Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.
Full text not available from this repository.Item Type: | Article |
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Status: | Published |
Official URL: | https://doi.org/10.1056/NEJMoa2104205 |
Journal or Publication Title: | New England Journal of Medicine |
Volume: | 385 |
Number: | 21 |
Page Range: | pp. 1961-1973 |
Date: | 18 November 2021 |
Divisions: | Gene and Stem Cell Therapy |
Depositing User: | General Admin |
Identification Number: | 10.1056/NEJMoa2104205 |
ISSN: | 0028-4793 |
Date Deposited: | 07 Dec 2021 09:22 |
Abstract: | Abstract 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 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. 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. |
Creators: | Creators Email George, Lindsey A. UNSPECIFIED Monahan, Paul E. UNSPECIFIED Eyster, M. Elaine UNSPECIFIED Sullivan, Spencer K. UNSPECIFIED Ragni, Margaret V. UNSPECIFIED Croteau, Stacy E. UNSPECIFIED Rasko, John E.J. UNSPECIFIED Recht, Michael UNSPECIFIED Samelson-Jones, Benjamin J. UNSPECIFIED MacDougall, Amy UNSPECIFIED Jaworski, Kristen UNSPECIFIED Noble, Robert UNSPECIFIED Curran, Marla UNSPECIFIED Kuranda, Klaudia UNSPECIFIED Mingozzi, Federico UNSPECIFIED Chang, Tiffany UNSPECIFIED Reape, Kathleen Z. UNSPECIFIED Anguela, Xavier M. UNSPECIFIED High, Katherine A. UNSPECIFIED |
Last Modified: | 07 Dec 2021 09:22 |
URI: | https://eprints.centenary.org.au/id/eprint/1175 |
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