Search

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.)

Independent data collection is crucial in addressing the challenges associated with gene therapy for hemophilia, which is a promising treatment option but requires careful monitoring and management of short-term and potential long-term safety concerns. The International Society on Thrombosis and Haemostasis has identified a minimum efficacy and safety data set included in the World Federation of Hemophilia Gene Therapy Registry that should be collected on a national basis at specific time points for each patient who has been treated with the gene therapy products. This Gene Therapy Minimum Data Set (GT-MDS) was developed to facilitate data collection and to ensure capturing the most relevant data and most known and unknown safety and efficacy parameters recently cited by the European Medicine Agencies. The concept of assembling a minimum data set is not about creating a new data set but rather about identifying a subset of critical and essential topics that should always be included. The GT-MDS is structured into 3 sections and comprises an abridged list of 6 topics during routine gene therapy follow-up, keeping the number of data points low but allowing for rapid and independent data evaluation. The World Federation of Hemophilia Gene Therapy Registry data set, developed by the World Federation of Hemophilia, the International Society on Thrombosis and Haemostasis, and other organizations, including industry partners in 2020, is comprehensive. The GT-MDS reports the minimum relevant information that should not be lost and is mandatory to be collected for all patients who undergo gene therapy. Therefore, the implementation of the gene therapy registry and the minimum data set empowers and enhances data collection at a global level., Competing Interests: Declaration of competing interests W.M.: Bayer, BioMarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, Sigilon, Sobi, Takeda/Shire, uniQure. B.K.: Grant/research support from CSL Behring, Pfizer, Sanofi, Spark Therapeutics, Takeda, and uniQure; Consultant fees from Be Biopharma, BioMarin, Regeneron, Pfizer, Sanofi; Leadership roles: World Federation for Hemophilia, Foundation for Women and Girls with Blood Disorders. P.C.: Bayer, Boehringer Ingelheim, CSL Behring, Chugai, Freeline, NovoNordisk, Pfizer, Roche, Sanofi, Spark, Sobi, and Takeda. R.K.: Grants from Bayer; consulting fees from BioMarin, Pfizer; honoraria for lectures from Pfizer; participation on a data safety monitoring board or advisory board: BioMarin, Pfizer. F.L.: Grant/research support from CSL Behring, Takeda, uniQure, Sobi; consultant fees from uniQure, Sobi, BioMarin; Research support from CLE Behring, Takeda, Sobi, uniQure. J.M.: Grant/research support from BioMarin, Novartis, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Spark Therapeutics, and uniQure; consultant fees for BioMarin, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, Spark Therapeutics and Takeda; Speaker bureau fees from Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Takeda, WFH, and ISTH. M.M.: Leadership roles: EAHAD council member 2018-2022. ISTH council member 2018-2022. S.W.P.: Consulting fees from Apcintex, ASC Therapeutics, Bayer, BioMarin, CSL Behring, Equilibra Bioscience, HEMA Biologics, Freeline, LFB, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, and uniQure; Scientific Advisory Board member: Equilibra Bioscience, GeneVentiv. G.P.: consultant to ASC Therapeutics, BioMarin, Pfizer, Regeneron, and Spark Therapeutics and on the scientific advisory boards of Be Bio, Frontera, and Metagenomic. A.S.: speaker: Novo Nordisk, Roche, Sanofi, Takeda, Octapharma, and BioMarin; advisory board: Novo Nordisk, Roche, Sanofi, Takeda, Pfizer, BioMarin, and Spark; research grant: Roche, Novo Nordisk, Sanofi, and Pfizer. J.V.: no personal fees. F.P.: consulting fees from CSL Behring, Biomarin, Roche, Sobi, and Sanofi; payment or honoraria for lectures: Takeda and Spark., (Copyright © 2024 International Society on Thrombosis and Haemostasis. All rights reserved.)

Background: Mim8 (denecimig) is a factor VIII (FVIII) mimetic bispecific antibody in development for the treatment of hemophilia. Data from the phase 1 part of FRONTIER1 (EudraCT: 2019-000465-20, NCT04204408, and NN7769-4513) suggested that Mim8 was well tolerated in healthy participants and exhibited pharmacokinetic (PK) properties consistent with dose proportionality., Objectives: The partially randomized, phase 2, multiple ascending dose (MAD) part of FRONTIER1 aimed to evaluate the safety, PK, pharmacodynamics (PD), and exploratory efficacy of Mim8 in participants with hemophilia A with or without FVIII inhibitors., Methods: The MAD part of FRONTIER1 consisted of 42 participants, assigned to 5 cohorts, with participants in cohorts 3 and 4 randomized 1:1 to dosing weekly or every 4 weeks, respectively. Four of the 42 participants (9.5%) had FVIII inhibitors prior to study enrolment. The primary endpoint was treatment-emergent adverse events (TEAEs). PK and PD were evaluated by Mim8 plasma concentration and thrombin generation, respectively. Exploratory efficacy was assessed via the number of treated bleeds. Safety and PD parameters were also evaluated from an exploratory cohort treated with emicizumab., Results: Mim8 was well tolerated, with 1 serious TEAE (anxiety-related chest pain) deemed unrelated to Mim8. There was no dose dependency on the number, causality, type, or severity of TEAEs. PK/PD properties supported weekly to monthly dosing approaches, and few participants experienced treated bleeds beyond the lowest dose cohort (1 in cohorts 2 and 3, and 3 in cohort 5)., Conclusion: These data support the continued clinical development of Mim8, and FRONTIER1 has proceeded onto an extension phase., Competing Interests: Declaration of competing interests S.R.L. has consulted for Argenx, Novo Nordisk, and Takeda. P.C. has served on advisory boards for ApcinteX, Bayer, Boehringer Ingelheim, CSL Behring, Chugai, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Spark, Sobi, and Takeda, and has received research funding from Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer, Sobi, and Takeda. F.L.J. has served as a speaker or on advisory boards for Amgen, Bayer, CSL Behring, Novartis, Novo Nordisk, Pfizer, Roche, Rovi, Sobi, and Takeda, and has received research funding from Sobi. J.M. has received research grants from BioMarin, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Spark, and UniQure; served as a consultant for BioMarin, Novo Nordisk, Roche, Sanofi, Spark, and Takeda; and served on a speaker’s bureau for the International Society on Thrombosis and Haemostasis, Novo Nordisk, Pfizer, Roche, Sanofi, Takeda, and World Federation of Hemophilia. I.M. and A.L.N. are employed at Novo Nordisk and own stocks in the company. J.W. has received research funding and honorarium from AlfaSigma, Alnylam, Amgen, AstraZeneca, Bayer AG, CSL Behring, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Siemens, Sobi, Swixx BioPharma, and Takeda. L.G. has no competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL)., Objectives: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1., Methods: Participant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS). Participants completed the questionnaires at baseline and through 104 weeks postinfusion with 6 × 10 13 vg/kg of valoctocogene roxaparvovec. Scores were analyzed per participant characteristics and outcomes., Results: For 132 HIV-negative participants, mean change from baseline in Haemo-QOL-A Total Score met the anchor-based clinically important difference (CID: 5.5) by week 12; the mean (SD) increase was 7.0 (12.6) at week 104. At week 104, improvement in Consequences of Bleeding, Treatment Concern, Worry, and Role Functioning domain scores exceeded the CID (6). EQ-5D-5L Utility Index scores improved above the CID at week 52, but not at week 104. EQ-5D-5L visual analog scale and HAL scores increased from baseline to week 104. Participants reported less activity and work impairment at week 104 than baseline. Participants with problem joints had lower mean baseline Haemo-QOL-A Total and domain scores than those without them, but improved over 104 weeks, except for 11 participants with ≥3 problem joints. Participants with 0 bleeds during the baseline prophylaxis period reported Haemo-QOL-A score improvements above the CID, including in the Consequences of Bleeding domain., Conclusion: Valoctocogene roxaparvovec provided clinically meaningful HRQOL improvement for men with severe HA., Competing Interests: Declaration of competing interests B.O.M. reports consulting fees from BioMarin Pharmaceutical Inc and Freeline. A.L.D. reports research funding from Sanofi, Takeda, Freeline, BioMarin Pharmaceutical Inc, and the American Thrombosis and Hemostasis Network; consulting fees from BioMarin Pharmaceutical Inc, Genentech/Roche, Kedrion, CSL Behring, and uniQure; and service on the board of the World Federation of Hemophilia USA. A.D.L. reports consulting or advisory panel fees from BioMarin Pharmaceutical Inc, Dova, CSL Behring, Merck, Catalyst, and HEME Biologics; and participation as a clinical trial investigator in trials sponsored by BioMarin Pharmaceutical Inc, Sangamo, and Pfizer. F.P. reports honoraria as a speaker for educational symposia by Grifols, Sanofi, and Takeda and as an advisory member for Sanofi and Roche. M.C.O. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; research grants from Pfizer, Roche, and Takeda; service as a clinical trial investigator for BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; speaker honoraria from Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Roche, and Takeda; travel support from Novo Nordisk, Roche, and Takeda; and participation in grant reviewing for Grifols. J.M. reports consulting fees from Baxalta, CSL Behring, Catalyst Biosciences, Freeline, LFB, Novo Nordisk, and Spark; research grants from and service as a clinical trial investigator for BioMarin Pharmaceutical Inc, CSL Behring, Novo Nordisk, Pfizer, Sobi, Roche, Novartis, Sanofi, and Unique; and speaker fees from Novo Nordisk, Pfizer, Sanofi, Sobi, Shire, Roche, Takeda, the International Society on Thrombosis and Haemostasis, and the World Federation of Hemophilia. K.P. reports consulting fees and research grants from Sobi, Octapharma, Novo Nordisk, and Pfizer; and served as a clinical trial investigator for uniQure, BioMarin Pharmaceutical Inc, and Roche. J-D.W. reports consulting fees from Bayer, Novo Nordisk, Pfizer, Chugai, Sanofi, Takeda, and Sobi; speaker fees from Bayer, CSL Behring, Novo Nordisk, Pfizer, Chugai, Sanofi, and Takeda; and service as a clinical trial investigator for Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche/Chugai, and Sanofi. G.L. has received honoraria for participating in educational events from Novartis, LEO, Sobi, Alexion, Takeda, Novo Nordisk, and Sanofi; and consulting fees from UCB. A.G. reports honoraria for service on advisory boards from BioMarin Pharmaceutical Inc, Genentech, Pfizer, Bayer, ATHN, Novo Nordisk, uniQure, and Sanofi Genzyme; and travel grants from BioMarin Pharmaceutical Inc. E.C. reports consulting fees from Genentech, BioMarin Pharmaceutical Inc, Novo Nordisk, Takeda, Sanofi, HEMA Biologics, and CSL Behring; and speaker fees from Genentech. D.P. reports a travel grant from Pfizer. H.C. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Roche, and Sobi; served as a clinical trial investigator for BioMarin Pharmaceutical Inc, Bioverativ, CSL Behring, LFB, Octapharma, Roche, Pfizer, Sobi, and Takeda; reports speaker fees from BioMarin Pharmaceutical Inc, Pfizer, Roche, and Sobi; and reports travel grants from BioMarin Pharmaceutical Inc, CSL Behring, Octapharma, Roche, and Sobi. M.F.L.F. reports participation in advisory boards and receiving speaking fees from Shire/Takeda, Amgen, CSL Behring, Novo Nordisk, Bayer, LFB, Pfizer, and Sobi. E.M. reports consulting fees and travel support from BioMarin Pharmaceutical Inc and served as a clinical trial investigator for BioMarin Pharmaceutical Inc. M.W.S. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Pfizer (DMC), Roche/Genentech, Sanofi, Spark (DMC), and Takeda; and research grants from BioMarin Pharmaceutical Inc, Freeline, Roche, Takeda, and uniQure. R.Klamroth reports consulting fees from Bayer, Biotest, BioMarin Pharmaceutical Inc, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; research grants from Bayer and LEO; speaker fees from Bayer, Biotest, BioMarin Pharmaceutical Inc, CSL Behring, Daiichi Sankyo, LEO, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; travel support from Bayer, Biotest, BioMarin Pharmaceutical Inc, CSL Behring, Daiichi Sankyo, LEO, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; and service as a clinical trial investigator for Bayer, BioMarin Pharmaceutical Inc, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, Sobi, and uniQure. S.W.P. reports consulting fees from Apcintex, ASC Therapeutics, Bayer, BioMarin Pharmaceutical Inc, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, Roche/Genentech, Sanofi, Spark Therapeutics, Takeda, and uniQure; and service as a clinical trial investigator for BioMarin Pharmaceutical Inc, Freeline, Genentech/Roche, Sanofi, and uniQure. J.Q. is a former employee of BioMarin Pharmaceutical and may hold stock. H.Y., T.M.R., and W.Y.W. are employees and stockholders of BioMarin Pharmaceutical Inc. C.W.T., H.T., R.Kazmi, and T-L.K. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Hemophilia is classified into mild, moderate, and severe based on coagulation factor activity levels. Factor replacement and prophylaxis regimens in persons with hemophilia have helped to reduce bleeding and its related complications. With several newer treatments, some already approved and others soon to be, there may be a need to consider health-related quality of life in addition to bleed prevention as the goals of providing comprehensive care to persons with hemophilia. In this article, we discussed the reasons why such an approach may be relevant and call for the International Society of Thrombosis and Haemostasis to revisit the current classification of hemophilia., Competing Interests: Declaration of competing interests J.T. received honoraria from Roche, Octapharma, Takeda, Grifols, Novo Nordisk, and Sobi pharmaceuticals. J.M. received grant/research support from Biomarin, Norvatis, Novo Nordisk, Pfizer, Roche, Sanofi, Spark, UniQure; was a consultant/on the scientific board for Biomarin, Novo Nordisk, Roche, Takeda, Sanofi, and Spark; and participated in the Speaker bureau of ISTH, Novo Nordisk, Pfizer, Roche, Sanofi, Takeda, and WFH. J.C. and M.S. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Hemophilia A and B predominantly attracts clinical attention in males due to X-linked inheritance, introducing a bias toward female carriers to be asymptomatic. This common misconception is contradicted by an increasing body of evidence with consistent reporting on an increased bleeding tendency in hemophilia carriers (HCs), including those with normal factor VIII/IX (FVIII/IX) levels. The term HC can hamper diagnosis, clinical care, and research. Therefore, a new nomenclature has been defined based on an open iterative process involving hemophilia experts, patients, and the International Society on Thrombosis and Haemostasis (ISTH) community. The resulting nomenclature accounts for personal bleeding history and baseline plasma FVIII/IX level. It distinguishes five clinically relevant HC categories: women/girls with mild, moderate, or severe hemophilia (FVIII/IX >0.05 and <0.40 IU/ml, 0.01-0.05 IU/ml, and <0.01 IU/ml, respectively), symptomatic and asymptomatic HC (FVIII/IX ≥0.40 IU/ml with and without a bleeding phenotype, respectively). This new nomenclature is aimed at improving diagnosis and management and applying uniform terminologies for clinical research., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: As the first non-factor replacement therapy for persons with congenital hemophilia A (PwcHA), emicizumab's safety profile is of particular interest to the community., Objectives: We applied an algorithm for categorization of fatal events contemporaneous to emicizumab using reporter-assessed causality documented in the Roche Emicizumab Global Safety Database., Patients/methods: All fatalities in PwcHA reported to the database (from clinical trials, pre-market access, and spontaneous post-marketing reports) were categorized into: associated with hemophilia A-hemorrhagic, thrombotic, human immunodeficiency virus (HIV)/hepatitis C virus (HCV), hepatic (non-HCV); associated with general population-trauma/suicide, non-HA-associated conditions; or, unspecified. Reported cause of death was not reassessed., Results: As of cut-off May 15, 2020, 31 fatalities in PwcHA taking emicizumab were reported. Median age at death was 58 years; 51% had factor VIII inhibitors. Fifteen fatalities were considered associated with HA; overall, the most frequent category was hemorrhage (11/31). Of these, six had a history of life-threatening bleeds, and four had a history of intracranial hemorrhage. The remaining HA-associated fatalities were related to HIV/HCV (3/31) and other hepatic causes (1/31). No cases were categorized as thrombotic. Of 10 cases considered not associated with HA, two were categorized as cardiovascular (non-thrombotic), five as infection/sepsis, and one each of trauma/suicide, pulmonary, and malignancy. Six cases were unspecified., Conclusions: No unique risk of death was associated with emicizumab prophylaxis in PwcHA. The data reveal that mortality in PwcHA receiving emicizumab was primarily associated with hemorrhage or non-HA-associated conditions, and was not reported by treaters to be related to emicizumab treatment., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Despite recent therapeutic advances, life expectancy in persons with congenital hemophilia A (PwcHA) remains below that of the non-HA population. As new therapies are introduced, a uniform approach to the assessment of mortality is required for comprehensive evaluation of risk-benefit profiles, timely identification of emerging safety signals, and comparisons between treatments., Objectives: Develop and test a framework for consistent reporting and analysis of mortality across past, current, and future therapies., Patients/methods: We identified known causes of mortality in PwcHA through literature review, analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, and expert insights. Leading causes of death in general populations are those recognized by the Centers for Disease Control and Prevention and the World Health Organization. We developed an algorithm for assessing fatalities in PwcHA and used this to categorize FAERS data as a proof of concept., Results: PwcHA share mortality causes with the non-HA population including cardiovascular disease, malignancy, infections, pulmonary disease, dementias, and trauma/suicide. Causes associated with HA include hemorrhage, thrombosis, human immunodeficiency virus, hepatitis C virus, and liver dysfunction. We propose an algorithm employing these classes to categorize fatalities and use it to classify FAERS fatality data between 01/01/2000 and 03/31/2020; the most common causes were hemorrhage (22.2%) and thrombosis (10.4%)., Conclusions: A conceptual framework for examining mortality in PwcHA receiving any hemophilia therapy is proposed to analyze and interpret fatalities, enabling consistent and objective assessment. Application of the framework using FAERS data suggests a generally consistent pattern of reported mortality across HA treatments, supporting the utility of this unified approach., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Gene therapy for people with hemophilia (PWH) will soon become available outside current clinical trials. The World Federation of Hemophilia (WFH), in collaboration with International Society of Thrombosis and Hemostasis Scientific and Standardization Committee (ISTH SSC), the European Haemophilia Consortium (EHC), the US National Hemophilia Foundation (NHF), the American Thrombosis and Hemostasis Network (ATHN), industry gene therapy development partners and Regulatory liaisons have developed the Gene Therapy Registry (GTR), designed to collect long-term data on all PWH who receive hemophilia gene therapy., Objective: The objectives of the GTR are to record the long-term safety and efficacy data post gene therapy infusion and to assess the changes in quality of life and burden of disease post-gene-therapy infusion., Methods: The GTR is a prospective, observational, and longitudinal registry developed under the guidance of a multi-stakeholder GTR Steering Committee (GTR SC), composed of health care professionals, patient advocates, industry representatives, and regulatory agency liaisons. All PWH who receive gene therapy by clinical trial or commercial product will be invited to enrol in the registry through their hemophilia treatment centers (HTCs). The registry aims to recruit 100% of eligible post gene therapy PWH globally. Through an iterative process, and following the guidance of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), the GTR SC has developed a core set of data to be collected on all patients post gene therapy., Results: The core data set includes demographic information, vector infusion details, safety, efficacy, quality of life and burden of disease., Conclusions: The GTR is a global effort to ensure that long term safety and efficacy outcomes are recorded and analysed and rare adverse events, in a small patient population, are identified. Many unknowns on the long-term safety and efficacy of gene therapy for hemophilia may also be addressed., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: A recombinant factor VIIa analog (NN1731; vatreptacog alfa [activated]) was developed to provide safe, rapid and sustained resolution of bleeds in patients with hemophilia and inhibitors., Patients/methods: This global, prospective, randomized, double-blinded, active-controlled, dose-escalation trial evaluated and compared one to three doses of vatreptacog alfa at 5, 10, 20, 40, and 80 lg kg(-1) with one to three doses of recombinant FVIIa (rFVIIa) at 90 lg kg(-1) in the treatment of acute joint bleeds in hemophilia patients with inhibitors. The primary endpoint comprised adverse events; secondary endpoints were evaluations of immunogenicity, pharmacokinetics, and efficacy., Results and Conclusions: Overall, 96 joint bleeds in 51 patients (> 12 years of age) were dosed. Vatreptacog alfa was well tolerated, with a low frequency of adverse events. No immunogenic or thrombotic events related to vatreptacog alfa were reported. A high efficacy rate of vatreptacog alfa in controlling acute joint bleeds was observed; 98% of bleeds were controlled within 9 h of the initial dose in a combined evaluation of 20–80 lg kg(-1) vatreptacog alfa. The efficacy rate observed for rFVIIa (90%) is consistent with data from published clinical trials. The trial was not powered to compare efficacy, and further trials are needed to investigate the efficacy of vatreptacog alfa as compared with that of rFVIIa. The trial was registered at ClinicalTrials.gov (, Registration Number: NCT00486278).