titer. The Kaplan-Meier estimate of success for achievement of first negative titer at 18 months of ITI therapy was 68.3% (95% confidence interval 51.8-83.6%) among completers. Of patients with partial or complete success post-ITI, 87% (20/23) maintained immune tolerance at 12-month follow-up. CONCLUSION: Data suggest that rAHF ITI therapy in the PAIR study was effective, with no unexpected safety signals reported.

The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors.

INTRODUCTION: Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. AIM: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. METHODS: Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 µg/kg EB initially followed by 75 µg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 µg/kg (minor procedures) or 200 µg/kg EB (major surgeries) with subsequent 75 µg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. RESULTS: Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. CONCLUSION: Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.