Durability of efficacy, safety, and quality of life 5 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A: final phase 3 GENEr8-1 trial results
Year: 2026
Type: article
Abstract: Background Valoctocogene roxaparvovec, a gene therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) expression and confers bleed control. Objectives To present the final 5-year efficacy and safety results from the phase 3 GENEr8-1 trial. Methods Adult men ( N = 134) with severe hemophilia A without inhibitors who were using FVIII prophylaxis received one 6 × 10 13 vg/kg infusion of valoctocogene roxaparvovec. End points included annualized bleeding rate (ABR), FVIII infusion rate, FVIII activity, Haemophilia-Specific Quality of Life Questionnaire for Adults, adverse events, and immunosuppressant use. Results Median follow-up was 261.1 weeks; 128 of 134 participants completed the study. For the 112 participants who enrolled from a previous noninterventional study (rollover population), mean ABR for treated bleeds declined by 83.3% ( P < .0001), mean FVIII infusion rate declined by 94.9% ( P < .0001), and mean ABR for all bleeds declined by 78.1% in the 5-year efficacy evaluation period vs baseline. In 132 modified intention-to-treat participants, mean and median FVIII activity at week 260 was 13.7 and 6.2 IU/dL, respectively (chromogenic assay). In year 5, 77.8% of rollover participants had 0 treated bleeds. One participant resumed prophylaxis since the 4-year data cutoff (25/134 across all follow-up). Haemophilia-Specific Quality of Life Questionnaire for Adults total score was improved from baseline at year 5. In year 5, alanine aminotransferase elevations occurred in 51 of 129 participants who entered year 5. Immunosuppressants were not used to manage them. No serious treatment-related adverse events occurred after year 1. Conclusion Valoctocogene roxaparvovec provides durable hemostatic efficacy, FVIII activity, and improved health-related quality of life for ≥5 years, with no new safety signals.
Authors: Andrew D. Leavitt, Johnny Mahlangu, Priyanka Raheja, Emily Symington, Doris V. Quon, Adam Giermasz, Gili Kenet, Gillian Lowe, Nigel S. Key, Carolyn M. Millar, Steven W. Pipe, Sheng-Chieh Chou, Robert Klamroth, Jane Mason, Hervé Chambost, Flora Peyvandi, Elaine Majerus, Dominic Pepperell, Chee Wee Tan, Hua Yu, Konstantia-Maria Chavele, Margareth C. Ozelo
Institutions: University of California, San Francisco, University of the Witwatersrand, Barts Health NHS Trust, Royal London Hospital, Cambridge University Hospitals NHS Foundation Trust, University of California Davis Medical Center, University of California, Davis, Tel Aviv University, Sheba Medical Center, University Hospitals Birmingham NHS Foundation Trust, University of North Carolina at Chapel Hill, Imperial College Healthcare NHS Trust, Imperial College London, University of Michigan, National Taiwan University Hospital, University of Bonn, University Hospital Bonn, Klinikum im Friedrichshain, The University of Queensland, Royal Brisbane and Women's Hospital, Inserm, Aix-Marseille Université, Assistance Publique Hôpitaux de Marseille, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Washington University in St. Louis, Fiona Stanley Hospital, Royal Adelaide Hospital, BioMarin (United States), BioMarin (United Kingdom), Universidade Estadual de Campinas (UNICAMP)
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,250
Funders: Translational Research and Applied Medicine, School of Medicine, Stanford University, American Diabetes Association, U.S. Department of Veterans Affairs, Pfizer, Brown University, University of Kentucky, University of Utah, BioMarin Pharmaceutical, Canadian Food Inspection Agency, Ministerio de Ciencia, Innovación y Universidades, Harmony Biosciences, National Institute for Health and Care Research, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Natural Science Foundation of China, Grantová Agentura České Republiky, Chinese Academy of Sciences, China Postdoctoral Science Foundation, Fonds Wetenschappelijk Onderzoek, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, University of Toronto, National Research Foundation of Korea, University of Hong Kong, KU Leuven, Knut och Alice Wallenbergs Stiftelse, Shiraz University of Medical Sciences, Vetenskapsrådet, Natural Science Foundation of Guangxi Province, Natural Science Foundation of Jiangsu Province, Veterinární a Farmaceutická Univerzita Brno, Uniwersytet Medyczny w Lodzi, Natural Science Foundation of Tianjin City, Russian Science Foundation, Nanjing Tech University, Department of Education of Zhejiang Province, Agrifutures Australia, Stichting Vrienden van het Sophia, Science and Technology Department of Gansu Province, Junta de Andalucía, Kementerian Pendidikan Malaysia, National Science and Technology Major Project, Sickkids Research Institute, Fondation Médicale Reine Elisabeth, National Institutes of Health, Horizon 2020 Framework Programme, College of Medicine, Seoul National University, Qatar National Library, Biotechnology and Biological Sciences Research Council, Australian Research Council, Wageningen University and Research, Basic Research Program of Jiangsu Province, Guangzhou Municipal Science and Technology Project, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities, Institute for Materials Research, Tohoku University, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Division of Chemistry, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Stanford Maternal and Child Health Research Institute, Natural Science Foundation of Zhejiang Province
OpenAlex ID: W7141064933