A novel gene therapy for hemophilia A has demonstrated sustained expression of the missing clotting factor, leading to a significant reduction in bleeding events, according to a study led by researchers at Children's Hospital of Philadelphia (CHOP). The phase 1/2 trial, published in the New England Journal of Medicine, is the first to show stable coagulation factor VIII (FVIII) levels in hemophilia A patients following gene therapy.
The multicenter, international trial involved 18 males with hemophilia A, aged 18-52 years. Participants received SPK-8011, a recombinant adeno-associated viral (AAV) vector designed to produce FVIII in the patient's liver cells. The study followed participants for up to four years to assess the therapy's expression, safety, and efficacy.
Sustained FVIII Expression and Reduced Bleeding
The results showed that 16 of the 18 participants maintained FVIII expression throughout the trial. Twelve of these participants were followed for over two years and exhibited no apparent decrease in FVIII activity. Overall, the trial participants experienced a 91.5% reduction in bleeding episodes. Lead study author Dr. Lindsey A. George, Director of Clinical In Vivo Gene Therapy at CHOP, stated that the data supports the approach of hemophilia A gene transfer, conferring stable FVIII expression over multiple years.
Hemophilia A, the most common inherited bleeding disorder, affects 1 in 5,000 males worldwide. It results from a deficiency in FVIII, leading to uncontrolled bleeding, joint disease, and increased mortality risk. Current treatment involves regular FVIII protein infusions, which require significant coordination and do not fully address joint disease or mortality risks.
Addressing Prior Setbacks in Gene Therapy
Previous gene therapy trials using AAV vectors showed initial success but were hampered by a decline in FVIII expression after one year. The CHOP-led study aimed to overcome this limitation by hypothesizing that liver-directed gene therapy could produce safe and durable FVIII levels sufficient for prophylactic treatment.
Most participants in the trial received steroids to mitigate potential immune responses to the AAV vector. However, two participants experienced a loss of FVIII expression within a year due to a presumed immune response, indicating that steroids do not universally prevent expression loss.
Future Directions
Dr. George emphasized that future research will focus on improving the therapy to achieve sustained, stable, and predictable FVIII levels in all hemophilia A patients. The trial was funded by Spark Therapeutics, which originated from CHOP in 2013, and received support from the National Institutes of Health (NIH).
