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Robert Klamroth,1 Piotr Wojciechowski,2 Samuel Aballéa,3 Françoise Diamand,4 Zalmai Hakimi,5 Jameel Nazir,5 Lydia Abad-Franch,6 Stefan Lethagen,7 Elena Santagostino,8 Michael D Tarantino9 1Department of Internal Medicine, Hemophilia Treatment Centre, Vivantes Klinikum im Friedrichshain, Berlin, Germany; 2Creativ-Ceutical, Krakow, Poland; 3Creativ-Ceutical, Rotterdam, the Netherlands; 4Creativ-Ceutical, Paris, France; 5Health Economics and Outcomes Research (Global), Sobi, Stockholm, Sweden; 6Global Medical Affairs Hematology, Sobi, Stockholm, Sweden; 7Medical and Clinical Sciences, Sobi, Stockholm, Sweden; 8Medical Affairs Hematology, Sobi, Stockholm, Sweden; 9The Bleeding and Clotting Disorders Institute, University of Illinois College of Medicine-Peoria, Peoria, IL, USACorrespondence: Robert KlamrothDepartment of Internal Medicine – Angiology and Hemostaseology, Center for Vascular Medicine, Hämophiliezentrum/Gerinnungssprechstunde, Vivantes Klinikum im Friedrichshain, Landsberger Allee 49, D, Berlin, 10249, Germany, Tel +49 (0)30 130 231575Fax +49 (0)30 130 231313Email robert.klamroth@vivantes.dePurpose: Primary prophylaxis, using factor VIII replacement, is the recognized standard of care for severe hemophilia A. Recombinant factor VIII-Fc fusion protein (rFVIIIFc) and emicizumab, a humanized, bispecific antibody, are approved for routine prophylaxis of bleeding episodes in severe hemophilia A. These products have different mechanisms of action, methods of administration and treatment schedules. In the absence of head-to-head trials, indirect treatment comparisons can provide informative evidence on the relative efficacy of the two treatments. The aim of the study was to compare the approved dosing regimens for each product, rFVIIIFc individualized prophylaxis and emicizumab administered once every week (Q1W), every 2 weeks (Q2W) or every 4 weeks (Q4W), based on clinical trial evidence.Patients and Methods: The comparison was conducted using matching-adjusted indirect comparison since clinical evidence did not form a connected network. Individual patient data for rFVIIIFc (A-LONG) were compared with data for emicizumab (HAVEN trial program) for mean annualized bleeding rate (ABR) and proportion of patients with zero bleeds. Safety data reported across the analyzed treatment arms were tabularized but not formally compared.Results: After matching, no significant differences were observed between mean ABR for rFVIIIFc and emicizumab administered Q1W, Q2W or Q4W. The proportion of patients with zero bleeds was significantly higher with rFVIIIFc compared with emicizumab administered Q4W (51.2% versus 29.3%, respectively; odds ratio 2.53; 95% confidence interval 1.09– 5.89); no significant differences noted when rFVIIIFc was compared with emicizumab administered Q1W or Q2W. The mean number of adverse events expressed per participant was 1.9 for individualized prophylaxis with rFVIIIFc and 3.7– 4.0, 4.1 and 3.6 for emicizumab administered Q1W, Q2W or Q4W, respectively.Conclusion: This indirect treatment comparison suggests that rFVIIIFc individualized prophylaxis is more efficacious than emicizumab Q4W, and at least as effective as more frequent emicizumab regimens, for the management of hemophilia A.Keywords: annualized bleeding rate, antibodies, bispecific, comparative effectiveness research, efmoroctocog alfa, factor VIII deficiency, treatment outcome

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products (“true PUPs”) and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

Introduction Real‐world data are lacking regarding the relationship between prospectively collected patient‐reported outcomes (PROs), clinical outcomes and treatment in people with haemophilia (PWH). The Expanding Communications on Hemophilia A Outcomes (ECHO) registry was designed to address this data gap, but a range of difficulties led to early study closure. Aim To describe the challenges faced and lessons learned from implementing a multinational haemophilia registry. Methods The Expanding Communications on Hemophilia A Outcomes was planned as a five‐year observational cohort study to collect data from 2000 patients in nine countries. Based on direct observations, feedback from patients enrolled in ECHO, challenges of the study design and input from study‐sponsor representatives, the ECHO Steering Committee systematically identified the challenges faced and developed recommendations for overcoming or avoiding them in future studies. Results The study closed after two years because few countries were activated and patient recruitment was low. This was related to multiple challenges including delayed implementation, stringent pharmacovigilance requirements, objections of investigators and patients to the burden of multiple PROs, data collection issues, lack of resources at study sites, little engagement of patients and competing clinical trials, which further limited recruitment. At study closure, 269 patients had been enrolled in four of nine participating countries. Conclusions Researchers planning studies similar to ECHO may want to consider the barriers identified in this global registry of PWH and suggestions to mitigate these limitations, such as greater patient involvement in design and analysis, clearer assessment and understanding of local infrastructure and potential changes to the administration of the study.

The performance of surgery and invasive procedures in patients with haemophilia is currently facing new challenges globally. The first is the appropriate application of low-dose protocols of clotting factor concentrates (CFC) achieving adequate perioperative haemostasis in resource constraint environments. The increasing availability of CFC through humanitarian aid programmes allows more invasive surgeries to be performed for which efficacy and safety data should be more widely collected and reported. Second, extended half-life CFC that are increasingly available in many countries represent valuable alternatives to standard half-life products in surgical patients allowing reduced number of infusions and lower consumption, in particular for extended half-life factor IX. Third, in the era of recently introduced non-factor prophylaxis, some minor surgical procedures can now be performed without additional haemostatic treatment, others with few low-dose administrations of CFC or bypassing agents. Additional factor VIII or bypassing treatment has proven to be safe and effective in association with emicizumab for major surgeries, and it was effectively given at low doses in association with fitusiran. No thrombotic complications have been reported in the surgical setting so far. A multidisciplinary team/facility remains crucial to manage major surgery in patients on prophylaxis with these new agents.

Long-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis (N = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%).

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.

Introduction Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half‐life developed for prophylaxis, treatment of bleeds and perioperative management in patients with haemophilia A. Aim Evaluate the efficacy and safety of turoctocog alfa pegol treatment for major and minor surgeries in the pathfinder 3 and 5 phase III trials. Methods Adults/adolescents aged ≥12 years with severe haemophilia A (FVIII 80% during major surgery (pathfinder 3). The primary end point was haemostatic efficacy during surgery; secondary end points were blood loss, haemostatic effect postsurgery, consumption, transfusions, safety and health economics. Children (0‐11 years) undergoing minor surgeries received 20‐75 IU/kg turoctocog alfa pegol at Investigator's discretion (pathfinder 5). Results pathfinder 3 included 35 patients undergoing 49 major surgeries. Haemostasis was successful in 47/49 (95.9%) surgeries; two had moderate haemostatic responses. Median (mean) blood loss during major surgery was 75 (322.6) mL. Four bleeds were reported postsurgery; three were successfully treated with turoctocog alfa pegol (one was not evaluated). On the day of surgery, overall mean (median) dose was 75.5 (74.5) IU/kg and mean (median) number of doses was 1.7 (2.0). Five procedures required 11 transfusions on the day of surgery or days 1‐6. No safety concerns or inhibitors were identified. Forty‐five minor surgeries in 23 children were performed without complications. Conclusion Turoctocog alfa pegol was effective for perioperative haemostatic management of major and minor surgeries in patients across age groups with severe haemophilia A.

Introduction Long-acting recombinant factor IX (FIX) products may simplify the surgical treatment of haemophilia B patients. The impact of rIX-FP, a recombinant FIX fused to recombinant albumin, on FIX consumption and surgical management was assessed in patients with haemophilia B. Materials and methods Male patients, ≤65 years old with severe haemophilia B (FIX activity ≤2%) requiring non-emergency surgery were enrolled in the surgical substudy of PROLONG-9FP. Dosing was based on World Federation of Hemophilia guidelines and patients' pharmacokinetics. Haemostatic efficacy was assessed on a 4-point scale. rIX-FP consumption and safety were monitored throughout the perioperative period. Results This updated dataset reports on thirty (8 minor and 22 major) surgeries conducted in 21 patients. A single preoperative bolus was used in 96.7% (n = 29) of surgeries. After minor surgery, patients received a median (range) of 0 (0–3) infusions with a median (range) consumption of 0 (0–178.89) IU/kg in the 14-day postoperative period. In patients who underwent major surgery (including 15 patients undergoing joint replacement surgery), the median (range) number of infusions in the 14-day postoperative period was 5 (0−11) and median consumption was 221.7 (0–444.07) IU/kg. Haemostatic efficacy was rated as excellent or good in 87.5% (7/8) of minor surgeries and 95.5% (21/22) of major surgeries. Conclusion Surgical procedures can be performed using a single preoperative bolus of rIX-FP in nearly all patients. During postoperative care, use of rIX-FP necessitated infrequent infusions and low FIX consumption. Overall, data suggest rIX-FP simplifies perioperative care in patients with haemophilia B.

Objectives BAY 81‐8973 (Kovaltry®), a full‐length, unmodified, recombinant human factor VIII, provided excellent bleeding control for patients with haemophilia A in the pivotal 1‐year LEOPOLD I trial. The LEOPOLD I extension evaluated long‐term efficacy and safety of BAY 81‐8973 prophylaxis. Methods After completing LEOPOLD I, patients continued receiving 20‒50 IU/kg BAY 81‐8973 two‐ or three‐times weekly in the extension. Outcomes included annualised bleeding rate (ABR) and haemostasis during surgery. Results Fifty‐five patients aged 12‐65 years participated in the extension. Median (range) exposure days during the 2‐year total study period was 309 (115‐355). No patient switched regimens. Median (Q1; Q3) ABR for all bleeds was 2.0 (1.0; 6.1) during the pivotal study, 2.0 (0.0; 5.2) during the extension, and 2.0 (0.5; 5.5) combined. The proportion of joint bleeds affecting target joints decreased (pivotal study: 90.9%, extension: 60.0%). Haemostasis was assessed as excellent/good in all five major surgeries. One serious adverse event (myocardial infarction) occurred in a patient with cardiovascular risk factors. No patients developed inhibitors. Conclusions BAY 81‐8973 prophylaxis efficacy outcomes in the pivotal study were maintained or, in the case of joint protection, improved during the extension, with a safety and tolerability profile consistent with previous experience.

Introduction The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half‐life treatment for severe haemophilia A were demonstrated in the Phase 3 A‐LONG and Kids A‐LONG studies. Eligible subjects who completed A‐LONG and Kids A‐LONG could enrol in ASPIRE (NCT01454739), an open‐label extension study. Aim To report the long‐term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. Methods Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. Results A total of 150 subjects from A‐LONG and 61 subjects from Kids A‐LONG enrolled in ASPIRE. Most subjects received the IP regimen (A‐LONG: n = 110; Kids A‐LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A‐LONG and Kids A‐LONG was 3.9 (0.1‐5.3) years and 3.2 (0.3‐3.9) years, respectively. No inhibitors were observed (0 per 1000 subject‐years; 95% confidence interval, 0‐5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was

INTRODUCTION: Recurrent bleeding in severe haemophilia B causes painful hemarthroses and reduces capacity for physical activity. Recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis results in low annualised bleeding rates, with the potential to improve patients' health-related quality of life (HRQoL). AIM: To present a post hoc analysis of data from B-LONG describing change over time in patient-reported outcomes associated with pain and physical activity. METHODS: Patients (≥12 years) who received weekly dose-adjusted or interval-adjusted rFIXFc prophylaxis and completed the Haemophilia-Specific QoL questionnaire for adolescents (Haemo-QoL) or adults (Haem-A-QoL) at baseline (BL) and end of study (EoS). Individual level changes in items of the 'Physical Health' and 'Sports and Leisure' domains, categorised as 'never/rarely/seldom' or 'sometimes/often/all the time', were analysed using McNemar's test to compare distribution of responses at EoS versus BL. RESULTS: At EoS versus BL, a significantly greater proportion of patients did not experience painful swellings (64% vs. 44%; P = .004), painful joints (44% vs. 28%; P = .003) or pain when moving (54% vs. 41%; P = .026). Additionally, at EoS versus BL, patients were less likely to avoid participating in sports like football (30% vs. 8%; P = .002), avoid sports due to their haemophilia (47% vs. 27%; P = .007), or experience difficulty walking as far as they wanted (63% vs. 43%; P = .001). The proportion of patients who played sports as much as the general population was numerically increased (52% vs. 37%; P = .033) at EoS versus BL. CONCLUSION: Results of the analysis suggest that over time, rFIXFc prophylaxis is associated with significant improvements in pain and physical functioning. This contributes to previous evidence of overall HRQoL improvements in patients with haemophilia B treated with rFIXFc.

Introduction Preliminary reports from the early phase of COVID-19 epidemic in Italy reported a dramatic reduction in hospital admission rates for acute coronary syndromes (ACS) coupled with longer times from symptoms onset to hospital presentation. Purpose To assess the impact of COVID-19 on hospital admission rates and ACS patterns, as well as time to presentation and clinical outcomes, following the acute pandemic phase in 2020 compared to previous year. Methods We conducted a single institution retrospective analysis conducted in a cardiovascular hub serving a large metropolitan area in Italy. Number and monthly distribution of hospital admissions for ACS from January 1 to December 31, 2020 were compared to the respective figures in 2019. Baseline clinical features, time from symptoms onset to hospital admission and main clinical outcomes were collected. Results A total of 599 ACS cases were recorded in 2020 vs. 386 cases in 2019, with a net 55% increase. ACS presentation rate in 2020 showed a bimodal pattern, paralleling the most contagious outbreak periods (Figure 1). SARS-CoB-2 nasopharyngeal swab or specific antibody tests were positive in 34 (5.7%) patients. Time from symptoms onset to hospital presentation tended to be longer in 2020 than in 2019, being two-fold longer during the peak epidemic phase (February 21-May 3, 2020; median time 2.0 vs. 5.0 hours, p=0.030). The proportion of late-presenting STEMI (>8 hrs from symptoms onset) was higher in 2020 compared to 2019 (30% vs. 18%, p=0.003),as well as higher was in-hospital mortality (15% in 2020 vs 6% in 2019, p=0.001), partly due to a three-fold increase in cardiogenic shock on ACS presentation. Conclusions ACS admission rate significantly increased during the 2020 COVID-19 epidemic outbreak for several reasons only partially explained by a SARS-CoV-2 infection trigger effect on ACS. Longer presentation times and higher rates of cardiogenic shock and mortality were observed, urging the need health-care systems to keep a high priority on cardiovascular emergencies response networks. Funding Acknowledgement Type of funding sources: None. Figure 1

BACKGROUND Immune tolerance induction (ITI) is the only proven strategy to eradicate factor VIII inhibitors in patients with haemophilia A (HA). AIM To identify patients and treatment options with the highest chance of inhibitor eradication by primary ITI. PATIENTS AND METHODS In the frame of the Italian ITI Registry, carried out from 1995 to 2015 (last follow-up 2018), 137 primary ITI courses in severe HA patients (90/137 with poor prognosis) were analysed for predictors of outcome (complete/partial response or failure). Sixty-six of them (48%) were prospectively evaluated. RESULTS ITI was successful in 91/137 patients (66.4%) and 70 (51.1%) achieved complete response within 11 months (median). Historical peak titres ≤200 BU/ml (P = .033), inhibitor titres ≤5 BU/ml at ITI start (P = .001), peak titres ≤100 BU/ml during ITI (P

Background and aims Chronic hepatitis C is the main co-morbidity in adult patients with haemophilia (PwH). It causes progressive liver damage leading to end-stage liver disease and/or hepatocellular carcinoma. Eradication of HCV was possible with interferon (IFN)-based regimens in the past and direct-acting antivirals (DAAs) more recently. PwH have been considered "difficult-to-treat" because of several bad predictors of response. The advent of DAAs has provided high rates of sustained virological response (SVR) despite bad prognostic factors. Here, we present the results of antiviral treatment with DAAs in PwH treated in 2 large Italian Hemophilia Treatment Centers. Methods PwH and chronic hepatitis C sustained by any HCV genotype were eligible for therapy with DAAs, including those with compensated cirrhosis, HIV infection and/or previous failure to IFN-based antiviral therapy. Patients received DAAs for 8-24 weeks according to existing guidelines. SVR was defined as persistent negative serum HCV-RNA at 12 weeks after treatment completion (SVR12). Results Between January 2015 and November 2018, 200 patients aged 21-84 years (median: 50.5) received DAAs. HCV genotype 1 was the most prevalent (158, 79%). Forty patients (20%) were HIV positive, 56 (28%) had cirrhosis and 91 (46%) previously failed interferon-based treatment. Ribavirin was used in 70 (35%). HCV-RNA was undetectable at week 4 in 124/192 (65%) and SVR12 was achieved in 193/195 (99%). No patient had serious side effects related to DAAs. Conclusions DAAs were safe and highly effective in PwH irrespective of HIV status, stage of liver disease severity and/or previous failure to IFN-based therapy.

Inadvertent perforation of the left internal mammary artery during a blind approach to the subclavian vein for pacemaker or central venous catheter insertion is an emergency that requires immediate treatment. Covered stent deployment is a quick and effective treatment, especially in patients with hemodynamic instability. The procedure may be safely performed by using the radial approach. (Level of Difficulty: Intermediate.), Graphical abstract, Inadvertent perforation of the left internal mammary artery during a blind approach to the subclavian vein for pacemaker or central venous catheter…

BackgroundGuidelines indicate that a low-protein diet (LPD) delays dialysis in severe chronic kidney disease (CKD). We assessed the value of these guidelines by performing a retrospective analysis in our renal clinical practice.MethodsThe analysis was performed from 1 January 2010 to 31 March 2018 in 299 CKD Stage 4 patients followed for 70 months in collaboration with a skilled nutritionist. The patients included 43 patients on a controlled protein diet (CPD) of 0.8 g/kg/day [estimated glomerular filtration rate (eGFR) 20–30 mL/min/1.73 m2 body surface (b.s.)], 171 patients on an LPD of 0.6 g/kg/day and 85 patients on an unrestricted protein diet (UPD) who were not followed by our nutritionist (LPD and UPD, eGFR ResultseGFR was higher in CPD patients than in UPD and LPD patients (21.9 ± 7.4 mL/min/1.73 m2 versus 17.6 ± 8.00 mL/min/1.73 m2 and 17.1 ± 7.5 mL/min/1.73 m2; P = 0.008). The real daily protein intake was higher in UPD patients than in LPD and CDP patients (0.80 ± 0.1 g/kg/day versus 0.6 ± 0.2 and 0.63 ± 0.2 g/kg/day; P = 0.01). Body mass index (BMI) was stable in the LPD and CPD groups but decreased from 28.5 ± 4.52 to 25.4 ± 3.94 kg/m2 in the UPD group (P ConclusionsAn LPD recommended by nephrologists in conjunction with skilled dietitians delays dialysis and preserves nutritional status in severe CKD.

Background N8‐GP is an extended half‐life recombinant factor VIII developed for prophylaxis and treatment of bleeds in patients with hemophilia A. Objective To assess pharmacokinetic (PK) characteristics of N8‐GP in previously treated patients with severe hemophilia A, model the time spent at hemophilia thresholds of ≥1 and ≤5 IU/dL (moderate) or >5 IU/dL (mild) FVIII levels during N8‐GP prophylaxis, and investigate the relationship between N8‐GP half‐life and von Willebrand factor (vWF). Methods PK assessments were obtained from patients with severe hemophilia A (FVIII < 1 IU/dL) participating in 4 clinical trials: pathfinder 1 (20‐60 years); pathfinder 2 (12‐17 and ≥18 years); pathfinder 5 (0‐11 years), and pathfinder 7 (25‐71 years). All PK profiles were assessed after washout and considered single‐dose PK profiles. Pre‐ and postdose FVIII activity at steady state was measured at all visits. Results From 69 patients, 108 PK profiles of N8‐GP 50 IU/kg were assessed. Adults/adolescents received 50 IU/kg every 4 days, achieving mean trough levels of 3.0 IU/dL (95% confidence interval, 2.6‐3.5, adults) and 2.7 IU/dL (1.8‐4.0, adolescents). Children received 60 IU/kg twice weekly, leading to mean trough levels of 1.2 IU/dL (0.8‐1.6, 0‐ to 5‐year‐olds) and 2.0 IU/dL (1.5‐2.7, 6‐ to 11‐year‐olds). PK modeling predicted children dosed every 3 days and adults/adolescents dosed every 3 to 4 days would maintain FVIII levels >5 and >1 IU/dL for >80% and 100% of the time, respectively. N8‐GP half‐life correlated linearly with von Willebrand factor levels in adults/adolescents, less in children. Conclusions Prophylaxis with fixed intervals (Q4D/twice weekly) and fixed weight‐based dosing (50/60 IU/kg) ensured >1 IU/dL FVIII trough levels in both adults and children.

Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations.

Monoclonal antibodies, such as bamlanivimab and etesevimab combination (BEC), have been proposed for patients with mild or moderate coronavirus disease 2019 (COVID-19). However, few studies have assessed the factors associated with the early administration of BEC or the impact of early BEC treatment on the clinical evolution of the patients. We conducted a retrospective cohort study of all adults with COVID-19 who received BEC at three institutions in the Liguria region. The primary endpoint was to investigate the clinical variables associated with early BEC infusion. Secondary endpoints were 30-day overall mortality and the composite endpoint of requirement of hospital admission or need for supplemental oxygen during the 30-day follow-up period. A total of 127 patients (median age 70 years, 56.7% males) received BEC. Of those, 93 (73.2%) received BEC within 5 days from symptoms onset (early BEC). Patients with a higher Charlson comorbidity index were more likely to receive early treatment (odds ratio (OR) 1.60, 95% confidence interval (CI) 1.04–2.45, p = 0.03) in contrast to those reporting fever at presentation (OR 0.26, 0.08–0.82, p = 0.02). Early BEC was associated with lower likelihood of hospital admission or need for supplemental oxygen (OR 0.19, 0.06–0.65, p = 0.008). Five patients who received early BEC died during the follow-up period, but only one of them due to COVID-19-related causes. Early bamlanivimab and etesevimab combination was more frequently administered to patients with a high Charlson comorbidity index. Despite this, early BEC was associated with a lower rate of hospital admission or need for any supplementary oxygen compared to late administration. These results suggest that efforts should focus on encouraging early BEC use in patients with mild–moderate COVID-19 at risk for complications.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.

New therapeutic agents for haemophilia with inhibitors that are in development or already licensed are expected to provide transformative treatment options. Many of these new therapies are not based on simply replacing the missing factor; new strategies include bispecific antibody technology that mimics factor VIII coagulation function (emicizumab), and inhibition of anticoagulant proteins such as tissue factor pathway inhibitor (eg PF-06741086) and antithrombin (eg fitusiran). These agents are administered subcutaneously and should significantly reduce treatment burden and increase the ability to deliver prophylaxis for patients. Limited real-world data and validated practical guidance on these recently licensed/upcoming treatments resulted in the authors convening to discuss recommendations on their use. Emicizumab is currently the only licenced nonfactor therapy; thus, our recommendations focus on this product. Target candidates for emicizumab prophylaxis are difficult-to-treat patients with haemophilia A and inhibitors and/or venous access issues, frequent bleeds and target joints. In case of breakthrough bleeding while receiving emicizumab, patients still require treatment with bypassing agents; the adjunct treatment of choice is recombinant activated factor VII. This treatment is also recommended to prevent bleeds in patients with inhibitors undergoing surgery. Our recommendations on suitable laboratory assays and monitoring new products, as well as the benefit of patient-reported outcomes (such as pain and physical activity levels), are included. We also briefly discuss future treatment options for patients with haemophilia B and inhibitors. Although these nonfactor treatments offer great promise, further data and real-world evidence are needed.

Introduction. The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions. Materials and Methods. In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( F 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded. Results. At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( χ 2 10.4; p < 0.001 ), neutrophil-to-lymphocyte (NL) ratio ( χ 2 7.6; p = 0.006 ), and platelet count ( χ 2 5.39; p = 0.02 ), along with age ( χ 2 87.6; p < 0.001 ) and gender ( χ 2 17.3; p < 0.001 ), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality OR = 3.40 (2.40-4.82), while the OR for a RDW > 13.7 % was 4.09 (2.87-5.83); a platelet count > 166,000 /μL was, conversely, protective (OR: 0.45 (0.32-0.63)). Conclusion. Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.

Objective To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management. Method These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists. Results The 10 proposed principles for AHA care are as follows: (a) Improving initial diagnosis of AHA; (b) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; (c) Effective communication between laboratories, physicians, and specialists; (d) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; (e) Comprehensive assessment of bleeding; (f) Appropriate use of bypassing agents; (g) Long‐term follow‐up and monitoring for efficacy and safety of immunosuppressive treatment; (h) Inpatient/outpatient settings; (i) Access to innovative and disruptive treatments; (j) Promotion of international collaborative research. Conclusion The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non‐specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts toward improving its practical, multidisciplinary management.

The incidence of factor IX (FIX) inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date have been small, including patients with different severities, and without prospective follow up for inhibitor incidence. The study objective was to investigate the inhibitor incidence in patients with SHB followed up for to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUP) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by the annual collection of the inhibitor status and allergic re-actions. The presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on FIX gene mutation was collected. One hundred and fifty-four PUP with SHB were included; 75% were followed up until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (seven high-titer). The median number of ED at inhibitor manifestation was 11 (interquartile range [IQR]: 6.5-36.5). The cumulative inhibitor incidence was 9.3% (95% Confidence Interval [CI]: 4.4-14.1) at 75 ED, and 10.2% (95% CI: 5.1-15.3) at 500 ED. Allergic reactions occurred in four (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUP with SHB, the cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The ‘PedNet Registry’ is registered at clinicaltrials.gov; identifier: NCT02979119.

Background: The pandemic spread of the COVID-19 pneumonia caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) lead to severe social containing measures in Italy. We evaluated changes in hospitalization rates for acute coronary syndromes (ACS) during SARS-CoV-2 outbreak compared to both intra-year and inter-year control periods. Methods: ACS-related hospitalization rates at the Centro Cardiologico Monzino in Milan were retrospectively assessed during SARS-CoV-2 outbreak. The timespan from the first confirmed case of SARS-CoV-2 in Italy and lockdown ending (February 21-May 3, 2020) was the case-period (epidemic peak period). Hospitalization rates of the case-period and two control periods, one preceding (January, 1- February 20, 2020) the epidemic outbreak and the other following the end of lockdown (May 3-June 30, 2020) were analyzed and compared to same inter-year (2019) control periods. Results: 183 ACS patients were included: 80 in the case-period; and 103 in the two intra-year control periods (33 pre-case period and 70 post-case period, respectively) and compared to same periods of the previous year. ACS-related hospitalization rate was significantly higher in the case period compared to previous year, mainly driven by an increase in ST- and non-ST-elevation MI. Conclusions: ACS-related hospitalizations dramatically increased after SARS-CoV-2 outbreak onset and consequential restrictive measures, conversely to early pandemic phase observations leading to a significant decrease in emergency room accesses led by citizens’ fear of viral infection.

INTRODUCTION European regulatory authorities request postmarketing safety and efficacy data for factor IX (FIX) products. AIM Collect additional clinical data from routine nonacog alfa use in children aged

Background: Handwriting is a complex task that requires the integrity of different sensorimotor components to be performed successfully. Patients with hemophilia suffer from recurrent joint bleeds that may occur in the elbow, causing elbow dysfunction with handwriting performance impairment. In our study, we described instrumental dysgraphia that is related to functional disturbances. This pilot study aims to evaluate the handwriting performance in a group of patients with hemophilia. Methods: The study was performed at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan. Boys with severe and moderate hemophilia A and B regularly followed-up at that Center, with age between 6&ndash, 19 years, were eligible. Patients were invited to the Center for one multidisciplinary evaluation of the upper limbs that included: Clinical examination, surface electromyography, and handwriting assessment. Results: All patients, but one, completed handwriting assessment. Overall, 14/19 (74%) had abnormal handwriting, which was overt instrumental dysgraphia in six (32%). There was no difference in Hemophilia Joint Health Score (HJHS) between dysgraphic and non-dysgraphic boys, while surface electromyography (sEMG) revealed a prevalence of flexor muscles of the upper limb in dysgraphic as compared with non-dysgraphic boys. Conclusions: The rather high prevalence of instrumental dysgraphia found in this pilot study deserves a further development of this preliminary experience by increasing the number of examined patients and comparing them with a control group, including quality of life and psychological assessment.

Background Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype. Methods The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry. It included unselected children with severe hemophilia A (factor VIII [FVIII] Results A total of 260 patients with inhibitors were identified and 68 of them (26%) had low-responding inhibitors (peak Conclusion In children with low-responding inhibitors negative titers were reached with regular FVIII treatment irrespective of the regimen (i.e., prophylaxis or ITI).

Background FuseNGO is a relatively new device consisting of a prefilled dual-chamber syringe (DCS) that was recently introduced for the reconstitution of recombinant factor VIII. Herein, the DCS device was assessed using five questionnaires with the primary aim of evaluating patient perceptions and preferences. Methods An observational, non-interventional, longitudinal study on 86 patients with a confirmed diagnosis of hemophilia A was carried out at 21 sites in Italy. Each patient underwent a baseline visit and final study visit within 3-6 months. Patients were administered five questionnaires: HemoPREF; Treatment Satisfaction Questionnaire for Medication (TSQM); VeritasPRO; Hemophilia Well-being Index (HWBI); Work Productivity and Activity Impairment Questionnaire (WPAI) + Classroom Impairment Questions (CIQ): Hemophilia Specific (HS). Results Compared to baseline, scores for HemoPREF were higher at follow-up; significant increases in the percentage of positive responses were seen for all questions regarding the ease of use (P 70% in the VeritasPRO questionnaire, and the majority of patients reported in the HWBI that hemophilia A did not affect their lives in a significant way. The perceived level of overall impairment was 30% as reported in the WPAI + CIQ: HS, indicating little impairment. There were no safety concerns. Conclusion Considering patient-reported outcomes, the DCS device was associated with easier preparation, storage, disposal of equipment, and overall use. Of particular note, preparation times were reduced by around 50%. The majority of patients were satisfied with the device and overall adherence scores were high. Considering these results, the device has the potential to increase adherence to therapy and, possibly, reduce healthcare costs.

Introduction A phase 3b extension study evaluated the long-term safety and efficacy of a recombinant fusion protein-linking coagulation factor IX (FIX) with albumin (rIX-FP) for the routine prophylaxis and on-demand treatment of bleeding in pediatric hemophilia B patients. Methods Previously treated patients aged Results Compared with their initial regimen, by the end of the study, dosing intervals were the same, extended, and shortened in 16, 4, and 4 patients, respectively. Very low annualized spontaneous bleeding rates (AsBRs) were observed; median AsBR was 0.0 for the 7- and 10-day regimens, and 1.1 for the 14-day regimen. The 7- and 14-day regimens were comparable in preventing spontaneous bleeds; mean (95% confidence interval) difference in AsBR of −1.2 (−2.6 to 0.3) bleeding episodes/year/subject. Overall, 96% of bleeding episodes were successfully treated with one or two injections of rIX-FP. Patients on a 14-day regimen maintained a mean steady-state trough FIX level of >7.2 IU/dL. No patient developed an inhibitor. Conclusion This extension study demonstrated the long-term safety and efficacy of weekly rIX-FP in pediatric patients. Additionally, it showed that adequate bleed protection can be achieved with 10- or 14-day rIX-FP regimens in selected pediatric patients while maintaining safety.

Introduction Adherence to prophylaxis regimens is essential for bleed prevention in haemophilia but remains a challenge due to the need for frequent infusions. Aim To evaluate patient adherence to prophylaxis regimens with a long-acting recombinant factor IX (rIX-FP; IDELVION® ) in clinical studies and real-world practice. Methods In two phase 3 clinical studies, patients with haemophilia B (FIX ≤2%) recorded their dose, dosing frequency and rIX-FP consumption in an e-diary. Adherence to prescribed prophylaxis regimens was assessed in all patients and to prescribed dose in patients ≥12 years only. Additionally, adherence to rIX-FP prophylaxis regimens in real-world practice was captured. Results In clinical studies, 94.9% (n = 56/59) of patients ≥12 years and 100% (n = 27) of paediatric patients received ≥80% of the expected number of infusions for their assigned prophylaxis schedule. Overall, mean adherence rate was 95.5% across all prophylaxis regimens in patients ≥12 years and 97.9% with a 7-day regimen in paediatric patients. In patients ≥12 years, 85.7% (n = 54/63) were dose adherent, defined as receiving within 10% of their prescribed dose ≥80% of the time. In real-world practice, adherence was observed in 100% (n = 14 and n = 15, respectively) of patients in two haemophilia treatment centres and 57.1% (n = 4/7) of patients in a third centre; non-adherence (n = 3/7) was linked to insurance-related and parental issues. Conclusion In clinical studies, patients with haemophilia B had high adherence rates to rIX-FP prophylaxis regimens with a variety of dosing intervals, enabling them to achieve very low bleeding rates. High adherence may also be achievable in real-world practice.

International audience; Patients with haemophilia and high-titre inhibitors were often denied surgery due to the high risk of perioperative bleeding. However, data on bypassing agents for the management of major orthopaedic surgery showed efficacy values between 81% and 85% for activated recombinant human factor VII (rFVIIa) (Novoseven®, Novo Nordisk, Bagsværd, Denmark) and between 81% and 91% for plasma-derived activated prothrombin complex concentrates (aPCC) (Giangrande et al., 2018).

Introduction Persons with haemophilia A (PwHA) with inhibitors to factor VIII often experience decreased health-related outcomes. In HAVEN 1 (NCT02622321), there was a statistically significant reduction in bleeding with emicizumab prophylaxis versus no prophylaxis. Aim Describe health-related outcomes in PwHA with inhibitors in HAVEN 1. Methods PwHA with inhibitors aged ≥12 years previously on episodic bypassing agents (BPAs) were randomized to emicizumab prophylaxis (Arm A; n = 35) or no prophylaxis (Arm B; n = 18); participants previously on BPA prophylaxis received emicizumab prophylaxis (Arm C; n = 49). Health-related outcomes assessed at baseline and monthly thereafter: Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), Haemophilia-specific Quality of Life Questionnaire for Children Short Form (Haemo-QoL SF), EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score (IUS) and visual analogue scale (EQ-VAS) and work/school days. Days hospitalized also recorded. Results At week 25, differences (ANCOVA) in adjusted mean scores (95% confidence interval) favoured Arm A versus B for Haem-A-QoL "Total" score (14.0 [5.6, 22.5]; P = 0.002) and "Physical Health" (21.6 [7.9, 35.2]; P = 0.003); EQ-VAS (-9.7 [-17.6, -1.82]; P = 0.017); and IUS (-0.16 [-0.25, -0.07]; P = 0.001); mean scores are comparable in Arms A and C. Throughout the study, a greater proportion of participants on emicizumab prophylaxis than no prophylaxis exceeded questionnaire-specific responder thresholds. Mean proportion of missed work days and number of days hospitalized were lower with emicizumab prophylaxis than no prophylaxis. Conclusions In PwHA with inhibitors, emicizumab prophylaxis was associated with substantial and meaningful improvements in health-related outcomes.

Introduction Prospectively collected, real-world data on bleeds, haemophilic treatment and safety outcomes in persons with haemophilia A (PwHA) with factor VIII (FVIII) inhibitors are limited. A prospective, global, multi-centre, non-interventional study (NIS; NCT02476942) collected detailed real-world data in PwHA treated per local routine clinical practice. Aim To characterize bleeding rates, haemophilic treatment practices, prophylaxis adherence and adverse events (AEs) in adult/adolescent PwHA with inhibitors in the NIS. Methods Participants aged ≥12 years with congenital haemophilia A/documented high-titre FVIII inhibitor history were enrolled. Participants remained on their usual treatment; no interventions were applied. Results Overall, 103 PwHA with inhibitors enrolled, (median [range] age 31 [12-75] years) and were monitored for median (range) 26.0 (4.1-69.6) weeks. In the episodic (n = 75) and prophylactic (n = 28) treatment groups, respectively, 1244 and 325 bleeds were reported, and 528 (42.4%) and 104 (32.0%) were not treated; annualized bleeding rates (ABRs; 95% confidence interval) were 18.6 (15.2-22.8) and 14.9 (10.5-21.2) for treated bleeds, and 32.7 (27.3-39.1) and 25.0 (18.4-34.0) for all bleeds. Coagulation products used included activated prothrombin complex concentrate (aPCC) and/or recombinant activated FVII. Among participants prescribed aPCC prophylaxis, 35.0% adhered to both prescribed frequency of aPCC administration and prescribed dose. Serious AEs of haemarthrosis and muscle haemorrhage were reported; most common AEs were arthralgia, viral upper respiratory tract infection and pyrexia. Conclusions ABRs (treated bleeds and all bleeds) remain high on standard treatment; this prospective NIS demonstrates the need for more effective treatments for PwHA with inhibitors to reduce/prevent bleeds, with potential to improve prophylaxis adherence and further improve outcomes.

Inhibitors against factor VIII (FVIII), which develop in around 20-30% of patients with severe hemophilia A, represent a significant complication of on-demand or prophylactic FVIII therapy. Currently, the main treatment option for inhibitor patients is eradication using immune tolerance induction (ITI) therapy. Areas covered: This article reviews inhibitor eradication in clinically complicated hemophilia A patients. The benefits and disadvantages of ITI therapy are discussed, with reference to the new nonfactor replacement agents such as emicizumab, which are becoming available. Expert commentary: At present, ITI therapy is the method of choice for all inhibitor patients, but as alternative treatment options become increasingly available, this may change in the future. Despite the development of nonfactor replacement agents, ITI therapy is likely to maintain a key role in the management of inhibitor patients, although changes in ITI therapy regimens including the timing of ITI initiation, the dosing regimen, the management of thrombotic risk or safety, laboratory assessment of ITI outcomes, and maintenance treatment after ITI success, may be necessary.

Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 μg kg-1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX. Summary Background Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia. Objectives To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non-bleeding patients with congenital hemophilia A or B with or without inhibitors. Methods This international, phase 1, open-label study (NCT01439971) enrolled males aged 18-64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single-dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 μg kg-1 ). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD. Results Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose-limiting toxicity. No treatment-emergent severe or serious adverse events occurred. MarzAA showed linear dose-response PK across the 4.5-30 μg kg-1 dose range, with a terminal half-life of ⁓ 3.5 h. Dose-dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses. Conclusions MarzAA was tolerated at doses up to 30 μg kg-1 . The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.

Introduction Haemophilia is a recessive X-linked inherited bleeding disorder, whose typical symptom is spontaneous intra-articular haemorrhage leading to joint damage, which can be quantified by the Haemophilia Joint Health Score (HJHS). Arthropathy and other characteristics of haemophilic patients may reduce bone mineral density (BMD), increasing the risk for fragility fractures, which also may occur due to bone quality impairment. Aim To evaluate bone quantity by BMD and bone quality by Trabecular Bone Score (TBS), bone strain (BS) and hip structural analysis (HSA) in a haemophilic population, and to relate these parameters to general and specific risk factors for osteoporosis and to HJHS. Methods Seventy haemophilic patients ≥18 years were enrolled. Densitometric derived lumbar spine and femoral BMD with TBS, BS and HSA were performed. Data regarding risk factors for osteoporosis, presence of arthroprosthesis or arthrodesis were collected, and HJHS was calculated. A Z-score ≤-2.0 defined a low bone mass. Results Overall, a reduced bone mass was present in 52 patients at the femur and in 38 at the lumbar spine. Lumbar spine BMD, TBS and BS did not correlate with HJHS. HSA bone geometric parameters correlated negatively with HJHS. BMD and HSA correlated with some risk factors for osteoporosis, namely HIV and its therapy, hepatitis C and smoking. Conclusions Haemophilic patients showed a reduced BMD at lumbar spine and/or femur. Femoral bone density and geometry correlated with HJHS. The microarchitecture of the trabecular vertebral bone seemed to be not influenced by the haemophilic joint damage.

Decisions over hemophilia treatment selection and switching involve balancing many clinical and patient-related factors. The current standard of care for patients with hemophilia B is prophylaxis with plasma-derived or recombinant factor IX (rFIX) concentrates. However, several extended half-life (EHL) rFIX products have recently been developed to improve treatment convenience and clinical outcomes for these patients. Nonacog beta pegol, an rFIX product that combines the FIX protein with a 40 kDa polyethylene glycol moiety, has been evaluated in 115 previously treated patients with hemophilia B (including 25 children) in the paradigm clinical trial program. FIX activity levels and pharmacokinetics were monitored throughout these trials and showed that nonacog beta pegol offers significant pharmacological improvements over standard FIX products. Once-weekly prophylaxis with nonacog beta pegol 40 IU/kg resulted in fewer bleeds in all patients (median annualized bleeding rate of 1.0 across all ages), resolved 90% of target joints, and improved health-related quality of life. No patients developed FIX inhibitors, and there were no thromboembolic events or unexpected safety concerns. Nonacog beta pegol was also safe and effective in the perioperative setting. These findings show that nonacog beta pegol is highly effective, while also offering more convenient dosing than standard FIX products. Nonacog beta pegol represents a significant advance in the current context of treatment for hemophilia B, offering effective management across several treatment modalities and settings, and potentially easing the treatment burden for patients of all ages. Meanwhile, the development of novel treatment strategies, such as gene therapy, anti-tissue factor pathway inhibitor antibodies, and RNA interference therapy, may provide patients with additional therapeutic options, which would require reassessment of the role of EHL products in the future.

Demodex musculi is a prostigmatid follicular mite that has rarely been reported in laboratory mice. Although prevalence of this species has not been assessed formally, we have found that many imported mouse strains from noncommercial sources harbor Demodex mites. To assess whether an acaricide can be used to eradicate this mite, infested immunocompromised mice were provided ivermectin-compounded (12 ppm) feed without restriction for 8 wk (n = 10), were treated topically with moxidectin and imidacloprid (MI; 3 and 13 mg/kg, respectively) weekly for 8 wk (n = 10), or remained untreated (n = 10). Mice were confirmed to be mite-infested before treatment and were tested after treatment by using fur plucks (FP), deep skin scrapes (DSS), and PCR analysis of fur swabs. In addition, the presence of mites was confirmed through skin biopsies at 2 study endpoints (1 wk [n = 5] and 12 wk [ n = 5] after treatment). Samples collected before treatment and from untreated mice were positive for D. musculi at all time points and by all test modalities. After treatment, all ivermectin-treated animals remained infested, whereas mice treated with MI were repeatedly negative by all test modalities. An additional shortened treatment trial revealed that 4 wk of MI (n = 7) was insufficient to eradicate mites. Neither treatment produced any evidence of adverse effects according to hematology, serum chemistry parameters, behavior, body weight, and histopathology. Of the 70 PCR assays performed in treated mice, 14 were positive when FP+DSS was negative. In 6 cases where PCR results were negative, 5 were positive by FP+DSS and a single sample was positive on skin biopsy. Although PCR analysis has a high detection rate for D. musculi, FP+DSS can further enhance the detection rate. In conclusion, topical MI administered for 8 consecutive weeks can safely eradicate D. musculi from an immunocompromised mouse strain.

BACKGROUND In older people, multiple chronic ailments lead to the intake of multiple medications (polypharmacy) that carry a number of negative consequences (adverse events, prescription and intake errors, poor adherence, higher mortality). Because ageing patients with haemophilia (PWHs) may be particularly at risk due to their pre-existing multiple comorbidities (arthropathy, liver disease), we chose to analyse the pattern of chronic drug intake in a cohort of PWHs aged 60 years or more. PATIENTS AND METHODS S + PHERA is a multicentre observational study, with the broad goal to evaluate prospectively the health status and medication intake in 102 older patients with severe haemophilia A or B compared with 204 age- and residence-matched controls chosen randomly from the same general practices of PWHs. The rate of potential drug-drug interactions (PDDI) was evaluated as a proxy of prescription appropriateness. RESULTS After excluding replacement therapies and antiviral drugs, PWHs took in average less daily drugs than controls (2.4 ± 2.5 vs 3.0 ± 2.4) and had a lower rate of polypharmacy. Moreover, their prevalence of PDDI was lower (16.7% vs 27%). CONCLUSIONS The rate of polypharmacy and the appropriateness of medications other than those for haemophilia and related comorbidities are acceptable in Italian PWHs, and better than those in their age peers without haemophilia, perhaps owing to drug tailoring and deprescribing by the specialized haemophilia centres at the time of regular visits. However, the PWHs investigated herewith were relatively young and the rate of polypharmacy and related PDDIs may become more prominent and crucial when older ages are reached, suggesting the need of continuous surveillance on prescribed drugs and the risk of drug-drug interactions.

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts caused by a combination of both impaired platelet production and increased peripheral platelet destruction. Current first-line ITP treatments include glucocorticoids and intravenous immunoglobulin (IVIG). However, these drugs have variable and transient efficacy, significant toxicities, and relapse is common upon discontinuation. Subsequent treatment options include the thrombopoietin receptor agonists (TPO-RAs). Avatrombopag (AVA) is an orally administered small molecule TPO-RA. It binds to the human TPO receptor (c-Mpl) at a site that is different from the endogenous TPO binding, stimulating signal transduction and mimicking the biological effects of endogenous TPO. In phase 2 and 3 studies in patients with ITP, AVA was administered to 128 patients for a median duration of 7 months (maximum duration >2 years; Birhiray R, et al. EHA 2020). In a phase 3 trial (NCT01438840), the primary efficacy endpoint of cumulative number of weeks with platelet count ≥50×10 9/L during 6 months of treatment in the absence of rescue therapy was statistically significant favoring AVA over placebo. The most common treatment-emergent adverse events (AEs) in these phase 2 and 3 trials were headache, fatigue, and contusion. AVA has no significant hepatotoxicity and is administered with food without restrictions on meal composition. AVA is approved by FDA and EMA for the treatment of primary chronic ITP in adult patients who are refractory to other treatments (e.g. corticosteroids, IVIG). However, there is a need to provide data to treaters and the ITP community on the real-world usage and effectiveness of AVA (including patients previously treated with TPO-RAs). Described here is the rationale and design of the ADOPT study (NCT04943042), evaluating the use and effectiveness of AVA in adult patients with ITP in routine clinical practice in Europe. Study design and methods: This is a multicenter, observational, phase 4 study, with the primary objective to describe the real-world effectiveness of AVA treatment over a prospective period of 12 months in adult patients with ITP. Prospective data will be collected at routine clinical visits. In addition, retrospective data will be collected from patients' medical records for up to 12 months prior to AVA treatment start. Eligible patients must be ≥18 years, have provided informed consent, have an established and well documented ITP diagnosis, and are treated with or initiating treatment with AVA for ITP at enrollment. Decision to initiate treatment shall be made by the treating physician, independently from the decision to include the patient in the study. Exclusion criteria include enrollment in other clinical interventional study or intake of an investigational medicinal product ≤3 months prior to inclusion, and secondary ITP. The primary endpoint is cumulative number of weeks with a platelet count ≥30×10 9/L during AVA treatment. Platelet counts during rescue medication use and within 4 weeks after stopping a rescue medication or following splenectomy are considered non-response and thus not included in the primary endpoint cumulative number. Secondary endpoints supporting the primary objective include cumulative number of weeks with a platelet count ≥50×10 9/L, patients (n [%]) with a platelet count ≥30×10 9/L and ≥50×10 9/L for at least 8 consecutive weeks, patients (n [%]) experiencing WHO bleeding grade ≥2, patients (n [%]) requiring rescue medication, and time from AVA treatment start to platelet count ≥30×10 9/L and ≥50×10 9/L. Additional secondary endpoints are AVA dose and dosing frequency, reason for ITP treatment discontinuation or change from one ITP treatment to another (prior to and during the study), use of concomitant ITP medications, physician satisfaction with outcome of AVA treatment (5-point scale), physician assessment of clinical change of AVA treatment (Clinical Global Impression of Change scale), healthcare resource use, as well as a number of patient reported outcomes (Table 1). Secondary safety endpoints include serious AEs, AEs of special interest (thromboembolic events, significant bleeding) and AEs leading to AVA discontinuation. Data will be summarized using descriptive statistics. Study status: The study is planned to start 2021 and aims to enroll 150 patients. Figure 1 Figure 1. Disclosures McDonald: Grifols: Research Funding; Bayer, Sobi, Novartis, Amgen, argenx: Honoraria. Matzdorff: Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Current holder of individual stocks in a privately-held company. Mellbring: Sobi: Current Employment. Nazir: Sobi: Current Employment. Lindqvist: Sobi: Current Employment. Santagostino: Sobi: Current Employment.