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.