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Introduction: Haemophilia A is an X-linked bleeding disorder resulting from a deficiency of factor VIII (FVIII). To date, multiple gene therapies have entered clinical trials with the goal of providing durable haemostatic protection from a single dose. TAK 754 (BAX 888) is an investigational AAV8-based gene therapy containing a FVIII transgene. Reduction in CpG motifs was performed to reduce immunogenicity based on prior observations. Here, we describe the results of the first two cohorts treated with TAK 754., Aim: To report clinical and translational results of the TAK-754 phase 1/2 AAV gene therapy study for the treatment of haemophilia A., Methods: A phase 1/2 single arm open-label dose escalation study of TAK-754 was performed in participants with severe haemophilia A (NCT03370172). Participants were monitored for safety events, endogenous FVIII activity and bleeding rates. Glucocorticoids were implemented to preserve transgene expression. A transcriptomics analysis was performed to evaluate immunogenicity along with additional post-hoc analyses., Results: Four participants were dosed in two cohorts. Infusion of TAK 754 was well-tolerated. All participants developed mild transient transaminase elevation and subsequent loss of FVIII expression within the first 12 months of treatment despite use of glucocorticoids. Transcriptomic analysis did not demonstrate significant changes in immunogenicity signals in peripheral blood. One serious adverse event of hypophosphatemia occurred in the second cohort without obvious risk factors., Conclusions: Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow-up periods., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Aim: To evaluate the impact of haemophilia A without inhibitors on humanistic outcomes in patients and caregivers. Herein, we report a cross-sectional analysis of the baseline data of persons with haemophilia (PWH) participating in the prospective study HEMOLIFE., Methods: These data are part of a prospective, observational, and multicentre study currently being conducted in 20 hospitals in Spain by haematologists. We included subjects 12 years or older diagnosed with haemophilia. The evaluations included the Maladjustment Scale, Haemophilia-Specific Quality of Life Questionnaire for Adults (HaemoQol)/HaemoQol Short Form (Children), haemophilia-specific version of the Work Productivity and Impairment Questionnaire plus the Classroom Impairment Questionnaire (WPAI+CIQ:HS), Haemophilia Activity List (HAL)/Paediatric Haemophilia Activities List (pedHAL), visual analogue scale (VAS) for evaluating pain, Coping Pain Questionnaire-Reduced (CAD-R), and Hospital Anxiety and Depression Scale (HADS)., Results: A total of 81 PWH were recruited at 18 centres; 66 PWH were ≥18 years (i.e., adults), and PWH 15 were <18 years (i.e., paediatric patients). Out of the 79 evaluable subjects, 16 (20%) showed an impact of haemophilia on daily life, and the areas most affected were "leisure time" (58% showed maladjustment) and "work/studies" (47% showed maladjustment). Patients reported a higher impact of haemophilia on quality of life (mean [SD] of the transformed score) in the dimensions of "sport" (49.4 [28.6]), "physical health" (40.5 [25.8]) and "future" (37.7 [28.9]). In adults, according to HAL scores, greater impairment of function was observed in "lying/sitting/kneeling/standing," "function of legs" and "leisure activities and sports," with mean normalized scores of 64.7, 65.1 and 69.0, respectively. Productivity was mostly impacted by presenteeism. The pain was infrequent and moderate. According to the HADS scores, nine (11.5%) patients had clinical anxiety and depression., Conclusion: PWH without inhibitors exhibited impairments in adjustment, quality of life and functionality, especially related to leisure and sports activities, and exhibit relevant levels of anxiety and depression., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

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.)