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Background: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in development as a once-daily, subcutaneous prophylaxis for patients with haemophilia A or haemophilia B with or without inhibitors. We aimed to assess the efficacy and safety of concizumab in patients with haemophilia A or B without inhibitors. Here we report the results from the confirmatory analysis cutoff., Methods: This prospective, multicentre, open-label, randomised, phase 3a trial (explorer8) was conducted at 69 investigational sites in 31 countries. Eligible patients were male, aged 12 years or older, and had congenital severe haemophilia A or moderate or severe haemophilia B without inhibitors and with documented treatment with clotting factor concentrate in the 24 weeks before screening. The trial was paused because of non-fatal thromboembolic events in three patients (two from this trial [explorer8] and one from a related trial in haemophilia with inhibitors [explorer7; NCT04083781]) and restarted with mitigation measures, including a revised dosing regimen of subcutaneous concizumab at 1·0 mg/kg loading dose on day 1 and subsequent daily doses of 0·20 mg/kg from day 2, with options to decrease to 0·15 mg/kg, stay on 0·20 mg/kg, or increase to 0·25 mg/kg on the basis of concizumab plasma concentration measured after 4 weeks on concizumab. Patients recruited after treatment restart were randomly assigned 1:2 using an interactive web response system to receive no prophylaxis and continue on-demand clotting factor (group 1) or concizumab prophylaxis (group 2). The primary endpoints were the number of treated spontaneous and traumatic bleeding episodes for patients with haemophilia A and haemophilia B separately, assessed at the confirmatory analysis cutoff in randomly assigned patients. Analyses were by intention-to-treat. There were two additional groups containing non-randomly-assigned patients: group 3 contained patients who entered the trial before the trial pause and were receiving concizumab in the phase 2 trial (explorer5; NCT03196297), and group 4 contained patients who received previous clotting factor concentrate prophylaxis or on-demand treatment in the non-interventional trial (explorer6; NCT03741881), patients randomly assigned to groups 1 or 2 before the treatment pause, and patients from explorer5 enrolled after the treatment pause. The safety analysis set contained all patients who received concizumab. Superiority of concizumab over no prophylaxis was established if the two-sided 95% CI of the treatment ratio was less than 1 for haemophilia A and for haemophilia B. This trial is registered with ClinicalTrials.gov, NCT04082429, and its extension part is ongoing., Findings: Patients were recruited between Nov 13, 2019 and Nov 30, 2021; the cutoff date for the analyses presented was July 12, 2022. 173 patients were screened, of whom 148 (86%) were randomly assigned or allocated to the four groups in the study after trial restart on Sept 30, 2020 (nine with haemophilia A and 12 with haemophilia B in group 1; 18 with haemophilia A and 24 with haemophilia B in group 2; nine with haemophilia A in group 3; and 46 with haemophilia A and 30 with haemophilia B in group 4). The estimated mean annualised bleeding rate ratio for treated spontaneous and traumatic bleeding episodes during concizumab prophylaxis versus no prophylaxis was 0·14 (95% CI 0·07-0·29; p<0·0001) for patients with haemophilia A and 0·21 (0·10-0·45; p<0·0001) for patients with haemophilia B. The most frequent adverse events in patients who received concizumab were SARS-CoV-2 infection (19 [13%] of 151 patients), an increase in fibrin D-dimers (12 [8%] patients), and upper respiratory tract infection (ten [7%] patients). There was one fatal adverse event possibly related to treatment (intra-abdominal haemorrhage in a patient from group 4 with haemophilia A with a long-standing history of hypertension). No thromboembolic events were reported between the trial restart and confirmatory analysis cutoff., Interpretation: Concizumab was effective in reducing the bleeding rate compared with no prophylaxis and was considered safe in patients with haemophilia A or B without inhibitors. The results of this trial suggest that concizumab has the potential to be one of the first subcutaneous treatment options for patients with haemophilia B without inhibitors., Funding: Novo Nordisk., Competing Interests: Declaration of interests PC reports grants paid to their institution from Bayer, CSL Behring, Freeline Therapeutics, Novo Nordisk, Pfizer, and Sobi; honoraria from BioMarin, CSL Behring, Chugai Pharmaceutical, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, and Takeda; support for attending meetings and/or travel from CSL Behring, Novo Nordisk, Pfizer, Sobi, and Takeda; and is a chairperson of the United Kingdom Haemophilia Centre Doctors' Organisation and an executive member of the European Association for Haemophilia and Allied Disorders. PA reports grants from Novo Nordisk, Sanofi, and Spark Therapeutics. JA reports grants to their institution from Bayer, CSL Behring, Sobi, and Takeda/Shire; honoraria as a consultant and member of advisory boards for Bayer, BioMarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Sobi, Takeda/Shire, and Roche; and support for attending meetings and/or travel from Bayer, BioMarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Sobi, Takeda/Shire, and Roche. AKCC reports grants from Bayer, Pfizer, Daiichi Sankyo, Bayer, Sanofi, Sobi, Novo Nordisk, Pfizer, Takeda, Institute for Advanced Clinical Trials for Children, AceAge Novo Nordisk, C(17) Children's Cancer & Blood Disorders, and the Canadian Hemophilia Society; honoraria from Bayer, Novo Nordisk, Takeda, Pfizer, Sanofi, and Octapharma; a patent for Attwill Medical Solutions; participation on data safety monitoring boards and advisory boards for Takeda, Novo Nordisk, Sanofi, and Octapharma; and a leadership or fiduciary role in other board, society, committee, or advocacy groups for Bayer and Daiichi Sankyo. VJY reports grants from Roche, Novo Nordisk, Sobi, Takeda, Grifols, Bayer, Pfizer, Octapharma, and CSL Behring; consulting fees from Roche, Novo Nordisk, Sanofi, Sobi, Takeda, Grifols, Bayer, Pfizer, Spark Therapeutics, BioMarin, Octapharma, and CSL Behring; and honoraria from Roche, Novo Nordisk, Sanofi, Sobi, Takeda, Grifols, Bayer, Pfizer, Spark Therapeutics, BioMarin, Octapharma, and CSL Behring. TM reports honoraria from Takeda, Bayer, Novo Nordisk, Chugai, Pfizer, Sanofi, CSL, KM Biologics, and Sysmex. ARHN is an employee of Novo Nordisk. JS reports honoraria for lectures from Zuelling Pharma, Roche, and Takeda. HT reports grants from Sanofi and AstraZeneca; consulting fees from BioMarin, CSL Behring, Novo Nordisk, Pfizer, and Roche; honoraria from BioMarin, CSL Behring, Novo Nordisk, Pfizer, and Roche; support for attending meetings and/or travel from Chugai and CSL Behring; and a leadership or fiduciary role in other board, society, committee or advocacy groups for the Australian Haemophilia Centres Directors' Organisation. LVM reports honoraria from CSL Behring, Novo Nordisk, Pfizer, Roche, Grifols, Octapharma, Sanofi, Takeda, and Bayer; support for attending meetings and/or travel from Novo Nordisk, CSL Behring, Octapharma, Roche, Pfizer, and Takeda; and participation on data safety monitoring boards or advisory boards for CSL Behring, Novo Nordisk, and Pfizer. APW reports grants from Octapharma; and consulting fees from Bayer, BioMarin, Bioverativ, CSL Behring, Genentech, HEMA Biologics, Novo Nordisk, Pfizer, Sanofi-Aventis USA, Shire North America, Spark Therapeutics, and Takeda Pharmaceuticals. JW reports grants and honoraria from Alnylam, Amgen, AstraZeneca, Bayer, CSL Behring, LFB Corp, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, and Takeda; consulting fees from Amgen, AstraZeneca, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, and Takeda; support for attending meetings and/or travel from CSL Behring, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, and Takeda; and participation on data safety monitoring boards or advisory boards for Amgen, AstraZeneca, Bayer, CSL Behring, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Siemens, Sobi, and Takeda. GY reports grants from Sanofi; payment for licensed data on fondaparinux use in children from Viatris; consultation fees from BioMarin, CSL Behring, Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark Therapeutics, and Takeda; honoraria from BioMarin, CSL Behring, Genentech, Octapharma, Sanofi, Spark Therapeutics, and Takeda; support for attending meetings and/or travel from BioMarin, CSL Behring, Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark Therapeutics, and Takeda; and participation on a data safety monitoring or advisory board for ASC Therapeutics. JJTZ is an employee of Novo Nordisk. HE reports grants from Bayer Vital and CSL Behring; consulting fees from Bayer Vital, BioMarin, CSL Behring, Novo Nordisk, Pfizer, and Roche; honoraria from Bayer Vital, BioMarin, CSL Behring, Novo Nordisk, Pfizer, Sobi, and Roche; support for attending meetings and/or travel from Bayer Vital, BioMarin, Novo Nordisk, and Sobi; participation on data safety monitoring boards or advisory boards for Bayer Vital, BioMarin, CSL Behring, Novo Nordisk, Pfizer, and Sobi; and a leadership or fiduciary role on the German Society for Transfusion Medicine and Immunohaematology board. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background:  Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Standard treatment consists of bleeding control with bypassing agents and immunosuppressive therapy. Emicizumab is a bispecific antibody that mimics the function of activated FVIII irrespective of the presence of neutralizing antibodies. Recently, the GTH-AHA-EMI study demonstrated that emicizumab prevents bleeds and allows to postpone immunosuppression, which may influence future treatment strategies., Aim:  To provide clinical practice recommendations on the use of emicizumab in AHA., Methods:  A Delphi procedure was conducted among 33 experts from 16 German and Austrian hemophilia care centers. Statements were scored on a scale of 1 to 9, and agreement was defined as a score of ≥7. Consensus was defined as ≥75% agreement among participants, and strong consensus as ≥95% agreement., Results:  Strong consensus was reached that emicizumab is effective for bleed prophylaxis and should be considered from the time of diagnosis (100% consensus). A fast-loading regimen of 6 mg/kg on day 1 and 3 mg/kg on day 2 should be used if rapid bleeding prophylaxis is required (94%). Maintenance doses of 1.5 mg/kg once weekly should be given (91%). Immunosuppression should be offered to patients on emicizumab if they are eligible based on physical status (97%). Emicizumab should be discontinued when remission of AHA is achieved (97%)., Conclusion:  These GTH consensus recommendations provide guidance to physicians on the use of emicizumab in AHA and follow the results of clinical trials that have shown emicizumab is effective in preventing bleeding in AHA., Competing Interests: CP reports institutional grants or contracts from Takeda, Zacros, Leo Pharma, Chugai and Roche; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chugai, Takeda, BMS, Roche, Pfizer, NovoNordisk, Biomarin, CSL Behring, Zacros, Sobi, and Leo Pharma, Participation on a Data Safety Monitoring Board or Advisory Board with Chugai, Takeda, Roche, Novenaries, Biomarin CSL Behring, Bayer and Alexion.RK reports institutional grants or contracts from Bayer, CSL Behring, Leo Pharma and Octapharma; Consulting fees from Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, CSL Behring, Daiichi Sankyo, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, Viatris; Participation on a Data Safety Monitoring Board or Advisory Board with Bayer, CSL Behring, NovoNordisk, Octapharma, Pfizer, Sanofi, Takeda. He holds a position as president of EAHAD and GTH.JO reports institutional grants or contracts from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Swedish Orphan Biovitrum and Takeda, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, Biogen Idec, Biomarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum and Takeda; Support for attending meetings and/or travel from Bayer, Biogen Idec, Biomarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum and Takeda; Participation on a Data Safety Monitoring Board or Advisory Board from Biogen Idec, Biomarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum and Takeda; Receipt of equipment, materials, drugs, medical writing, gifts and other services from Bayer. He is part of the GTH and the Foundation “Hämotherapie Forschung”.KH reports institutional grants or contracts from Sobi, Bayer, Norvo Nordisk, Roche, GWT/Roche and CSL Behring; consulting fees from Bayer, Biotest, CSL Behring, LFB, Novo Nordisk, Sobi and Roche/ Chugai; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biotest, Pfizer, Sobi, Takeda, LFB and Novo Nordisk; Support for attending meetings and/or travel from Sobi, Pfizer, Bayer, Novo Nordisk, CSL Behring and is holding a position as medical advisor for “Deutsche Hämophilie Gesellschaft” as well as speaker for “Ständige Kommission Hämophilie der Gesellschaft für Thrombose und Hämostaseforschung (GTH)”.HE reports institutional Grants or contracts from Bayer, BioMarin, Biotest, CSL Behring, Novo Nordisk, Pfizer and Sobi; Consulting fees from Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer and Sobi; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novo Nordisk and Pfizer; Support for attending meetings and/or travel from Bayer, BioMarin, Biotest and Novo Nordisk; Participation on a Data Safety Monitoring Board or Advisory Board with Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer and Sobi.CH reports Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, Sobi, Pfizer, BMS, Daiichi Sankyo and Leopharma; Support for attending meetings and/or travel from Bayer, Takeda, Octapharma, Novo Nordisk, Sobi, Roche/Chugai and Participation on a Data Safety Monitoring Board or Advisory Board with Novo Nordisk, Bayer, Sobi, Takeda, Sanofi and Roche/Chugai.PM reports institutional Grants or contracts from Baxter Innovations, Bayer, LFB and Octapharma; Consulting fees from Alexion Pharma, CSL Behring and Novo Nordisk; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion Pahrma, Astra Zeneca, Biotest, CSL Behring and Octapharma; Support for attending meetings and/ or travel from Bayer, Biotest and Takeda.KS has nothing to report.KTG reports Consulting fees from Takeda, Roche, Grifols and Sobi; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Takeda, Roche, Grifols and Sobi; Support for attending meetings and/ or travel from Grifols and Takeda; Participation on a Data Safety Monitoring Board or Advisory Board with Grifols.MA has nothing to report.CA reports consulting fees from Bayer, Novo Nordisk, CSL Behring, Pfizer, Octapharma, LFB and Swedish Orphan Biovitrium; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, Novo Nordisk, Takeda, CSL Behring, Pfizer, Octapharma, Roche, LFB and Swedish Orphan Biovitrium.WM reports institutional grants or contracts from Bayer, Novo Nordisk and Pfizer; Consulting fees from Bayer, Biomarin, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sigilon, Sobi, Takeda/Shire and uniQure; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sigilon, sobi, Takeda/Shire, uniQure; Support for attending meetings and/or travel from Bayer, Biomarin, Biotest, CSL Behring, Chugai, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, sobi, Takeda/Shire and uniQure and Participation on a Data Safety Monitoring Board or Advisory Board with Octapharma.PK reports institutional grants or contracts from Novo Nordisk, Roche and Takeda; Consulting fees from Novo Nordisk, Roche and Takeda; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novo Nordisk, Roche and Takeda and Participation on a Data Safety Monitoring Board or Advisory Board from Novo Nordisk, Roche and Takeda.AT reports Consulting fees from Bayer, Biomarin, Biotest, Chugai, Roche, Takeda, CSL Behring, Novo Nordisk, Octapharma, Pfizer and Sobi; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, Biomarin, Biotest, Chugai, Roche, Takeda, CSL Behring, Novo Nordisk, Octapharma, Pfizer and Sobi and Support for attending meetings and/ or travel from Bayer, Biomarin, Biotest, Chugai, Roche, Takeda, CSL Behring, Novo Nordisk, Octapharma, Pfizer and Sobi., (Thieme. All rights reserved.)

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.)

To identify recurrent inflammation in hemophilia, we assessed the acute-phase response in the blood of patients with hemophilia A and B. Compared to age- and weight-matched controls, blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), and LPS-binding protein (LBP) were significantly elevated in the entire cohort of hemophilia patients but exhibited a particularly pronounced increase in obese hemophilia patients with a body mass index (BMI) ≥30. Subgroup analysis of the remaining nonobese hemophilia patients (BMI: 18-29.9) revealed a significant spike of IL-6, CRP, and LBP in connection with a de-novo increase of soluble IL-6 receptor α (sIL-6Rα) in patients with bleeding events within the last month. Hemophilia patients who did not experience recent bleeding had IL-6, CRP, and sIL-6Rα blood levels similar to healthy controls. We did not find increased IL-6 or acute-phase reactants in hemophilia patients with arthropathy or infectious disease. The role of IL-6 as a marker of bleeding in hemophilia was confirmed in hemophilia patients with acute bleeding events as well as in transgenic hemophilia mice after needle puncture of the knee, which exhibited an extensive hematoma and a 150-fold increase of IL-6 blood levels within 7 days of the injury compared to needle-punctured control mice. Notably, IL-6 blood levels shrunk to a fourfold elevation in hemophilia mice over controls after 28 days, when the hematoma was replaced by arthrofibrosis. These findings indicate that acute-phase reactants in combination with sIL-6Rα could be sensitive biomarkers for the detection of acute and recent bleeding events in hemophilia., Competing Interests: None declared., (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/).)

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/).)

The root cause of autoantibody formation against factor VIII (FVIII) in acquired hemophilia A (AHA) remains unclear. We aimed to assess whether AHA is exclusively associated with autoantibodies toward FVIII or whether patients also produce increased levels of autoantibodies against other targets. A case-control study was performed enrolling patients with AHA and age-matched controls. Human epithelial cell (HEp-2) immunofluorescence was applied to screen for antinuclear (ANA) and anticytoplasmic autoantibodies. Screening for autoantibodies against extractable nuclear antigens was performed by enzyme immunoassay detecting SS-A/Ro, SS-B/La, U1RNP, Scl-70, Jo-1, centromere B, Sm, double-stranded DNA, and α-fodrin (AF). Patients with AHA were more often positive for ANA than control patients (64% vs 30%; odds ratio [OR] 4.02, 1.98-8.18) and had higher ANA titers detected than controls. Cytoplasmic autoantibodies and anti-AF immunoglobulin A autoantibodies were also more frequent in patients with AHA compared with controls. Autoantibodies against any target other than FVIII were found in 78% of patients with AHA compared with 46% of controls (OR 4.16, 1.98-8.39). Results were similar preforming sensitivity analyses (excluding either subjects with autoimmune disorders, cancer, pregnancy, or immunosuppressive medication at baseline) and in multivariable binary logistic regression. To exclude that autoantibody staining was merely a result of cross-reactivity of anti-FVIII autoantibodies, we tested a mix of 7 well-characterized monoclonal anti-FVIII antibodies. These antibodies did not stain HEp-2 cells used for ANA detection. In conclusion, a diverse pattern of autoantibodies is associated with AHA, suggesting that a more general breakdown of immune tolerance might be involved in its pathology., (© 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.)

Hemophilia A, a single gene disorder leading to deficient Factor VIII (FVIII), is a suitable candidate for gene therapy. The aspiration is for single administration of a genetic therapy that would allow the production of endogenous FVIII sufficient to restore hemostasis and other biological processes. This would potentially result in reliable protection from bleeding and its associated physical and emotional impacts. Gene therapy offers the possibility of a clinically relevant improvement in disease phenotype and transformational improvement in quality of life, including an opportunity to engage in physical activities more confidently. Gene therapy products for hemophilia A in advanced clinical development use adeno-associated viral (AAV) vectors and a codon-optimized B-domain deleted FVIII transgene. However, the different AAV-based gene therapies have distinct design features, such as choice of vector capsid, enhancer and promoter regions, FVIII transgene sequence and manufacturing processes. These, in turn, impact patient eligibility, safety and efficacy. Ideally, gene therapy technology for hemophilia A should offer bleed protection, durable FVIII expression, broad eligibility and limited response variability between patients, and long-term safety. However, several limitations and challenges must be overcome. Here, we introduce the characteristics of the BAY 2599023 (AAVhu37.hFVIIIco, DTX 201) gene therapy product, including the low prevalence in the general population of anti-AAV-hu37 antibodies, as well as other gene therapy AAV products and approaches. We will examine how these can potentially meet the challenges of gene therapy, with the ultimate aim of improving the lives of patients with hemophilia A., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.)

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.)

The mainstay of hemophilia treatment is to prevent bleeding through regular long-term prophylaxis and to control acute breakthrough bleeds. Various treatment options are currently available for prophylaxis, and treatment decision-making is a challenging and multifaceted process of identifying the most appropriate option for each patient. A multidisciplinary expert panel convened to develop a practical, patient-oriented algorithm to facilitate shared treatment decision-making between clinicians and patients. Key variables were identified, and an algorithm proposed based on five variables: bleeding phenotype, musculoskeletal status, treatment adherence, venous access, and lifestyle. A complementary, patient-focused preference tool was also hypothesized, with the aim of exploring individual patients' priorities, preferences, and goals. It is hoped that the proposed algorithm and the hypothesized patient preference tool will assist in selecting a treatment for each patient that is as efficient as possible in preventing bleeds while also accounting for the patient's expectations and priorities., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Emergence of new therapies are anticipated to improve clinical outcomes and quality of life of persons with haemophilia. Challenges in conducting randomized clinical trials in rare diseases have resulted in a lack of direct head-to-head comparisons to support value-based decision-making between different treatments., Methods: We conducted a literature review for new and emerging haemophilia A and B therapies (extended half-life [EHL] replacement factor, non-replacement therapies [NRT], and gene therapies [GT]) to identify differentiating patient-centred outcomes defined previously in a haemophilia value framework. Since the literature included all publication types (e.g., surveys, modelling studies, commentaries/reviews), collected data were assigned level of evidence scores., Results: Across different classes of therapies, bleeding was determined as the most frequently reported differentiating outcome, with EHL, NRT, and GT each demonstrating an advantage over comparator replacement therapies. EHL therapies for haemophilia A and B and NRT for haemophilia A showed good representation across Tier 1 outcomes (health status achieved/retained), while more publications were identified with Tier 2 (process of recovery) outcomes for NRT than EHL or GT. In Tier 3 (sustainability of health), frequency of breakthrough bleeds represented a differentiating outcome for EHL (both haemophilia A and B), NRT (haemophilia A only), and GT (haemophilia B only), whereas sustained good health was differentiating for most comparisons., Conclusions: We demonstrate the utility of the haemophilia value framework as a common core outcome set for effectively comparing therapies. Application of this framework will serve as a useful decision-making tool for patients, clinicians, and within health technology assessments., Key Points of Consideration: With the emergence of high-cost, paradigm changing treatments across multiple areas of medicine, we, the haemophilia community, need to be equipped to meet the growing demands for more rigorous evidence-based value assessments using the tools expected by assessors. The traditional access toolbox needs to evolve to meet the paradigm shift in treatment options. Value can no longer be defined by annualized bleed rates alone. To realize the full impact of new therapies, we need to utilize tools, such as a value framework, to organize evidence, identify data gaps, and assess patient-defined, meaningful outcomes across a multi-faceted dimension. The haemophilia value framework is an effective tool for organizing the available evidence and identifying gaps in the evidence. This can be used for assessing the value of emerging therapies in haemophilia utilizing data generated through randomized clinical trials and real world evidence generation. This is a call for incorporating the Value Framework into official submissions to authorities, as it captures a broader range of outcomes, including patient meaningful outcomes, in ways that better assess the potential benefits of new therapies., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Objective: To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management., Method: These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists., Results: The 10 proposed principles for AHA care are as follows: (a) Improving initial diagnosis of AHA; (b) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; (c) Effective communication between laboratories, physicians, and specialists; (d) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; (e) Comprehensive assessment of bleeding; (f) Appropriate use of bypassing agents; (g) Long-term follow-up and monitoring for efficacy and safety of immunosuppressive treatment; (h) Inpatient/outpatient settings; (i) Access to innovative and disruptive treatments; (j) Promotion of international collaborative research., Conclusion: The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non-specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts toward improving its practical, multidisciplinary management., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

In the context of the 'Mobile Haemophilia Outpatient Care (MHOC)' project we aimed to gather insights into the health-related quality of life (HRQoL), treatment satisfaction (TS) and adherence of persons with haemophilia (PWHs) who get treated at the Saarland University Hospital Haemophilia Treatment Centre (HTC). PWHs were visited at home at least twice (baseline, follow-up) by trained medical staff. Individual interviews were performed to measure patients' HRQoL and TS with validated questionnaires (Haem-A-QoL/Haemo-QoL and Hemo-Sat A /Hemo-Sat P ). Socio-demographic and clinical data were collected. In total, 79 PWHs were enrolled; 56 adults with a mean age of 37.4 ± 16.4 years (17-78) and 23 children [mean age of 9.8 ± 4.2 years (3-16)]. In total, 62% were severely affected; 48.1% received prophylaxis. Patients reported good HRQoL (adults: 23.1 ± 17.1; kids: 24.3 ± 11.1). Patients ( M  = 11.2 ± 9.5) and parents ( M  = 14.3 ± 7.4) were very satisfied with their provided treatment. The majority of study participants were evaluated to have a good treatment adherence. After 1-year follow-up of the MHOC, a significant improvement in HRQoL was seen in adults ( p  < 0.033) and in proxy ratings of parents ( p  < 0.0001); TS remained high with no change by MHOC intervention. Patients reported good HRQoL and TS. Most of them were evaluated as having a good treatment adherence. After implementation of the MHOC, adult patients reported a better HRQoL. Such a mobile medical care service is considered beneficial for patients, especially with limited access to a HTC., Competing Interests: S.v.M. received travel expenses from UKS in the frame of the project grant. H.E. and C.S. received travel expenses from Baxter Deutschland GmbH pertaining to the project. S.H. and N.G. have nothing to disclose., (Thieme. All rights reserved.)

Acquired hemophilia A (AHA) is due to autoantibodies against coagulation factor VIII (FVIII) and most often presents with unexpected bleeding. In contrast to congenital hemophilia, the patient's residual FVIII activity does not seem to correlate with the risk of bleeding as suggested from previous studies. Risk factors for bleeding have not been described. We used data from the prospective GTH-AH 01/2010 study to assess the risk of bleeding and the efficacy of hemostatic therapy. FVIII activity was measured at baseline and weekly thereafter. Bleeding events were assessed by treating physicians. A total of 289 bleeds were recorded in 102 patients. There were 141 new bleeds observed starting after day 1 in 59% of the patients, with a mean rate of 0.13 bleed per patient-week in weeks 1 to 12, or 0.27 bleed per patient-week before achieving partial remission. Weekly measured FVIII activity was significantly associated with the bleeding rate, but only achieving FVIII activity ≥50% abolished the risk of bleeding. A good World Health Organization performance status assessed at baseline (score 0 vs higher) was associated with a lower bleeding rate. Hemostatic treatment was reportedly effective in 96% of bleeds. Thus, the risk of new bleeds after a first diagnosis of AHA remains high until partial remission is achieved, and weekly measured FVIII activity may aid in assessing the individual risk of bleeding. These results will help to define future strategies for prophylaxis of bleeding in AHA., (© 2020 by The American Society of Hematology.)

Background: Recombinant porcine factor VIII (rpFVIII, OBI-1, susoctocog alfa) is used for the treatment of acute bleeds in patients with acquired hemophilia A (AHA). Inhibitors in AHA can sometimes cross-react with rpFVIII., Objectives: To assess the frequency, strength, and determinants of cross-reactivity., Patients/methods: Baseline samples from 70 patients of the prospective, observational cohort study GTH-AH 01/2010 were assessed for anti-human FVIII and anti-rpFVIII inhibitors using modified Nijmegen-Bethesda assays, as well as anti-human FVIII domain reactivity using enzyme-linked immunoassay (ELISA)., Results: Anti-human FVIII inhibitors were present in all samples ranging between 0.7 and 3891 Bethesda Units (BU)/mL. Inhibitors from 31 of 70 patients (44%) partially inhibited rpFVIII with anti-rpFVIII titers ranging between 0.5 and 471 BU/mL. Anti-rpFVIII titers were ≤5 BU in most patients. Patients with cross-reacting inhibitors, as compared to patients without, had significantly higher anti-human FVIII titers (27.8 versus 5.4 BU/mL) and lower baseline FVIII activity (<1 versus 2.6 IU/dL). The ratio between anti-rpFVIII to anti-human titers was highest for inhibitors involving the C1 domain. Cross-reactivity was very rare, if inhibitors reacted only with the C2 domain of FVIII (6%). An anti-human FVIII titer of >100 BU/mL predicted cross-reactivity with 97% likelihood, whereas an anti-human FVIII titer of <3.8 BU/mL predicted absent cross-reactivity with 90% likelihood., Conclusion: Cross-reacting inhibitors should be considered when choosing a treatment for bleeding patients with AHA. Cross-reactivity is frequent in patients with anti-human FVIII titers of >100 BU/mL., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of InternationalSociety on Thrombosis and Haemostasis.)

Results from the main parts (24 weeks) of 2 concizumab phase 2 trials are presented: explorer4 in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI) and explorer5 in HA. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level), with secondary objectives being safety and immunogenicity (assessed as number of adverse events [AEs] and antidrug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if ≥3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic (PK/PD) parameters were assessed. Thirty-six HA, 9 HAwI, and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15 of 17; 88.2%) did not escalate the dose; all patients chose to continue to the extension phase of the trials. Clinical proof of concept for prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs HA: 3.0 (95% confidence interval [CI], 1.7; 5.3) and 5.9 (95% CI, 4.2; 8.5) vs 7.0 (95% CI, 4.6; 10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin fragment 1+2, and d-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very low to medium titer) ADA+ tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297., (© 2019 by The American Society of Hematology.)

This report describes the technical features and potential advantages of the application of electronic haemophilia treatment diary smart medication ™ and an evaluation of real-life electronic treatment data collected from haemophilia patients. Since 2012, a total of 663 patients from 30 German haemophilia treatment centres (HTCs) have used the device. Data of nine HTCs were merged for real-life data analysis. Patients were divided into four subgroups according to above versus below mean values for annual factor consumption (AFC) and annual joint bleeds (AJB), respectively. The largest subgroup comprised patients with low mean AFC and AJB less than 2.25 (group A: 42%). Second largest was the group with low mean AJB but high AFC (group B: 32%), suggesting that resources could be saved in some patients. The group with low AFC but high AJB may need increased factor dosing (group D: 13%). Patients who showed a high mean AJB despite high AFC (group C: 13%) may require special medical attention, such as pharmacokinetic-adapted treatment modification or orthopaedic measures. Smart medication ™ enables the HTC to quickly identify patients in need of treatment changes and, thus, to plan individualized therapy modifications prior to patient visits. The growing pool of real-life data facilitates data analysis and may play an important role in the optimization of resource distribution., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Macrophages make important contributions to inflammation and wound healing. We show here that macrophage polarization is deregulated in haemophilia in response to macrophage colony-stimulating factor (M-CSF) and partially in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). As a result, haemophilia macrophages exhibit a specific impairment of M-CSF-mediated functions involved in wound healing such as clot invasion and phagocytosis. Haemophilia monocytes express reduced amounts of the receptors for M-CSF and GM-CSF, which correlates with a failure to express tumour necrosis factor α (TNFα) and CD163 in M-CSF-treated haemophilia macrophages and reduced expression of TNFα and CD206 after treatment with GM-CSF. Protein expression in response to M-CSF was regained with respect to CD163 and CD206 after embedding haemophilia monocytes in clotted plasma suggesting that a functioning coagulation system has positive effects on macrophage M2 polarization. Mimicking the functional deficits of haemophilia macrophages in normal macrophages was possible by adding leptin, which we found to be elevated in the blood of haemophilia patients, to a monocyte cell line. The increase of leptin occurred in conjunction with C-reactive protein in a body mass index-controlled cohort suggesting that haemophilia patients harbour chronic low-grade inflammation. Together, our data indicate that impaired clotting in haemophilia patients leads to increased inflammation and a deregulation in macrophage differentiation, which may explain the commonly observed deficits in wound healing and tissue regeneration., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential., Aim: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy., Methods: Free TFPI predictions were generated using an estimated concizumab-free TFPI exposure-response (E max ) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 μg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an E max model were constructed based on EXPLORER3 observations., Results: The E max model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re-established TG potential to within the normal reference range. Estimated EC 50 values for the identified concizumab-free TFPI and concizumab-TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once-daily dosing would minimize within-patient concizumab PK variability., Conclusion: Concizumab phase 2 trials will target an exposure ≥100 ng/mL, with a once-daily regimen., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction:  Regular visits at haemophilia treatment centres (HTCs) in rural regions are often dependent on the access to a private car due to lack of or limited availability of public means. Therefore, a mobile haemophilia outpatient care (MHOC) concept providing home visits to haemophilia patients has been developed by the Saarland HTC, which is located in a rural German region., Methods:  Haemophilia patients and their parents were home visited at least twice (baseline, follow-up) by trained medical staff. Socio-demographic and clinical data were collected and interviews were performed asking the patients and parents about their needs and expectations towards such a MHOC., Results:  Seventy-nine patients were enrolled (56 adults, 23 children), 62.0% severely affected, 48.1% on prophylaxis, with a mean age of 37.4 ± 16.4 years (17-78) and 9.8 ± 4.2 years (3-16), respectively. Median travel distance to the HTC was 43.5 km (3-200). Note that 92.4% considered an intense binding to the HTC and a MHOC concept as 'rather/very important' (88.6%). They expected from a MHOC to provide consulting and educating activities, support in elderhood issues and treatment. For 35.4%, a MHOC could currently provide additional support, mainly due to patient's immobility and need of consultancy. They mainly used services in terms of consultancy in social-legal affairs and support in contacting authorities., Conclusion:  The results of this study support the hypothesis that a MHOC concept is a needful supplement in haemophilia comprehensive care and will improve the challenging haemophilia treatment, especially for those with limited access to HTCs or with disabilities., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Turoctocog alfa pegol (N8-GP) is an extended half-life recombinant factor VIII molecule used for the treatment of hemophilia A (HA). The purpose of this study was to investigate real-world experiences of patients with HA treated with N8-GP.Patients and Methods: A 25-minute online survey was completed by adults (≥ 18 years) and caregivers of adolescents (12– 16 years) with HA receiving N8-GP across six countries (Germany, Italy, Portugal, Spain, UK and US). Patients were recruited using a multichannel approach through recruitment panels, referrals from healthcare professionals and patient associations. The survey comprised a questionnaire with metrics including satisfaction and preferences for N8-GP, quality of life (QoL) and long-term impact.Results: A total of 62 participants (98% male [n=61], mean age 29 years) comprising 46 patients and 16 caregivers completed the survey. Patients (60% non-severe [n=37] and 40% severe [25]) were on N8-GP for a mean period of 1.4 years. Patients expressed satisfaction (95% vs 42%, p< 0.001) and preference (91% vs 9%, p< 0.001) for N8-GP vs their previous treatments. Most patients with severe HA (87%, p=0.038) and patients on prophylaxis (84%, p< 0.001) stated lower frequency of injections as their main reason for satisfaction, while improved QoL drove satisfaction for non-severe patients (81%, p=0.053). Overall, patients perceived that QoL score improved (74.8 vs 65.9, p=0.01) with N8-GP treatment compared with previous treatments. Flexibility to store at room temperature was one of the key convenience factors driving satisfaction. Patients believed that N8-GP can offer a long-term impact in areas such as ability to perform day-to-day activities (68%), independence to live like a person without hemophilia (63%), ability to travel (60%) with a feeling of optimism and hopefulness (82%).Conclusion: Lower frequency of injections, storage flexibility and improved QoL drove satisfaction and preference for N8-GP over previous treatments among patients with HA.Plain Language Summary: Hemophilia A is a rare bleeding disorder that often runs in families. Although there is no cure, several therapeutic options are available to help control bleeding in people with hemophilia A. However, most treatments require intravenous (directly into a vein) or subcutaneous (directly under the skin) injections, which is a significant burden for all patients. In this study, adults and caregivers of adolescents, with hemophilia A answered a survey about their treatment experience with a medicine called N8-GP (turoctocog alfa pegol) compared with previous treatments.This is the first real-world evidence study focused on satisfaction with and preference for N8-GP compared with previous treatments. Survey results showed that adults and adolescents with hemophilia A were very satisfied with N8-GP compared with previous medicines. The main reasons for satisfaction included less frequent injections, the flexibility to store at room temperature, and improved quality-of-life.In addition, many patients expressed hopes for the future while taking N8-GP, such as confidence in ability to undertake physical activities and ability to plan and go on a holiday. Compared with previous treatments, patients were feeling optimistic and hopeful about N8-GP and expressed that they have started to think less about the disease.Despite the unique advantages of taking N8-GP, patients overall still perceive their quality-of-life to be less than an average person's, presenting an opportunity for future advancements. Overall, this study sheds light on the unique experiences of people with hemophilia A taking N8-GP and further opens up the scope for addressing the unmet needs. [ABSTRACT FROM AUTHOR]

Purpose: The stability under high-temperature conditions of factor VIII (FVIII) concentrates for replacement therapy is of critical importance to patients, particularly those who reside in, or travel to, regions with high ambient temperatures. Concerns about product stability may limit or prevent access to treatment for patients and may limit their ability to live a close-to-normal life. This study evaluated the effect of hot and humid storage conditions on the long-term stability of the recombinant FVIII products, turoctocog alfa and turoctocog alfa pegol. Methods: Turoctocog alfa samples were assessed for stability at 30°C for 9 months or 40°C for 3 months following storage at 5°C for 21 or 27 months, respectively, while turoctocog alfa pegol samples were assessed at 30°C for 12 months or 40°C for 3 months following storage at 5°C for 18 or 27 months, respectively. In addition, turoctocog alfa and turoctocog alfa pegol dry powders were evaluated for stability at 5°C/ambient humidity (AH) for 30 months, 30°C/75% relative humidity (RH) for 12 months and 40°C/75% RH for 6 months. Both studies utilized a range of product strengths. Key stability assessments included oxidized forms, potency, water content and high molecular weight protein (HMWP). Results: Both turoctocog alfa and turoctocog alfa pegol remained stable following storage at 40°C/75% RH for 3 months, and at single temperatures (5°C/AH, 30 and 40°C/75% RH), without any major increase in HMWP or any impairment of potency or water content. Conclusion: Turoctocog alfa and turoctocog alfa pegol offer stability at 40°C for up to 3 months without jeopardizing the quality of each product. These stability characteristics may offer patients flexibility with product storage and daily use. [ABSTRACT FROM AUTHOR]