Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities in health services; diversity, equity, and inclusion; and implementation science.

BACKGROUND: The National Hemophilia Foundation (NHF) conducted extensive all-stakeholder inherited bleeding disorder (BD) community consultations to inform a blueprint for future research. Sustaining and expanding the specialized and comprehensive Hemophilia Treatment Center care model, to better serve all people with inherited BDs (PWIBD), and increasing equitable access to optimal health emerged as top priorities. RESEARCH DESIGN AND METHODS: NHF, with the American Thrombosis and Hemostasis Network (ATHN), convened multidisciplinary expert working groups (WG) to distill priority research initiatives from consultation findings. WG5 was charged with prioritizing health services research (HSR); diversity, equity, and inclusion (DEI); and implementation science (IS) research initiatives to advance community-identified priorities. RESULTS: WG5 identified multiple priority research themes and initiatives essential to capitalizing on this potential. Formative studies using qualitative and mixed methods approaches should be conducted to characterize issues and meaningfully investigate interventions. Investment in HSR, DEI and IS education, training, and workforce development are vital. CONCLUSIONS: An enormous amount of work is required in the areas of HSR, DEI, and IS, which have received inadequate attention in inherited BDs. This research has great potential to evolve the experiences of PWIBD, deliver transformational community-based care, and advance health equity.

Research into how people get their health care, called health services research, is important to understand if care is being delivered equitably and efficiently. This research figures out how to provide the best care at the lowest cost and finds out if everyone gets equally good care. Diversity and inclusion research focuses on whether all marginalized and minoritized populations (such as a given social standing, race, ethnicity, sex, gender identity, sexuality, age, income, disability status, language, culture, faith, geographic location, or country of birth) receive equitable care. This includes checking whether different populations are all getting the care they need and looking for ways to improve the care. Implementation science studies how to make a potential improvement work in the real world. The improvement could be a new way to diagnose or treat a health condition, a better way to deliver health care or do research, or a strategy to remove barriers preventing specific populations from getting the best available care. The National Hemophilia Foundation focuses on improving the lives of all people with bleeding disorders (BD). They brought BDs doctors, nurses, physical therapists, social workers, professors, and government and industry partners together with people and families living with BDs to discuss research in the areas described above. The group came up with important future research questions to address racism and other biases, and other changes to policies, procedures, and practices to make BD care equitable, efficient, and effective.

Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B.

BACKGROUND: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).

Stable and durable factor IX levels in patients with hemophilia B over 3 years after etranacogene dezaparvovec gene therapy.

Etranacogene dezaparvovec (AMT-061) is a recombinant adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) transgene with a liver-specific promoter. Here, we report 3-year outcomes from a phase 2b, open-label, single-dose, single-arm, multicenter trial conducted among adults with severe or moderately severe hemophilia B (FIX ≤2%). All participants (n = 3) received a single intravenous dose (2 × 1013 gene copies per kg) and will be followed up for 5 years. The primary end point of FIX activity ≥5% at 6 weeks was met. Secondary end points included bleed frequency, FIX concentrate use, joint health, and adverse events (AEs). All participants required routine FIX prophylaxis and had neutralizing antibodies to AAV5 before etranacogene dezaparvovec treatment. After administration, FIX activity rose to a mean of 40.8% in year 1 and was sustained in year 3 at 36.9%. All participants discontinued FIX prophylaxis. Bleeding was completely eliminated in 2 out of 3 participants. One participant required on-demand FIX replacement therapy per protocol because of elective surgical procedures, for 2 reported bleeding episodes, and twice for a single self-administered infusion because of an unreported reason. One participant experienced 2 mild, self-limiting AEs shortly after dosing. During the 3-year study period, there were no clinically significant elevations in liver enzymes, no requirement for steroids, no FIX inhibitor development, and no late-emergent safety events in any participant. Etranacogene dezaparvovec was safe and effective in adults with hemophilia B over 3 years after administration. This trial was registered at www.clinicaltrials.gov as #NCT03489291.

Integrated Hemophilia Patient Care via a National Network of Care Centers in the United States: A Model for Rare Coagulation Disorders.

Rare, chronic diseases such as hemophilia and other congenital coagulation disorders require coordinated delivery of services for optimal outcomes. Hemophilia Treatment Centers (HTCs) are specialized, multidisciplinary health-care centers providing team-based care to meet the physical, psychosocial, and emotional needs of people with hemophilia (PWH) and may serve as a model for other rare coagulation disorders. Health-care purchasers, as well as the general medical community, may not appreciate the breadth and quality of services provided by HTCs. They exemplify the acculturalization and actualization of integrated care by providing comprehensive diagnostic and treatment services that reduce morbidity, mortality, avoidable emergency room visits, hospitalizations, and overall costs, while promoting a longer lifespan and improved patient functioning and outcomes. This is accomplished by a team-based approach relying upon a shared decision-making model to effectively prevent complications and manage symptoms in PWH, who are dependent on high-cost treatments. This article provides a concise yet comprehensive description of the core components of an HTC and the regional and national networks in the United States, which together achieve their incomparable value for all stakeholders.

Pharmacokinetic-tailored approach to hemophilia prophylaxis: Medical decision making and outcomes.

BACKGROUND: Clinical application of population pharmacokinetics (popPK) is of increasing interest to patients with hemophilia, providers, and payers. Routine use of popPK profiles in factor replacement prophylaxis decision making has the potential to maintain or improve efficacy and reduce product consumption. AIM: To investigate the feasibility of implementation and longitudinal assessment of pharmacokinetic (PK)-tailored prophylaxis in routine clinical practice for hemophilia A and to describe factors that influence decision making for prescribed hemophilia prophylaxis. METHODS: This longitudinal, multicenter, prospective feasibility study of children and adults with hemophilia A without inhibitors used the Web Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) to generate PK profiles. Assessments over 12 weeks captured data on prescribed prophylaxis, popPK tool use, provider decision making, and patient-reported outcomes. RESULTS: Eighteen participants aged 6 to 39 years enrolled; half used extended half-life concentrates. Patient interest in their PK centered on general curiosity followed by a desire for participation in physical activity and decrease in infusion frequency. Providers used the WAPPS clinical calculator feature to simulate prophylaxis regimens under different dose, infusion, and trough conditions. Most targeted troughs were 1 to 3 IU/dL. The feasibility assessment demonstrated challenges with patient recruitment; however, the majority of participants successfully completed study assessments meeting feasibility targets. CONCLUSION: A larger-scale study powered to evaluate the impact of PK-tailored prophylaxis on clinical and patient-reported outcomes is feasible with study design modifications to support increased recruitment rate. Shared decision making incorporating patient and provider goals is important and facilitated by regimen simulations with the clinical calculator.

Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B.

Etranacogene dezaparvovec (AMT-061) is a recombinant AAV5 vector including a gene cassette containing the factor IX (FIX) Padua variant under the control of a liver-specific promoter. A phase 2b study was conducted to confirm that a single dose of 2 × 1013 genome copies per kilogram of etranacogene dezaparvovec will result in FIX activity ≥5% 6 weeks after dosing. Secondary end points included FIX activity at other time points, bleed frequency, FIX replacement, and safety. Etranacogene dezaparvovec was administered as a single IV infusion to 3 adults with severe to moderately severe hemophilia B. Before treatment, participants had low levels of preexisting neutralizing antibodies to AAV5. This article reports a planned 26-week interim assessment. At week 6, mean FIX activity was 31% (23.9%-37.8%), increasing to 47% (33.2%-57.0%) at 26 weeks, with 2 subjects exhibiting sustained activity >40%. Consistent with the FIX activity, etranacogene dezaparvovec was associated with a complete bleed cessation with no need for FIX replacement therapy up to 26 weeks. Etranacogene dezaparvovec was generally well tolerated. No clinically significant elevations in levels of liver enzymes or inflammatory markers were observed, and no use of corticosteroids related to treatment was required. In individuals with severe to moderately severe hemophilia B, etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity, cessation of bleeds, and abrogation of the need for FIX replacement, despite the presence of preexisting anti-AAV5 neutralizing antibodies detected by using a highly sensitive luciferase assay. Consistency of results in the 3 participants supported an expanded evaluation of the safety/efficacy of etranacogene dezaparvovec in the HOPE-B (Health Outcomes With Padua Gene; Evaluation in Hemophilia-B) phase 3 trial. The current trial was registered at www.clinicaltrials.gov as #NCT03489291.

Pilot study of novel lab methodology and testing of platelet function in adolescent women with heavy menstrual bleeding.

BackgroundApproximately 40% of adolescent women experience heavy menstrual bleeding (HMB), and 10-62% of them have an underlying bleeding disorder (BD). Diagnosing a BD remains challenging because of limitations of available clinical platelet function assays. The aim of this study was to characterize platelet function in a population of adolescent women with HMB using small-volume whole-blood assays.MethodsAnticoagulated whole blood was used to assess platelet GPIIbIIIa activation, α-granule secretion, and aggregation in response to multiple agonists. Platelet adhesion on collagen or von Willebrand Factor (VWF) under static and shear flow was also assessed.ResultsFifteen participants with HMB were included in the study, of which eight were diagnosed with a clinically identifiable BD. Platelet activation was blunted in response to calcium ionophore in participants without a BD diagnosis compared with that in all other participants. Impaired GPIIbIIIa activation was observed in response to all GPCR agonists, except adenosine diphosphate (ADP), in participants with qualitative platelet disorders. Our assays detected platelet aggregation in the majority of participants with a BD in response to ADP, collagen-related peptide (CRP), thrombin receptor activator 6 (TRAP-6), or U46619. Platelet adhesion and aggregation on collagen and VWF was decreased for participants with VWD.ConclusionParticipants with and without BD exhibited aberrant platelet function in several assays in response to select agonists.

Silent ischemic lesion recurrence on magnetic resonance imaging predicts subsequent clinical vascular events.

BACKGROUND: Previous studies identified a high frequency of silent ischemic lesion recurrence on magnetic resonance imaging (MRI) after an index stroke. OBJECTIVE: To investigate whether ischemic lesion recurrence on MRI predicts subsequent clinical events. DESIGN: Retrospective cohort study. SETTING: General community hospital. Patients We recruited 120 patients who experienced an acute ischemic stroke (IS) and who underwent initial MRI within 24 hours of onset and subsequent MRI on day 5. Of those patients, 68 underwent follow-up MRI up to 90 days after onset. MAIN OUTCOME MEASURES: Early silent lesion recurrence was defined as new asymptomatic ischemic lesions on 5-day MRI, and late silent lesion recurrence was defined as those on 30- or 90-day MRI. Patients were followed up for recurrent vascular events by interviews. RESULTS: Among the 104 patients (86.7%) who had available clinical outcome data, 35 (33.7%) had early silent lesion recurrence; 15 (22.1%) of 68 patients had late silent lesion recurrence. Of the patients, 8 experienced a recurrent IS, 3 experienced a transient ischemic attack, and 3 had vascular deaths during a mean +/- SD follow-up of 19.3 +/- 9.0 months. For recurrent IS as a clinical end point, late silent lesion recurrence independently predicted recurrent IS (odds ratio, 6.55; 95% confidence interval, 1.09-39.55) by the Cox proportional hazards model. For combined clinical end points, early (odds ratio, 3.19; 95% confidence interval, 1.02-10.00) and late (odds ratio, 8.09; 95% confidence interval, 1.29-50.91) silent lesion recurrences independently predicted clinical recurrent IS, transient ischemic attack, or vascular deaths. CONCLUSION: These data suggest that silent ischemic lesion recurrence on MRI may be a potential surrogate marker of clinical recurrence.

Impact of establishing a primary stroke center at a community hospital on the use of thrombolytic therapy: the NINDS Suburban Hospital Stroke Center experience.

BACKGROUND AND PURPOSE: To increase the proportion of ischemic stroke patients treated with thrombolytic therapy, the establishment of primary stroke centers in community hospitals has been advocated. We evaluated the use of thrombolytic therapy before and after institution of a primary stroke center in a community hospital. METHODS: The availability of an on-call stroke emergency response team was the only significant additional resource required for this hospital. All eligible patients were treated with intravenous tissue plasminogen activator (tPA). The number of patients with cerebrovascular disease, number and proportion of patients treated with tPA, times to treatment, and patient outcomes were recorded during the first 2 years of the stroke center. RESULTS: During the 12 months before institution of the stroke center, 3 ischemic stroke patients (1.5%) were treated with tPA. During the 2-year period of around-the-clock coverage, 44 of 420 ischemic stroke patients (10.5%) were treated with intravenous tPA, a significant increase in tPA use (P<0.0001). CONCLUSIONS: Establishment of a primary stroke center at a community hospital resulted in a substantial increase in the proportion of patients receiving thrombolytic therapy for ischemic stroke. If this experience is generalized, the beneficial impact of primary stroke centers on stroke outcomes and costs to the healthcare system may be substantial.