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Patients with severe and sometimes moderate hemophilia B are prophylactically treated with factor IX concentrates to prevent bleeding. For some time now, various extended terminal half-life (EHL) recombinant factor IX concentrates are available allowing less frequent administration during prophylaxis in comparison to standard half-life recombinant FIX (rFIX). Especially, recombinant FIX-Fc fusion protein (rFIXFc; Alprolix®) exhibits a rapid distribution phase, potentially due to binding to type IV collagen (Col4) in the extravascular space. Studies suggest that the presence of extravascular rFIXFc is protective against bleeding as without measurable FIX activity in plasma, and no extra bleeding seems to occur. The physiologically based pharmacokinetic (PBPK) model for rFIXFc which we describe in this study, is able to accurately predict the observed concentration-time profiles of rFIXFc in plasma and is able to quantify the binding of rFIXFc to Col4 in the extravascular space after an intravenous dose of 50 IU/kg rFIXFc in a male population. Our model predicts that the total AUC of rFIXFc bound to Col4 in the extravascular space is approximately 19 times higher compared to the AUC of rFIXFc in plasma. This suggests that rFIXFc present in the extravascular compartment may play an important role in achieving hemostasis after rFIXFc administration. Further studies on extravascular distribution of rFIXFc and the distribution profile of other EHL-FIX concentrates are needed to evaluate the predictions of our PBPK model and to investigate its clinical relevance., (© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Haemophilia B (HB), characterised by deficient factor IX (FIX), leads to spontaneous bleeds. Severe cases require prophylactic FIX replacement. This post hoc analysis assessed the first spontaneous bleeds among previously untreated patients (PUPs) with HB treated with recombinant FIX Fc fusion protein (rFIXFc) (NCT02234310) to identify factors influencing bleeds., Methods: Subjects included paediatric PUPs with HB (≤2 IU/dL endogenous FIX). Analyses described treatment patterns (on demand [OD] vs. prophylaxis) and prophylaxis type (started on vs. switched to prophylaxis). Kaplan-Meier analyses assessed the time to first spontaneous bleed, including median time to event and fitting models with predictors for treatment regimen and/or baseline age., Results: PUPs B-LONG enrolled 33 subjects. Baseline age did not influence the time to first spontaneous bleed for any rFIXFc regimen. Those who started on prophylaxis with rFIXFc (n = 11), compared with those treated OD (n = 22), had an extended time to first spontaneous bleed. Starting prophylaxis afforded a 93% reduced risk of first spontaneous bleed versus starting OD (hazard ratio [95% confidence interval]: 0.071 [0.009-0.592]) (p = .015)., Conclusion: rFIXFc prophylaxis, particularly starting early, reduced the risk of bleeding and delayed time to first spontaneous bleed compared with rFIXFc OD. Hence, initial treatment regimens impact bleed patterns in paediatric PUPs., (© 2024 Sanofi and The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Hemophilia B is characterized by a deficiency of clotting factor IX (FIX), leading to excessive bleeding. Hemophilia B is commonly treated using replacement FIX therapy, which may be administered prophylactically or on-demand following a bleeding episode. Previous research has found high health care resource use (HCRU) and costs among Medicare and commercially insured people with hemophilia B (PwHB), with FIX therapy being a primary driver of health care costs., Objective: To assess HCRU, outcomes, and costs among US Medicaid beneficiaries receiving FIX prophylaxis for hemophilia B., Methods: This study employed a retrospective comparative cohort design to assess HCRU, outcomes, and costs among adult male Medicaid beneficiaries receiving FIX prophylaxis for hemophilia B, relative to a matched comparator population of beneficiaries without bleeding disorders. Nationwide Medicaid claims and enrollment data from 2015 to 2020 were used for this analysis. Adult male PwHB who received FIX prophylaxis, defined as not having identified gaps in FIX therapy exceeding 60-days during a 1-year measurement period, and were continuously enrolled in Medicaid for at least 2 years, were matched 1:4 to comparator beneficiaries without bleeding disorders based on baseline demographic and clinical characteristics. Key measures of HCRU and outcomes included inpatient hospital admissions, outpatient hematologist visits, and bleeding events. Measures of health care costs were assessed among a subset of beneficiaries enrolled in fee-for-service Medicaid., Results: PwHB receiving FIX prophylaxis were significantly more likely to have multiple inpatient hospital admissions and had a longer cumulative length of stay per person relative to comparator beneficiaries (30.2 vs 14.8 days, respectively; P = 0.0473). PwHB receiving FIX prophylaxis also had significantly higher rates of bleeding events relative to comparator beneficiaries (0.54 vs 0.02 per person, respectively; P < 0.0001) and outpatient hematologist visits (1.58 vs 0.20 per person, respectively; P < 0.0001). Annual costs among PwHB receiving FIX prophylaxis were significantly higher than costs among comparator beneficiaries ($928,370 vs $34,553 per person, respectively; P < 0.0001) and were overwhelmingly driven by costs associated with FIX therapy., Conclusions: This analysis found higher rates of HCRU and costs among Medicaid beneficiaries receiving FIX prophylaxis for hemophilia B relative to a matched comparator population of beneficiaries without bleeding disorders. Future research should examine hemophilia B costs and outcomes within the context of new treatments with innovative mechanisms of action, such as gene therapies, RNA interference therapies, and antitissue factor pathway inhibitor therapies.

Hemophilia B is an inherited hemorrhagic disorder characterized by a deficiency of blood coagulation factor IX (FIX) that results in abnormal blood coagulation. The blood coagulation is already evident in hemophiliacs at the fetal stage, and thus intracranial hemorrhage and other bleeding complications can occur at birth, leading to sequelae. Therefore, it is important to develop effective treatments for hemophiliacs in utero. In this study, in order to transplacentally deliver FIX from pregnant mice to their fetuses, an improved adenovirus (Ad) vector expressing human FIX fused with the IgG Fc domain (FIX Fc fusion protein), which plays a crucial role in neonatal Fc receptor (FcRn)-mediated transcytosis across the placenta, was intravenously administered to E13.5 pregnant mice. Significant levels of FIX Fc fusion protein were detected in 0-day-old newborn mice whose mothers were administered an Ad vector expressing FIX Fc fusion protein. Wild-type FIX overexpressed in the pregnant mice was not delivered to the fetuses. Plasma FIX levels in the newborn mice were relatively well correlated with those in their mothers, although transplacental delivery efficiencies of FIX Fc fusion protein were slightly reduced when the FIX Fc fusion protein was highly expressed in the mother mice. Plasma FIX levels in the newborn mice were about 3.6-6.4% of those in their mothers, Transplacental delivery of FIX Fc fusion protein to their fetuses successfully improved the blood clotting ability in the newborn mice., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The X-linked bleeding disorder hemophilia B, caused by mutation(s) in the coagulation factor (F)IX gene, leads to partial or total loss of its function, requiring lifelong FIX replacement therapy. Although new recombinant FIX (rIX) therapeutics like albumin fusion proteins (rIX-FP) enable longer plasma half-life and thus less frequent administration, the complexity of intravenous (i.v.) injection remains., Objectives: The study aimed to characterize rIX-FP variants with anticipated enhanced specific activity, which would leverage rIX-FP's superior pharmacokinetic profile with beneficial characteristics for subcutaneous (s.c.) administration., Methods: Two rIX-FP variants, R338L ("Padua variant") and R338L/E410K, were characterized in vitro. Pharmacokinetic profiles of FIX antigen and activity levels were evaluated in FIX-deficient mice after i.v. and s.c. administration of these variants (dosing based on antigen levels). The efficacy of the most promising variant was tested after i.v. and s.c. administration (dosing based on activity) in a tail clip bleeding model. A marketed wild-type (WT) rIX-FP product served as the comparator., Results: Both rIX-FP variants showed a 4- to 5-fold increase in specific activity in vitro compared with rIX(WT)-FP, while FXIa-mediated activation was the fastest for rIX(WT)-FP and rIX(R338L)-FP. Compared with rIX(WT)-FP and rIX(R338L/E410K)-FP, rIX(R338L)-FP exhibited higher FIX activity exposure after i.v. and s.c. administration and demonstrated comparable efficacy with rIX(WT)-FP in reducing bleeding time and blood loss in FIX-deficient mice requiring ∼4 times lower protein amount., Conclusion: rIX(R338L)-FP was shown to be a promising candidate for s.c. administration, exhibiting increased specific activity combined with higher activity-based exposure and indicating efficacy at a lower protein dose., Competing Interests: Declaration of competing interests K.S. is a patient representative for one of CSL’s products. J.R., W.S.-B., P.P., P.C., M.W.N., and S.P. are employees of CSL Innovation GmbH. E.H. is an employee of CSL Behring LLC, and A.R.-S. is an employee of CSL Limited. Furthermore, M.W.N., S.P., E.H., and P.P. hold shares of CSL Limited., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fidanacogene elaparvovec, an adeno-associated virus (AAV) gene-therapy vector for hemophilia B containing a high-activity human factor IX variant (FIX-R338L/FIX-Padua), was associated with sustained factor IX activity in a phase 1-2a study., Methods: We conducted a phase 3 open-label study of fidanacogene elaparvovec at a dose of 5×10 11 vector genome copies per kilogram of body weight. Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were eligible for screening if they had received at least 6 months of therapy with prophylactic factor IX concentrate. The primary end point, tested for noninferiority, was the annualized bleeding rate (treated and untreated bleeding episodes) from week 12 to month 15 after treatment with fidanacogene elaparvovec as compared with the prophylaxis lead-in period. Superiority, additional efficacy end points, and safety were also assessed., Results: Of 316 men who underwent screening for the lead-in study, 204 (64.6%) were not eligible; 188 (59.5%) of those were ineligible owing to the presence of anti-AAV neutralizing antibodies. Of the 45 participants who received fidanacogene elaparvovec, 44 completed at least 15 months of follow-up. The annualized rate of bleeding for all bleeding episodes decreased by 71%, from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after gene therapy, a treatment difference of -3.15 episodes (95% CI, -5.46 to -0.83; P = 0.008). This result shows the noninferiority and superiority of fidanacogene elaparvovec to prophylaxis. At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0) by one-stage SynthASil assay. A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, development of factor IX inhibitors, or malignant conditions were observed., Conclusions: Fidanacogene elaparvovec was superior to prophylaxis for the treatment of participants with hemophilia B, leading to reduced bleeding and stable factor IX expression. (Funded by Pfizer; BENEGENE-2 ClinicalTrials.gov number, NCT03861273.)., (Copyright © 2024 Massachusetts Medical Society.)

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product's optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences., (© 2024. The Author(s).)

Introduction: Hemophilia B is a X-linked rare inherited bleeding disorder characterized by coagulation factor IX (FIX) deficiency. Therapy for hemophilia B is aimed at replacing the FIX deficiency by means of several plasma-derived or recombinant FIX products. The recent availability of recombinant FIX concentrates with a prolonged FIX half-life represented a great technological advance, permitting more spaced drug infusions and reducing treatment burden among hemophilia B patients., Areas Covered: This review summarizes the main preclinical and phase 1/2 studies investigating the innovative hemostatic products for hemophilia B replacement therapy., Expert Opinion: The significant recent technological advantages in the treatment of hemophilia B has led to the development of innovative FIX products aimed at further extending FIX half-life and using increasingly effective and convenient modes of administration. These novel hemostatic agents, currently in the preclinical or early clinical phase of development, carry the potential of improving patients' health status and quality of life. Continuous research is anyway needed to offer such patients a concrete chance of conducting a normal existence, like to non-affected age-matched individuals.

Case: A 29-year-old man with hemophilia B presented with advanced arthropathy of the right knee, resulting in poor knee functional scores and difficulties in his livelihood. The patient underwent total knee replacement while receiving nonacog beta pegol factor IX by a multidisciplinary approach., Conclusion: Hemophilias commonly result in end-stage hemophilic arthropathy of the joints at a young age that may warrant joint replacement surgeries. This case report illustrates the surgical protocol of total knee arthroplasty in a patient who received a long-acting factor IX preparation., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C405)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Importance: Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption., Objective: To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion., Design, Setting, and Participants: Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021., Interventions: Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines., Main Outcomes and Measures: The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety)., Results: Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03)., Conclusions and Relevance: Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion., Trial Registration: ClinicalTrials.gov Identifier: NCT03218722.

In the rare co-occurrence of childhood cancer and severe hemophilia, hemostatic management is of paramount therapeutic importance. We present the case of an 11-month-old boy with severe congenital hemophilia B, who was diagnosed with metastatic high-risk neuroblastoma. He consequently developed paraneoplastic coagulopathy with life-threatening tumor hemorrhage and intracranial hemorrhage, showing central nervous system relapse. Management consisted of factor IX replacement with extended half-life factor IX fusion protein, adjusted to bleeding risk. Additional interventions included factor XIII, fibrinogen, fresh frozen plasma, tranexamic acid, and platelet transfusions. The half-life of factor IX products was markedly reduced requiring close factor IX monitoring and adequate replacement. This intensified treatment allowed chemotherapy, autologous stem cell transplantation, and GD2 antibody immune therapy without bleeding or thrombosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The current mainstay of therapy for hemophilia is to replace the deficient clotting factor with the intravenous administration of exogenous clotting factor concentrates. Prophylaxis factor replacement therapy is now considered the standard of care in both pediatric and adult patients with hemophilia with a severe phenotype to protect musculoskeletal health and improve quality of life. Heterogeneity in bleeding presentation among patients with hemophilia due to genetic, environmental, and treatment-related factors has been well described. Accordingly, the World Federation of Hemophilia recommends an individualized prophylaxis regimen that considers the factors mentioned above to meet the clinical needs of the patient, which can vary over time. This review focuses on the practical points of choosing the type of factor concentrate, dose, and interval while evaluating appropriate target trough factor levels and bleeding triggers such as level of physical activity and joint status. We also discuss the use of a pharmacokinetics assessment and its incorporation in the clinic for a tailored approach toward individualized management. Overall, adopting an individualized prophylaxis regimen leads to an optimal utilization of factor concentrates with maximum efficacy and minimum waste., (Copyright © 2021 by The American Society of Hematology.)

Purpose: Pharmacokinetic (PK) differences between the extended half-life (EHL) factor IX (FIX) concentrates for hemophilia B exist, which may influence hemostatic efficacy of replacement therapy in patients. Therefore, we aimed to evaluate the PK properties of three EHL-FIX concentrates and compare them to a standard half-life (SHL) recombinant FIX (rFIX) concentrate., Methods: Activity-time profiles of PEGylated FIX (N9-GP), FIX linked with human albumin (rIX-FP), FIX coupled to human IgG1 Fc-domain (rFIXFc), and SHL rFIX were simulated for 10,000 patients during steady-state dosing of 40 IU/kg once weekly (EHL-FIX) and biweekly (rFIX) using published concentrate specific population PK models., Results: Half-lives were respectively 80, 104, and 82 h for N9-GP, rIX-FP, and rFIXFc versus 22 h for rFIX. Between the EHL concentrates, exposure was different with area under the curve (AUC) values of 78.5, 49.6, and 12.1 IU/h/mL and time above FIX target values of 0.10 IU/mL of 168, 168, and 36 h for N9-GP, rIX-FP, and rFIXFc, respectively. N9-GP produced the highest median in vivo recovery value (1.70 IU/dL per IU/kg) compared with 1.18, 1.00, and 1.05 IU/dL per IU/kg for rIX-FP, rFIXFc, and rFIX, respectively., Conclusions: When comparing EHL products, not only half-life but also exposure must be considered. In addition, variation in extravascular distribution of the FIX concentrates must be taken into account. This study provides insight into the different PK properties of these concentrates and may aid in determination of dosing regimens of EHL-FIX concentrates in real-life., (© 2021. The Author(s).)

To prevent bleeding in severe haemophilia A [SHA, defined as factor VIII (FVIII) activity < 1%] regular prophylactic FVIII replacement therapy is required, and the benefits of factor products with extended half-life (EHL) over traditional standard half-life (SHL) are still being debated. We performed a multi-centre, retrospective cohort study of persons with SHA in Austria aiming to compare clinical outcomes and factor utilization in patients with SHA, who switched from prophylaxis with SHL to an EHL. Data were collected from haemophilia-specific patient diaries and medical records. Twenty male persons with SHA (median age: 32.5 years) were included. The most common reason for switching to the EHL was a high bleeding rate with SHL. Switch to rFVIII-Fc resulted in a significantly decreased annualized bleeding rate (ABR; median difference (IQR): - 0.3 (- 4.5-0); Wilcoxon signed-rank test for matched pairs: Z = - 2.7, p = 0.008) and number of prophylactic infusions per week (- 0.75 (- 1.0-0.0); Z = - 2.7, p = 0.007). Factor utilization was comparable to prior prophylaxis with SHL (0.0 (- 15.8-24.8) IU/kg/week; Z = - 0.4, p = 0.691). In summary, switch to EHL (rFVIII-Fc) was associated with an improved clinical outcome, reflected by ABR reduction, and less frequent infusions, without significantly higher factor usage.

Background: Nonacog alfa (recombinant factor IX [FIX]) is approved in China for the control and prevention of bleeding events in patients with hemophilia B. This was the first study to assess prophylaxis and on-demand therapy with recombinant FIX replacement in a real-world setting in China. This study aimed to evaluate the safety and efficacy of nonacog alfa in Chinese patients with hemophilia B., Methods: In this open-label, multicenter study (clinicaltrials.gov identifier NCT02336178), patients received on-demand or prophylactic treatment with intravenous nonacog alfa for approximately 6 months or 50 exposure days, whichever occurred first. The primary safety outcome was medically important events (i.e., development of FIX inhibitors, allergic reactions, and thrombotic events). Key secondary efficacy outcomes included the annualized bleeding rate for on-demand treatment and prophylaxis, response to on-demand treatment, the number of infusions per bleeding event, and the number of breakthrough bleeding events within 48 hours of prophylaxis., Results: Seventy male patients (mean [standard deviation] age 7.8 [7.2] years) were enrolled (on-demand, n = 37; prophylaxis, n = 57 [24 patients were included in both groups]). Thirty-eight (54%) patients had up to 50 FIX exposure days before the study. The only medically important event was a transient low-titer FIX inhibitor (incidence 1.4%, 95% confidence interval, 0-7.7). The mean annualized bleeding rate was 26.3 for on-demand treatment and 6.5 for prophylaxis. A mean (standard deviation) of 1.5 (1.7) nonacog alfa infusions were given per bleeding episode; 78.8% of episodes resolved with 1 infusion. Response was "excellent" or "good" for 88% of the on-demand infusions. Twenty-three bleeding events (n = 11 patients) occurred within 48 hours of 2032 prophylaxis doses (1.13%)., Conclusion: In the real-world setting, nonacog alfa is safe and effective for on-demand treatment and for prophylaxis for patients with hemophilia B in China., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The current standard of care treatment for severe hemophilia A and B (SHA and SHB) is the prophylactic intravenous replacement of coagulation factor VIII or IX (FVIII/FIX) to prevent spontaneous bleeding. Persons with hemophilia without prophylactic treatment receive therapy in case of bleeding, i.e., on demand. To assess treatment patterns, utilization of products, and bleeding outcomes in a real-world cohort of persons with SHA and SHB, defined as FVIII or FIX activity < 1%, data was retrospectively collected from hemophilia-specific patient diaries used for home treatment, medical records, and entries into the Austrian Hemophilia Registry from the year 2012 to 2017. Fifty-three male persons with SHA (n = 47) and SHB (n = 6) were included; 26 with SHA and 5 with SHB were on prophylaxis, 8 and 1 switched therapy regimen, and 13 and 0 received on-demand therapy. Persons on prophylaxis used a mean factor FVIII or FIX dose of 71.7 and 40.1 IU/kg/week. Median (IQR) annualized bleeding rates (ABR) in SHA were 28.0 (23.4-31.3) in the on-demand, 4.9 (1.6-13.5) in the prophylaxis group, and 3.0 (2.0-6.8) in the prophylactic group of SHB. Three persons with SHA had zero bleeds during the observation period. On-demand therapy and hepatitis B and C were associated with higher ABR but not age, weight, and HIV positivity. Bleeding rates and the proportion of on-demand therapy in persons with hemophilia were high in our real-world cohort. Further improvement is needed, which might be facilitated with the advent of factor products with extended half-life or non-factor therapies.

A 57-year-old man with mild haemophilia B was admitted for coronary artery bypass graft surgery. His factor IX (FIX) activity was 15% on admission. Our goal was to maintain his FIX activity at 80%-100% for post-op days (PODs) 0-3, and at 60%-80% for PODs 4-14. Preoperatively, the patient was given recombinant FIX (rFIX) bolus using the formula:Dosage needed=%(desired FIX level-current level of FIX)×weight (kg)×1.3.This increased his activity to 100%. One IU of rFIX increased FIX activity by 0.8%; the half-life of rFIX is 18-24 hours. The rFIX infusion was started intraoperatively and continued after surgery to maintain target FIX activity. He was discharged on POD 9 on rFIX bolus dosing of 5000 IU every 12 hours for an additional 5 days. Using continuous factor infusion, we managed to decrease the amount rFIX used by >60% while maintaining steady state FIX activity level., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Dosing of coagulation factor products is mainly determined based on a patient's body weight; however, several studies have reported high interindividual variability in their pharmacokinetics (PK). The objective of this study was to develop and evaluate 2 sparse sampling methods for the estimation of AUC of recombinant factor IX (BeneFIX) as proof of concept for dose individualization. A population pharmacokinetic model was used to generate the plasma factor IX activity-versus-time data. The linear limited sampling model (LLSM) was developed based on the correlation of factor IX activity versus AUC 0-72 hours following screening of several blood sampling times in adolescent and adult subjects (n = 90 subjects). Factor IX trough concentrations were predicted from a relationship established from AUC versus factor IX activity measured 72 hours postdosing. Using the best selected sampling time, the LLSM and Bayesian model were validated in separate data sets (n = 75 subjects). Using the LLSM and Bayesian analysis, a blood sample at 24 hours predicted AUC with bias and root mean square error < 5% and < 15%, respectively. The predicted trough concentrations were ≥1 IU/dL in 99% and 100% of subjects by the LLSM and Bayesian model, respectively. The average factor IX dose for a target AUC of 800 IU·h/dL was 61, 60, and 63 IU/kg using the extensive (reference), LLSM and Bayesian model, respectively. Overall, the AUC, trough concentrations and individualized dosing of recombinant factor IX could be reasonably predicted using the LLSM and Bayesian model., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Introduction: The rapid clearance of factor IX necessitates frequent intravenous administrations to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous administration has historically been limited by low bioavailability and potency. Dalcinonacog alfa was developed using a rational design approach to be a subcutaneously administered, next-generation coagulation prophylactic factor IX therapy., Aim: This study aimed to investigate the pharmacokinetic, pharmacodynamic, and safety profile of dalcinonacog alfa administered subcutaneously in hemophilia B dogs., Methods: Two hemophilia B dogs received single-dose daily subcutaneous dalcinonacog alfa injections for six days. Factor IX antigen and activity, whole blood clotting time, and activated partial thromboplastin time were measured at various time points. Additionally, safety assessments for clinical adverse events and evaluations of laboratory test results were conducted., Results: There was an increase in plasma factor IX antigen with daily subcutaneous dalcinonacog alfa. Bioavailability of subcutaneous dalcinonacog alfa was 10.3% in hemophilia B dogs. Daily subcutaneous dosing of dalcinonacog alfa demonstrated the effects of bioavailability, time to maximal concentration, and half-life by reaching a steady-state activity sufficient to correct severe hemophilia to normal, after four days., Conclusion: The increased potency of dalcinonacog alfa facilitated the initiation and completion of the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B., Competing Interests: T.N., E.M., and R.R. received a research grant from Catalyst Bioscience, Inc., M.L. is a paid consultant to Catalyst Bioscience, Inc. and H.L. is an employee and stockholder of Catalyst Bioscience, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Extended half-life of factor IX (FIX) demonstrated clinical benefit and lower treatment burden than standard half-life FIX products in clinical trials. We analysed the impact in efficacy, pharmacokinetics (PKs) and costs of the switch from nonacog alfa (rFIX) to albutrepenonacog alfa (rFIX-FP) in the first patient with haemophilia B (HB) treated in Spain outside clinical trials. A 7-year-old boy presented with HB with poor venous access and repetition infections using rFIX, which was switched to rFIX-FP. Prophylaxis was adjusted by PKs using WAPPS-Hemo tailoring from 100 IU/kg/week of rFIX to 80 IU/kg/3 weeks of rFIX-FP. Comparing 6 months before, rFIX-FP reduced 68.5% FIX consumption/kg and 58.3% infusion frequency, but total costs/weight showed a slight increase. Ratio of half-life between rFIX and rFIX-FP was 3.4-3.7. This case report revealed that switch to rFIX-FP decreased frequency and FIX consumption, without adverse events and bleeds., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The bispecific antibody emicizumab is increasingly used for hemophilia A treatment. However, its specificity for human factors IX and X (FIX and FX) has limited its in vivo functional analysis to primate models of acquired hemophilia. Here, we describe a novel mouse model that allows emicizumab function to be examined. Briefly, FVIII-deficient mice received IV emicizumab 24 hours before tail-clip bleeding was performed. A second infusion with human FIX and FX, administered 5 minutes before bleeding, generated consistent levels of emicizumab (0.7-19 mg/dL for 0.5-10 mg/kg doses) and of both FIX and FX (85 and 101 U/dL, respectively, after dosing at 100 U/kg). Plasma from these mice display FVIII-like activity in assays (diluted activated partial thromboplastin time and thrombin generation), similar to human samples containing emicizumab. Emicizumab doses of 1.5 mg/kg and higher significantly reduced blood loss in a tail-clip-bleeding model using FVIII-deficient mice. However, reduction was incomplete compared with mice treated with human FVIII concentrate, and no difference in efficacy between doses was observed. From this model, we deducted FVIII-like activity from emicizumab that corresponded to a dose of 4.5 U of FVIII per kilogram (ie, 9.0 U/dL). Interestingly, combined with a low FVIII dose (5 U/kg), emicizumab provided enough additive activity to allow complete bleeding arrest. This model could be useful for further in vivo analysis of emicizumab., (© 2020 by The American Society of Hematology.)

Replacement therapy with plasma-derived or recombinant FVIII and FIX (pdFVIII/pdFIX or rFVIII/rFIX) concentrates is the standard of treatment in patients with haemophilia A and B, respectively. Measurement of factor VIII (FVIII:C) or factor IX (FIX:C) levels can be done by one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). The French study group on the Biology of Hemorrhagic Diseases (a collaborative group of the GFHT and MHEMO network) presents a literature review and proposals for the monitoring of FVIII:C and FIX:C levels in treated haemophilia A and B patients, respectively. The use of CSA is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. Except for rFVIII-Fc, great caution is required when measuring FVIII:C levels by OSA in patients substituted by EHL-rFVIII. The OSA is recommended for the monitoring of patients treated with pdFIX or rFIX. Large discordances in the FIX:C levels measured for extended half-life rFIX (EHL-rFIX), depending on the method and reagents used, must lead to great attention when OSA is used for measuring FIX:C levels in patients substituted by EHL-rFIX. Data of most of recent studies, obtained with spiked plasmas, deserve to be confirmed in plasma samples of treated patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hemophilia A (HA) and B (HB) are X-linked bleeding disorders caused by mutations in the F8 or F9 gene that result in the absence, or reduced activity, of the corresponding clotting factor. The severity of bleeding and related complications is proportional to the amount of residual circulating functional factor. The development of a safe and effective hemophilia treatment lasted several decades and has been mainly based on clotting factor replacement. Advances in the engineering and manufacturing of clotting concentrates have led to the widespread availability of extended half-life products that reduced the number of intravenous infusions needed to achieve adequate trough levels. The recent development of new nonfactor replacement treatments and biotechnology techniques has offered therapeutic alternatives for hemophilia patients with and without inhibitors. These are characterized by an easier route of administration, low immunogenicity, and, regarding gene therapy and cell-based treatments, potential long-term protection from bleeding after a single treatment course. In this review, we analyze recent progresses in the management of hemophilia and discuss opportunities and challenges., Competing Interests: Dr. Matino reports personal fees from Sanofi, grants and personal fees from Sobi, personal fees from UBS, grants and personal fees from Pfizer, personal fees from NovoNordisk, personal fees from BIOVIIIX, outside the submitted work., (Georg Thieme Verlag KG Stuttgart · New York.)

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., (© 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: A number of new FVIII/IX concentrates enriched the portfolio of products available for the treatment of hemophilia A/B patients. Due to the large inter-patient variability, accurate tailoring of the therapy became essential to improve patients' adherence, clinical outcomes, and cost/effectiveness ratio. Recently, non-replacement therapies have taken the limelight and succeeded in decreasing the bleedings of patients., Areas Covered: The PK characteristics, efficacy, and safety of the new rFVIII and rFIX concentrates and of non-replacement therapy, are reported in detail in the published clinical trials., Expert Opinion: Outstanding improvements of rFIX concentrates' pharmacokinetics and pharmacodynamics have allowed to reduce the bleedings in hemophilia B patients, in order to increase their adherence to prophylaxis and quality of life. Less significant are the effects of pegylation or Fc fusion on the pharmacokinetics of the new rFVIII concentrates. The new non-replacement therapy is achieving the favor of many treaters and patients, in particular those with Factor VIII inhibitors. Great attention must be paid to the dangerous synergy of APCC and emicizumab, responsible for some fatal events during the clinical trials and compassionate use of this drug. So far, replacement therapy should be the standard of care for hemophilia patients without inhibitors or difficulties in venous access.

Introduction: Monitoring of factor IX (FIX) replacement therapy in haemophilia B relies on accurate coagulation assays. However, considerable interlaboratory variability has been reported for one-stage clotting (OSC) assays. This study aimed to evaluate the real-world, interlaboratory variability of routine FIX activity assays used in clinical haemostasis laboratories for the measurement of recombinant FIX Fc fusion protein (rFIXFc) activity., Methods: Human FIX-depleted plasma was spiked with rFIXFc at 0.80, 0.20 or 0.05 IU/mL based on label potency. Participating laboratories tested samples using their own routine OSC or chromogenic substrate (CS) assay protocols, reagents and FIX plasma standards. Laboratories could perform more than one measurement and method, and were not fully blinded to nominal activity values., Results: A total of 142 laboratories contributed OSC results from 175 sample kits using 11 different activated partial thromboplastin time (aPTT) reagents. The median recovered FIX activity for the 0.80, 0.20 and 0.05 IU/mL samples was 0.72 IU/mL, 0.21 IU/mL and 0.060 IU/mL, respectively. Across all OSC reagents, interlaboratory variability (% CV) per aPTT reagent ranged from 9.4% to 32.1%, 8.2% to 32.6% and 12.2% to 42.0% at the 0.80, 0.20 and 0.05 IU/mL levels, respectively. CS results showed excellent median recoveries at all nominal levels (87.5% to 115.0%; n = 11) with low interlaboratory variability (CV 3.6% to 15.4%)., Conclusion: This large, real-world data set indicates that rFIXFc activity in plasma samples can be accurately measured with the majority of routine OSC and CS assay methods. Given the variation in FIX assay procedures between sites, it is important that individual laboratories qualify their in-house methods for monitoring of rFIXFc activity., (© 2020 Swedish Orphan Biovitrum AB. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

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%)., Competing Interests: M.C. has received grant/research support from: Baxalta (Shire), Bayer, Biogen, Novo Nordisk and Pfizer, has been a consultant for Baxalta/Shire/Takeda, Bayer, Biogen/Bioverativ/Sanofi, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, and Roche, and is a member of speaker bureaus of Baxalta (Shire), Bayer, Biogen, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, and Roche.S.K. has received grant/research support from: local principal investigator (PI) research funding for Bayer, Bioverativ, Daiichi Sankyo, Grifols, and Novo Nordisk, and is a member of speaker bureaus/advisory boards for Bayer, Bioverativ, and Novo Nordisk.M.Y.L. has no conflict of interest.M.T. has served on advisory boards for Bayer, Bioverativ, Chugai, and Novo Nordisk; has received research support in clinical trials as a local PI for Bioverativ, Chugai, CSL Behring, and Novo Nordisk, and has received speaker's fees from Bayer, Bioverativ, Chugai, CSL Behring, Novo Nordisk, and Shire.D.R. and C.S. are employees of Novo Nordisk A/S, Søborg, Denmark.E.S. has served on advisory boards for Bayer, Bioverativ, CSL Behring, Grifols, Kedrion, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI, Spark, and Uniqure and has been a member of speaker bureaus for Bayer, CSL Behring, Grifols, Kedrion, Novo Nordisk, Pfizer, Roche, Shire/Takeda, and SOBI., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: The one-stage clotting assay is used to measure factor IX (FIX) activity in patients' plasma samples and in FIX products for hemophilia treatment. However, the diversity of reagents and instruments has resulted in significant FIX assay variability., Methods: The accuracy of the one-stage clotting assay to measure recombinant FIX Fc fusion protein (rFIXFc) activity was evaluated by major Japanese hemophilia treatment centers and commercial laboratories that measure factor IX activity for a majority of hemophilia B patients in Japan. Plasma-derived FIX (pdFIX) and recombinant FIX (rFIX) products were used as comparators. FIX-deficient plasma was spiked with four levels of FIX products based on label potency and measured under blinded conditions by routine one-stage clotting assay procedures in 19 participating laboratories. Interlaboratory coefficient of variation and spike recovery were calculated., Results: Interlaboratory coefficient of variation of rFIXFc was not significantly different from that of rFIX, but appeared larger than that of pdFIX. Mean spike recovery for rFIXFc was generally comparable to rFIX and pdFIX. However, larger discrepancies between pdFIX and rFIX were observed in three of nine laboratories using ellagic acid-based activated partial thromboplastin time reagents., Conclusion: Recombinant FIX Fc fusion protein activity was found to be similar to that of rFIX or pdFIX by the one-stage clotting assay. However, minimizing interlaboratory variability is vital for optimizing future patient care., (2019 Sanofi K.K. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Objective: An extended half-life factor IX (FIX) fusion protein linking recombinant FIX with recombinant human albumin (rIX-FP), indicated for the treatment of hemophilia B, was approved by the European Medicines Agency in May 2016. We aimed to compare clinical outcomes and drug utilization in patients who switched from prior FIX therapies to rIX-FP. Methods: Anonymized patient chart data were collected from German institutions treating patients with hemophilia B. Patients were included if they had been treated with rIX-FP for ≥8 weeks at the time of data collection. Bleeding rates and FIX consumption were compared between rIX-FP and patients' prior FIX products. Results: Data were obtained for 81 male patients treated with rIX-FP, including 59 who received prophylaxis with both their prior drug and rIX-FP (prophylaxis-to-prophylaxis group). Mean factor consumption in this group was 44.2 IU/kg/wk for rIX-FP compared with 82.3 IU/kg/wk for all prior FIX products. In addition, intra-patient analysis of factor consumption showed lower consumption of rIX-FP compared with prior FIX in 56 of 59 patients. Among the patients for whom bleed data were available ( n  = 42), annualized bleeding rate decreased from a mean (standard deviation) of 2.6 ± 2.9 on prior product to 0.3 ± 0.6 on rIX-FP. The proportion of patients with zero bleeds increased from 24% with prior therapy to 81% with rIX-FP. Conclusion: rIX-FP was associated with substantial reductions in bleeding rates and consumption of FIX compared with standard half-life products that require more frequent administration.

Aims: Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals, and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients. Materials and methods: A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated hemophilia B patients aged ≥12 years (FIX ≤2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A z -test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated. Results: Seven articles investigating six rFIX products were identified. Median ABR, AsBR, and AjBR ranged from 0-3.0, 0-1.0, and 0-1.1 (means = 0.8-4.26, 0.13-2.6, and 0.34-2.85), respectively. rIX-FP achieved the lowest median and mean values in all three parameters. Z -tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products. Limitations: The low number of appropriate trials available for comparison limits the quantity of data available for comparison, and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field. Conclusion: This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably vs other rFIX products for prophylaxis in hemophilia B.

Adeno-associated virus (AAV)-based liver gene therapy has been shown to be clinically successful. However, the presence of circulating neutralizing antibodies (NABs) against AAV vector capsids remains a major challenge as it may prevent successful transduction of the target cells. Therefore, there is a need to develop strategies that would enable AAV-mediated gene delivery to patients with preexisting anti-AAV NABs. In the current study, the feasibility of using an immunoadsorption (IA) procedure for repeated, liver-targeted gene delivery in nonhuman primates was explored. The animals were administered IV with recombinant AAV5 (rAAV5) carrying the reporter gene human secreted embryonic alkaline phosphatase (hSEAP). Seven weeks after the first rAAV treatment, all of the animals were readministered with rAAV5 carrying the therapeutic hemophilia B gene human factor IX (hFIX). Half of the animals administered with rAAV5-hSEAP underwent IA prior to the second rAAV5 exposure. The transduction efficacies of rAAV5-hSEAP and rAAV5-hFIX were assessed by measuring the levels of hSEAP and hFIX proteins. Although no hFIX was detected after rAAV5-hFIX readministration without prior IA, all animals submitted to IA showed therapeutic levels of hFIX expression, and a threshold of anti-AAV5 NAB levels compatible with successful readministration was demonstrated. In summary, our data demonstrate that the use of a clinically applicable IA procedure enables successful readministration of an rAAV5-based gene transfer in a clinically relevant animal model. Finally, the analysis of anti-AAV NAB levels in human subjects submitted to IA confirmed the safety and efficacy of the procedure to reduce anti-AAV NABs. Furthermore, clinical translation was assessed using an immunoglobulin G assay as surrogate., (© 2019 by The American Society of Hematology.)

Background: Following induced joint hemorrhage, hemophilia B results in the abnormal persistence of iron deposition, inflammation, and neovascularity of the synovial tissue, as well as deterioration of the bone articular surface and strength. Previously, we demonstrated that a factor IX (FIX) replacement protein with extended circulating FIX activity, glycoPEGylated FIX nonacog beta pegol (N9-GP), could improve synovial and osteochondral parameters in F9 knockout mice when administered after joint injury., Objective: We explored the use of N9-GP prior to unilateral joint hemorrhage and compared to unmodified recombinant FIX (rFIX)., Methods: Pharmacodynamics, histology, and microcomputed tomography were used to assess the effects of prophylactic administration of glycoPEGylated FIX., Results: In comparison to rFIX, N9-GP significantly improved soft tissue histological parameters, as well as bone outcome at 2 weeks post injury, while performing equally in reduction of blood present in the joint space assessed 1 day after injury., Conclusions: These results indicate that, in comparison to rFIX, the prophylactic use of extended half-life FIX provides superior protection from bleeding-induced joint damage, manifested by improved correction of histologic parameters., (© 2019 International Society on Thrombosis and Haemostasis.)

The mainstay of hemophilia management has been the regular, prophylactic infusion of missing coagulation factors VIII/IX. This approach is limited by the need for frequent intravenous infusions, high cost, limited availability, and the development of inhibitory antibodies to factors VIII/IX. Numerous recent breakthroughs are addressing many of these limitations. These include the development of extended half-life factors that require less frequent infusions and the development of various novel agents that can be given subcutaneously and infrequently, including FVIII-mimetic antibody and downregulators of natural anticoagulants. Finally, gene therapy is set to offer patients a possibility for a cure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Allometric scaling is a method that can be used for the extrapolation of pharmacokinetic parameters from adults to children. Subsequently, these allometrically predicted PK parameters can be used to project a suitable dose to initiate a pediatric clinical trial. The objective of this study was to predict clearance and in vivo recovery of coagulation factors VIII and IX allometrically in children from 1 year of age to adolescents and then project the first-in-children dose. The values for observed clearance, in vivo recovery, and dose for pediatric as well as adult subjects for 7 factor VIII and 3 factor IX products were obtained from the US Food and Drug Administration package insert and the allometrically predicted clearance, in vivo recovery, and dose were compared with the observed values. The clearance of factors VIII and IX were predicted with reasonable accuracy. Of 27 predicted clearance values, all 27 (100%) were predicted with ≤30% prediction error (range, 5%-28%). Of 27 predicted in vivo recovery values, 26 (96%) were predicted with ≤30% prediction error (range, 0%-45%). The projected doses of factor VIII or IX, either by clearance or in vivo recovery, were generally within the recommended dose range indicating an accurate prediction of pediatric dose for both factors. The proposed allometric methods can be used to select first-in-children dose in pediatric clinical trials., (© 2019, The American College of Clinical Pharmacology.)

Four-factor prothrombin complex concentrate (4F-PCC) has emerged as the preferred option for emergent reversal of vitamin K antagonists (VKAs); however, the optimal dosing strategy is unknown. Although several studies have attempted to determine the optimal dose of 4F-PCC using a variety of dosing regimens, no dosing strategy has been found to be superior. Many of these studies have evaluated a low, fixed dose of 4F-PCC rather than individualized dosing as recommended in product labeling. The purpose of this review was to evaluate the efficacy and safety of various fixed-dose strategies of 4F-PCC for emergent VKA reversal and to assess limitations of the existing literature. A search of the PubMed database was performed from the earliest available date through 2018 for relevant articles describing fixed-dose 4F-PCC for VKA reversal. Reference lists of relevant articles were also manually reviewed. Most currently available studies are primarily observational and heterogeneous in design. A very low fixed dose of 500 IU is likely inadequate for successful VKA reversal, but increased fixed doses of 1000-1500 IU have found some degree of success and may be considered for VKA reversal. However, many of these studies consistently identified a trend toward international normalized ratio (INR) reversal failure in patients presenting with high baseline INR values or intracranial hemorrhage, suggesting that higher 4F-PCC doses are needed in these patients. Available studies are underpowered to determine whether a dose-dependent association with thrombotic risk exists. Additional large, randomized studies are needed to determine the optimal dosing strategy and ascertain the role for fixed-dose 4F-PCC., (© 2019 Pharmacotherapy Publications, Inc.)

Background: Intracerebral hemorrhage (ICH) is a life-threatening complication of oral anticoagulant therapy that sometimes results in hematoma expansion after onset. Our facility did not have a standardized process for treating oral anticoagulant-associated ICH; this resulted in lag times from order to reversal agent administration., Purpose: The aim of this study was to examine the impact of a rapid anticoagulant reversal protocol, combined with warfarin and direct-acting oral anticoagulant therapy, in decreasing door to first intervention times., Methods: This study used a retrospective quality assessment research approach in examining an oral anticoagulant reversal protocol to compare the control and intervention groups. Phytonadione was the first intervention treatment for most study participants diagnosed with warfarin-associated ICH with an international normalized ratio greater than 1.4. Factor IX was the first intervention treatment for all but one study participant with DOAC-associated ICH., Results: Findings were statistically significant (P < .05) for door to first intervention treatments. Door to phytonadione in minutes decreased from 232.7 (SD, 199.4) to posttest findings of 111.4 (SD, 64.6). Door to factor IX in minutes decreased from 183.9 (SD, 230.2) to posttest findings of 116.6 (SD, 69.1)., Conclusion: Study findings support the hypothesis that the new protocol was associated with lower door-to-treatment times for eligible patients.

Case: A 7-year-old boy presented with excruciating hip pain for 1 day, unable to bear weight. Magnetic resonance imaging (MRI) revealed small hip joint effusion and synovitis, which was treated by urgent operative aspiration to rule out infection. Subsequently, the postoperative site bled continuously, despite compression. The hip wound and blood cultures showed no growth. He was examined by a hematologist and had normal coagulopathy lab results. He was discharged and went home 4 days after aspiration and was scheduled for outpatient hematology work-up. He was readmitted 11 days after aspiration with continued pain and MRI was repeated, showing large hip hemarthrosis. Lab results at that time showed a prolonged partial thromboplastin time of 43.9 seconds. The patient was given fresh frozen plasma. The hip effusion was stable on ultrasound. He was found to have low factor IX <17% consistent with hemophilia B and was given recombinant factor IX (Benefix) of 2,000 units. The following day, his pain was markedly improved and he was discharged. At the 4-month follow-up, the patient was fully ambulatory., Conclusions: This is a case of unexpected bleeding after hip aspiration which led to the life-changing diagnosis of Hemophilia B in a pediatric patient. Orthopedists should be wary of bleeding dyscrasias and involve consultants as needed.

Due to blood derivative requirements, many patients with hemophilia were exposed to Hepatitis C virus infection (HCV) before the availability of HCV testing. We report a 46-year-old male with Hemophilia A with a hepatitis virus C infection since 2004 causing a cirrhosis. Due to a hepatopulmonary syndrome, he received a liver allograph using a factor VIII replacement protocol, after eradicating the virus C. He had a good postoperative evolution, and no more factor VIII was required after transplantation until his last assessment.

Introduction: During the last decade, new FVIII/IX concentrates have been developed for the treatment of patients affected by hemophilia A/B. Significant progress has been achieved regarding their half-life, but the old issue of immunogenicity and new concerns about safety need to be addressed., Areas Covered: After the implementation of virucidal methods, both plasma-derived and recombinant clotting factor concentrates achieved a very safe profile. The development of anti-FVIII antibodies is the major adverse event of replacement therapy with both FVIII concentrates. Furthermore, the new extended half-life concentrates, protein fused or pegylated, raised some concerns about their side effects., Expert Opinion: The treatment of hemophilia A with inhibitors by induction of immunotolerance and using by-passing concentrates, improved the quality of life of patients but did not allow them to have a life expectancy like that of patients without inhibitors. The new humanized monoclonal antibody (MAb) ACE910, mimicking FVIII function, seems to be able to reduce the bleedings of hemophilia A patients with inhibitors. The post-marketing surveillance will clarify if the adverse events observed during the phase III clinical trials and compassionate use were due to the association with a Prothrombin activated complex concentrate or to the prothrombotic effect of the drug itself.

Introduction : Prophylaxis with factor replacement therapy is the gold standard for the treatment of hemophilia, but this often requires frequent infusions. A number of long-acting factor products have been developed to reduce the burden on patients. Areas covered : This is an overview of information presented at two symposia held at the World Federation of Hemophilia and International Society on Thrombosis and Haemostasis - Scientific and Standardization Committee annual meetings. The pharmacokinetic, safety and efficacy data for long-acting recombinant products are reviewed, with a focus on recombinant factor IX albumin fusion protein (rIX-FP) and rVIII-SingleChain. This overview also provides a guide for managing a patient's switch to long-acting products. Expert opinion : Long-acting products may allow patients to maintain or decrease bleeding rates whilst increasing their dosing interval, which may in turn reduce the burden on patients and caregivers. When switching patients to long-acting products health-care professionals should provide balanced and thorough education to the patient, whilst supporting their emotional well-being. Regimens should address patients' needs and goals but should also be guided by clinical phenotype and pharmacokinetic assessment. Follow-up should assess safety concerns, bleeding rates, joint health and the impact of the regimen on patients' lifestyle.

: The murine FeCl3 model is a widely used model for studying arterial thrombosis, yet provides limited information from each mouse, often only a single time point for the onset of occlusion (defined as the time to occlusion; TTO). To optimize data from the murine ferric chloride model of thrombosis. FeCl3 injury was induced in the carotid arteries of wild-type and Factor IX (FIX) knockout mice, with infusion of recombinant FIX (rFIX) to normalize FIX deficiency at various times around FeCl3 injury. The TTO was recorded as a percentage of baseline flow as occlusion continued to zero flow, with identification of reflow events. The TTO among the treatment groups of FIX-deficient mice showed no statistical differences, except with physiological saline-treated FIX-deficient mice and those receiving delayed treatment. Incidences of occlusion were 100% for wild-type mice and FIX-deficient mice receiving slow infusions of rFIX at early times around the FeCl3 application. In contrast, only 68% of FIX-deficient mice achieved occlusion with preinfusion of rFIX and none occluded with delayed rFIX infusion. A majority of occluded vessels exhibited reflow events, with significantly lower incidence for slow infusion of rFIX starting 4 min after FeCl3 application in comparison with preinjury bolus, demonstrating characterization of a differential response to timing and infusion rates of treatment. Simple use of the time to occlusion may not maximize data available from the FeCl3 arterial thrombosis model. Inclusion of documenting reflow events can extend the useful data obtained with application of this model.

Introduction: Prophylaxis with replacement factor IX (FIX) reduces bleeding frequency and improves quality of life in haemophilia B patients. With prophylaxis, the likelihood of bleeding is lowered with increasing trough levels. New products with extended half-life (EHL) can maintain high factor activity levels over prolonged periods, compared with standard FIX products., Aim: To evaluate the safety, efficacy and pharmacokinetics of the new recombinant FIX EHL product, nonacog beta pegol (N9-GP), using pooled data, with a focus on-but not limited to-prophylaxis at 40 IU/kg., Methods: N9-GP has been investigated in males with congenital haemophilia B and FIX activity ≤2% in the paradigm™ clinical trial programme. This analysis includes pooled data from five completed paradigm™ trials conducted in previously treated adults, adolescents and children, focusing on results of prophylaxis with 40 IU/kg once-weekly intravenous dosing., Results: In total, 115 previously treated patients were exposed to N9-GP. Of 54 patients (47%) treated with N9-GP 40 IU/kg once-weekly prophylaxis, 72% experienced no spontaneous bleeds over 1 year. In all patients receiving 40 IU/kg once-weekly, median overall annualized bleeding rate (ABR) was 1.03 (interquartile range 0.00; 2.89); median spontaneous ABR was 0.00 (0.00; 0.80). No patients developed inhibitors. Estimated mean steady-state trough levels with N9-GP 40 IU/kg once-weekly were ≥15% overall; 27.3% in adolescents and adults., Conclusion: N9-GP 40 IU/kg once-weekly was well tolerated and effective in preventing bleeding, maintaining mean FIX activity levels ≥15% across all age groups. N9-GP may provide a new treatment option for preventing bleeding in haemophilia B patients., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction: The health benefits of prophylactic dosing regimens for clotting factor therapy in patients with hemophilia include reduced joint damage and improved quality of life; as such, prophylaxis is recommended in treatment guidelines. However, many patients with hemophilia B are treated on demand, and prophylaxis has been utilized less frequently than in hemophilia A. Areas covered: This review discusses the opportunities and evidence for prophylaxis in hemophilia B, in the context of treatment guidelines and with regard to factor IX (FIX) replacement therapies, including long-acting recombinant FIX (rFIX). Expert commentary: Long-acting rFIX concentrates may increase uptake of and adherence to prophylaxis regimens through attainment of higher trough levels with longer dosing intervals. In this new era of hemophilia B treatment, physicians may be able to achieve better clinical outcomes for their patients and reconsider treatment goals. Maintaining higher FIX trough levels will undoubtedly have long-term benefits for patients, such as preserving joint function. The long-acting rFIX concentrates support robust prophylaxis regimens and offer physician's flexibility in treating patients to best suit their needs, whether to enable an active lifestyle, to achieve higher trough levels for better bleed protection, or simply to decrease the burden of treatment by reducing injection frequency.

Objectives: We aimed to summarize the evidence for periprocedural and long-term strategies to both minimize the bleeding risk and ensure sufficient anticoagulation and antiaggregation in hemophilia patients undergoing coronary angiography with or without percutaneous coronary interventions (PCI)., Background: Hemophilia patients undergoing coronary angiography and PCI are at risk of bleeding due to deficiency of the essential clotting factors VIII or IX combined with the need of peri-interventional anticoagulation and antiaggregation and dual antiplatelet therapy (DAPT) after PCI., Methods: We report on a patient with moderate hemophilia B undergoing single-vessel PCI with administration of factor IX concentrate during the procedure and during the 1-month DAPT period. In addition, a systematic review of patients (n = 54, mean age 58 ± 10 years) with hemophilia A (n = 45, 83%) or B (n = 9, 17%) undergoing coronary angiography with or without PCI is presented., Results: Peri-interventional factor substitution was performed in the majority (42 of 54, 78%) but not all patients. In 38 of 54 (70%) patients undergoing coronary angiography, PCI with balloon dilation (n = 5), bare metal (n = 31), or drug-eluting stents (n = 2) was performed. For PCI unfractioned heparin (n = 24), low molecular weight heparin (n = 2), bivalirudin (n = 4), or no periprocedural anticoagulation at all (n = 8) were used. PCI was successful in all cases. After stenting, the majority (28 of 33; 85%) was treated with DAPT (median duration 1 month). Major periprocedural bleeding episodes occurred in 3 of 54 (6%) patients. Bleeding during follow-up occurred in 11 of 54 (20%) patients., Conclusions: Coronary angiography and PCI in patients with hemophilia are effective and safe when applying individualized measures to prevent bleeding., (© 2017 Wiley Periodicals, Inc.)

Replacement therapy with clotting factor concentrates (CFC) is the mainstay of treatment in hemophilia. Its widespread application has led to a dramatic decrease in morbidity and mortality in patients, with concomitant improvement of quality of life. However, dosing is challenging and costs are high. This review discusses benefits and limitations of pharmacokinetic (PK)-guided dosing of replacement therapy as an alternative for current dosing regimens. Dosing of CFC is now primarily based on body weight and based on its in vivo recovery (IVR). Benefits of PK-guided dosing include individualization of treatment with better targeting, more flexible blood sampling, increased insight into association of coagulation factor levels and bleeding, and potential overall lowering of overall costs. Limitations include a slight burden for the patient, and availability of closely collaborating, experienced clinical pharmacologists., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)