Risk of Intracranial Hemorrhage in Persons with Hemophilia A in the United States: Real-World Retrospective Cohort Study Using the ATHNdataset.

Introduction: Intracranial hemorrhage (ICH), a serious complication in persons with hemophilia A (PWHA), causes high rates of mortality and morbidity. Identified ICH risk factors from patient data spanning 1998-2008 require reassessment in light of changes in the current treatment landscape. Aim and methods: PWHA identified in the ATHNdataset were evaluated retrospectively to assess incidence of ICH and determine the association between ICH risk and key characteristics using time-to-event analyses (Cox proportional-hazards models, survival curves, and sensitivity analyses). Results: Over a median follow-up time of 10.7 patient-years, 135 of 7837 PWHA over 2 years of age in the ATHNdataset (1.7%) experienced an ICH. Stratification by prophylaxis status and inhibitor status resulted in an incidence rate (IR) ratio (IRR) (IR+/IR-) of 0.63 (95% confidence interval [CI], 0.43-0.94; P=0.020) and 1.76 (95% CI, 0.97-3.20; P=0.059), respectively. Characteristics associated with greater risk of developing ICH include being aged 2-12 years; being covered by Medicaid; having had HIV, hepatitis C, or hypertension; and never having received factor VIII or prophylactic treatment. In multivariable analysis with interaction, the estimated hazard ratio for PWHA never receiving prophylaxis was 7.67 (95% CI, 2.24-26.30), which shrunk to 2.03 (95% CI, 1.30-9.12) in bootstrapping analysis and 3.09 in the highest-penalty ridge-regression analysis but was still significant. Inhibitor status was found not to be statistically associated with ICH in all analyses. Conclusion: These results align with previous studies demonstrating that prophylaxis confers a protective effect against ICH. Previously, inhibitor positivity had been shown to increase risk for ICH; however, this study did not corroborate those findings.

Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial.

BACKGROUND: Etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment, was shown to be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after gene therapy in a phase 3 trial. We report post-hoc 24-month efficacy and safety data from this trial to evaluate the longer-term effects of etranacogene dezaparvovec in individuals with haemophilia B. METHODS: The phase 3 HOPE-B trial enrolled males aged 18 years or older with inherited haemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%), with a severe bleeding phenotype and who were on stable continuous factor IX prophylaxis. Participants were treated with a single infusion of etranacogene dezaparvovec (2 × 1013 genome copies per kg of bodyweight). The primary endpoint, reported previously, was non-inferiority of the annualised bleeding rate (ABR) during the 52 weeks following stable factor IX expression (defined as months 7-18 after treatment) versus an at least 6-month lead-in period in which participants received their usual continuous factor IX prophylaxis, and is updated here up to month 24. Additional, post-hoc efficacy analyses, including adjusted ABR, factor IX activity, participants within factor IX ranges, and factor IX use, and safety analyses were performed at 24 months after gene therapy. Data were analysed in the full analysis set, which comprised the 54 patients who received at least a partial dose of gene therapy. The trial is ongoing and is registered with ClinicalTrials.gov, number NCT03569891. FINDINGS: The study began on June 27, 2018, and participants were treated between January, 2019, and March, 2020; the date of data cutoff was April 21, 2022. 54 adult males (40 White, two Asian, one Black or African American, 11 other or missing) received a single intravenous infusion of etranacogene dezaparvovec and were followed for a median of 26·51 months (IQR 24·54-27·99), after a lead-in period of 7·13 months (6·51-7·82). In the updated analysis comparing months 7-24 after gene therapy to the lead-in period, mean adjusted ABR significantly reduced from 4·18 to 1·51 (p=0·0002) for all bleeds and from 3·65 to 0·99 (p=0·0001) for factor IX-treated bleeds. During each 6-month period after gene therapy, at least 67% of participants experienced no bleeding (36 of 54 during months 0-6 and stable thereafter), compared with 14 (26%) of 54 during the lead-in period. 24 months after gene therapy, 1 (2%) participant had one-stage factor IX activity less than 5%, whereas 18 (33%) had factor IX activity more than 40% (non-haemophilia range), with mean factor IX activity stable and sustained at 36·7% (SD 19·0%). 52 (96%) of 54 participants expressed endogenous factor IX, remaining free of factor IX prophylaxis at month 24. No new safety concerns were identified and no treatment-related serious adverse events or treatment-related deaths occurred. The most common treatment-related adverse events were an increase in alanine aminotransferase (nine [17%] of 54 patients), headache (eight [15%]), influenza-like illness (seven [13%]), and an increase in aspartate aminotransferase (five [9%]). INTERPRETATION: By providing durable disease correction throughout the 24 months after gene therapy, etranacogene dezaparvovec provides a safe and effective therapeutic option for patients with severe or moderately severe haemophilia B. FUNDING: uniQure and CSL Behring.

Evaluation of collagen turnover biomarkers as an objective measure for efficacy of treatment with rurioctocog alfa pegol in patients with hemophilia A: a secondary analysis of a randomized controlled trial.

BACKGROUND: Patients with hemophilia who have recurrent hemarthroses develop hemophilic arthropathy (HA). Regular prophylaxis with factor (F) VIII (FVIII) can reduce HA, but there is a need for objective outcome measures to evaluate treatment efficacy. OBJECTIVES: Evaluate and assess collagen turnover biomarkers in patients with hemophilia A to determine the efficacy of rurioctocog alfa pegol treatment and understand their potential as tools for guiding treatment decisions and monitoring outcomes. METHODS: Joint remodeling was assessed by analyzing serum levels of collagen remodeling products at baseline and months 3, 6, 9, and 12 in a 98 patient subset receiving pharmacokinetics-guided prophylaxis with rurioctocog alfa pegol, targeting FVIII trough levels of 1 to 3 International Units (IU)/dL or 8 to 12 IU/dL (PROPEL study, NCT0285960). RESULTS: Basement membrane metabolism-related type 4 collagen remodeling products (C4M and PRO-C4) decreased after 3 months at all time points by up to 25% at 1 to 3 IU/dL (P = .049, P < .0001) and 8 to 12 IU/dL FVIII trough levels (P = .0002, P < .0001). Interstitial tissue metabolism-related type 3 (C3M) and 5 (PRO-C5) collagen remodeling products decreased after 3 months, by up to 19% at 1 to 3 IU/dL FVIII trough level (P = .0001, P = .009) and 23% at 8 to 12 IU/dL FVIII trough level (P = .0002, P = .001). An increase of up to 12% was seen for cartilage metabolism-related type 2 collagen product (PRO-C2, not C2M) after 6 months at both trough levels (P = .01, P = .005). When stratified by prior treatment, changes in C3M (P = .03) and C4M (P = .02) levels were observed between trough levels for prior on-demand treatment but not for prophylaxis prior to study entry. CONCLUSION: Joint improvement measured by collagen remodeling biomarkers specific to the basement membrane, interstitial matrix, and cartilage was seen with pharmacokinetics-guided prophylaxis. These collagen remodeling biomarkers warrant further exploration as biomarkers to guide treatment toward improvement in HA.

Immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients with severe hemophilia A: interim results from a phase 3, prospective, multicenter, open-label study.

AIM: To determine the immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients (PUPs) with severe hemophilia A (HA). METHODS: This prospective, phase 3 study (NCT02615691) was conducted in PUPs, or patients with ≤2 exposure days (EDs) prior to screening, aged <6 years with severe HA. The primary endpoint was incidence of factor VIII (FVIII) inhibitor development. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing FVIII inhibitors or had developed a confirmed inhibitor at any time. RESULTS: Of the enrolled patients, 59/80 (73.8%) received ≥1 dose of rurioctocog alfa pegol; 54 received prophylaxis, and 35 on-demand treatment. Incidence of inhibitor development was 0.19 (10/52). Total annualized bleeding rate (95% CIs) was 3.2 (2.0-5.0) for patients receiving prophylaxis and 3.2 (1.6-6.3) for on-demand treatment. Hemostatic efficacy of most bleedings was rated as 'excellent' or 'good' after 24 hours (122/131 [93.1%]) and at resolution (161/170 [94.7%]). Five patients received ≥1 dose of rurioctocog alfa pegol for immune tolerance induction (ITI) and 1 patient was defined as having ITI success. Thirteen patients experienced 14 treatment-related adverse events, including 10 cases of FVIII inhibitor development. CONCLUSION: This is the first prospective study of rurioctocog alfa pegol for the treatment of PUPs with severe HA. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02615691).

Inhibition of protein arginine deiminase 4 prevents inflammation-mediated heart failure in arthritis.

Rheumatoid arthritis is a prototypic inflammatory condition with affected patients being at greater risk of incident heart failure (HF). Targeting innate immune cell function in the pathogenesis of HF bears the potential to guide the development of future therapies. A collagen-induced arthritis (CIA) model in DBA/1 J mice was used to generate arthritis. Mice with CIA developed concentric hypertrophic myocardial remodeling, left ventricular (LV) diastolic dysfunction, and HF with elevated plasma B-type natriuretic peptide levels but preserved LV ejection fraction. Key features of HF in CIA were increased infiltration of activated neutrophils, deposition of neutrophil extracellular traps in the myocardium, and increased tissue levels of the proinflammatory cytokine IL-1ß. Specific inhibition of protein arginine deiminase 4 (PAD4) by an orally available inhibitor (JBI-589), administered after the onset of clinical arthritis, prevented HF with reduced neutrophil infiltration. We identify PAD4-mediated neutrophil activation and recruitment as the key thromboinflammatory pathway driving HF development in arthritis. Targeting PAD4 may be a viable therapeutic approach for the prevention of HF secondary to chronic inflammation.

Psychometric evaluation of a patient-reported outcomes instrument for congenital thrombotic thrombocytopenic purpura.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening hereditary disorder that causes patients to experience significant morbidity and decreased health-related quality of life (HRQoL). A cTTP disease-specific patient-reported outcome (PRO) instrument that is reflective of patients' experiences with the disorder does not currently exist. The objective of this study was to evaluate and validate the psychometric properties of the Congenital Thrombotic Thrombocytopenic Purpura-Patient Experience Questionnaire (cTTP-PEQ), developed using a literature review, interviews with expert clinicians, and qualitative concept elicitation and cognitive debriefing interviews. METHODS: This prospective, observational study (NCT03519672) was conducted with patients diagnosed with cTTP currently receiving treatment. Patients were enrolled through investigator sites and direct-to-patient recruitment. Individuals completed electronic self-administered PRO measures, including the cTTP-PEQ, at baseline and Day 14 (+ up to 10 days). The cTTP-PEQ consisted of five multi-item domains (Pain/Bruising, Cognitive Impairment, Visual Impairment, Mood, Treatment Burden) and three single-item domains (Fatigue, Headache, Activity Limitation), and assessed symptoms and impact of cTTP in the previous 24 h, 7 days, and 2 weeks. Convergent and discriminant validity were evaluated using Spearman's rank correlation coefficients. Known-groups validity was assessed between patient groups separated by Patient Global Impression of Severity (PGI-S; normal vs. mild/moderate/severe). Internal reliability was assessed using Cronbach's alpha. Test-retest reliability was assessed using intraclass correlation coefficients (ICCs). RESULTS: Thirty-six patients participated in this study. Convergent validity was confirmed with high-to-moderate correlations (r ≥ 0.4) for 12/15 hypothesized relationships between pairs of domains and/or total scores. Discriminant validity was confirmed with low correlations (r < 0.3) observed for 5/7 hypothesized relationships. Known-groups validity was confirmed with significant differences (p ≤ 0.05) in mean cTTP-PEQ scores between the two PGI-S groups for most domains and items at both timepoints. Cronbach's alpha was 0.88 at baseline and 0.91 at Day 14, confirming internal consistency of the instrument. Test-retest reliability was also confirmed with a high ICC (0.96). CONCLUSION: This study validates the psychometric properties of the novel cTTP-PEQ for use in research and clinical practice to assess HRQoL among patients with cTTP. This instrument will be particularly useful when assessing cTTP disease burden and the impact of new treatments.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: facilitating research through infrastructure, workforce, resources and funding.

BACKGROUND: The National Hemophilia Foundation (NHF) conducted extensive, inclusive community consultations to guide prioritization of research in coming decades in alignment with its mission to find cures and address and prevent complications enabling people and families with blood disorders to thrive. RESEARCH DESIGN AND METHODS: With the American Thrombosis and Hemostasis Network, NHF recruited multidisciplinary expert working groups (WG) to distill the community-identified priorities into concrete research questions and score their feasibility, impact, and risk. WG6 was charged with identifying the infrastructure, workforce development, and funding and resources to facilitate the prioritized research. Community input on conclusions was gathered at the NHF State of the Science Research Summit. RESULTS: WG6 detailed a minimal research capacity infrastructure threshold, and opportunities to enable its attainment, for bleeding disorders centers to participate in prospective, multicenter national registries. They identified challenges and opportunities to recruit, retain, and train the diverse multidisciplinary care and research workforce required into the future. Innovative collaborative approaches to trial design, resource networking, and funding to surmount obstacles facing research in rare disorders were elucidated. CONCLUSIONS: The innovations in infrastructure, workforce development, and resources and funding proposed herein may contribute to facilitating a National Research Blueprint for Inherited Bleeding Disorders.

Research is critical to advancing the diagnosis and care of people with inherited bleeding disorders (PWIBD). This research requires significant infrastructure, including people and resources. Hemophilia treatment centers (HTC) need many different skilled care professionals including doctors, nurses, and other providers; also statisticians, data managers, and other experts to process patients' clinical information into research. Attracting diverse qualified professionals to the clinical and research work requires long-term planning, recruiting individuals in training programs and retaining them as they become experts. Research infrastructure includes physical servers running database software, networks that link them, and the environment in which these components function. US Centers for Disease Control and Prevention (CDC) and American Thrombosis and Hemostasis Network (ATHN) coordinate and fund data collection at HTCs on the health and well-being of thousands of PWIBD into a registry used in research studies.National Hemophilia Foundation (NHF) and ATHN asked our group of health care professionals, technology experts, and lived experience experts (LEE) to identify the infrastructure, workforce, and resources needed to do the research most important to PWIBD. We identified the types of CDC/ATHN studies all HTCs should be able to perform, and the physical and human infrastructure this requires. We prioritized finding the best clinical trial designs to study inherited bleeding disorders, identifying ways to share personnel and tools between HTCs, and innovating how research is governed and funded. Involving LEEs in designing, managing, and carrying out research will be key in conducting research to improve the lives of PWIBD.

Structure and Function of Recombinant versus Plasma-Derived von Willebrand Factor and Impact on Multimer Pharmacokinetics in von Willebrand Disease.

Background: Recombinant von Willebrand factor (rVWF, vonicog alfa) is a purified VWF concentrate produced from Chinese hamster ovary cells. rVWF is not exposed to the VWF-cleaving protease ADAMTS13 and so is not subject to proteolytic degradation of large (L) and ultra-large (UL) VWF multimers by that enzyme. Purpose: To compare the structure and function of rVWF with the human plasma-derived VWF [pdVWF] concentrates Haemate P®/Humate-P®, Voncento®, Wilate®/Eqwilate®, and Wilfactin®/Willfact®; to investigate the relationship between VWF multimeric pattern and VWF:ristocetin cofactor (VWF:RCo) activity through population pharmacokinetic (PK) modeling in patients with severe von Willebrand disease (VWD) treated with rVWF. Methods: Analyses included VWF:RCo activity, VWF:collagen-binding activity, VWF:platelet glycoprotein Ib receptor binding, factor VIII (FVIII) binding capacity, and VWF-mediated platelet adhesion under flow conditions. VWF multimeric structure was determined by agarose gel electrophoresis. Population PK models describing the activity-time profile of small, medium, and L/UL multimers following intravenous administration of rVWF in patients with severe VWD were developed. Results: Findings demonstrate that rVWF contains a non-degraded VWF multimer pattern including the UL multimers not present in pdVWF concentrates. rVWF displayed higher specific platelet-binding activity, and faster mediation of platelet adhesion to collagen under shear stress versus pdVWF concentrates. rVWF also demonstrated higher FVIII binding capacity than Haemate P®, Voncento® and Wilate®. Modeling provided evidence that VWF:RCo activity in patients with severe VWD treated with rVWF is associated with L/UL VWF multimers in the circulation. Conclusions: Findings suggest that the L and UL multimers preserved in rVWF contribute to high biological activity and might be important for providing hemostatic efficacy.

Economic Burden Associated with Major Surgery in Patients with von Willebrand Disease: A United States Retrospective Administrative Database Analysis.

PURPOSE: To estimate the incremental economic burden of major surgeries in patients with von Willebrand disease (VWD). PATIENTS AND METHODS: This was a retrospective analysis of the IBM Health MarketScan® database (2008-2018). Patients with at least two healthcare visits for VWD in the database who had undergone at least one major surgery unrelated to VWD (identified via International Classification of Diseases, Ninth and Tenth Revisions procedure codes) were included. Patients without VWD with major surgeries were selected from a 1% random database sample. All patients had ≥12 months of continuous healthcare plan enrollment before and following their first major surgery. Patients with VWD were matched (1:1) with patients without VWD using propensity score matching. Regression models compared healthcare resource utilization and costs between the matched cohorts over a 12-month period after patients' index major surgery. RESULTS: After propensity score matching, 2972 pairs were selected. Musculoskeletal and digestive surgeries were the two most common major surgeries (patients with VWD, 39.6% and 25.0%; without VWD, 37.1% and 23.4%, respectively). Patients with VWD were significantly more likely (p<0.0001) to have an inpatient admission (odds ratio = 1.71; 95% confidence interval [CI] 1.52-1.92) or emergency room visit (odds ratio = 1.41; 95% CI 1.25-1.59) than patients without VWD. The numbers of inpatient admissions (incidence rate ratio [IRR] = 1.47; 95% CI 1.35-1.60), emergency room visits (IRR = 1.44; 95% CI 1.31-1.59), and outpatient visits (IRR = 1.16; 95% CI 1.11-1.21) per patient were also significantly greater for patients with VWD than for those without VWD (p<0.0001). Patients with VWD incurred significantly higher (p<0.0001) total healthcare costs (medical and pharmacy) per patient than patients without VWD ($50,733.89 versus $30,154.84, respectively). CONCLUSION: Healthcare resource utilization and associated costs among patients undergoing major surgeries were significantly higher for those with VWD than for patients without VWD.

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19.

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients.

Results of a randomized phase III/IV trial comparing intermittent bolus versus continuous infusion of antihaemophilic factor (recombinant) in adults with severe or moderately severe haemophilia A undergoing major orthopaedic surgery.

INTRODUCTION: In patients with haemophilia A undergoing surgery, factor VIII (FVIII) replacement therapy by continuous infusion (CI) may offer an alternative to bolus infusion (BI). AIM: To compare the perioperative haemostatic efficacy and safety of antihaemophilic factor (recombinant) (ADVATE® ; Baxalta US Inc., a Takeda company, Lexington, MA, USA) CI or BI administration. METHODS: In this multicentre, phase III/IV, controlled study (NCT00357656), 60 previously treated adult patients with severe or moderately severe disease undergoing elective unilateral major orthopaedic surgery (knee replacement, n = 48; hip surgery, n = 4; other, n = 8) requiring drain placement were randomized to receive antihaemophilic factor (recombinant) CI (n = 29) or BI (n = 31) through postoperative day 7. Primary outcome measure was cumulative packed red blood cell (PRBC)/blood volume in the drainage fluid within 24 h after surgery, used to establish non-inferiority of CI to BI. RESULTS: CI:BI ratio of cumulative PRBC volume in the 24-h drainage fluid was 0.92 (p-value <.001 for non-inferiority; 95% confidence interval, 0.82-1.05). Total antihaemophilic factor (recombinant) dose per kg body weight received in the combined trans- and postoperative periods was similar with CI and BI to maintain targeted FVIII levels during/after surgery. Treatment-related adverse events (AEs) were reported in five patients treated by CI (eight events) and five treated by BI (six events), including two serious AEs in each arm. CONCLUSION: CI administration of antihaemophilic factor (recombinant) is a viable alternative to BI in patients with haemophilia A undergoing major orthopaedic surgery, providing comparable efficacy and safety.

Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study.

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.

Economic burden of major bleeding events in commercially insured patients with von Willebrand disease based on claims data from the United States.

BACKGROUND: von Willebrand disease (VWD) can lead to serious, life-threatening bleeding events associated with substantial clinical and economic burden. OBJECTIVE: To estimate the prevalence, health care resource utilization (HCRU), and costs associated with major bleeding events in patients with VWD. METHODS: This was a retrospective analysis of the IBM MarketScan database (2008-2016). Selected patients had ≥ 2 VWD diagnoses, no diagnosis of acquired coagulation factor deficiency, and continuous health care plan enrollment for ≥ 12 months from eligibility start date. Prevalence was calculated as the proportion of eligible patients with ≥ 1 major bleeding event during the observation period (start to end of continuous eligibility). HCRU and costs in the 12-month continuous enrollment period following the first major bleeding event were compared with those from a comparable 12-month period for patients without major bleeding events. RESULTS: Of the 19,785 patients with VWD, 15% experienced ≥ 1 major bleeding event during a median follow-up of 4 years; 89% of these events were gastrointestinal bleeds. For the economic analysis, 773 patients with ≥ 1 major bleeding event and 4,285 patients without major bleeding events met the selection criteria. Controlling for baseline covariates, patients with major bleeding events had significantly (P < 0.0001) more inpatient admissions (incidence rate ratio [IRR] = 3.2; 95% CI = 2.78-3.77), longer inpatient stays (IRR = 3.9; 95% CI = 3.12-4.93), and more emergency department visits (IRR = 2.0; 95% CI = 1.77-2.27) and outpatient visits (IRR = 1.3; 95% CI = 1.19-1.34) than patients without major bleeding events. Annual health care costs were significantly higher (P < 0.01) for patients with major bleeding events than those without them (predicted mean cost differences: total = $20,890, pharmacy = $2,593, and medical = $18,293). CONCLUSIONS: Major bleeding events were associated with increased HCRU and costs, mostly inpatient costs. Therefore, optimizing therapy to prevent or reduce major bleeding events has the potential to reduce health care use and costs in patients with VWD. DISCLOSURES: This study was funded by Baxalta U.S. Inc., a Takeda company (Lexington, MA). The study sponsor was involved with the study design, analysis, and interpretation of data; writing of the manuscript; and the decision to publish the article. Lu, Wu, and Ewenstein are employees of Baxalta U.S. Inc., a Takeda company, and are Takeda stock owners. Farahbakhshian is an employee of Shire U.S. Inc., a Takeda company, and is a Takeda stock owner. Oladapo was an employee of Baxalta U.S. Inc., a Takeda company, at the time the analysis was completed and the manuscript developed, and is a Takeda stock owner.

BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression.

Gene therapy has the potential to maintain therapeutic blood clotting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene into liver cells. This phase 1/2, open-label dose-escalation study investigated BAX 335 (AskBio009, AAV8.sc-TTR-FIXR338Lopt), an adeno-associated virus serotype 8 (AAV8)-based FIX Padua gene therapy, in patients with hemophilia B. This report focuses on 12-month interim analyses of safety, pharmacokinetic variables, effects on FIX activity, and immune responses for dosed participants. Eight adult male participants (aged 20-69 years; range FIX activity, 0.5% to 2.0%) received 1 of 3 BAX 335 IV doses: 2.0 × 1011; 1.0 × 1012; or 3.0 × 1012 vector genomes/kg. Three (37.5%) participants had 4 serious adverse events, all considered unrelated to BAX 335. No serious adverse event led to death. No clinical thrombosis, inhibitors, or other FIX Padua-directed immunity was reported. FIX expression was measurable in 7 of 8 participants; peak FIX activity displayed dose dependence (32.0% to 58.5% in cohort 3). One participant achieved sustained therapeutic FIX activity of ∼20%, without bleeding or replacement therapy, for 4 years; in others, FIX activity was not sustained beyond 5 to 11 weeks. In contrast to some previous studies, corticosteroid treatment did not stabilize FIX activity loss. We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses, including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization. This trial was registered at www.clinicaltrials.gov as #NCT01687608.

Patient Experience with Congenital (Hereditary) Thrombotic Thrombocytopenic Purpura: A Conceptual Framework of Symptoms and Impacts.

BACKGROUND AND OBJECTIVE: Thrombotic thrombocytopenic purpura is a rare, life-threatening disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia, with variable clinical manifestations (e.g., central nervous system, renal, gastrointestinal, and cardiac effects). This study's objective was to gain an in-depth understanding of patients' experiences with the congenital form of thrombotic thrombocytopenic purpura, including the most salient symptoms and impacts associated with congenital thrombotic thrombocytopenic purpura and its treatment. METHODS: An initial conceptual model of thrombotic thrombocytopenic purpura symptoms and impacts was derived from a targeted literature review, refined by interviews with expert hematologists, and further refined by concept elicitation telephone interviews with adults with congenital thrombotic thrombocytopenic purpura in the USA. Patients reported the duration, frequency, and severity experienced for each concept, and rated level of disturbance on a minimum to maximum scale of 0-10. RESULTS: Interviews were conducted with 11 patients (mean age, 38.2 years; range 21-52 years) in three waves (n = 4, n = 4, n = 3). The most salient symptoms (reported most frequently and rated by patients as most disturbing) were fatigue, headache, bruising, joint pain, muscular pain, forgetfulness, and difficulty communicating. The most salient impacts included diminished ability to work/study, financial distress, feeling depressed, feeling anxious, and mood swings. Patients' comments reflected the pervasive nature of congenital thrombotic thrombocytopenic purpura symptoms and impacts, and unmet treatment needs. CONCLUSIONS: The final conceptual model, which includes salient symptoms and impacts of congenital thrombotic thrombocytopenic purpura and reflects the disease burden, was derived by integrating inputs from the literature review, expert opinion, and patient interviews, and will be used to develop a congenital thrombotic thrombocytopenic purpura-specific, patient-reported outcome instrument.

Use of Bypassing Agents and Risk of Thromboembolic Events in Patients with Haemophilia and Inhibitors.

Patients with haemophilia and inhibitors to factors VIII or IX require bypassing therapy. The primary safety concern of bypassing agents is thromboembolism; however, the incidence of thromboembolic adverse events (TAEs) in haemophilia patients with inhibitors remains poorly characterized. The aim of this study was to assess the incidence of TAEs following exposure to bypassing agents in patients with haemophilia. Using U.S. Medicaid database (2000­2010), we identified a cohort of 719 males (mean age: 10 years at cohort entry) with haemophilia A or B and use of either recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC). Patients were followed up until loss of insurance eligibility, end of study period, or the first occurrence of TAE. Exposure was assessed on as-treated basis, and outcomes were adjudicated through review of healthcare claims. During the observation of a total of 2,823 person-years (py; mean follow-up: 3.9 years), 22 TAEs were identified, leading to incidence rates of 4.2 events (95% confidence interval [CI]: 1.8­8.3) per 1,000 unexposed py; 15.4 events (95% CI: 6.7­30.3) per 1,000 aPCC-exposed py; 18.2 events (95% CI: 8.3­34.6) per 1,000 rFVIIa-exposed py; and 29.7 events (95% CI: 6.1­86.7) per 1,000 py of concomitant exposure to both agents. The results were consistent across sensitivity analyses. In conclusion, we found no difference in the rate of TAEs across agents, but the data are compatible with a possibly increased rate associated with a combination therapy, highlighting the need for continuing safety monitoring through prospective registries or observational data.

Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura.

Safety, tolerability, and pharmacokinetics of recombinant ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; BAX 930; SHP655) were investigated in 15 patients diagnosed with severe congenital ADAMTS-13 deficiency (plasma ADAMTS-13 activity <6%) in a prospective phase 1, first-in-human, multicenter dose escalation study. BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed. After single-dose administration of BAX 930 at 5, 20, or 40 U/kg body weight to adolescents and adults, there was approximate dose proportionality with respect to maximum plasma concentration (Cmax [U/mL]) and area under the concentration-time curve (AUC [h∙U/mL]). Dose-related increases of individual ADAMTS-13:Ag and activity were observed and reached a maximum within 1 hour. With escalating BAX 930 doses administered, a dose-dependent persistence of ADAMTS-13-mediated von Willebrand factor (VWF) cleavage products and reduced VWF multimeric size were observed. This study demonstrated that pharmacokinetic parameters of BAX 930 were comparable to those estimated in previous plasma infusion studies and provided evidence of pharmacodynamic activity. This study was registered at www.clinicaltrials.gov as #NCT02216084.

The role of ultralarge multimers in recombinant human von Willebrand factor - a review of physico-and biochemical studies and findings in in vivo models and in humans with von Willebrand disease.

Ultralarge multimers (ULM) of VWF are considered to be the most active with respect to binding to platelets and to subendothelial structures and therefore are of critical importance for the function of VWF in stabilizing the primary hemostatic plug. In contrast to plasma-derived FVIII-VWF concentrates, human rVWF obtained from mammalian cell culture retains the full-spectrum of intact multimers, including ULM, as physiologically formed in the Golgi apparatus and stored in platelet α-granules and endothelial cell Weibel-Palade bodies. In the course of physico and biochemical, functional and animal studies, rVWF exhibited superiority in structure and function compared to pdVWF. These effects seemed to correlate with the multimer size and therefore might be attributed to the presence of ULM in rVWF preparations. The pharmacokinetic (PK), safety and efficacy characteristics seen in preclinical studies were further demonstrated in clinical trials.