Treatment of thrombotic cardiovascular diseases in people with haemophilia: A Japanese consensus study.

INTRODUCTION: Cardiovascular diseases (CVD) that require long-term anticoagulant and antiplatelet therapy presents a problem in people with haemophilia (PWH) who receive factor replacement therapy to reduce bleeding risk. Currently, there are no Japanese guidelines for the management of PWH with CVD. AIM: To develop expert guidance on managing CVD in PWH in Japan. METHODS: A steering committee of four experts (two haemophilia specialists, one thrombosis specialist, one cardiologist) identified 44 statements related to five key themes. An online questionnaire was produced comprising a mix of 4-point Likert scale and multiple-choice questions that was sent to specialists in the management of PWH with CVD in Japan. Consensus was defined as high or very high if a respective ≥75% or ≥90% of respondents agreed with a statement. RESULTS: Of 16 potential respondents, responses were received from 15 specialists. Of the Likert scale questions, 71% (29/41) achieved ≥90% agreement (very strong agreement), 17% (7/41) achieved 75%-89% agreement (strong agreement) and 15% (6/41) did not achieve consensus agreement. The three multiple-choice questions failed to identify a strong preference. Agreement on specific target trough clotting factor levels for managing certain clinical situations, such as when in the presence of non-valvular atrial fibrillation or myocardial infarction, was also achieved. CONCLUSION: The results of this consensus study provide a framework for cardiologists and haematologists to manage PWH who are at risk of, or who have, CVD. Implementation of the recommendations provided herein may improve outcomes for PWH with CVD.

Noninterventional study assessing joint health in persons with hemophilia A after switching to turoctocog alfa pegol: design of pathfinderReal.

Background: Joint damage affects the quality of life of persons with hemophilia A. The long-term safety and efficacy of turoctocog alfa pegol (N8-GP) prophylaxis in persons with hemophilia A has been investigated in pivotal phase 3 trials in children, adolescents, and adults (pathfinder program). However, there is a lack of data on joint health in adult persons with hemophilia A treated with N8-GP. Objectives: To describe the design of the ongoing pathfinderReal study investigating the joint health status in adult persons with hemophilia A after switching to N8-GP. Methods: pathfinderReal is a multicountry, noninterventional, single-arm study (NCT05621746) of joint health in adult (≥18 years) male persons with hemophilia A who have switched to N8-GP. Patients enrolled in other interventional studies and those who have previously terminated N8-GP treatment will be excluded. Approximately 124 adults with hemophilia A will be enrolled and followed up for a maximum of 24 months. Data from routine clinical assessments of patients' joint health will be collected. The primary endpoint is change in Hemophilia Joint Health Score (defined as a change in total score of ≤2) from initiation of N8-GP treatment until the end of the study. Secondary endpoints include number of bleeding episodes, number and resolution of target joints, patient-reported outcomes of problem joint score, pain score, and change in physical function levels. An exploratory endpoint is included to measure the number of patients achieving improved Hemophilia Joint Health Score from the initiation of N8-GP until the end of the study. Conclusion: The pathfinderReal study will provide insights regarding the impact of N8-GP on joint health in persons with hemophilia A in a real-world setting.

Real-world long-term safety and effectiveness of turoctocog alfa in the treatment of haemophilia A in Japan: results from a multicentre, non-interventional, post-marketing study.

OBJECTIVES: To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan. METHODS: This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period. RESULTS: The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69-10.38). The mean (SD) total consumption of turoctocog alfa (n = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis. DISCUSSION: The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens. CONCLUSION: Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan.

Association of patient, treatment and disease characteristics with patient-reported outcomes: Results of the ECHO Registry.

INTRODUCTION: Patient-reported outcomes (PROs) in people living with haemophilia A (PLWHA) are often under-reported. Investigating PROs from a single study with a diverse population of PLWHA is valuable, irrespective of FVIII product or regimen. AIM: To report available data from the Expanding Communications on Haemophilia A Outcomes (ECHO) registry investigating the associations of patient, treatment and disease characteristics with PROs and clinical outcomes in PLWHA. METHODS: ECHO (NCT02396862), a prospective, multinational, observational registry, enrolled participants aged ≥16 years with moderate or severe haemophilia A using any product or treatment regimen. Data collection, including a variety of PRO questionnaires, was planned at baseline and annually for ≥2 years. Associations between PRO scores and patient, treatment and disease characteristics were determined by statistical analyses. RESULTS: ECHO was terminated early owing to logistical constraints. Baseline data were available from 269 PLWHA from Europe, the United States and Japan. Most participants received prophylactic treatment (76.2%), with those using extended-half-life products (10.0%) reporting higher treatment satisfaction. Older age and body weight >30 kg/m2 (>BMI) were associated with poorer joint health. Older age was associated with poorer physical functioning and work productivity. Health-related quality of life and pain interference also deteriorated with age and >BMI; >BMI also increased pain severity scores. CONCLUSION: ECHO captured a variety of disease characteristics, treatment patterns, PROs and clinical outcomes obtained in real-world practice with ≤1 year's follow-up. Older age, poorer joint health and >BMI adversely affected multiple aspects of participant well-being.

Association of physical activity with bleeding events and safety in patients with haemophilia A starting emicizumab prophylaxis: an interim analysis of the TSUBASA study.

INTRODUCTION: Little information exists on the relationship between bleeding outcomes and physical activity in patients with haemophilia A (PwHA). AIM: This interim analysis of the TSUBASA study (UMIN-CTR ID: UMIN000037448) evaluated the association of physical activity with bleeding and safety in PwHA starting emicizumab. METHODS: PwHA without factor VIII inhibitors were recruited. Physical activity and bleed data were obtained using an electronic patient-reported outcome application and wearable activity tracker. Adverse events (AEs) were documented. RESULTS: At data cut-off (31-May-2021), 107 PwHA were enrolled, with a median (range) age of 35 (0-73) years. Physical activity data were obtained for 74 participants. Of these, 47 (63.5%) recorded a total of 396 exercise events. The most common exercise events were walking (32.4%), cycling (14.9%), and football (5.4%). Two (0.5%) exercise events in the same individual were associated with bleeding (running, weight training). The safety analysis population consisted of 106 participants treated with emicizumab (median observation period: 241.5 days). Twenty-one (19.8%) participants experienced a total of 39 AEs. Five (4.7%) experienced a serious AE, none of which was emicizumab-related, and three (2.8%) experienced an adverse drug reaction. CONCLUSIONS: PwHA receiving emicizumab in the TSUBASA study experienced minimal bleeding associated with physical activity. TRIAL REGISTRATION: Trial registration: UMIN-CTR ID: UMIN000037448.

Real-World Experience of People with Hemophilia A Receiving Turoctocog Alfa Pegol (N8-GP): Results from a Patient Experience Survey.

Purpose: Turoctocog alfa pegol (N8-GP) is an extended half-life recombinant factor VIII molecule used for the treatment of hemophilia A (HA). The purpose of this study was to investigate real-world experiences of patients with HA treated with N8-GP. Patients and Methods: A 25-minute online survey was completed by adults (≥18 years) and caregivers of adolescents (12-16 years) with HA receiving N8-GP across six countries (Germany, Italy, Portugal, Spain, UK and US). Patients were recruited using a multichannel approach through recruitment panels, referrals from healthcare professionals and patient associations. The survey comprised a questionnaire with metrics including satisfaction and preferences for N8-GP, quality of life (QoL) and long-term impact. Results: A total of 62 participants (98% male [n=61], mean age 29 years) comprising 46 patients and 16 caregivers completed the survey. Patients (60% non-severe [n=37] and 40% severe [25]) were on N8-GP for a mean period of 1.4 years. Patients expressed satisfaction (95% vs 42%, p<0.001) and preference (91% vs 9%, p<0.001) for N8-GP vs their previous treatments. Most patients with severe HA (87%, p=0.038) and patients on prophylaxis (84%, p<0.001) stated lower frequency of injections as their main reason for satisfaction, while improved QoL drove satisfaction for non-severe patients (81%, p=0.053). Overall, patients perceived that QoL score improved (74.8 vs 65.9, p=0.01) with N8-GP treatment compared with previous treatments. Flexibility to store at room temperature was one of the key convenience factors driving satisfaction. Patients believed that N8-GP can offer a long-term impact in areas such as ability to perform day-to-day activities (68%), independence to live like a person without hemophilia (63%), ability to travel (60%) with a feeling of optimism and hopefulness (82%). Conclusion: Lower frequency of injections, storage flexibility and improved QoL drove satisfaction and preference for N8-GP over previous treatments among patients with HA.

Haemophilia and cardiovascular disease in Japan: Low incidence rates from ADVANCE Japan baseline data.

INTRODUCTION: With the increasing life expectancy of people with haemophilia, the risk of cardiovascular disease (CVD) and thrombotic events has become a growing concern. Longitudinal studies on the incidence and risk factors of CVD in this population are limited, and optimal prevention and treatment strategies are yet to be established. AIM: This study aimed to present the baseline data of a prospective longitudinal study focusing on a subset of Japanese patients with haemophilia, specifically investigated the incidence, risk factors and treatment modalities for CVD and thrombotic diseases in people aged 40 years in Japan over 10 years through the ADVANCE Japan study. METHODS: The ADVANCE Japan study is a prospective multicentre cohort study involving 600 adult individuals with haemophilia A/B aged 40 years in Japan. The primary endpoint was the incidence of CVD, with secondary endpoints encompassing anticoagulant use, mortality rates, and comparison with the general population. RESULTS: Baseline data from the 600 participants revealed that thrombotic events occurred in 13 individuals (2.2%), mostly in those with haemophilia A. Atrial fibrillation was observed in 11 participants (1.8%). Hypertension and dyslipidaemia were identified as the prevalent risk factors. Various prophylactic treatments were employed, and no severe bleeding events were observed during the study period. CONCLUSION: This study provides vital baseline data for a 10-year prospective investigation of CVD and thrombotic disease risk in people with haemophilia. These findings will contribute to refining prevention and treatment approaches and improving patients' quality of life.

The length of the sanitary napkins can be used as a handier index than pictorial blood loss assessment chart to predict the heavy menstrual bleeding.

AIM: Many women with inherited bleeding disorders are not diagnosed because of a lack of appropriate indicators. This study aimed to assess the predictability of the pictorial blood loss assessment chart (PBAC) as an indicator of menorrhagia and identify an easy indicator of menorrhagia resulting from bleeding disorders. METHODS: A multicenter study enrolled 9 patients with von Willebrand disease (VWD), 23 hemophilia carriers, and 71 controls aged 20-45 years who completed PBACs for two menstrual cycles as well as questionnaires. RESULTS: The PBAC scores of the VWD were significantly higher than those of other groups, even in multivariate analysis with age and sanitary item factors (p = 0.014). A PBAC score of 100 was not an appropriate cutoff because of its low specificity (VWD: sensitivity, 100; specificity, 29.5; hemophilia carriers: 74 and 29.5, respectively). In the ROC analysis, the cutoff of optimal PBAC for VWD was 171 (sensitivity, 66.7; specificity, 72.3; AUC, 0.7296). As the pad length increased, the total length of the pads used during one menstrual period could be a new and easy indicator. However, the cutoff for VWD was 735 cm (sensitivity, 42.9; specificity, 94.3; AUC 0.6837). A threshold could not be established for the hemophilia carrier. Therefore, we multiplied the coefficient by the length of thick pads, which caused a lower PBAC. For the VWD, the sensitivity increased to 85.7 (specificity, 77.1). For the hemophilia carrier, sensitivity (66.7) and specificity (88.6) could be separated from the control. CONCLUSIONS: The total length of the pads with a thick-pad adjustment can be a simple method to identify bleeding disorders.

Real-World Use of Albutrepenonacog Alfa, A Recombinant Coagulation Factor IX Albumin Fusion Protein, for Personalized Prophylaxis in Japanese Individuals With Hemophilia B: A Case Series.

Currently, the mainstay of disease management for hemophilia B, a hemorrhagic disease caused by a congenital deficiency or molecular abnormalities of blood coagulation factor IX (FIX), is prophylaxis using FIX concentrate. On-demand injections of FIX concentrate may also be required, even during prophylaxis, when a patient with hemophilia B is bleeding. Albutrepenonacog alfa (rFIX-FP) is a human albumin fusion gene recombinant FIX, which is administered once every seven, 14, or 21 days, depending on patient preferences and symptoms. Studies have demonstrated its efficacy and safety in a range of patients; however, to date, reports of real-world experiences of the use of rFIX-FP in Japan are limited. We present a case series of three Japanese individuals with moderately severe (FIX activity 1 to <2%) or severe (FIX activity <1%) hemophilia B who benefited from prophylaxis using rFIX-FP in our clinical practice setting. We highlighted the good effectiveness of rFIX-FP in a patient with moderately severe hemophilia B who required prophylaxis due to joint bleeding, which was causing deterioration of his left ankle joint, as well as in a patient with severe hemophilia B and atherothrombotic cerebral infarction, whose trough level had to be ≥5% for concomitant use of an antiplatelet drug, and in a patient with severe hemophilia B who was working in nursing care, which involved heavy labor and night shifts, and who had previously been treated with on-demand FIX concentrate. In all three cases, rFIX-FP improved disease symptoms, and the patients were able to maintain steady states of therapy due to the treatment characteristics of rFIX-FP, which stabilizes FIX at high trough levels.

Burden of congenital hemophilia A requiring treatment in Japan: The HIKOBOSHI study.

Background: Treatment of congenital hemophilia A (HA) in Japan has greatly improved with the widespread adoption of prophylactic factor (F)VIII concentrates. However, it is unknown if this has translated into a real-world reduction in disease and treatment burden. Objectives: To describe HA disease burden in Japan based on information from two medical information databases, JMDC and Real World Data Co., Ltd. (RWD). Methods: Eligible individuals were diagnosed with congenital HA and prescribed FVIII concentrates, bypassing agents, or emicizumab. Treatment patterns and disease burden data were derived from health insurance claims and electronic medical records. Results: Data on 459 people with HA were retrospectively collected from 2005 to 2020 in the JMDC database (median [min, max] of 37 [2, 186] months of available records), and 229 people with HA from 1985 to 2020 in the RWD database (median [min, max] of 154 [0, 409] months of available records). Mean (standard deviation) ages at the time of the first record were 25.0 (16.8) years (JMDC) and 19.2 (20.3) years (RWD). In the JMDC database, mean monthly FVIII dose increased from 2201 IU in 2005 to 8239 IU in 2013 to 11,377 IU in 2019; HA-related drug costs increased accordingly. Mean (95% confidence interval) annual outpatient and out-of-hours visits decreased slightly between 2013 and 2019 (outpatient visits: from 22.9 [16.8-29.0] to 14.3 [12.6-16.1] per person; out-of-hours visits: from 1.3 [0.2-2.5] to 0.6 [0-1.4]). There was no change in mean number of hospitalizations. Conclusions: Challenges remain in HA, including treatment burden, outpatient visits, and hospitalizations.

The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs.

Adeno-associated virus (AAV) vectors are promising modalities of gene therapy to address unmet medical needs. However, anti-AAV neutralizing antibodies (NAbs) hamper the vector-mediated therapeutic effect. Therefore, NAb prevalence in the target population is vital in designing clinical trials with AAV vectors. Hence, updating the seroprevalence of anti-AAV NAbs, herein we analyzed sera from 100 healthy individuals and 216 hemophiliacs in Japan. In both groups, the overall seroprevalence against various AAV serotypes was 20%-30%, and the ratio of the NAb-positive population increased with age. The seroprevalence did not differ between healthy participants and hemophiliacs and was not biased by the concomitant blood-borne viral infections. The high neutralizing activity, which strongly inhibits the transduction with all serotypes in vitro, was mostly found in people in their 60s or of older age. The multivariate analysis suggested that "60s or older age" was the only independent factor related to the high titer of NAbs. Conversely, a large proportion of younger hemophiliacs was seronegative, rendering them eligible for AAV-mediated gene therapy in Japan. Compared with our previous study, the peak of seroprevalences has shifted to older populations, indicating that natural AAV exposure in the elderly occurred in their youth but not during the last decade.

AOZORA: long-term safety and joint health in paediatric persons with haemophilia A without factor VIII inhibitors receiving emicizumab - protocol for a multicentre, open-label, phase IV clinical study.

INTRODUCTION: Persons with haemophilia A (PwHA) commonly experience regular bleeding into joints, which may result in joint damage and complications such as degenerative arthritis. Emicizumab has previously demonstrated efficacy in reducing the occurrence of joint bleeds and target joints, along with having a favourable safety profile; however, data on the long-term effects on joint health are lacking. The AOZORA study will evaluate the long-term safety and joint health of paediatric PwHA without factor (F)VIII inhibitors taking emicizumab; here, we report the details of the study protocol and baseline data. METHODS AND ANALYSIS: AOZORA is a multicentre, open-label, phase IV clinical study in Japan that aims to enrol approximately 30 PwHA aged <12 years without FVIII inhibitors. The primary endpoints include a long-term safety evaluation of adverse events, laboratory test abnormalities and FVIII inhibitor development; and a long-term joint health assessment using MRI and the Hemophilia Joint Health Score. Exploratory endpoints include characterising participants' physical activities and the number of activity-related bleeds requiring coagulation factor treatment. Currently, 30 participants have been enrolled, including 20 emicizumab-naïve participants and 10 who transferred from HOHOEMI, a previous study in paediatric PwHA. ETHICS AND DISSEMINATION: The AOZORA study was approved by the Institutional Review Boards of Nara Medical University and the St Marianna University Group. The study will be conducted in compliance with the Declaration of Helsinki, the standards stipulated in paragraph 3 of Article 14 and Article 80-2 of the Pharmaceuticals, Medical Devices and Other Therapeutic Products Act, the Ministerial Ordinance on Good Clinical Practice and the Ministerial Ordinance on Good Post-marketing Study Practice. Data will be published in peer-reviewed journals and presented at Global congresses. TRIAL REGISTRATION NUMBER: JapicCTI-194701.

Turoctocog alfa pegol (N8-GP) in severe hemophilia A: Long-term safety and efficacy in previously treated patients of all ages in the pathfinder8 study.

Background: N8-GP (turoctocog alfa pegol; Esperoct) is a glycoPEGylated human recombinant factor VIII (FVIII). Objectives: Pathfinder8 (NCT01480180) was a phase 3, multinational, open-label, nonrandomized trial to investigate the long-term safety and efficacy of N8-GP in people of all ages with severe hemophilia A previously treated with N8-GP. Patients/Method: Patients were recruited from the completed phase 3 pathfinder2 and pathfinder5 trials to receive intravenous N8-GP prophylaxis for up to 104 weeks, administered every 7 days, twice weekly, or three times weekly. Primary and secondary end points were the number of adverse events (AEs) reported and efficacy of treatment, respectively. Results: Overall, 160 patients were exposed to N8-GP for a mean of 179 exposure days and 681 calendar days (≈1.9 years) per patient. In total, 119 patients experienced 510 AEs, corresponding to a rate of 1.71 AEs per patient-year of exposure; 97.5% of AEs were mild or moderate in severity, and no AEs led to withdrawal. No patients developed FVIII inhibitors during the trial. The Poisson estimate of mean annualized bleeding rate for all bleeds (excluding surgery) and across all regimens was 1.10 (median, 0.00), and for spontaneous bleeds was 0.61 (median, 0.00). Most (55.6%) patients experienced no bleeds that required FVIII treatment (excluding perioperative bleeds). The estimated hemostatic success rate for the treatment of 322 bleeding episodes (excluding surgery) was 95.8%, including missing values as failure. Conclusions: Long-term prophylactic use of N8-GP appeared safe and efficacious across all age groups in people with severe hemophilia A previously treated with N8-GP.

AKATSUKI study: a prospective, multicentre, phase IV study evaluating the safety of emicizumab under and immediately after immune tolerance induction therapy in persons with congenital haemophilia A with factor VIII inhibitors.

INTRODUCTION: For persons with haemophilia A with factor (F) VIII inhibitors (PwHAwI), immune tolerance induction (ITI) therapy is indicated for inhibitor eradication; however, since PwHAwI on ITI were excluded from the emicizumab clinical development programme, there are limited safety data for emicizumab treatment under/immediately after ITI in PwHAwI. Accordingly, there is a need to collect safety and efficacy data on this concomitant treatment strategy. The AKATSUKI study aims to evaluate the safety of emicizumab under/immediately after ITI in PwHAwI; here we report details of the study protocol. METHODS AND ANALYSIS: AKATSUKI is an open-label, non-randomised, interventional, multicentre study. Twenty participants with congenital HA with FVIII inhibitors will be enrolled from 17 sites across Japan. Emicizumab will be administered subcutaneously, with an initial loading dose of 3 mg/kg once per week (QW) for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg QW, 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks. For ITI therapy, 50 IU/kg FVIII will be administered three times per week. For extended half-life FVIII, a dosing frequency of twice per week will be permitted. The primary endpoint is a comprehensive safety evaluation of adverse events (mainly thromboembolic events) and abnormal laboratory values over time. Secondary endpoints are the number of bleeds requiring coagulation factor treatment, the number of participants achieving a partially successful ITI response, FVIII inhibitor titres under/immediately after ITI, quality of life and time to achieve a negative FVIII inhibitor result (<0.6 BU/mL) and partial success in PwHAwI starting ITI after study enrolment. CONCLUSIONS: AKATSUKI will evaluate the safety of emicizumab administered under/immediately after ITI, providing reference data to inform treatment strategies in PwHAwI. ETHICS AND DISSEMINATION: The results of this study will be published in a peer-reviewed international journal and presented at national and/or international medical scientific conferences; the major findings of this study will be published on the jRCT registry website (https://jrct.niph.go.jp). TRIAL REGISTRATION NUMBER: jRCTs041200037.

Long-term safety and efficacy of emicizumab for up to 5.8 years and patients' perceptions of symptoms and daily life: A phase 1/2 study in patients with severe haemophilia A.

INTRODUCTION: Safety and efficacy results of the phase 1 study and phase 1/2 extension study of the bispecific antibody emicizumab in patients with severe haemophilia A with or without factor VIII inhibitors for up to 2.8 years were reported previously. AIM: To evaluate further longer-term data including patients' perceptions at study completion. METHODS: Emicizumab was administered subcutaneously once weekly at maintenance doses of 0.3, 1 or 3 mg/kg with potential up-titration. All patients were later switched to the approved maintenance dose of 1.5 mg/kg. RESULTS: Eighteen patients received emicizumab for up to 5.8 years. Most adverse events were mild and unrelated to emicizumab. Annualized bleeding rates (ABRs) for bleeds treated with coagulation factors decreased from pre-emicizumab rates or remained zero in all patients. The median ABRs were low at 1.25, 0.83 and 0.22 during the 0.3, 1 and 3 mg/kg dosing periods, respectively. Of 8 patients who decreased their doses from 3 to 1.5 mg/kg, ABRs decreased in 4, remained at zero in 2, and increased in 2. Total time spent with symptoms associated with treated bleeds decreased in all patients except 2. All patients answered 'improved' for bleeding severity and time until bleeding stops, except 1 answering 'slightly improved'. Most patients answered 'improved' or 'slightly improved'' for daily life and feelings; in particular, all patients except 1 answered 'improved' or 'slightly improved' for anxiety. CONCLUSIONS: Long-term emicizumab prophylaxis for up to 5.8 years was safe and efficacious, and may improve patients' daily lives and feelings, regardless of inhibitor status.

Long-term safety and efficacy of rIX-FP prophylaxis with extended dosing intervals up to 21 days in adults/adolescents with hemophilia B.

BACKGROUND: An international, multicenter extension study evaluated recombinant fusion protein linking recombinant coagulation factor IX (FIX) with recombinant human albumin (rIX-FP) in hemophilia B (FIX ≤ 2%) patients previously enrolled in a phase III study or who initiated rIX-FP prophylaxis following surgery. OBJECTIVES: To investigate the long-term safety and efficacy of rIX-FP prophylaxis in adult previously treated patients (PTPs) with hemophilia B. METHODS: Male PTPs were treated with a 7- (35-50 IU/kg), 10- or 14-day regimen (50-75 IU/kg). Patients ≥18 years who were well-controlled on a 14-day regimen for ≥6 months could switch to a 21-day regimen (100 IU/kg). RESULTS: A total of 59 patients (aged 13-63 years) participated in the study. Following a single dose of 100 IU/kg rIX-FP, in patients eligible for the 21-day regimen, the mean terminal half-life was 143.2 hours. Mean steady-state FIX trough activity levels ranged from 22% with the 7-day regimen to 7.6% with the 21-day regimen. Median (Q1, Q3) annualized spontaneous bleeding rates were 0.00 (0.00, 1.67), 0.28 (0.00, 1.10), 0.37 (0.00, 1.68), and 0.00 (0.00, 0.45) for the 7-, 10-, 14-, and 21-day regimens, respectively. Comparable efficacy was demonstrated for both the 14- and 21-day regimens compared to the 7-day regimen. Overall, 96.5% of bleeding episodes were treated successfully with 1 to 2 rIX-FP infusions. No patients developed an inhibitor and treatment was well tolerated. CONCLUSIONS: rIX-FP extended interval prophylaxis provides dosing flexibility and, in selected patients, a 21-day regimen may provide an alternative option to minimize treatment burden and individualize treatment.

Development and Validation of a Population-Pharmacokinetic Model for Rurioctacog Alfa Pegol (Adynovate®): A Report on Behalf of the WAPPS-Hemo Investigators Ad Hoc Subgroup.

BACKGROUND AND OBJECTIVE: Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design. METHODS: Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date. RESULTS: The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay - 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations. CONCLUSIONS: The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.