An Australian and international study has shown gene therapy can help reduce bleeding episodes in haemophilia A patients for up to four years, despite previous studies suggesting otherwise.
The phase 1–2 trial, funded by vector manufacturer Roche Group-member Spark Therapeutics, assessed adeno-associated viral (AAV) vector SPK-8011’s ability to support safe and durable hepatocyte expression of factor VIII in 18 male haemophilia A patients over a median observation period of 36 months.
It found single, intravenous doses up to 2 x 1012 vector genomes per kilogram led to a 91.5% reduction in annualised bleeding events from median 8.5 per year pre-treatment to 0.3 post treatment.
Sixteen patients sustained factor VIII expression throughout the study, with the 12 patients followed for more than two years showing “no apparent decrease in factor VIII activity over time” (mean: 12.9% of normal at 26 to 52 weeks while patients weren’t receiving glucocorticoids versus 12% of normal > 52 weeks after vector administration), University of Sydney haematologist Professor John Rasko and colleagues wrote in the New England Journal of Medicine.
The annualised bleeding rate of 0 events in 60 to 100% of those 16 patients with sustained expression was “similar to the results with emicizumab prophylaxis in severe haemophilia A”.
Only two patients lost all factor VIII expression during the trial due to an anti-AAV capsid cellular immune response that wasn’t sensitive to suppression.
While the authors noted no major safety concerns, they did report 33 treatment-related adverse events in eight patients, including vector-related alanine and liver aminotransferase elevation, pyrexia, myalgia, back pain and vomiting and glucocorticoid-related adrenal insufficiency, gastroesophageal reflux, osteoporosis, generalised oedema and muscle spasms, among other symptoms.
“These data provide support for our hypothesis that hepatocyte expression of factor VIII after AAV gene transfer is a viable approach for long-term stable phenotypic amelioration of haemophilia A,” the authors wrote.