Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A

Author(s): Johnny Mahlangu, M.B., B.Ch., M.Med., Radoslaw Kaczmarek, Ph.D., Annette von Drygalski, M.D., Pharm.D., Susan Shapiro, M.D., Ph.D., Sheng-Chieh Chou, M.D., Margareth C. Ozelo, M.D., Ph.D., Gili Kenet, M.D., Flora Peyvandi, M.D., Ph.D., Michael Wang, M.D., Bella Madan, M.D., Nigel S. Key, M.D., Michael Laffan, D.M., Ph.D., et al., for the GENEr8-1 Trial Group*
Source: N Engl J Med 2023; 388:694-705 DOI: 10.1056/NEJMoa2211075
Maem Hussein MD

Dr. Maen Hussein's Thoughts

For benign hematology, this is a good article about gene therapy in Hemophilia A.


Valoctocogene roxaparvovec delivers a B-domain–deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously.


We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII.


At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred.


The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A.  Funded by BioMarin Pharmaceutical; GENEr8-1 number, NCT03370913.

Author Affiliations

From the Hemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, and National Health Laboratory Service, Johannesburg (J. Mahlangu); the Department of Pediatrics, Indiana University School of Medicine, IUPUI-Wells Center for Pediatric Research, Indianapolis (R.K.); the Laboratory of Glycobiology, Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland (R.K.); the Department of Medicine, University of California, San Diego, La Jolla (A.D.), the Orthopedic Hemophilia Treatment Center, Los Angeles (D.V.Q.), the University of California, San Francisco, San Francisco (A.D.L.), and BioMarin Pharmaceutical, Novato (K.J., H.Y., R.M., K.-M.C., D.B.R., J.H., T.M.R., W.Y.W.) — all in California; Oxford University Hospitals NHS Foundation Trust, the Radcliffe Department of Medicine, University of Oxford, and the Oxford National Institute for Health Research Biomedical Research Centre, Oxford (S.S.), Guy’s and St. Thomas’ NHS Foundation Trust (B.M.) and the Centre for Haematology, Imperial College London (M.L.), London, and Cambridge University Hospitals NHS Foundation Trust, Cambridge (E.S.) — all in the United Kingdom; the Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei (S.-C.C.); Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil (M.C.O.); the National Hemophilia Center, Sheba Medical Center, Tel Hashomer, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Tel Aviv University, Tel Aviv (G.K.) — both in Israel; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, and Università degli Studi di Milano, Department of Pathophysiology and Transplantation — both in Milan (F.P.); the Hemophilia and Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora (M.W.); the UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill (N.S.K.); Nationwide Children’s Hospital and the Ohio State University College of Medicine, Columbus (A.L.D.); the Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women’s Hospital, and the University of Queensland — both in Brisbane, Australia (J. Mason); the Institute of Experimental Haematology and Transfusion Medicine and Center for Rare Diseases, University Hospital Bonn, Bonn, Germany (J.O.); Assistance Publique–Hôpitaux de Marseille, Department of Pediatric Hematology Oncology, Children’s Hospital La Timone and Aix Marseille University, INSERM, Institut National de la Recherche Agronomique, Center for Cardiovascular and Nutrition Research, Marseille, France (H.C.); the Center for Bleeding and Clotting Disorders, University of Minnesota, Minneapolis (M.T.R.); and the Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor (S.W.P.). Dr. Mahlangu can be contacted at or at the Faculty of Health Sciences, University of the Witwatersrand, 7 York Rd., Parktown 2194, Johannesburg, South Africa. A list of the members of the GENEr8-1 Trial Group is provided in the Supplementary Appendix, available at

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