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Vol. 42. Issue S2.
Pages 60 (November 2020)
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Vol. 42. Issue S2.
Pages 60 (November 2020)
98
DOI: 10.1016/j.htct.2020.10.099
Open Access
A FIRST-IN-HUMAN FOUR-YEAR FOLLOW-UP STUDY OF DURABLE THERAPEUTIC EFFICACY AND SAFETY OF AAV GENE THERAPY WITH VALOCTOCOGENE ROXAPARVOVEC FOR SEVERE HEMOPHILIA A
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M.C. Ozeloa, K.J. Pasib, S. Rangarajanc, N. Mitchelld, W. Lestere, E. Symingtonf, B. Madang, M. Laffanh, C.B. Russelld, M. Lid, B. Kimd, G.F. Piercei, W.Y. Wongd
a Centro de Hematologia e Hemoterapia (Hemocentro), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
b Barts and the London School of Medicine and Dentistry, London, United Kingdom
c University Hospital Southampton, Southampton, United Kingdom
d BioMarin Pharmaceutical Inc., Novato, United States
e University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
f Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
g Guy's & St. Thomas’NHS Foundation Trust, London, United Kingdom
h Centre for Haematology, Imperial College London, London, United Kingdom
i Consultant, La Jolla, United States
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Background: Long-term clinical benefit has been demonstrated in people with hemophilia A following a single administration of the investigational gene therapy valoctocogene roxaparvovec (AAV5-hFVIII-SQ). Safety, clinical effectiveness, and mechanisms of episomal vector DNA persistence have been previously described, but outstanding questions pertain to the maintenance of these attributes over increasing durations of follow-up. Aims: The four-year safety, efficacy, and durability of valoctocogene roxaparvovec is evaluated in a Phase 1/2 clinical study for severe hemophilia A. Methods: Adult male study participants with severe hemophilia A were followed for up to four years after receiving a single intravenous dose of valoctocogene roxaparvovec at 6×1013 vg/kg (n=7) or 4×1013 vg/kg (n=6). Results: After four (6×1013 vg/kg) or three (4×1013 vg/kg) years, all study participants demonstrated clinically meaningful FVIII activity levels with reductions in bleeds and FVIII usage. Following withdrawal from prophylaxis, annualized bleeding rate declined from pre-treatment mean by 95% at year four in 6×1013 vg/kg participants, and 93% at year three in 4×1013 vg/kg participants. Despite FVIII activity levels continuing to decline at a shallow rate, all patients in both cohorts remained off prophylaxis. After four years, the safety profile of valoctocogene roxaparvovec remained favorable and unchanged, with no inhibitor development or treatment-related ALT elevations beyond year one. Conclusions: Four-year follow-up data demonstrate that gene transfer with valoctocogene roxaparvovec leads to substantial and sustained FVIII activity levels, clinically relevant reductions in self-reported bleeding episodes, and significant reductions in FVIII replacement infusions. These data from the first-in-human trial represent the most up-to-date, long term follow-up data currently available for the investigational use of AAV-mediated therapy for hemophilia A.

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Hematology, Transfusion and Cell Therapy

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