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Introduction: In recent years, there has been increased focus on individualizing treatment for persons with hemophilia including pharmacokinetic‐guided (PK) dosing. Aims: In this retrospective study clinical outcomes before and after PK‐guided prophylaxis were examined. Materials and methods: Eight Haemophilia Treatment Centres from the United States participated in the study and included 132 patients classified into two cohorts: those undergoing a PK‐assessment for product switch (switchers) or to optimize treatment (non‐switchers). Subset analyses for the two most common products and patients with dosing per prescription label were included for annual bleeding rates (ABR), mean weekly consumption outcomes, and annualized cost of prophylaxis. Results: The most common products before and after index date were octocog alfa, rurioctocog alfa pegol, and efmoroctocog alfa. Seventy‐four (56%) patients were identified as switchers and 58 (44%) patients were classified as non‐switchers. The majority of patients (78.0%) experienced either a decrease in ABR post‐index or maintained 0 ABR during pre‐ and post‐index time periods, with similar proportions identified in both switchers (77.0%) and non‐switchers (79.3%) populations. Non‐switchers were identified as having no significant change in cost of therapy, while switchers experienced increased cost of therapy driven by higher price of extended half‐life products. Within subset analyses, patients receiving rurioctocog alfa pegol and efmoroctocog alfa had mean ABR under 1 after index date. Conclusion: PK‐guided prophylaxis has the potential to improve clinical outcomes without increase in cost of therapy for patients maintaining product and can aid in maintaining effective protection against bleeds in those switching product. [ABSTRACT FROM AUTHOR]

Introduction: Health literacy (HL) and health numeracy (HN) are underestimated barriers to treatment adherence in patients with haemophilia. Aim: To test the ability of an educational intervention to improve knowledge, HL, HN, adherence and joint health in adolescent and young adult (AYA) males with haemophilia. Methods: We performed a longitudinal pilot study of 41 participants aged 12–21 years with haemophilia A or B during two clinic visits 6–12 months apart. The first visit included a comprehensive pre‐intervention assessment: demographics, knowledge survey, Montreal Cognitive Assessment testing, 5‐question tool to assess baseline HN, assessment of HL with the Rapid Estimate of Adolescent Literacy in Medicine tool, history of adherence and Haemophilia Joint Health Score (HJHS). An educational intervention using a visual aid explained basic pharmacokinetic (PK) concepts and personal teaching regarding haemophilia treatment regimens was used during this visit. The second visit included a post‐intervention assessment: a reassessment of knowledge, HL, HN, HJHS, adherence to prescribed therapy and number of joint bleeds since the pre‐intervention visit. Results: Forty‐one males with haemophilia A or B were enrolled in the study. Of these, 33 completed the post‐intervention assessment. Knowledge (p =.002) and HN (p =.05) were significantly improved post‐intervention, although the HL, number of joint bleeds, adherence to prescribed therapy and HJHS were not. Conclusions: Participants with low HL and/or HN may benefit from alternate methods of education such as audiovisual material. Education using audiovisual materials improved knowledge and HN in this study; however, this did not affect adherence to prescribed therapy. [ABSTRACT FROM AUTHOR]

Aim/objective: Understanding pharmacokinetic (PK) differences between standard and extended half-life (EHL) products is important, particularly for factor IX (FIX), where differences are more significant than for factor VIII. Two single-dose PK trials showed N9-GP achieves higher FIX levels and greater area-under-the-curve than pdFIX, rFIX, and rFIXFc through higher recovery and longer terminal half-life. In paradigm 7, N9-GP demonstrated consistently favorable PK characteristics compared with rFIXFc. Collins et al explored population PK differences between N9-GP and pdFIX/rFIX based upon paradigm 1 data. This analysis uses population PK models based upon the paradigm 7 trial. Methods: 15 patients (21–65 years) with hemophilia B received single 50-IU/kg doses of N9-GP and rFIXFc ≥21 days apart. A population PK model developed from single-dose PK profiles simulated plasma FIX activity following dosing for surgery and on-demand treatment of bleeds. Simulations explored doses and frequencies required to sustain target World Federation of Hemophilia (WFH) factor activity levels. Results: PK profiles of N9-GP and rFIXFc were described by one- and three-compartment models, respectively. Simulations predicted significantly reduced dosing frequency and consumption for N9-GP than rFIXFc. For severe bleeds, a single N9-GP dose (80 IU/kg) is sufficient to maintain WFH-recommended FIX levels, whereas multiple rFIXFc doses are required. For surgery, redosing in the first week with N9-GP is modeled at day 6 vs rFIXFc dosing at 6, 30, 54, 78, and 126 hrs. For life-threatening bleeds, N9-GP is required at days 0, 3, 6, 13, and 18 vs rFIXFc redosing after 6 hrs with 10 additional doses at 24-, 48-, and 72 hr intervals. Conclusion: PK modeling approaches based upon direct comparative studies offer insights into PK differences between EHL FIX products. Model simulations show N9-GP may allow on-demand treatment and perioperative management with 55–75% fewer injections and 65–74% lower overall factor concentrate consumption than rFIXFc. [ABSTRACT FROM AUTHOR]

Background: Patients with hemophilia A are commonly treated with replacement recombinant factor VIII (rFVIII) products, which can be standard-acting or long-acting. Long-acting products have modifications, offering the potential for reduced dosing frequency while maintaining therapeutic benefit. Extended dosing intervals reduce patient burden and can improve quality of life and adherence., Objective: To assess real-world data for the use of 6 commonly prescribed standard-acting and long-acting FVIII products in the United States: octocog alfa, BAY 14-2222, BAY 81-8973, rVIII-SingleChain, rFVIIIFc, and polyethylene glycol (PEG)-rFVIII. We summarized annualized bleeding rates (ABRs), dosing frequency, and factor consumption in patients treated with each product, with subgroup analyses for patients with severe disease., Methods: De-identified patient data were collected from 11 hemophilia treatment centers in the United States. Patients treated with octocog alfa, BAY 14-2222, BAY 81-8973, rVIII-SingleChain, rFVIIIFc, or PEG-rFVIII prophylaxis for ≥ 8 weeks at the time of data collection were included in the analysis. Among the 6 treatment groups, matching was attempted for patient age and disease severity where possible., Results: Data were obtained for 240 patients, of whom 191 patients had severe disease. Patients receiving long-acting FVIII products were dosed less frequently than those receiving standard-acting FVIII products. The proportion of patients dosed 2 times weekly or less was 65.0%, 70.0%, 72.5%, 25.0%, 40.0%, and 47.5% with rVIII-SingleChain, rFVIIIFc, PEG-rFVIII, octocog alfa, BAY 14-2222, and BAY 81-8973, respectively. Median ABRs ranged from 2.0 to 3.0 (mean 2.6 to 4.4) across the 6 products for all patients and were similar for patients with severe disease (median 2.0 to 3.0 and mean 2.5 to 4.8). The proportion of patients experiencing 0 bleeding episodes ranged from 7.5% to 25.0% for all patients and 12.0% to 28.6% for patients with severe disease. For all patients, median (mean) weekly FVIII product consumption was lowest for rVIII-SingleChain among the 6 products ( P = 0.045); 91.9 (91.1) IU per kg per week for rVIII-SingleChain, 108.5 (103.6) for rFVIIIFc, 97.6 (111.0) for PEG-rFVIII, 114.0 (117.5) for octocog alfa, 102.5 (102.6) for BAY 14-2222, and 95.1 (100.7) for BAY 81-8973. Similar differences in weekly consumption among the 6 products were observed for patients with severe disease ( P = 0.014)., Conclusions: Real-world data demonstrate that long-acting products may be beneficial compared with standard-acting products because of reduced dosing frequency while maintaining effectiveness. The 6 products evaluated showed statistically comparable ABRs and percentage of patients with 0 bleeds for all patients including those with severe disease. rVIII-SingleChain demonstrated lowest mean consumption for all patients, as well as for patients with severe hemophilia A, which may lead to potential savings in health care costs., Disclosures: This study was funded by CSL Behring. Simpson reports consulting honoraria for participation in advisory boards for Bayer, CSL Behring, HEMA Biologics, Novo Nordisk, Octapharma, and Takeda and speakers bureau for Bayer and Novo Nordisk. Yan and Desai are employees of CSL Behring. Maro is an employee of Adivo Associates, which conducted the analyses for this study. Data were presented in part at the Hemostasis and Thrombosis Research Society; May 9-11, 2019; New Orleans, LA; at the International Society on Thrombosis and Haemostasis; July 6-10, 2019; Melbourne, Australia; and have been published in part in "Comparing Factor Use and Bleed Rates in U.S. Hemophilia A Patients Receiving Prophylaxis with 3 Different Long-Acting Recombinant Factor VIII Products," by Mindy L. Simpson, Vidhi Desai, Géraldine S. Maro, Songkai Yan ( J Manag Care Spec Pharm. 2020;26[4]:504-12).

Background: Recombinant factor VIII (rFVIII) products have been developed with improved pharmacokinetics, offering some patients the potential to extend dosing intervals, thereby reducing their dosing frequency while minimizing the occurrence of bleeding events. No clinical trials have been conducted to compare the bleeding rates and use of these long-acting products., Objectives: To (a) assess real-world use of prophylaxis regimens in patients using 1 of 3 different long-acting products-rVIII-SingleChain, rFVIIIFc, or PEG-rFVIII; and (b) compare bleeding rates, dosing frequency, and factor consumption in 3 cohorts of patients. For rVIII-SingleChain patients, these measures were also compared with the prior products these patients used., Methods: De-identified patient chart data were collected from 11 hemophilia treatment centers in the United States. Patients were included if they had been treated with rVIII-SingleChain, rFVIIIFc, or PEG-rFVIII prophylaxis for ≥ 8 weeks at the time of data collection. Matching for age and disease severity was attempted between the 3 patient groups. Data were also collected for patients who switched from their prior FVIII product to prophylaxis with rVIII-SingleChain., Results: Data were obtained for 120 male patients. The majority of patients were dosing 2 times per week or less frequently (rVIII-SingleChain 65.0%, rFVIIIFc 70.0%, and PEG-rFVIII 72.5%). Annualized bleeding rates were comparable among the 3 cohorts, with median (mean) values of 2.0 (2.6) with rVIII-SingleChain and rFVIIIFc, and 3.0 (3.7) with PEG-rFVIII. The overall median (mean) FVIII consumption in IU per kg per week (IU/kg/week) was 91.9 (91.1) with rVIII-SingleChain, 108.5 (103.6) with rFVIIIFc, and 97.6 (111.0) with PEG-rFVIII, resulting in expected mean annual consumption of 322,140 IU, 361,816 IU, and 373,100 IU, respectively, for a 70 kg patient aged ≥12 years. The mean consumption was significantly different among the 3 products for all patients ( P = 0.0164) and for those dosed 2 times per week ( P < 0.0001). Among patients infusing 2 times per week, median (mean) consumption with rVIII-SingleChain was 83.8 (81.2) IU/kg/week, compared with 109.6 (104.4) IU/kg/week for rFVIIIFc and 92.1 (91.5) IU/kg/week for PEG-rFVIII. Additionally, switching from prophylaxis with prior FVIII products to rVIII-SingleChain increased the proportion of patients dosing ≤ 2 times per week (20% to 65%), decreased mean consumption (103.3 to 91.9 IU/kg/week; P = 0.0164), and maintained the mean annualized bleeding rates (2.9 to 2.6; P = 0.5665)., Conclusions: Results for rVIII-SingleChain confirm the findings from its pivotal trial. Analyses of annualized bleeding rates demonstrate comparable clinical outcomes of rVIII-SingleChain to the other 2 long-acting products assessed. In patients aged ≥ 12 years, rVIII-SingleChain prophylaxis may result in an 11.0% and 13.7% lower mean factor consumption than rFVIIIFc and PEG-rFVIII, respectively, representing a potential cost-saving opportunity of 34% in both cases-at the current wholesale acquisition cost of the corresponding products. In addition, in patients using rVIII-SingleChain prophylactically, consumption was reduced compared with their prior products, while bleeding control was well maintained., Disclosures: This study was funded by CSL Behring. Analyses were conducted by Adivo Associates. Maro is an employee of Adivo Associates. Desai and Yan are employees of CSL Behring. Simpson has received consulting honoraria for participation in advisory boards for CSL Behring, Genentech, Octapharma, and Bioverativ and speakers bureau for Bayer and Novo Nordisk. Data were presented in part at the Hemostasis and Thrombosis Research Society; May 9-11, 2019; New Orleans, LA, and at the International Society on Thrombosis and Haemostasis; July 6-10, 2019; Melbourne, Australia.

Background: People with hemophilia A or B with inhibitors are at high risk of bleeding complications. Infusion of bypassing agents, such as recombinant activated FVII (rFVIIa) and plasma-derived activated prothrombin complex concentrate, are suggested as alternative therapies to factor VIII (haemophilia A) or IX (haemophilia B) for individuals who no longer respond to these treatments because they develop inhibitory antibodies. The ultimate goal of treatment is to preserve the individual's joints, otherwise destroyed by recurrent bleeds., Objectives: To assess the effects of bypassing agent prophylaxis to prevent bleeding in people with hemophilia A or B and inhibitors., Search Methods: We searched for relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries (16 February 2017) and bibliographic references of retrieved studies were reviewed for potential articles to be included in the review.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Coagulopathies Trials Register: 12 December 2016., Selection Criteria: We included randomized and quasi-randomized controlled studies (cross-over or parallel design) evaluating the effect of prophylaxis treatment with bypassing agents compared with on-demand treatment, or studies evaluating the effects of high-dose compared with low-dose prophylaxis in males of any age with hemophilia with inhibitors., Data Collection and Analysis: Two authors independently selected studies and extracted data and assessed the risk of bias according to standard Cochrane criteria. They assessed the quality of the evidence using the GRADE criteria., Main Results: We included four randomized studies (duration 7 to 15 months) involving 116 males. Risk of bias was judged to be high in two studies due to the open-label study design and in one study due to attrition bias.Two studies compared on-demand treatment to prophylaxis with bypassing agents. In one study (34 males) prophylaxis significantly reduced mean overall bleeding rates, MD - 7.27 (95% CI -9.92 to -4.62) (low quality evidence), mean number of overall bleeding events per month, MD -1.10 (95% CI -1.54 to -0.66), mean number of hemarthrosis, MD -6.60 (95% CI -9.32 to -3.88) (low quality evidence) and mean number of joints that had hemarthrosis, MD -0.90 (95% CI -1.36 to -0.44). The meta-analysis did not conclusively demonstrate significant benefit of prophylaxis on health-related quality of life as measured by Haem-A-QoL score, EQ-5D total score and utility score, EQ-5D VAS and SF-36 physical summary and mental summary score (low quality evidence for all health-related quality of life analyses).The remaining two studies compared dose regimens. The results from one study (22 males) did not conclusively demonstrate benefit or harm of high-dose versus low-dose recombinant activated factor VIIa (rFVIIa) as a prophylaxis for overall bleeding rate, MD -0.82 (95% CI -2.27 to 0.63) (moderate quality evidence), target joint bleeding rate, MD -3.20 (95% CI -7.23 to 0.83) (moderate quality evidence) and serious adverse events, RR 9.00 (95% CI, 0.54 to 149.50) (moderate quality evidence).The overall quality of evidence was moderate to low due to imprecision from limited information provided by studies with small sample sizes and incomplete outcome data in one study., Authors' Conclusions: The evidence suggests that prophylaxis with bypassing agents may be effective in reducing bleeding in males with hemophilia with inhibitors. However, there is a lack of evidence for the superiority of one agent over the other or for the optimum dosage regimen. Further studies are needed to evaluate the benefits and harms of prophylaxis treatment on health-related quality of life, as well as the effects of dose of bypassing agents on the outcomes.