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Background: Acquired hemophilia A (AHA) is an autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII. Immunosuppressive therapy (IST) is standard of care to eradicate autoantibody production and protect from further bleeding but carries a risk of severe infection and mortality in frail patients with AHA. Recently, emicizumab has been studied for its potential to reduce the need for early and aggressive IST., Objectives: To compare outcomes of 2 studies that used either IST (GTH-AH 01/2010; N = 101) or prophylaxis with emicizumab (GTH-AHA-EMI; N = 47) early after diagnosis of AHA., Methods: Baseline characteristics were balanced by propensity score matching. Primary endpoint was the rate of clinically relevant new bleeds during the first 12 weeks; secondary endpoints were adverse events and overall survival., Results: The negative binominal model-based bleeding rate was 68% lower with emicizumab as compared with IST (incident rate ratio, 0.325; 95% CI, 0.182-0.581). No difference was apparent in the overall frequency of infections (emicizumab 21%, IST 29%) during the first 12 weeks, but infections were less often fatal in emicizumab-treated patients (0%) compared with IST-treated patients (11%). Thromboembolic events occurred less often with emicizumab (2%) than with IST (7%). Overall survival after 24 weeks was better with emicizumab (90% vs 76%; hazard ratio, 0.44; 95%, CI, 0.24-0.81)., Conclusion: Using emicizumab instead of IST in the early phase after initial diagnosis of AHA reduced bleeding and fatal infections and improved overall survival., Competing Interests: Declaration of competing interests C.H. reports honoraria for lectures or consultancy from Bayer, BMS, SOBI, Daiichi Sankyo, Roche/Chugai, Pfizer, Sanofi, and Takeda. R.K. reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Octapharma, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, BioMarin, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, SOBI, and Takeda. U.J.S. reports institutional grants for research and studies from Octapharma and honoraria for lectures or consultancy from Bayer, SOBI, CSL Behring, and Pfizer. R.G. reports institutional grants for research and studies from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo, and honoraria for lectures or consultancy from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Sanofi. P.K. reports institutional grants for research and studies from Ablynx/Sanofi, Novo Nordisk, Roche, and Takeda, and honoraria for lectures or consultancy from Ablynx/Sanofi, Alexion, Biotest, CSL Behring, Novo Nordisk, Roche, Takeda, and Technoclone. J.O. reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biogen Idec, BioMarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, SOBI, and Takeda. W.M. reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, and Takeda/Shire, and honoraria for lectures or consultancy from Bayer, BioMarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, Takeda/Shire, and uniQure. C.P. reports institutional grants for research and studies from Chugai/Roche, Takeda, Zacros, and LeoPharma, and honoraria for lectures or consultancy from Bayer, BioMarin, Chugai/Roche, CSL Behring, Novo Nordisk, Pfizer, BMS, SOBI, and Takeda. K.T.G. reports honoraria for lectures or consultancy from Takeda, Roche, Grifols, and SOBI. I.P. reports institutional grants for research and studies from Takeda and honoraria for lectures or consultancy from BMS and Novo Nordisk. K.H. reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Chugai, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, SOBI, and Takeda. H.E. reports institutional grants for research and studies from Bayer Vital and CSL Behring and honoraria for lectures or consultancy from Bayer Vital, BioMarin, CSL Behring, Novo Nordisk, Pfizer, Roche, and SOBI. C.W. has nothing to disclose. D.S. has nothing to disclose. S.W. reports institutional grants for research and studies from Biotest and Octapharma, and honoraria for lectures or consultancy from Biotest and Stago. A.T. reports institutional grants for research and studies from Bayer, Biotest, Chugai, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, BioMarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Valoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection., Objectives: To present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial., Methods: GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate, annualized FVIII utilization, FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Safety was assessed by adverse events (AEs)., Results: At week 156, 131 of 134 participants remained in the study; overall, 17 of 134 resumed prophylaxis. Mean annualized bleeding rate for treated bleeds decreased from 4.8 (SD, 6.5) bleeds/y at baseline to 0.8 (SD, 2.3; P < .0001) bleeds/y after prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/y during year 3. Annualized FVIII utilization decreased 96.8% from baseline after prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2 and 3 than between years 1 and 2. At the end of year 3, clinically meaningful improvements in the Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score were observed (mean change from baseline, 6.6; 95% CI, 4.24-8.87; P < .0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment., Conclusion: Hemostatic efficacy was maintained, and safety remained unchanged from previous years., Competing Interests: Declaration of competing interests M.C.O. has participated in advisory boards for Bayer, BioMarin Pharmaceutical Inc, Pfizer, Sanofi, and Takeda and received honoraria from BioMarin Pharmaceutical Inc, Biotest, Novo Nordisk, Pfizer, Roche, Takeda, and Sanofi. P.R. has received grant/travel support from CSL Behring, Sobi, and Takeda and advisory honoraria from Idogen, Pfizer, Sigilon, and Sobi. E.S. has received travel grants from CSL Behring and Novo Nordisk. D.V.Q. has served on advisory boards and speakers bureaus or as a consultant for Bayer, BioMarin Pharmaceutical Inc, Genentech, Novo Nordisk, Octapharma, Sanofi, Takeda, and uniQure. A.D.L. has served as an investigator for BioMarin Pharmaceutical Inc and Pfizer. S.W.P. has served as a consultant for ApcinteX, Bayer, BioMarin Pharmaceutical Inc, CSL Behring, Equilibra Bioscience, GeneVentiv, HEMA Biologics, LFB, Novo Nordisk, Pfizer, Regeneron, Roche, Sanofi, Siemens, Spark, Takeda, and uniQure. G.L. has received honoraria for participating in educational events from Alexion, LEO Pharma, Novartis, Novo Nordisk, Sanofi, Sobi, and Takeda and consulting fees from UCB. G.K. has received grant funding from Genentech and Pfizer and served on advisory boards or as a consultant for Bayer, BioMarin Pharmaceutical Inc, Genentech, Novo Nordisk, Sanofi, Sobi, Spark, and Takeda. M.T.R. has served as an investigator for Bayer and BioMarin Pharmaceutical Inc and served on advisory boards or speakers bureaus for Bayer, CSL Behring, Genentech, HEMA Biologics, Novo Nordisk, Sanofi, and Takeda. M.W. has served as a consultant for Bayer, BioMarin Pharmaceutical Inc, Bioverativ, Catalyst, CSL Behring, Genentech, HEMA Biologics, and Novo Nordisk. A.v.D. has received research funding from Pfizer and Sanofi, is a cofounder and board member of Hematherix Inc, and served as a consultant for ASC Therapeutics, BioMarin Pharmaceutical Inc, CSL Behring, Genentech, Regeneron, Sanofi, Takeda, and uniQure. R.K. has received grants from Bayer, CSL Behring, and LEO Pharma; consulting fees from Bayer, BioMarin Pharmaceutical Inc, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, and Takeda; and payment of honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, BioMarin Pharmaceutical Inc, Biotest, CSL Behring, Daiichi Sankyo, Grifols, LEO Pharma, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, Shire/Takeda, and uniQure. S.S. has received speaking, educational, or travel honoraria from CSL Behring, Pfizer, Roche, Sobi, and Takeda. H.C. has served as a consultant for BioMarin Pharmaceutical Inc, Novo Nordisk, Roche, and Sobi. A.L.D has received research funding from BioMarin Pharmaceutical Inc, Novo Nordisk, Sanofi, and Takeda; served as a consultant for CSL Behring, Roche, and uniQure; and is a board member of the National Hemophilia Foundation and World Federation of Hemophilia USA. J.O. has received research funding from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda and consultancy, speakers bureau, honoraria, scientific advisory board, and travel expenses from Bayer, Biogen Idec, BioMarin Pharmaceutical Inc, Biotest, Chugai, CSL Behring, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda. F.P. has served as a consultant for BioMarin Pharmaceutical Inc, Grifols, Roche, Sanofi, Sobi, and Takeda. C.M.M. has received research funding from CSL Behring, Grifols, and Takeda and has served as a speaker or consultant for CSL Behring, LFB Pharma, Novo Nordisk, Octapharma, Takeda, and Sobi. D.O., H.Y., E.D.-A., and T.M.R. are employees and shareholders of BioMarin Pharmaceutical Inc. J.Mahlangu has received research funding from BioMarin Pharmaceutical Inc, Catalyst, Roche, Novo Nordisk, Pfizer, Sandoz, Sanofi, and Spark Therapeutics. B.M., J. Mason, and S.-C.C. have no conflicts to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction/aim: To evaluate whether patients with haemophilia (PwH) can be enabled to perform ultrasonography (US) of their knees without supervision according to the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) protocol and whether they would be able to recognize pathologies., Methods: Five PwH (mean age 29.6 years, range 20-48 years) were taught the use of a portable US device and the HEAD-US protocol. Subsequently, the patients performed US unsupervised at home three times a week for a total of 6 weeks with a reteaching after 2 weeks. All images were checked for mapping of the landmarks defined in the HEAD-US protocol by a radiologist. In a final test after the completion of the self-sonography period, participants were asked to identify scanning plane and potential pathology from US images of other PwH., Results: On the images of the self-performed scans, 82.7% of the possible anatomic landmarks could be identified and 67.5% of the requested images were unobjectionable, depicting 100% of the required landmarks. There was a highly significant improvement in image quality following reteaching after 2 weeks (74.80 ± 36.88% vs. 88.31 ± 19.87%, p < .001). In the final test, the participants identified the right scanning plane in 85.0% and they correctly identified pathology in 90.0% of images., Conclusion: Appropriately trained PwH can perform the HEAD-US protocol of their knee with high quality and are capable to identify pathologic findings on these standardized images. Asynchronous tele-sonography could enable early therapy adjustment and thereby possibly reduce costs., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Background: Antibodies against factor (F)VIII are a major complication in the treatment of patients with severe hemophilia A. The Nijmegen-Bethesda assay (NBA) is the gold standard for detection of neutralizing antibodies (inhibitors), whereas both inhibitors and nonneutralizing antibodies can be detected by immunoassays such as enzyme-linked immunosorbent assay (ELISA) and multiplex bead-based assays., Objectives: Evaluation of an in-house Luminex bead-based assay (LumiTope) compared with a commercially available ELISA and NBA., Methods: The LumiTope method comprised full-length and B-domain-deleted FVIII as well as 9 purified FVIII single or multidomains. The respective proteins were coupled to magnetic beads to detect domain-specific immunoglobulin (IgG; IgG 1-4 ) anti-FVIII antibodies in a large cohort of patients with hemophilia A with and without inhibitors., Results: Overall, LumiTope assay had a high sensitivity (94.9%) and specificity (91.2%), particularly in patients with low-titer inhibitors compared with ELISA (sensitivity of 72.2% vs 27.7%). IgG 4 was the most abundant IgG subclass in NBA-positive patients. NBA-positive and -negative patients showed different domain profiles. Patients with genetic variants in the heavy chain predominantly exhibited antibodies specific to this chain, while those with a light-chain variant showed a more diverse distribution of antibody specificities. Patients with an intron 22 inversion resembled those with a light-chain defect, with a majority of antibodies targeting the light chain., Conclusion: LumiTope assay provides a sensitive and specific method for not only detection but also domain specification of anti-FVIII-antibodies. Implementation of bead-based assays could improve antibody detection, profiling, and comparability of results and complement NBA., Competing Interests: Declaration of competing interests B.P. reports having received grants for research from Biotest and Octapharma as well as personal fees for lectures and advisory board meetings from Novo Nordisk and Octapharma. A.-C.B. and K.H. report no conflict of interest. T.A. reports having received grants for a patient support association from Bayer, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Roche, Swedish Orphan Biovitrum, and Takeda, as well as personal fees for advisory board meetings, consulting and/or travel support from Bayer, BioMarin, Biotest, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda. J.M. received honoraria from Siemens Healthineers and Octapharma. J.O. reports having received grants for studies and research from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Sobi, and Takeda and travel support as well as personal fees for lectures and advisory board meetings from Bayer, Biogen Idec, BioMarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sparks, Swedish Orphan Biovitrum, and Takeda., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: A prospective, non-interventional study (270-902) followed 294 adults with severe hemophilia A (SHA) receiving prophylactic factor VIII (FVIII). From these participants, 112 rolled over into a single-arm, multicenter, phase 3 trial (GENEr8-1; NCT03370913) that evaluated efficacy and safety of valoctocogene roxaparvovec, a gene therapy that provides endogenous FVIII in individuals with SHA. Participants from 270-902 who did not roll over provide an opportunity for a contemporaneous external control. Therefore, the comparative effectiveness of valoctocogene roxaparvovec vs FVIII prophylaxis was evaluated using propensity scoring (PS)., Methods: This post hoc analysis compared 112 participants from GENEr8-1 (treated cohort) to 73 participants in 270-902 who did not enroll in GENEr8-1 (control cohort). The primary analysis used standardized mortality ratio weighting to re-weight baseline characteristics of the control cohort to better match the treated cohort. Mean annualized bleeding rates (ABR) for treated and all bleeds were compared between cohorts along with the proportion of participants with zero bleeds (treated and all bleeds). Sensitivity and scenario analyses were also conducted., Results: PS adjustments reduced differences in baseline characteristics between cohorts. Mean treated (4.40 vs 0.85; P < 0.001) and all (5.01 vs 1.54; P < 0.001) ABR were significantly lower, and the proportions of participants with zero treated bleeds (82.1% vs 32.9%; P < 0.001) and all bleeds (58.0% vs 28.5%; P < 0.001) were significantly higher in GENEr8-1., Conclusions: PS-adjusted analyses were consistent with prior intra-individual comparisons. Compared with participants receiving prophylactic FVIII, the participants receiving valoctocogene roxaparvovec experienced lower ABR, and a higher proportion had zero bleeds., Trail Registration: ClinicalTrials.gov identifier, NCT03370913., (© 2024. The Author(s).)

Introduction: Consensus over the definition of recombinant factor VIII (rFVIII) product classification in haemophilia A is lacking. rFVIII products are often classified as standard half-life (SHL) or extended half-life (EHL); despite this, no universally accepted definition currently exists. One proposed definition includes half-life, area under the curve, and technology designed to extend half-life; however, the International Society on Thrombosis and Haemostasis defines activity over time as the most intuitive information for building treatment regimens and the World Federation of Hemophilia describes rFVIII product classification in terms of infusion frequency., Aim: To summarise published data on the clinical and pharmacokinetic criteria used to define rFVIII product classification., Methods: PubMed and EMBASE database searches of English-language articles (2002-2022) were conducted using search strings to identify the relevant population, intervention, and outcomes (e.g., clinical and pharmacokinetic parameters). Articles then underwent title/abstract and full-text screens., Results: Among 1147 identified articles, 62 were included. Half-life was the most widely reported outcome with no clear trends or product groupings observed. No clear groupings emerged among other outcomes, including infusion frequency, consumption, and efficacy. As activity over time was reported in few articles, further investigation of its relevance to rFVIII product classification is warranted., Conclusion: The findings of this systematic literature review suggest that parameters other than half-life might be important for the development of a comprehensive and clinically relevant rFVIII product classification definition. There seems to be an opportunity to consider parameters that are clinically meaningful and useful for shared decision-making in haemophilia A treatment., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Abstract: Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30-0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Regular physical activity (PA) is recommended for patients with haemophilia (PwH). For PwH it is crucial to ensure a sufficient factor level to prevent PA-induced bleedings. However, there is a gap in the literature dealing with specific factor levels, which are needed when performing specific types of PA., Aim: To provide data on factor VIII (FVIII) levels at the start of PA performed by PwH., Methods: In this prospective 12-month real-world observational study, 23 PwH recorded every PA they performed and the FVIII levels at the start of the PA using a pharmacokinetic application. PA types were clustered according to the collision and injury risk into three categories (Cat I = low, Cat II = medium, Cat III = high risk). Haemophilia Joint Health Scores (HJHS) were performed at baseline, after 6 and 12 months., Results: 795 PA sessions of Cat I, 193 of Cat II, and 23 of Cat III were documented. FVIII levels at the start of PA were different between categories (Cat I: 29.8 ± 32.1%, Cat II: 38.3 ± 33.4%, Cat III: 86.6 ± 29.2%). Out of all PA sessions, 145 (14%) were performed at a factor level of ≤3%. Three PA-induced bleeding occurred. Baseline HJHS was 14.5 ± 13.6 points and did not change throughout the study., Conclusion: This study provides real-life data on FVIII levels at the start of 1011 PA sessions. PwH are mainly active in low-risk sports with higher FVIII levels observed in Cat II and III, respectively. Only three PA-induced bleeding occurred, even though several PA were started with low FVIII levels., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Objectives: To assess effectiveness and safety of damoctocog alfa pegol in interim analyses of the ongoing real-world hemophilia A HEM-POWR study., Methods: HEM-POWR (NCT03932201) is a multinational Phase 4 prospective observational study. The primary objective was annualized bleeding rate (ABR) in previously treated patients (PTPs) with hemophilia A. Secondary objectives included adverse events and number of affected joints., Results: At data cut-off (August 17, 2022), the safety analysis set included 268 patients and the full analysis set (FAS) included 161 patients. The most common dosing regimen during observation period was prophylaxis (FAS = 158/161, 98.1%) every 3-4 days (twice weekly; FAS = 78/158, 49.4%) and a median (min, max) infusion dose of 37.5 (10, 72) IU/kg. PTPs receiving prophylactic damoctocog alfa pegol have fewer infusions compared with prior treatment. Median total ABR (Q1, Q3) was 0.0 (0.0, 1.8) and mean total ABR (SD) was 2.4 (8.2). The proportion of patients with no affected joints increased between initial visit and follow-up. No FVIII inhibitors, treatment-related adverse events, or deaths were reported., Conclusions: Damoctocog alfa pegol shows effectiveness and acceptable safety, as well as consistent utilization, in real-world PTPs with hemophilia A, including in patients with non-severe hemophilia and those with a history of inhibitors. Please see video for a summary of this study., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Abstract: Prevention of bleeding and its consequences is the main goal of hemophilia treatment and determines treatment choices for patients who develop inhibitors. To assess bleeding before and during immune tolerance induction (ITI) and its association with ITI regimen and inhibitor titer, we selected and analyzed data on patients receiving high-titer inhibitors from the international prospective PedNet cohort study. In total, 222 patients with severe hemophilia A and inhibitor titers of >5 Bethesda units (BU) were followed from the first positive to the first negative inhibitor result (median overall follow-up, 1.7 years). Mean annual (joint) bleeding rates (AJBR) and 95% confidence intervals (CIs) were compared according to treatment and inhibitor titer using multivariable negative binomial regression. Before ITI, 115 patients showed an ABR of 6.1 (5.0-7.4) and an AJBR 2.6 (2.1-3.2). Bleeding was independent of inhibitor titer. During ITI, 202 patients had an ABR of 4.4 (3.9-5.1) and an AJBR of 1.7 (1.5-2.0). AJBR during ITI increased with inhibitor titer (hazard ratio [HR] for ≥200 BU vs 5 to 39 BU [4.9; CI, 3.2-7.4]) and decreased with daily ITI infusions (HR, 0.4; CI, 0.3-0.6) or activated prothrombin complex concentrate prophylaxis (HR, 0.4; CI, 0.2-0.8), whereas ITI dose and recombinant activated factor VII prophylaxis did not independently affect bleeding. These data provide evidence for a protective effect of repeated FVIII infusions (ITI) on bleeding in patients who have developed inhibitors; these data should be used to plan ITI and/or serve as a comparator for prophylaxis with nonreplacement therapy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Patients with hemophilia A treated with coagulation Factor VIII (FVIII) products are at risk for developing anti-FVIII antibodies. The ABIRISK Consortium aimed to provide knowledge on the formation and detection of anti-drug antibodies against biopharmaceutical products, including FVIII. Accordingly, standardized and validated assays for the detection of binding (total) and neutralizing antibodies are needed., Aim: Two-center validation of an ELISA for the detection of total FVIII-binding IgG-antibodies and Nijmegen-Bethesda assays for the quantification of FVIII-neutralizing antibodies according to consensus validation guidelines., Methods: Validation of assays at both sites was done according to published recommendations and included preanalytics, the determination of key assay parameters, including cut-points, assay sensitivity, precision, and FVIII interference., Results: The validated assays reproducibly detected FVIII-binding and -neutralizing antibodies with comparable performance in both laboratories. Floating screening cut-points were established for both assays. Determined mass-based sensitivity of both assays (all values ≤66 ng/mL) complied with the minimum sensitivity for the detection of anti-drug antibodies as recommended by the FDA (<100 ng/mL). Intra- and inter-assay coefficients of variation did not exceed 25%. Assay validation further revealed that pre-analytical heat treatment led to potentially false-positive ELISA results, while up to 0.15 IU/mL, residual FVIII showed no significant impact. Overall, good agreement of results was found for patient samples analyzed at both study sites., Conclusion: Comprehensive validation of different anti-FVIII-antibody assays in two laboratories gave novel insights into the impact of pre-analytical sample treatment as well as the comparability of test results generated by the use of methodically different assays., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Accurate measurement of emicizumab in the presence of factor (F) VIII is required in patients with severe hemophilia A treated with emicizumab, as well as additional need for FVIII substitution or emicizumab prophylaxis in patients with acquired or moderate to mild hemophilia A. However, the presence of FVIII potentially biases the results., Objectives: To assess the impact of plasma FVIII activity on determined emicizumab levels and evaluate different strategies for correction for or preanalytical inhibition of FVIII., Methods: Evaluated strategies comprised of the following: (1) calculation of actual emicizumab plasma levels based on measured FVIII activities and FVIII-affected emicizumab values, (2) preanalytical heat treatment (56 °C for 40 minutes), and (3) neutralization of FVIII activity using FVIII inhibitors. Emicizumab levels and FVIII activities were measured using a modified FVIII one-stage clotting assay and a chromogenic FVIII assay based on bovine factors, respectively., Results: Spiking experiments revealed a consistent linear association between FVIII activities and determined (FVIII-affected) emicizumab results at different emicizumab input levels (∼0.12 μg/mL per IU/dL of FVIII). This principally allowed for mathematical correction of measured emicizumab levels in the presence of FVIII. While a 40% to 50% activity loss of intrinsic plasma emicizumab through heat treatment was observed in patient samples, emicizumab spiked into FVIII-deficient plasma was not or only marginally affected. Application of inhibitor-based FVIII neutralization led to good agreement of results when compared with direct quantification of emicizumab by liquid chromatography-tandem mass spectrometry., Conclusion: Inhibitor-based FVIII neutralization appears to be a feasible strategy for accurate measurement of plasma emicizumab levels in the presence of FVIII activity., Competing Interests: Declaration of competing interests J.M. has received honoraria from Octapharma and Siemens Healthineers. J.O. has received research funding from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda; consultancy, speakers bureau, honoraria, scientific advisory board, and travel expenses from Bayer, Biogen Idec, BioMarin, Biotest, Chugai Pharmaceutical Co, Ltd, CSL Behring, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda. N.S.H., A.D., M.v.L., S.G., H.R., C.K., T.A., M.A., and B.P. report no conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Acquired haemophilia A is caused by neutralising autoantibodies against coagulation factor VIII, leading to severe bleeding. Standard treatment involves immunosuppressive therapy, which is associated with adverse events and mortality in the frail population of patients with acquired haemophilia A. This study investigated whether emicizumab, a factor VIIIa mimetic antibody, protects patients with acquired haemophilia A from bleeding and allows deferral of immunosuppression during the first 12 weeks after diagnosis., Methods: We report final results of an open-label, single-arm, phase 2 clinical trial. Adult patients with acquired haemophilia A from 16 haemophilia treatment centres in Germany and Austria were eligible if they had not previously received immunosuppression. Patients received emicizumab subcutaneously (6 and 3 mg/kg on days 1 and 2, 1·5 mg/kg weekly until week 12), but no immunosuppression. Follow-up was until week 24. The primary endpoint was the number of clinically relevant bleeds per patient-week until week 12. Emicizumab was considered effective if the mean bleeding rate was significantly below 0·15 bleeds per patient-week, the rate observed in a previous study of patients with acquired haemophilia A treated with bypassing agents and immunosuppression but no emicizumab. The study is registered with clinicaltrials.gov, NCT04188639 and is complete., Findings: Of 49 patients screened from March 25, 2021, to June 10, 2022, 47 were enrolled (23 women, 24 men). Median age was 76 years (IQR 66-80), 46 (98%) of 47 patients were White, median factor VIII activity was 1·4 IU/dL (0·3-5·6), and median inhibitor concentration was 11·4 Bethesda units per mL (3·9-42·7). Mean breakthrough bleeding rate was 0·04 bleeds per patient-week (upper 97·5% CI 0·06). 33 (70%) of 47 patients had no bleeding events, seven patients (15%) had one bleed, six patients (13%) had two bleeds, and one patient (2%) had three bleeds. Adverse events of grade 3 or worse included COVID-19 (n=2), acute kidney injury (n=2), and stroke (n=1). Four of 47 patients died, including two deaths related to bleeding, one from COVID-19, and one from cardiac arrest (none were judged as related to emicizumab)., Interpretation: This study suggests that emicizumab prophylaxis prevents bleeding in patients with acquired haemophilia A and that immunosuppressive therapy can be deferred while patients are receiving this treatment. The low number of thromboembolic events, severe infections, and fatalities observed in this study are promising., Funding: This study was supported by funding from Hoffman-La Roche., Competing Interests: Declaration of interests AT reports institutional grants for research and studies from Bayer, Biotest, Chugai, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biomarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda. CH reports honoraria for lectures or consultancy from Bayer, SOBI, Roche, Pfizer, and Takeda. PK reports institutional grants for research and studies from Ablynx–Sanofi, Novo Nordisk, Roche, and Takeda, and honoraria for lectures or consultancy from Ablynx–Sanofi, Alexion, Biotest, CSL Behring, Novo Nordisk, Roche, Takeda, and Technoclone. RG reports institutional grants for research and studies from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo, and honoraria for lectures or consultancy from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Sanofi. JO reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biogen Idec, Biomarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, SOBI, and Takeda. UJS reports institutional grants for research and studies from Octapharma, and honoraria for lectures or consultancy from Bayer, SOBI, CSL Behring, and Pfizer. WM reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, and Takeda–Shire, and honoraria for lectures or consultancy from Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, Takeda–Shire, and uniQure. CP reports institutional grants for research and studies from Chugai–Roche, Takeda, Zacros, and LeoPharma, and honoraria for lectures or consultancy from Bayer, Biomarin, Chugai–Roche, CSL Behring, Novo Nordisk, Pfizer, BMS, SOBI, and Takeda. KT-G reports honoraria for lectures or consultancy from Grifols, SOBI, Takeda, and Roche. KH reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Chugai, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, SOBI, and Takeda. JP reports institutional grants for research and studies from Bayer, CSL Behring, and Pfizer, and honoraria for lectures or consultancy from Takeda, Bayer, and CSL Behring. PM reports institutional grants for research and studies from Baxter Innovations, Bayer, LFB, SOBI, Octapharma, Pfizer, and Roche, and honoraria for lectures or consultancy from Alexion, AstraZeneca, Biotest, CSL Behring, Shire, Octapharma, Pfizer, Roche, and Takeda. CD reports honoraria for lectures or consultancy from Novo Nordisk, Roche, and Takeda. SW reports institutional grants for research and studies from Biotest and Octapharma, and honoraria for lectures or consultancy from Biotest and Stago. RK reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Octapharma, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Biomarin, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche–Chugai, Sanofi, SOBI, and Takeda. CS, CW, DS, MM, and FJP have nothing to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Turoctocog alfa pegol (N8-GP) is a glycoPEGylated, extended half-life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019, > 800 patients have been treated worldwide., Aim: To present data from identified post-marketing cases of less-than-expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8-GP., Methods: The post-marketing safety database was searched using keywords such as 'coagulation FVIII level decreased'. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded., Results: Here we report 14 cases of less-than-expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post-dose) to 51% (2 days post-dose). Seven patients experienced bleeding episodes after switching to N8-GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti-PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product., Conclusion: In conclusion, the 14 reported cases of less-than-expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti-PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8-GP continues., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors., Aim: To report the efficacy and safety results from the NuProtect study., Methods: PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study., Results: Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events., Conclusion: Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Gene therapy has recently become a realistic treatment perspective for patients with hemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of hemophilia A and B gene therapy with vectors derived from adeno-associated virus, including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centers according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as a primary source of data for pharmacovigilance, postmarketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Introduction:  Patients with hemophilia (PWHs) suffer from an increased risk of osteoporosis. Multiple hemophilia and hemophilic arthropathy associated factors correlate with a low bone mineral density (BMD) in PWHs. The aim of this study was to assess the long-term development of BMD in PWH as well as to analyze potentially influencing factors., Methods:  A total of 33 adult PWHs were evaluated in a retrospective study. General medical history, specific-hemophilia-associated comorbidities, joint status using the Gilbert score, calcium level, and vitamin D level as well as at least two results of bone density measurements with a minimum range of 10 years per patient were taken into account., Results:  The BMD did not change significantly from one point of measurement to the other. A total of 7 (21.2%) cases of osteoporosis and 16 (48.5%) cases of osteopenia were identified. The two following significant correlations could be revealed: the higher the patients' body mass index, the higher their BMD ( r  = 0.41; p  = 0.022). Moreover, a high Gilbert score came along with a low BMD ( r  = -0.546; p  = 0.003)., Conclusion:  Even if PWHs frequently suffer from a reduced BMD, our data suggest that their BMD remains constant on a low level in the course of time. A risk factor of osteoporosis often found in PWHs is a vitamin D deficiency and joint destruction. Therefore, a standardized screening of PWHs on BMD reduction by collecting vitamin D blood level and assessing joint status seems appropriate., Competing Interests: The authors state that they have no interests which might be perceived as posing a conflict of bias., (Thieme. All rights reserved.)

Background: The standard therapy for patients with hemophilia A (HA) is the replacement with factor VIII (FVIII) therapeutics. To overcome the limitation of short half-life of wild-type FVIII protein, polyethylene glycol (PEG) can be coupled to therapeutic FVIII to improve pharmacokinetics., Objectives: We aimed to characterize antibodies developed against a FVIII therapeutic PEGylated with a 40-kDa PEG (40PEG-BDD FVIII ) in 2 patients with mild HA., Methods: An inhouse bead-based immunoassay was developed to characterize and confirm the specificity of the detected antibodies. The neutralizing nature of the antibodies toward PEGylated therapeutics was determined by a modified Nijmegen-Bethesda assay., Results: Two out of 46 patients treated with 40PEG-BDD FVIII developed inhibitory antibodies toward the drug. Switching to a non-PEGylated FVIII successfully increased the FVIII activity in both patients. In patient 1, antibodies were raised against FVIII and PEG. Anti-FVIII antibodies were of the immunoglobulin (Ig)G isotype, whereas anti-PEG antibodies were of IgG, IgM, and IgA isotypes. In patient 2, antibodies of IgG and IgA isotypes were directed only against the PEG moiety. Competitive assays confirmed the specificity of the antibodies against PEG. The applied Nijmegen-Bethesda assay revealed that patients' anti-PEG antibodies and AGP3, an antibody against the backbone of PEG, can inhibit all currently available PEGylated therapeutics but to different degrees. No inhibitory FVIII antibodies were detected., Conclusion: Antibodies against the PEG moiety of 40PEG-BDD FVIII abolished the efficacy of the drug. This is the first report on real-world experiences with the development of neutralizing anti-PEG antibodies after treatment with PEGylated FVIII therapeutics in mild HA., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Clinical trial data are scarce for the use of prophylaxis in people with non-severe haemophilia A. The HAVEN 6 study aims to assess safety and efficacy of emicizumab prophylaxis in people with non-severe haemophilia A without factor VIII (FVIII) inhibitors., Methods: HAVEN 6 is a multicentre, open-label, single-arm, phase 3 study taking place in 22 specialty clinics and hospitals in Europe, North America, and South Africa. Eligible participants were people of all ages weighing at least 3 kg with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII >5%-<40%) haemophilia A without FVIII inhibitors requiring prophylaxis as assessed by the treating physician. Participants received subcutaneous emicizumab 3 mg/kg of bodyweight once weekly for 4 weeks, followed by the participant's choice of maintenance dose: 1·5 mg/kg once weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. Safety was the primary objective of the study. Safety endpoints included adverse events, serious adverse events, and adverse events of special interest including thromboembolic events and thrombotic microangiopathies. The primary efficacy endpoint was the annualised bleed rate for treated bleeds. Analyses were done for participants who received at least one dose of emicizumab. This study is registered with ClinicalTrials.gov, number NCT04158648, and is active but not recruiting., Findings: Between Feb 10, 2020, and Aug 31, 2021, we assigned 73 people to treatment. 72 participants received at least one dose of emicizumab (51 moderate [71%]; 21 mild [29%]; 69 male [96%]; three female [4%]; and 61 White [85%]). Median age was 23·5 years (IQR 12·0-36·0); median follow-up was 55·6 weeks (IQR 52·3-61·6) weeks. At baseline, 24 participants (33%) had target joints and 37 (51%) were receiving FVIII prophylaxis. 60 participants (83%) had at least one adverse event; the most common adverse events were headache (in 12 participants [17%]), injection-site reaction (12 [17%]), and arthralgia (11 [15%]). 15 (21%) had at least one emicizumab-related adverse event; no adverse events led to treatment withdrawal, modification, or interruption. Eight participants (11%) reported ten serious adverse events in total, none emicizumab-related. There were no deaths or thrombotic microangiopathies. One participant had grade 1 thrombosed haemorrhoids (classified as a thromboembolic event), unrelated to emicizumab. The annualised bleed rate was 0·9 (95% CI 0·55-1·52) for treated bleeds. 48 participants (67%) had no treated bleeds. All-bleed annualised bleed rates were 10·1 (95% CI 6·93-14·76) from 24 weeks pre-study and 2·3 (1·67-3·12) on-study after a median follow-up of 55·6 weeks., Interpretation: These data show efficacy and a favourable safety profile of emicizumab in people with non-severe haemophilia A without FVIII inhibitors who warrant prophylaxis, confirming emicizumab as a valuable treatment option in this population., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests CN has served as a consultant to BioMarin, Novo Nordisk, F Hoffmann-La Roche/Genentech, Sanofi, Sobi, and Shire/Takeda; received research funding from Novo Nordisk, F Hoffmann-La Roche/Genentech, and Sobi; received honoraria from Bayer, Novo Nordisk, F Hoffmann-La Roche /Genentech, Sanofi, Sobi, Spark Therapeutics, and Shire/Takeda; and has been a member of a board of directors or advisory committee for Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer, F Hoffmann-La Roche/Genentech, Sanofi, Sobi, Spark Therapeutics, Shire/Takeda, and UniQure. JM is an employee of University of the Witwatersrand; has received grant or research support from BioMarin, Baxalta, Catalyst Biosciences, CSL, Novartis, Novo Nordisk, Pfizer, F Hoffmann-La Roche, Sanofi, Spark Therapeutics, and UniQure; consultant fees from BioMarin, Baxalta, CSL Behring, Catalyst Biosciences, Novo Nordisk, F Hoffmann-La Roche, Spark Therapeutics; and speaker bureau fees from Novo Nordisk, Pfizer, F Hoffmann-La Roche, Sanofi, Takeda, WFH, ISTH, and Springer. ML is an employee and holds stock in F Hoffmann-La Roche. PC has received research funding from Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer, Sobi, and Takeda; honoraria from ApcinteX, Bayer, Boehringer Ingelheim, CSL Behring, Chugai Pharmaceutical, Freeline, Novo Nordisk, Pfizer, F Hoffmann-La Roche, Sanofi, Spark Therapeutics, Sobi, and Takeda. OC is an employee of F Hoffmann-La Roche. RJB is an employee of Genentech, and stockholder in F Hoffmann-La Roche/Genentech. VJ-Y has received grant or research support from Grifols, Novo Nordisk, F Hoffmann-La Roche, Takeda, Bayer, CSL Behring, Pfizer, Sanofi, Sobi, and Octapharma; consultancy fees from Grifols, Novo Nordisk, F Hoffmann-La Roche, Takeda, Bayer, CSL Behring, Pfizer, BioMarin, Sanofi, Sobi, Spark Therapeutics, and Octapharma; honoraria from Grifols, Novo Nordisk, F Hoffmann-La Roche, Takeda, Bayer, CSL Behring, Pfizer, Sanofi, Sobi, Spark Therapeutics, and Octapharma. BMB is an employee and stockholder in F Hoffmann-La Roche. CS is an employee and stockholder in F Hoffmann-La Roche, and is co-inventor of a patent related to an anti-factor IXa/factor X bispecific antibody. GV is employee and stockholder in F Hoffmann-La Roche. JW is an employee at Institute of Hematology and Transfusion Medicine; received research funding from Baxalta, Novo Nordisk, Rigel Pharmaceuticals, F Hoffmann-La Roche, Shire, and Takeda; and received honoraria from Alfasigma, Bayer AG, Baxalta, CSL Behring, Novo Nordisk, Octapharma, Pfizer, F Hoffmann-La Roche, Sanofi-Aventis, Shire, Sobi, Swixx BioPharma, Takeda, and Werfen. Rd'O has received research funding from Takeda, CSL Behring, LFB, Novo Nordisk, Octapharma, F Hoffmann-La Roche, BioMarin, Sobi, and Sanofi; and honoraria from Takeda, CSL Behring, LFB, Novo Nordisk, Octapharma, F Hoffmann-La Roche, BioMarin, Sobi, Sanofi, and UniQure. PM is a member of a board of directors or advisory committee for F Hoffmann-La Roche Canada and Bayer. SK is an employee of Genentech. VT is an employee of F Hoffmann-La Roche. ADS is an employee of Indiana Hemophilia and Thrombosis Center,; received consultancy fees from Sangomo Biosciences, Prometic Life Sciences, and Sigilon; research funding from Bioverativ, Sanofi, Genentech, Kedrion Biopharma, Novo Nordisk, Pfizer, Sigilon, Takeda, ProMetic Life Sciences, and Freeline; and honoraria from Genentech, Sigilon, Novo Nordisk, Pfizer, and Catalyst Biosciences; speaker's bureau fees from Genentech and Novo Nordisk; and is a member of a board of directors or advisory committee for Hemophilia Foundation, Genentech, Sigilon, Novo Nordisk, and Sanofi. JO has received research funding from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda; and consultancy, speaker's bureau, honoraria, scientific advisory board, and travel expenses from Bayer, Biogen Idec, BioMarin, Biotest, Chugai Pharmaceutical, CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F Hoffmann-La Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda. CH has received research funding from Bayer, Shire/Takeda, Pfizer, Novo Nordisk, CSL Behring, and Sobi; honoraria and speaker's bureau fees from Bayer, Shire/Takeda, Pfizer, Novo Nordisk, CSL Behring, Octapharma, Sobi, LFB, CAF-DCF, F Hoffmann-La Roche, UniQure, and BioMarin., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously., Methods: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×10 13 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII., Results: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred., Conclusions: The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.)., (Copyright © 2023 Massachusetts Medical Society.)

Objective: Prophylaxis treatment is the current standard of care for patients with severe hemophilia. Factor concentrates with improved pharmacokinetics have offered more options for individualizing treatment. The treatment focus may be on increased protection, aiming for higher trough factor levels or longer dosing intervals to reduce the burden of hemophilia. Both aspects can have long-term effects on joint health. Products, such as rVIII‑SingleChain and rIX-FP have been developed to reduce the treatment burden for patients with hemophilia and optimize prophylactic efficacy. The objective of this report is to provide a summary of the clinical experience of different Hemophilia Treatment Centers in managing the switch to rVIII-SingleChain or rIX-FP in patients with hemophilia., Methods: This report summarizes a selection of patient cases presented at the 3rd Alliance for Coagulation Academy Meeting in October 2020. The cases from the participating centers provide examples of the clinical experience in managing patients' switch to rVIII-SingleChain and rIX‑FP, including which types of patients are suitable for switching, and practical steps in managing a switch., Results: It is important to take into consideration the physical and social fulfillment of the patient when deciding to switch to rVIII-SingleChain or rIX-FP. The physician plays an important role in the motivation of patients as they understand not only the patient's needs but the potential benefits of the new treatment., Conclusion: The selected patient cases reported here demonstrate that patients may wish to switch factor products for a variety of reasons; therefore, it is critical to understand why patients switch and what they expect from switching.

Background: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear., Methods: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health., Results: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected., Conclusions: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.)., (Copyright © 2023 Massachusetts Medical Society.)

Introduction: Emicizumab promotes effective haemostasis in people with haemophilia A (PwHA). It is indicated for routine prophylaxis of bleeding episodes in PwHA with or without factor (F)VIII inhibitors., Aim: To investigate the effect of emicizumab dose up-titration in PwHA with suboptimal bleeding control., Methods: Data from seven completed or ongoing phase III studies were pooled. Pharmacokinetics, pharmacodynamics and bleeding events were evaluated before and after dose up-titration. Adverse events (AEs) were compared between PwHA with and without dose up-titration., Results: Of 675 PwHA evaluable for the analysis, 24 (3.6%) had their maintenance dose up-titrated to 3 mg/kg once weekly (QW). Two participants had neutralising antibodies (nAbs) associated with decreased emicizumab exposure, and dose increase did not compensate for the effect of nAbs. In the other 22 participants, mean emicizumab steady-state trough concentrations increased from 44.0 to 86.2 μg/mL after up-titration. The median (interquartile range [IQR]) efficacy period prior to up-titration was 24.6 (24.0-32.0) weeks. The model-based annualised bleed rate for 'treated bleeds' and 'all bleeds' decreased by 70.2% and 72.9%, respectively, after a median (IQR) follow-up of 97.1 (48.4-123.3) weeks in the up-titration period. Incidences of injection-site reactions and serious AEs were higher in PwHA with up-titration; however, this was already observed in these participants before the dose up-titration. Overall, the safety profile appeared similar between PwHA with and without up-titration., Conclusion: The dose up-titration to 3 mg/kg QW was well tolerated. Bleed control improved in most participants whose bleeding tendency was inadequately controlled during clinical trials., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: AAV (adeno-associated virus)-based gene therapy is a new treatment for hemophilia and has recently received approval for the treatment of severe hemophilia A. It does not suffer from the limitations of the current standard treatment (regular prophylactic intravenous injections of the missing clotting factor; subcutaneous injection of a bispecific antibody in hemophilia A) and can, it is hoped, raise the concentration of the missing clotting factor over the long term. AAV-based gene therapy can only be performed once, however, because of the generation of antibodies to AAV., Methods: This review is based on publications retrieved by a selective search in the MEDLINE/PubMed database employing the relevant key words, supplemented by expert opinions and the recommendations of the relevant medical societies., Results: Data from non-randomized phase 1 to phase 3 trials reveal an adequate expression of factors VIII and IX in patients with mostly severe hemophilia A or B. Even though they were no longer receiving prophylactic treatment, most patients experienced a considerable reduction, by 53% to 96%, in the number of bleedings compared to previous therapy. Persistently elevated factor levels have been described for up to six years in hemophilia A and up to eight years in hemophilia B. The most common side effect of gene therapy is an inflammatory response with elevated alanine aminotransferase levels (17% to 89%, depending on the study), which may be associated with a reduced clotting factor level and requires treatment with transient immunosuppression., Conclusion: Gene therapy for hemophilia holds out the prospect of freedom from hemorrhage without the need for regular treatment with drugs. The various steps that need to be carried out in gene therapy should be coordinated in a graded and partly overlapping integrated care model (a so-called hub-and-spoke model). Electronic platforms should be used for data acquisition and transmission.

Many people with hemophilia A (PwHA) undergo surgery in their lifetime, often because of complications of their disease. Emicizumab is the first bispecific monoclonal antibody prophylactic therapy for PwHA, and its efficacy and safety have been previously demonstrated; however, there is a need to build an evidence base on the management of PwHA on emicizumab undergoing surgery. Data from the HAVEN 1-4 phase 3 clinical trials were pooled to provide a summary of all minor and major surgeries in PwHA with or without factor VIII (FVIII) inhibitors who were receiving emicizumab prophylaxis. Overall, 233 surgeries were carried out during the HAVEN 1-4 trials: 215 minor surgeries (including minor dental and joint procedures, central venous access device placement or removal, and endoscopies) in 115 PwHA (64 with FVIII inhibitors) and 18 major surgeries (including arthroplasty and synovectomy) in 18 PwHA (10 with FVIII inhibitors). Perioperative hemostatic support was at the discretion of the treating physician. Overall, the median (interquartile range [IQR]) age was 33.5 (13.0-49.0) years and the median (IQR) emicizumab exposure time before surgery was 278.0 (177.0-431.0) days. Among the 215 minor surgeries, 141 (65.6%) were managed without additional prophylactic factor concentrate, and of those, 121 (85.8%) were not associated with a postoperative bleed. The majority (15 of 18 [83.3%]) of major surgeries were managed with additional prophylactic factor concentrate. Twelve (80.0%) of these 15 surgeries were associated with no intraoperative or postoperative bleeds. The data demonstrate that minor and major surgeries can be performed safely in PwHA receiving emicizumab prophylaxis. These trials are registered at www.clinicaltrials.gov as #NCT02622321, #NCT02795767, #NCT02847637, and #NCT03020160., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Hemophilia A and hemophilia B are rare congenital, recessive X-linked disorders caused by lack or deficiency of clotting factor VIII (FVIII) or IX (FIX), respectively. The severity of the disease depends on the reduction of coagulation FVIII or FIX activity levels, which is determined by the type of the pathogenic variants in the genes encoding the two factors ( F8 and F9 , respectively). Molecular genetic analysis is widely applied in inherited bleeding disorders. The outcome of genetic analysis allows genetic counseling of affected families and helps find a link between the genotype and the phenotype. Genetic analysis in hemophilia has tremendously improved in the last decades. Many new techniques and modifications as well as analysis softwares became available, which made the genetic analysis and interpretation of the data faster and more accurate. Advances in genetic variant detection strategies facilitate identification of the causal variants in up to 97% of patients. In this review, we discuss the milestones in genetic analysis of hemophilia and highlight the importance of identification of the causative genetic variants for genetic counseling and particularly for the interpretation of the clinical presentation of hemophilia patients., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

A major complication of hemophilia A therapy is the development of alloantibodies (inhibitors) that neutralize intravenously administered coagulation factor VIII (FVIII). Immune tolerance induction therapy (ITI) by repetitive FVIII injection can eradicate inhibitors, and thereby reduce morbidity and treatment costs. However, ITI success is difficult to predict and the underlying immunological mechanisms are unknown. Here, we demonstrated that immune tolerance against FVIII under nonhemophilic conditions was maintained by programmed death (PD) ligand 1-expressing (PD-L1-expressing) regulatory T cells (Tregs) that ligated PD-1 on FVIII-specific B cells, causing them to undergo apoptosis. FVIII-deficient mice injected with FVIII lacked such Tregs and developed inhibitors. Using an ITI mouse model, we found that repetitive FVIII injection induced FVIII-specific PD-L1+ Tregs and reengaged removal of inhibitor-forming B cells. We also demonstrated the existence of FVIII-specific Tregs in humans and showed that such Tregs upregulated PD-L1 in patients with hemophilia after successful ITI. Simultaneously, FVIII-specific B cells upregulated PD-1 and became killable by Tregs. In summary, we showed that PD-1-mediated B cell tolerance against FVIII operated in healthy individuals and in patients with hemophilia A without inhibitors, and that ITI reengaged this mechanism. These findings may impact monitoring of ITI success and treatment of patients with hemophilia A.

Background: Guidelines recommend that patients with haemophilia should preferably receive vaccination subcutaneously. COVID-19 and other vaccines, however, are only licenced for intramuscular application., Aims: To assess the safety of intramuscular COVID-19 vaccination in patients living with haemophilia., Methods: Part A of this prospective observational study enrolled consecutive patients with haemophilia A (HA) and B (HB) of all ages and severities and assessed injection site bleeding and other complications within 30 days of vaccination. Part B enrolled patients providing informed consent for detailed data collection including medication and prophylaxis around the time of vaccination. Logistic regression was performed to assess potential risk factors for bleeding., Results: Four hundred and sixty-one patients were enrolled into part A. The primary endpoint injection site bleeding occurred in seven patients (1.5%, 95% confidence interval .7-3.1%). Comprehensive analysis of 214 patients (404 vaccinations, part B) revealed that 97% of patients with severe haemophilia had prophylaxis before vaccination, either as part of their routine prophylaxis or using additional doses. 56% and 30% of patients with moderate and mild haemophilia, respectively, received prophylaxis before vaccination. Among the seven bleeds recorded, three occurred when intramuscular vaccination was done without prophylaxis (odds ratio 12)., Conclusions: This is the first prospective study reporting on the safety of intramuscular vaccination in haemophilia. The rate of injection site bleeding was low in mild haemophilia, and in moderate and severe haemophilia if patients received factor prophylaxis., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Emicizumab mimics the hemostatic activity of activated factor VIII (FVIIIa) within the tenase complex. Despite functional similarities between FVIIIa and emicizumab, conventional laboratory methods designed for monitoring of FVIII activity are inappropriate for the measurement of emicizumab. At present, a modified one stage (FVIII) assay (mOSA) is mainly used for emicizumab monitoring. Two-stage chromogenic FVIII assays based on human factors can be used, although limited performance due to lack of corresponding optimization might be observed. Furthermore, the presence of FVIII or anticoagulants in the patient sample may falsify assay results. To address these issues, we optimized and evaluated a two-stage chromogenic assay (emi-tenase) for measurement of emicizumab in plasma samples. Heat inactivation of samples was established to abolish the influence of endogenous or substituted FVIII. The lower limit of quantification (LLoQ) was found to be 2 μg/ml in a manual assay format and 9.5 μg/ml on an automated coagulation analyzer. Intra- and inter-assay coefficients of variation (CV) did not exceed 20%. Analysis of 17 patient plasma samples with severe haemophilia A under emicizumab treatment showed good correlation of results between the emi-tenase assay and the mOSA (Cohens Kappa coefficient = 0.9). Taken together, the emi-tenase assay allows specific measurement of emicizumab plasma levels over a broad concentration range (10 μg/ml to 100 μg/ml). The assay can be applied on an automated coagulation analyzer, demonstrating its applicability within a routine laboratory setting., Competing Interests: The authors have declared that no competing interest exist.

Background: In patients with haemophilia (PwH), most frequently affected joints are the ankle, knee and elbow. Due to improved factor therapy in the last decades, these previous findings have to be verified in Germany., Aim: The aim of this study is to detect the most affected joint, evaluate the significance of the source of pain and determine the point prevalence of back pain in Germany today., Patients and Methods: In a retrospective study, data of n = 300 patients with severe moderate and mild haemophilia were evaluated regarding the most affected joint, the most common source of pain, and the point prevalence of back pain. An anamnesis questionnaire and the German Pain Questionnaire were used for this assessment., Results: The most affected joint in German PwH is still the ankle (41%), followed by the knee (27%) and the elbow (11%). The most common source of pain is also the ankle joint (32%). Back pain was also identified as one of the most common sources of pain, which is comparable to the elbow (elbow:15%; back:13%). The point prevalence in PwH for back pain was significantly higher compared to the general German population (P = .031)., Conclusion: Our data showed that the ankle is still the most affected joint and the most common source of pain in Germany. These results also showed the relevance of back pain as a pain source. The evaluations also demonstrated the high point prevalence of back pain in PwH. Future therapies should also focus on the spine because joint changes affect posture., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Despite current therapies, there remains an unmet need for treatment for patients with hemophilia. The main parts of two phase 2 trials established clinical proof-of-concept for once-daily, subcutaneous concizumab prophylaxis in patients with hemophilia A/B with inhibitors (HAwI/HBwI; explorer4) and severe hemophilia A without inhibitors (HA; explorer5). Here, we present results from extension parts of these trials, included to evaluate longer term safety and efficacy. Both trials included main (≥24 weeks) and extension (52-102 weeks) parts, with patients receiving concizumab 0.15 mg/kg with potential dose escalation to concizumab 0.20 or 0.25 mg/kg if they experienced ≥3 treated spontaneous bleeding episodes within 12 weeks. Endpoints included annualized bleeding rate (ABR), adverse events (AEs), and occurrence of antidrug antibodies. Thromboembolic events were AEs of special interest. Thirty-six patients with HA, 15 with HAwI, and 10 with HBwI were exposed to concizumab. Estimated ABRs during the main + extension parts at last dose level were 4.8 (95% confidence interval [CI], 3.2-7.2) and 6.4 (95% CI, 4.1-9.9) in explorer4 and explorer5, respectively (spontaneous ABRs were 1.8 [95% CI, 1.2-2.6] and 2.1 [95% CI, 1.3-3.3]). Most AEs were mild, with no deaths, events leading to withdrawal, or thromboembolic events. Anti-drug antibodies developed in 25% of patients and were low titer and transient, with no observed clinical effect in most cases. Results of the main + extension parts of these trials were consistent with results of the main parts. Ongoing phase 3 trials will further evaluate concizumab as a once-daily, subcutaneous treatment across hemophilia subtypes. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Hemophilia, von Willebrand disease (VWD), and thrombotic thrombocytopenic purpura (TTP) are rare diseases affecting normal hemostasis. Although they differ in their pathogenesis and clinical manifestation, if left undiagnosed and untreated, all these conditions can result in severe long-term consequences and can be potentially life-threatening. This article summarizes a poster series funded by Takeda and presented virtually at the 29th annual congress of the International Society on Thrombosis and Haemostasis (ISTH) in 2021: Data from real-world evidence highlight the importance of joint health and personalized prophylaxis to prevent bleeding for patients with hemophilia, the need to further raise disease awareness in support of timely diagnosis and access to treatment in general practice settings for patients with VWD, and describe the clinical burden for patients with TTP and the importance to advance treatment options for these patients.

Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa ( n  = 56), 46.2% in Russia ( n  = 91), 40% in Italy ( n  = 20), 37.2% in France ( n  = 86), 26.8% in the United States ( n  = 71), 26.9% in Brazil ( n  = 26), 28.1% in Germany ( n  = 89), 29.8% in Japan ( n  = 84), and 5.9% in the United Kingdom ( n  = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.

Introduction: Gene therapy (GT) is becoming a realistic treatment option for patients with haemophilia. Outside clinical trials, the complexity and potential complications of GT will pose unprecedented challenges to haemophilia care centres., Aim: To explore the potential use of electronic tools to improve the delivery of GT under real-world conditions., Methods: Considering the hub-and-spoke model, the GTH working group on GT considered the entire patient pathway and reached consensus on requirements for an integrative software tool to secure documenting and sharing information between treaters, pharmacies and patients., Results: Six steps of the gene therapy process were identified, each requiring completion of the previous step as a prerequisite for entry. The responsibilities of GT dosing and follow-up treatment centres, read/write access rules, and the minimum data set were outlined. Data contributed by patients through mobile devices was also considered., Conclusion: Important information needs to be shared between patients and treatment centres in a real-world GT hub-and-spoke model. Collecting and sharing this information in well-organised electronic applications will not only improve patient care but also enable national and international data collection in clinical registries., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Patients with severe haemophilia suffer from bleeding-related joint changes in which the ankle joint is most frequently affected. In the resulting gait changes, the forefoot is involved by reducing the foot pressure. However, it is unclear which changes in foot pressure are present in the individual's foot zones., Research Question: The aim of the study was to determine whether compensation mechanisms are present in the foot zones regarding the peak pressure under dynamic conditions and to identify possible underlying mechanisms for gait changes., Methods: In a controlled cross-sectional study, a pedobarography was performed during gait with a standardized speed (3 km/h) in patients with haemophilia (PwH;n = 40) and healthy controls (Con;n = 40). Pressure pain thresholds (PPT) were detected, and Haemophilia Joint Health Score (HJHS) was performed to determine the current joint status., Results: PwH showed a decreased peak pressure in metatarsals II-IV and heel compared to Con. Patients with major-affected ankle joints (determined with the HJHS) showed a decreased single-step length, stride-length and stride-time. Accordingly, the cadence was increased by 10 ± 11 steps/min in PwH compared to Con. Furthermore, PwH showed decreased ankle range of motion (ROM) in HJHS and an altered pain perception due to reduced PPT., Significance: PwH showed a changed gait pattern in peak pressure compared to Con. A restricted rolling behavior, which might be caused by movement restrictions and pain sensation, leads to reduced pressure in the center forefoot, resulting in a shorter stride-length. Future therapies should focus on maintaining joint mobility for better rolling behavior and improving ankle joints' stability to achieve a balanced load between the midfoot, heel, and forefoot. The use of insoles adapted to our data, based on group differences between PwH and Con, could be supportive in this case., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction:  FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line., Methods:  The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL -1 (≥0.6 to <5 low-titre, ≥5 high titre)., Results:  A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors., Conclusion:  In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations., Competing Interests: R. J. Liesner, A. Abraham, C. Altisent, M. J. Belletrutti, M. Carcao, M. Carvalho, H. Chambost, A. K. C. Chan, L. Dubey, J. Ducore, M. Gattens, P. Gresele, Y. Gruel, B. Guillet, V. J. Yuste, L. Kitanovski, A. Klukowska, S. Lohade, J. Oldenburg, A. Pavlova, B. Pollio, M. Sigaud, V. Vdovin, K. Vilchevska, J. K. M. Wu and E. J. Neufeld were clinical study investigators for the NuProtect Study (Octapharma-sponsored). R. J. Liesner has received grants/research support from Octapharma, Bayer, Baxalta, Novo Nordisk and Roche, has acted as a consultant for Bayer and Baxalta, and has participated in speaker bureaus for Novo Nordisk, Octapharma and SOBI. A. Abraham has received grants/research support from Novo Nordisk and Roche, and has received support for attending scientific meetings from Novo Nordisk. C. Altisent has been a member of advisory boards and/or speaker bureaus for Baxalta (Shire), Bayer, CSL Behring, Grifols, Octapharma, Novo Nordisk, Pfizer, Roche and SOBI. M. J. Belletrutti has received research support from Octapharma, has acted as a consultant for Roche Canada, Sanofi and Takeda Canada, and has participated in speaker bureaus for Octapharma Canada and Takeda Canada. M. Carcao received research support/grants from Bayer, Novo Nordisk, Pfizer, Sanofi and Takeda, and has participated in speaker bureaus for Bayer, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi and Takeda. M. Carvalho has been an investigator on clinical trials sponsored by CSL Behring, Novo Nordisk, Octapharma and Roche, and has received support for attending scientific meetings and honoraria (speaker fees/consultant in advisory boards) for Bayer, Baxalta (Shire), CSL Behring, Novo Nordisk, Octapharma, Pfizer, Siemens, SOBI and Stago. H. Chambost has received research support from CSL Behring, LFB, Novo Nordisk, Octapharma, Roche/Chugaï, Shire/Takeda, SOBI; honoraria from Bayer, LFB, Octapharma, Pfizer, Roche and SOBI. A. K. C. Chan has been an investigator on clinical trials sponsored by Bayer, Biogen, CSL, Novo Nordisk, Octapharma and Shire and has received grants/research support from Bayer and Pfizer, and has participated in advisory boards for Bayer, Biogen, BioMarin, Novo Nordisk and Octapharma. J. Ducore has been an investigator on clinical trials sponsored by Octapharma, CSL Behring, OPKO Biologics, Bayer, Baxalta (Shire), Sparks Therapeutics, Biogen, Pfizer, Genentech (Roche), LFB and RevBio, has provided consultancy services to Octapharma, Bayer, Baxalta (Shire), Biogen and LFB, and is a speaker for Bayer. Y. Gruel has received support for attending scientific meetings and honoraria (speaker fees/consultant in advisory boards) from Baxalta (Shire), Bayer Healthcare, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche and SOBI, has been an investigator in studies sponsored by Biogen, LFB and SOBI, and has received research support from CSL Behring, LFB and Octapharma. B. Guillet has been an investigator on clinical trials, or has received honoraria for speaking/consulting or funds for research from Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Roche, SOBI and Takeda/Shire. V. J. Yuste has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Shire, Bayer, CSL Behring, Grifols, Novo Nordisk, SOBI, Octapharma and Pfizer. A. Klukowska has received personal fees from CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire and SOBI. M. E. Mancuso has received speaker and/or consultancy fees from Bayer Healthcare, CSL Behring, Takeda, Octapharma, Roche, Pfizer, Kedrion, Grifols, Novo Nordisk and SOBI. J. Oldenburg has received reimbursement for attending symposia/congresses or honoraria for speaking or honoraria for consulting, or funds for research from Bayer, Biogen Idec, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire and SOBI. A. Pavlova has participated in studies sponsored by Octapharma AG. B. Pollio has received support for attending scientific meetings and honoraria (speaker fees/consultant in advisory boards) from Baxalta (Shire), Bayer Healthcare, CSL Behring, Kedrion, Novo Nordisk, Octapharma, Pfizer and SOBI. M. Sigaud has received reimbursement for attending symposia/congresses, honoraria for speaking or for consulting from Biomarin, CSL Behring, Novo Nordisk, Octapharma, Roche and Shire/Takeda. J. K. M. Wu received funding to attend meetings and has participated in Octapharma-funded clinical research. M. Jansen is a full-time employee of Octapharma GmbH, Vienna, Austria. L. Belyanskaya, O. Walter and S. Knaub are employees of Octapharma AG, Lachen, Switzerland. E. J. Neufeld has received honoraria and participated in advisory boards for Octapharma. He has been a consultant for Genentech and Pfizer, and has participated in advisory boards for Novo Nordisk, Kedrion, Genentech, Baxalta/Shire (now Takeda), Novartis and CSL-Behring during the course of the NuProtect study. He has served on data monitoring committees for Bayer, Acceleron Pharma and ApoPharma (now Chiesi), and received research funding from the American Thrombosis and Hemostasis Network (ATHN). L. Dubey, M. Gattens, P. Gresele, L. Kitanovski, S. Lohade, V. Vdovin and K. Vilchevska declare no competing financial interests., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Introduction: Haemophilic arthropathy results in a restricted range of motion and pain that often affects gait. The effect of these gait changes on spinal posture has not been studied., Aim: To evaluate whether the altered joint situation in patients with haemophilia (PwH) leads to compensatory mechanisms evident in the trunk and spine, considering static and dynamic conditions., Methods: PwH and healthy controls (20-65 years) were examined using rasterstereography in a controlled cohort study. Analysis was performed in static and dynamic conditions in regard to gait phases. Joint status was determined using the Haemophilia Joint Health Score (HJHS)., Results: Static measurements showed no group differences in PwH (n = 40) compared to healthy controls (n = 40) except pelvic torsion (median [25%-quartile;75%-quartile]: -1.9[-3.2;.9]° vs. .5[-1.1;1.9]°; P = .007). In contrast, under dynamic conditions PwH showed significantly higher trunk inclination and lower apex lumbar lordosis in all gait phases. Additionally, pelvic torsion was increased in mid stance and terminal swing. Considering joint status, PwH had a higher global HJHS (23.5[13.0;30.0] vs. 3.0[1.0;5.0]; P<.001). A significant moderate correlation was shown between the HJHS mobility score and spine parameters (r = .228-.588; P<.05)., Conclusion: Degenerative joint changes in PwH lead to altered spine posture during gait. A reason could be the reduced mobility in the affected joint. Changes in spinal and pelvic posture lead to higher structural burdens; therefore, clinicians should focus on posture of spinal column during gait in daily treatment., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Ankle arthropathy is a frequent complication of haemophilia, reducing the patients' quality of life. Despite intensive conservative therapy, end-stage arthropathy requires surgical treatment, either by ankle fusion (AF) or total ankle replacement (TAR)., Methods: Eleven consecutive AFs were performed in nine patients and 11 TARs were implemented in 10 patients. Outcomes were assessed clinically by AOFAS score and radiologically by the Pettersson and Gilbert scores., Results: The mean age of the patients in these groups were 35.7 years and 49.4 years, respectively. Of the 11 ankles that underwent fusion, 10 showed bony consolidation not later than 12 weeks after surgery, whereas one still showed non-union after 6 months. VAS pain scores decreased significantly in both groups. Mean AOFAS scores also improved significantly, from 28.1 before to 80.3 after AF and from 21.5 before to 68.0 after ankle replacement. No perioperative complications were observed in either group. Late deep infection was observed in two patients that underwent TAR, which required removal of the implant., Conclusion: Our data indicate that both AF and TAR result in significantly reduced pain in patients with haemophilia with end-stage haemophilic arthropathy. While TAR is associated with a higher risk of deep infection and minimal persistent pain, it preserves the pre-operative range of motion. AF on the other hand is associated with the risk of non-union and a longer post-operative recovery period but results in greater pain reduction., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Haemophilia A is a rare bleeding disorder caused by defects in coagulation factor VIII (FVIII). Damoctocog alfa pegol (BAY 94-9027, Jivi, Bayer, Germany) is a site-specifically PEGylated, extended-half-life, recombinant FVIII, approved for use in previously treated patients (PTPs) aged ≥12 years with haemophilia A. However, a real-world evidence regarding routine clinical use of damoctocog alfa pegol is limited., Methods and Analysis: HEM-POWR is a multinational, multicentre, non-interventional, prospective, postmarketing cohort study evaluating the effectiveness and safety of real-world treatment with damoctocog alfa pegol. Estimated enrolment is ≥200 PTPs with haemophilia A, receiving damoctocog alfa pegol (on-demand, prophylaxis or intermittent prophylaxis (as per local label)), observed for 36 months. Primary outcomes are total bleeding events and annualised bleeding rate; secondary outcomes include long-term safety, joint health, pharmacokinetics, patient-reported outcomes (PROs) from validated questionnaires and perioperative haemostasis. Where applicable, reasons for switching to damoctocog alfa pegol, choice of treatment regimen and dose will also be captured. Exploratory and descriptive statistical analyses will be performed, and will be stratified by parameters including, but not limited to, prophylaxis regimen and haemophilia severity. Patients can record bleeds and consumption in electronic (e) Diaries, ePROs, and can access non-promotional study information (videos explaining study procedures) via an online patient portal. Optionally, patients can enrol in the LIFE-ACTIVE substudy designed to investigate the relationship between activity (measured by the ActiGraph CP Insight watch) and effectiveness parameters collected from HEM-POWR., Ethics and Dissemination: Study approval was obtained by local independent ethics committees and authorities in participating study centres across Europe, the Americas and Asia. Informed consent from patients or their legal representative is a requirement for participation. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences., Trial Registration Numbers: NCT03932201, EUPAS26416., Protocol Version and Date: V.1.2, 27 September 2019., Competing Interests: Competing interests: MS: Bayer employee. MTAR: Grants/research support: Shire/Takeda. Company-sponsored speaker bureau: Shire/Takeda, Roche, Bayer, Amgen, Novartis, Novo Nordisk, Sobi, CSL Behring. GC: Grants/research support: Sobi, Pfizer, CSL Behring. Honoraria or consultation fees: Roche. Company-sponsored speaker bureau: Roche, CSL Behring, Sobi, Bayer, Novo Nordisk, uniQure, Kedrion, Shire. MJ: Consultant: Bayer, Takeda, Genentech, CSL Behring. Company-sponsored speaker bureau: Takeda. TM: Grants/research support: Bioverativ, KM Biologics. Honoraria or consultation fees: Shire, Chugai, Bayer, Novo Nordisk, CSL, Pfizer, uniQure, Bioverativ, KM Biologics. Honoraria or consultation fees: Shire, Chugai, Bayer, Novo Nordisk, CSL, Pfizer, Bioverativ. Grants/research support: Bayer, Sanquin, Pfizer. KM: Grants/research support: Bayer, Sanquin, Pfizer. Honoraria or consultation fees: uniQure. JO: Honoraria; fees for speaking, consulting or symposium/congress attendance; or research funding: Bayer, Biogen Idec, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, Swedish Orphan Biovitrum. SF: Bayer employee and shareholder. MTR: Grants/research support: Bayer, BioMarin. Honoraria or fees for advisory board/speaker bureau: Bayer, Novo Nordisk, Sanofi Genzyme, Takeda., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Severe haemophilia A (HA) has a major impact on health-related quality of life (HRQoL)., Aim: Assess the impact of emicizumab on HRQoL in persons with severe HA (PwHA) without factor VIII (FVIII) inhibitors in the phase 3 HAVEN 3 and 4 studies., Methods: This pooled analysis examines the HRQoL of PwHA aged ≥ 18 years treated with emicizumab prophylaxis via Haemophilia-Specific Quality of Life Questionnaire for Adults (Haem-A-QoL) and EuroQoL 5-Dimensions 5-levels (EQ-5D-5L). In particular, changes from baseline in Haem-A-QoL 'Physical Health' (PH) domain and 'Total Score' (TS) are evaluated., Results: Among 176 evaluable participants, 96 (55%) had received prior episodic treatment and 80 (45%) prophylaxis; 70% had ≥ 1 target joint and 51% had experienced ≥ 9 bleeds in the previous 24 weeks. Mean Haem-A-QoL PH and TS improved after emicizumab initiation. Mean (standard deviation) -12.0 (21.26)- and -8.6 (12.57)-point improvements were observed in PH and TS from baseline to Week 73; Week 73 scores were 27.9 (24.54) and 22.0 (14.38), respectively. Fifty-four percent of participants reported a clinically meaningful improvement in PH scores (≥ 10 points) by Week 73. Subgroups with poorer HRQoL prior to starting emicizumab (i.e. receiving episodic treatment, ≥ 9 bleeds, target joints) had the greatest improvements in PH scores, and corresponding reductions in missed workdays; change was not detected among those previously taking prophylaxis. No change over time was detected by the EQ-5D-5L questionnaire., Conclusions: Emicizumab prophylaxis in PwHA without FVIII inhibitors resulted in persistent and meaningful improvements in Haem-A-QoL PH and less work disruption than previous treatment., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs)., Objectives: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development., Patients/methods: Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression., Results: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases., Conclusions: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background:  Currently available coronavirus disease 2019 (COVID-19) vaccines are approved for intramuscular injection and efficacy may not be ensured when given subcutaneously. For years, subcutaneous vaccination was recommended in patients with hemophilia to avoid intramuscular bleeds. Therefore, recommendations for the application of COVID-19 vaccines are needed., Methods:  The Delphi methodology was used to develop consensus recommendations. An initial list of recommendations was prepared by a steering committee and evaluated by 39 hemophilia experts. Consensus was defined as ≥75% agreement and strong consensus as ≥95% agreement, and agreement as a score ≥7 on a scale of 1 to 9. After four rounds, a final list of statements was compiled., Recommendations:  Consensus was achieved that COVID-19 vaccines licensed only for intramuscular injection should be administered intramuscularly in hemophilia patients. Prophylactic factor replacement, given on the day of vaccination with a maximum interval between prophylaxis and vaccination of 24 hours (factor VIII and conventional factor IX concentrates) or 48 hours (half-life extended factor IX), should be provided in patients with moderate or severe hemophilia. Strong consensus was achieved that patients with mild hemophilia and residual factor activity greater than 10% with mild bleeding phenotype or patients on emicizumab usually do not need factor replacement before vaccination. Swelling, erythema, and hyperthermia after vaccination are not always signs of bleeding but should prompt consultation of a hemophilia care center. In case of injection-site hematoma, patients should receive replacement therapy until symptoms disappear., Conclusions:  Consensus was achieved on recommendations for intramuscular COVID-19 vaccination after replacement therapy for hemophilia patients depending on disease severity., Competing Interests: C.P. reports grants and personal fees from Roche, grants and personal fees from Takeda, personal fees from Bayer Healthcare, personal fees from Chugai, personal fees from CSL Behring, personal fees from Novo Nordisk, personal fees from Shire, grants from Fujimori, grants from LeoPharma, personal fees from BMS, and personal fees from Pfizer, outside the submitted work.K.H. reports grants, personal fees, and other from Bayer; personal fees and other from Biotest; personal fees from Chugai/Roche; personal fees and other from CSL Behring; personal fees and other from Novo Nordisk; grants, personal fees, and other from Pfizer; personal fees from Shire/Takeda; and personal fees and other from Sobi, outside the submitted work.C.K. reports grants and personal fees from Bayer, grants from Biotest, grants and personal fees from CSL Behring, grants from Intersero, grants and personal fees from Novo Nordisk, grants from Pfizer, grants and personal fees from Roche/Chugai, grants and personal fees from Takeda, and grants and personal fees from Sobi/Sanofi, outside the submitted work.C.H. reports grants from Bayer, grants and personal fees from Biotest, grants from CSL Behring, grants and personal fees from Intersero, grants from Novo Nordisk, grants from Pfizer, grants and personal fees from Roche/Chugai, grants and personal fees from Takeda, and grants and personal fees from Sobi/Sanofi, outside the submitted work.M.K. reports personal fees from Bayer Healthcare, CSL Behring, Chugai Pharma, Novo Nordisk, and Roche, outside the submitted work.M.O. reports grants and personal fees from Bayer, grants and personal fees from Biotest, grants and personal fees from Takeda, grants and personal fees from CSL Behring, grants from Octapharma, grants and personal fees from Pfizer, grants from Shire, grants and personal fees from Roche, grants and personal fees from Sobi, and personal fees from Novo Nordisk, outside the submitted work.C.B. reports personal fees from Bayer, grants and personal fees from CSL Behring, personal fees and other from Roche, personal fees from Biotest, personal fees from Takeda, personal fees from Pfizer, and personal fees from Sobi, outside the submitted work; and C.B. is coinvestigator of the German Pediatric Hemophilia Research Database. This registry is funded by most manufacturers of factor and nonfactor therapies for patients with hemophilia.M.S-K. reports grants from Pfizer, personal fees from Biotest AG, and personal fees from Novo Nordisk, outside the submitted work.J.W. has nothing to disclose.S.Ha. reports grants and personal fees from Bayer Healthcare, grants and personal fees from Baxalta Innovations, grants and personal fees from Biotest, grants and personal fees from CSL Behring, grants and personal fees from Novo Nordisk, grants and personal fees from Octapharma, grants and personal fees from Pfizer, grants and personal fees from Sobi, and personal fees from Roche, outside the submitted work.S.Ho. reports personal fees from Takeda/Shire, Bayer Healthcare, Novo Nordisk, Octapharma, Pfizer, Sobi und Roche, outside the submitted work.H.R. reports grants from Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, Roche/Chugai, Sobi, and Takeda, outside the submitted work.I.W. reports grants and personal fees from Bayer; grants and personal fees from Biotest; grants and personal fees from CSL; nonfinancial support from Pfizer; grants and personal fees from Roche/Chugai; grants, personal fees, and nonfinancial support from Sobi; and grants, personal fees, and nonfinancial support from Shire/Takeda, outside the submitted work.R.K. reports grants and personal fees from Bayer, personal fees from CSL Behring, personal fees from Roche, personal fees from Pfizer, grants and personal fees from BioMarin, grants and personal fees from Takeda/Shire, grants and personal fees from Novo Nordisk, and grants and personal fees from SOBI, outside the submitted work.J.O. reports grants and personal fees from Bayer, personal fees from Biogen Idec, personal fees from BioMarin, grants and personal fees from Biotest, personal fees from Chugai, grants and personal fees from CSL Behring, personal fees from Freeline, personal fees from Grifols, grants and personal fees from Novo Nordisk, grants and personal fees from Octapharma, personal fees from Pfizer, personal fees from Roche, personal fees from Sanofi, personal fees from Sparks, personal fees from Swedish Orphan Biovitrum, grants and personal fees from Takeda, outside the submitted work.A.T. reports grants and personal fees from Bayer, grants and personal fees from Biotest, grants and personal fees from Chugai/Roche, personal fees from CSL Behring, grants and personal fees from Novo Nordisk, grants and personal fees from Octapharma, grants and personal fees from Pfizer, grants and personal fees from SOBI, and grants and personal fees from Takeda, outside the submitted work., (Thieme. All rights reserved.)

Standard treatment of haemophilia A is based on replacing the missing coagulation factor VIII (FVIII) to treat and prevent bleeding episodes. The most challenging complication of FVIII therapy is the development of neutralizing antibodies (inhibitors) that can render treatment ineffective. Eradication of the inhibitor through immune tolerance induction (ITI) remains the most effective strategy for managing these patients. Bypassing agents can be used to help restore haemostasis in inhibitor patients. Several novel agents have recently been developed, such as the FVIII mimetic agent emicizumab, which has been effective in reducing the annualized bleeding rate in haemophilia A patients with inhibitors. When coadministered with repetitive high doses of activated prothrombin complex concentrate (ie >100 U/kg/d for ≥24 hours), emicizumab was associated with thrombotic microangiopathy and thrombosis events. As a consequence the United Kingdom Haemophilia Centres Doctors' Organisation (UKHCDO) issued the first guidance on the treatment of bleeding episodes in patients receiving emicizumab. To build on and extend this work, a panel of German haemophilia specialists met to discuss the UK guidance, review current evidence and provide additional guidance for German healthcare professionals on how to optimize the management of patients with haemophilia A receiving emicizumab. Recommendations are provided on the use of bypassing and other agents to manage breakthrough bleeding, ITI in the emicizumab era, haemostatic support during surgery and issues relating to laboratory monitoring., (© 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Real-world data on health-related outcomes in persons with haemophilia A (PwHA) can provide useful information for improving patient care. The global, non-interventional study (NIS; NCT02476942) prospectively collected high-quality data in PwHA, including those without factor VIII (FVIII) inhibitors treated according to local routine clinical practice., Aim: To report health-related quality of life (HRQoL) and health status of adult/adolescent PwHA without FVIII inhibitors., Methods: Participants were PwHA without FVIII inhibitors age ≥12 years; they remained on existing episodic treatment or prophylaxis. HRQoL was assessed by Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) or Haemophilia-Specific Quality of Life Assessment for Children and Adolescents Short Form (Haemo-QoL-SF II). Health status was assessed through EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score and visual analogue scale (EQ-VAS)., Results: Ninety-four participants enrolled; median age was 34.0 years (range 12-76). Forty-five received episodic treatment and 49 received prophylaxis for a median time of 27.7 weeks and 30.4 weeks, respectively. Mean (standard deviation) baseline Haem-A-QoL total scores were 40.1 (17.0) for the episodic group and 26.6 (14.6) for the prophylaxis group, indicating impairments in HRQoL, which remained consistent over time. Mean EQ-5D-5L IUS scores were similar between treatment regimens (0.8 episodic; 0.9 prophylaxis) and consistent over time. The mean EQ-VAS scores were similar between treatment regimens, and lower on days when bleeding occurred (79.0 vs 85.0 for episodic treatment; 77.0 vs 82.0 for prophylaxis, respectively)., Conclusions: Adult and adolescent PwHA without FVIII inhibitors had HRQoL impairments regardless of whether they were treated with episodic or prophylactic standard care with FVIII., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Prophylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified., (© 2021 by The American Society of Hematology.)

Introduction: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research., Aim: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations., Methods: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing., Results: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis., Conclusion: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB., (© 2020 John Wiley & Sons Ltd.)

Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and Emicizumab, the 'Ständige Kommission Hämophilie' of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the 'Ständige Kommission Hämophilie' and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary., Competing Interests: K.H. received honoraria for advisory boards, travel grants and/or speaker fees from Bayer, Biotest, Chugai, CSL Behring, NovoNordisk, Pfizer, Roche, Shire/Takeda and Sobi, and unrestricted research grants from Bayer, CSL Behring and Pfizer. M.A. received honoraria for advisory boards, travel grants, speaker fees and/or research funding from Biogen, Biotest, Novo Nordisk, Roche, Shire and Sobi. C.B. received honoraria for advisory boards, travel grants, research funding and/or speaker fees from Bayer, Biotest, CSL Behring, NovoNordisk, Pfizer, Roche, Shire/Takeda and Sobi. C.B. is investigator in the STASEY Trial (Roche). C.B. and C.K. are principal investigators of the German Pediatric Haemophilia Research Database (GEPHARD). GEPHARD is funded by manufacturers of haemophilia drugs. S.Ha. received honoraria for advisory boards or speaker's fees from Bayer, Baxalta/Shire/Takeda, Biotest, CSL Behring, Novartis, Novo Nordisk, Octapharma and Pfizer, and research grants from Bayer, Shire/Takeda, Biotest, CSL Behring, Novo Nordisk, Octapharma and Pfizer. S.He. received honoraria for advisory boards or speaker's fees from Bayer, Shire/Takeda, CSL Behring, Biotest, NovoNordisk, Pfizer, Roche and Sobi. R.K. has acted as a consultant, received speaker's fees and/or research funding from Bayer Healthcare, Biomarin, Biotest, CSL Behring, Grifols, Octapharma, Pfizer, NovoNordisk, Sanofi, Shire/Takeda, Sobiand Roche/Chugai. C.K. received honoraria for advisory boards, travel grants and/or speaker fees from Bayer, BFSH, Biotest, Bioverativ, CSL Behring, MSD, NovoNordisk, Pfizer, Roche, Shire and Sobi, and unrestricted research grants from the European Union, FP7 IMI, DFG, BMBF, FSKK-Foundation, Abbvie, Bayer, Biotest, Bioverativ, CSL Behring, Gilead, Intersero, Jansen, NovoNordisk, PENTA Foundation, Pfizer, Roche/Chugai, Shire and Sobi. K.K. received grants, travel support and/or lecture fees from Bayer, Biotest, CSL Behring, NovoNordisk, Roche, Sobi, Shire/Takeda and honoraria for advisory board from Shire/Takeda. C.M. has received personal honoraria (consultancy, speaker, chair) from Bayer, Biotest, CSL Behring, NovoNordisk, Roche; fees to the institution for study participation from Bayer, Shire/Takeda, Biotest, CSL Behring, NovoNordisk, Sobi; unrestricted grants to institution from Biotest, CSL Behring; travel support from Bayer, Biotest, CSL Behring, NovoNordisk. J.O. received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Bayer, Biogen Idec, Biotest, Chugai, CSL-Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, Swedish Orphan Biovitrum and Takeda. W.S. has received honoraria and research funding from Biotest, Octapharma, Pfizer, Sobiand Shire/Takeda. W.S. has been a member of expert panels and advisory committees from NovoNordisk, Roche, Sobi and Shire/Takeda. C.W. is an employee at Werlhof-Institut, received honoraria from Bayer, Biotest, CSL-Behring, LFB, Novo Nordisk, Pfizer, Shire and Sobi, and acted as a consultant in advisory boards for Bayer, CSL-Behring, Novo Nordisk, Pfizer, Shire and Sobi. C.E.E has acted as a consultant, received speaker's fees and/or research funding from Bayer Healthcare, Biotest, CSL Behring, Grifols, Octapharma, NovoNordisk, Shire/Takeda, Sobi, Roche/Chugai, Alnylam and Kedrion., (Thieme. 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Congenital haemophilia A (HA) is caused by deficiency of coagulation factor VIII (FVIII) activity, leading to spontaneous or traumatic bleeding events. While FVIII replacement therapy can treat and prevent bleeds, approximately 30% of patients with severe HA develop inhibitor antibodies that render FVIII replacement therapy ineffective. The bypassing agents (BPAs), activated prothrombin complex concentrate (aPCC) and recombinant activated FVII, first approved in 1977 and 1996, respectively, act to generate thrombin independent of pathways that involve factors IX and VIII. Both may be used in patients with congenital haemophilia and inhibitors (PwHIs) for the treatment and prevention of acute bleeds and quickly became standard of care. However, individual patients respond differently to different agents. While both agents are approved for on-demand treatment and perioperative management for patients with congenital haemophilia with inhibitors, aPCC is currently the only BPA approved worldwide for prophylaxis in PwHI. Non-factor therapies (NFTs) have a mechanism of action distinct from BPAs and have reported higher efficacy rates as prophylactic regimens. Nonetheless, treatment challenges remain with NFTs, particularly regarding the potential for synergistic action on thrombin generation with concomitant use of other haemostatic agents, such as BPAs, for the treatment of breakthrough bleeds and in perioperative management. Concomitant use of NFTs with other haemostatic agents could increase the risk of adverse events such as thromboembolic events or thrombotic microangiopathy. This review focuses on the origins, development and on-going role of aPCC in the evolving treatment landscape in the management of PwHI., Competing Interests: Hans Hermann Brackmann has received honoraria for presentations from Takeda, Sobi and Roche. Wolfgang Schramm has participated in advisory boards for Biotest, and received honoraria for lectures from Bio&Bio AG, Biotest, Novo, Roche and Shire, a Takeda company. Johannes Oldenburg has received grant/research support from Bayer, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer and Shire, a Takeda company, and fees for consultancy and speakers bureaus from Bayer, Biogen, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, a Takeda company, and Sobi. Viridiana Cano was an employee of Shire GmbH, a Takeda company, Zürich, Switzerland during the development of this review and a stockholder in Takeda Pharmaceutical Company Limited. Peter Turecek is an employee of Baxalta Innovations GmbH, a Takeda company, Vienna, Austria and a stockholder in Takeda Pharmaceutical Company Limited. Claude Négrier has received grant/research support from CSL Behring, Octapharma, Shire, a Takeda company, and Sobi; fees for consultancy from Alnylam, Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, a Takeda company, and Sobi; and as a paid instructor for Novo Nordisk., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)