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Longer-Term Follow-Up in Patients Receiving AAV Gene Therapy for Hemophilia A
Major aims in the treatment of hemophilia A include reducing bleeding events, avoiding severe arthropathy, and improving quality of life. Among the recent advances in the treatment of hemophilia, the most promising is the prospect of gene therapy. In a phase 1–2, open-label, multicenter study, investigators evaluated the safety and efficacy of an adeno-associated viral (AAV) vector (SPK-8011) in 18 patients (ages 18–52) with hemophilia A (factor VIII activity <2% of normal), lacking factor VIII inhibitor, and with SPK200 neutralizing antibodies at titers <1:5. All but one patient had baseline arthropathy. Patients were enrolled into four dose cohorts ranging from a dose of 5×1011 vector genomes (vg)/kg to 2×1012 vg/kg.
Key findings include:
- 1 patient had an infusion reaction and 7 patients had increases in alanine aminotransferase (1 with a serious adverse event).
- In 15 patients with factor VIII expression maintained during >52 weeks of follow-up, mean factor VIII activity levels were 11% of normal (6.9% when measured by chromogenic factor VIII assays).
- 12 patients followed for more than 2 years had multiyear stable expression.
- There was a 91.5% decrease in annualized bleeding events and a 96.4% reduction in annualized need for factor VIII infusions.
- 2 patients lost factor VIII expression due to capsid immune response that was not rescued by steroids.
This study shows continued promise for AAV gene therapy in hemophilia A. Most patients had sustained expression of factor VIII levels that were greater than 10% — a threshold which could potentially be considered as the minimum threshold for efficacy. Some patients could not wean off steroids and had to use steroid-sparing immunosuppression to protect from capsid immune response.
George LA et al.
Title: Multiyear factor VIII expression after AAV gene transfer for hemophilia A.
Source: N Engl J Med 2021 Nov 18; [e-pub]. (Abstract/FREE Full Text)