Stable and Durable Factor VIII Expression in Subjects Dosed with Investigational Hemophilia A Gene Therapy

More than two years after receiving Spark Therapeutics’ investigational adeno-associated virus (AAV)-mediated gene therapy (SPK-8011), five adult subjects with hemophilia A exhibited stable factor VIII (FVIII) expression, with no evidence of FVIII inhibitors or a cellular immune response.

Two subjects who received the lower-dose of 5 x 1011 g/kg cohort maintained steady-state FVIII:C levels of 6.9 percent to 8.4 percent, while three subjects in the higher-dose 1 x 1012 vg/kg cohort had FVIII:C levels ranging between 5.2 percent and 19.8 percent. Two of the three subjects in the 1 x 1012 vg/kg cohort were treated with steroids for about seven weeks in response to declining FVIII levels in the absence of alanine aminotransferase (ALT) elevation or positive IFN-g ELISPOTs to capsid-derived peptides. Once steady-state FVIII expression was achieved by eight to 12 weeks, and no meaningful change in FVIII:C was seen in any of the five subjects.

Over the 106- to 142-week observation period, there was an overall 95 percent reduction in the annualized exogenous FVIII infusion rate, and a 91 percent reduction in the annualized bleeding rate (ABR). Post-gene therapy administration ABRs for the five subjects were 0.4, 0.0, 0.4, 3.6 and 0.5. “Our data represent the longest stable expression of FVIII following gene transfer and support the ability of AAV-mediated hepatocyte-directed gene transfer to achieve durable FVIII expression for the potential treatment of hemophilia A,” the investigators concluded.