Gene Therapy for Hemophilia A: What is the Expression of Factor VIII Using the Adeno-Associated Viral Vector SPK-8011?
The goal of gene therapy for hemophilia A is to safely transfer stable and durable expression of coagulation factor VIII (FVIII), which predictably improves the bleeding phenotype at the lowest possible vector dose. Updated data from a study examining the use of the adeno-associated viral vector (AAV) SPK-8011 were presented during the virtual congress of the International Society on Thrombosis and Haemostasis (ISTH) 2021.
Methodology and Study Progress
George et al. presented fresh insights from an ongoing phase I/II clinical trial testing the gene therapy referred to as SPK-8011. It is based on AAV and is being developed as a treatment option for hemophilia A.
Researchers used SPK-8011 for hepatocyte expression of FVIII in 17 men aged 34–52 years diagnosed with hemophilia A. Monitoring lasted for up to nearly 4 years after administration of the SPK-8011 vector in 4 dosage cohorts (5 × 1011 vector genomes [vg]/kg to 2 × 1012 vg/kg).
Results
Six participants experienced vector-related adverse events (in 1 case, an infusion reaction; in 5, transient elevations of liver transaminases). FVIII expression vanished in 2 patients due to an assumed cellular immune response to the AAV capsid unresponsive to immunosuppression, but in the remaining 15 men, it was long-term sustained: 11 of them were observed for more than 2 years (median 132 weeks, range 107–182 weeks) with no significant decline in FVIII activity over time.
The mentioned 15 probands with sustained FVIII expression stopped prophylactic treatment used at study entry, and the annual bleeding rate (ABR) in this group decreased by 93% (median 12 [0–43] events per year before vector administration vs. 0.0 [0.0–5.2] after vector administration; 95% confidence interval [CI] 89.0–96.4%).
Conclusion
SPK-8011 demonstrates acceptable safety and sustained FVIII expression in 15 of the 17 study participants, allowing these men to stop prophylaxis and resulting in a significant reduction in bleeding events. Current findings suggest that FVIII expression in hepatocytes can be stable and durable for up to 3.5 years after vector administration, with an acceptable safety profile.
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Source: George L. A., Monahan P. E., Eyster M. E. et al. Phase I/II trial of SPK-8011: stable and durable FVIII expression after AAV gene transfer for hemophilia A. ISTH Congress 2021. Res Pract Thromb Haemost 2021; 5 (Suppl. 1): OC 67.2. Available at: https://abstracts.isth.org/abstract/phase-i-ii-trial-of-spk-8011-stable-and-durable-fviii-expression-after-aav-gene-transfer-for-hemophilia-a
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