Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A

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

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Item Type: Article
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
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; 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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