Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A

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 5x10(11) vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2x10(12) 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, and .) Gene Therapy for Hemophilia A At a median follow-up of 3.5 years after gene therapy with a factor VIII-containing adeno-associated virus, 16 of 18 men with hemophilia A had enough factor VIII expression that bleeding events were reduced to nearly zero and prophylaxis was discontinued. Vector-related hepatitis led to elimination of the vector in 2 men, but immunosuppressive therapy helped to maintain expression in the others.

Automated summary

A gene therapy trial using an AAV vector (SPK-8011) for factor VIII expression in 18 men with hemophilia A showed sustained expression in most participants, leading to reduced bleeding events and discontinuation of prophylaxis.