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George LA, Monahan PE, Eyster ME, et al. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. N Engl J Med. 2021;385(21):1961-1973doi: 10.1056/NEJMoa2104205.
George, L. A., Monahan, P. E., Eyster, M. E., Sullivan, S. K., Ragni, M. V., Croteau, S. E., Rasko, J. E. J., Recht, M., Samelson-Jones, B. J., MacDougall, A., Jaworski, K., Noble, R., Curran, M., Kuranda, K., Mingozzi, F., Chang, T., Reape, K. Z., Anguela, X. M., & High, K. A. (2021). Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. The New England journal of medicine, 385(21), 1961-1973. https://doi.org/10.1056/NEJMoa2104205
George, Lindsey A, et al. "Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A." The New England journal of medicine vol. 385,21 (2021): 1961-1973. doi: https://doi.org/10.1056/NEJMoa2104205
George LA, Monahan PE, Eyster ME, Sullivan SK, Ragni MV, Croteau SE, Rasko JEJ, Recht M, Samelson-Jones BJ, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape KZ, Anguela XM, High KA. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. N Engl J Med. 2021 Nov 18;385(21):1961-1973. doi: 10.1056/NEJMoa2104205. PMID: 34788507.
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N Engl J Med. 2021 Nov 18;385(21):1961-1973. doi: 10.1056/NEJMoa2104205.

Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.

The New England journal of medicine

Lindsey A George, Paul E Monahan, M Elaine Eyster, Spencer K Sullivan, Margaret V Ragni, Stacy E Croteau, John E J Rasko, Michael Recht, Benjamin J Samelson-Jones, Amy MacDougall, Kristen Jaworski, Robert Noble, Marla Curran, Klaudia Kuranda, Federico Mingozzi, Tiffany Chang, Kathleen Z Reape, Xavier M Anguela, Katherine A High

Affiliations

  1. From the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), and Spark Therapeutics (P.E.M., A.M., K.J., R.N., M.C., K.K., F.M., T.C., K.Z.R., X.M.A., K.A.H.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).

PMID: 34788507 DOI: 10.1056/NEJMoa2104205

Abstract

BACKGROUND: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose.

METHODS: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5  × 10

RESULTS: The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration).

CONCLUSIONS: Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).

Copyright © 2021 Massachusetts Medical Society.

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