Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A

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

Full text not available from this repository.
Item Type: Article
Status: Published
Official URL:
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

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 × 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; numbers, NCT03003533 and NCT03432520.).

Copyright © 2021 Massachusetts Medical Society.

George, Lindsey A.
Monahan, Paul E.
Eyster, M. Elaine
Sullivan, Spencer K.
Ragni, Margaret V.
Croteau, Stacy E.
Rasko, John E.J.
Recht, Michael
Samelson-Jones, Benjamin J.
MacDougall, Amy
Jaworski, Kristen
Noble, Robert
Curran, Marla
Kuranda, Klaudia
Mingozzi, Federico
Chang, Tiffany
Reape, Kathleen Z.
Anguela, Xavier M.
High, Katherine A.
Last Modified: 07 Dec 2021 09:22

Actions (login required)

View Item View Item