Hemophilia A Gene Therapy Shows Sustained Factor VIII Expression


A 1-stage factor VIII assay revealed no apparent decrease in factor VIII activity over time.

SPK-8011, an investigational gene therapy for hemophilia A, was well-tolerated and yielded sustained Factor VIII expression in treated men, according to data from a phase 1/2 study (NCT03003533) and its long-term follow-up study (NCT03432520).1

Sixteen of 18 patients had maintained factor VIII expression, with follow-up of over 2 years in 12 patients. Participants had an average 91.5% reduction (95% CI, 88.8-94.1) in annualized bleeding rate (ABR) after therapy.

“The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose,” first author Lindsey A. George, MD, and colleagues wrote.1

The study enrolled 18 men with hemophilia A in 4 cohorts with doses ranging from 5×1011 vector vg/kg to 2×1012 vg/kg. Primary outcomes were safety as measured by adverse events (AEs) and preliminary efficacy as measured by Factor VIII activity. Secondary outcomes include vector shedding and liver safety. Participants were between 18 and 52 years of age and were followed-up for a median of 36.6 months (range, 5.5-50.3) after treatment. Some participants received glucocorticoids within 52 weeks of treatment to prevent or treat a presumed adeno-associated virus (AAV) capsid immune response.

READ MORE: Gene Therapies for Hemophilia Have Positive Real-World Impact, Studies Show

“We are encouraged by the results from the phase 1/2 trial for investigational SPK-8011, which has been evaluated in the largest phase 1/2 gene therapy trial in this disease to date, and demonstrates continued response over time, a critical measure of a therapy’s potential to transform lives for people living with this chronic condition,” said Gallia Levy, MD, PhD, chief medical officer, Spark Therapeutics, in a previous statement.2 “We remain focused on optimizing the dose and immunomodulatory regimen in the phase 1/2 study and look forward to continuing our evaluation of this therapy in a Phase 3 study.”

A total of 33 treatment-related AEs occurred in 8 participants. Most were vector-related (n = 17), including 1 serious AE, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression due to an anti–AAV capsid cellular immune response unresponsive to immune suppression. 

Factor VIII expression was maintained in the remaining 16 participants. A 1-stage factor VIII assay showed no apparent decrease in factor VIII activity over time, with a mean of 12.9% (SD, 6.9) of the normal value at 26 to 52 weeks) compared to a mean of 12.0% (SD, 7.1) of the normal value after 52 weeks (95% CI, −2.4 to 0.6). Participants had a 91.5% reduction (95% CI, 88.8-94.1) in ABR, from a median of 8.5 (range, 0-43.0) before therapy to 0.3 events (range, 0-6.5) after therapy.

“Our trial provided data on multiyear, stable factor VIII expression after hepatocyte-directed AAV gene transfer. This trial began to answer questions that have emerged from previous trials of AAV-mediated gene transfer for hemophilia A. Close monitoring of participants to determine safety and efficacy and to confirm initial multiyear observations of durable expression are ongoing,” George and colleagues concluded.

1. George LA, Monahan PE, Eyster E, et al. Multiyear factor VIII expression after AAV gene transfer for hemophilia A. N Engl J Med 2021; 385:1961-1973. doi: 10.1056/NEJMoa2104205
2. Spark Therapeutics’ SPK-8011 suggests stable and durable Factor VIII expression in largest phase 1/2 gene therapy study in Hemophilia A to date. News release. Spark Therapeutics. July 21, 2021. https://sparktx.com/press_releases/spark-therapeutics-spk-8011-suggests-stable-and-durable-factor-viii-expression-in-largest-phase-1-2-gene-therapy-study-in-hemophilia-a-to-date/
Related Videos
Alexandra Gomez-Arteaga, MD
Pietro Genovese, PhD, the principal investigator at the Gene Therapy Program of Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
Akshay Sharma, MBBS, a bone marrow transplant physician at St. Jude Children’s Research Hospital
Caspian Oliai, MD, MS, the medical director of the UCLA Bone Marrow Transplantation Stem Cell Processing Center
Genovefa (Zenia) Papanicolaou, MD, an infectious diseases specialist at Memorial Sloan Kettering Cancer Center
Akshay Sharma, MBBS, a bone marrow transplant physician at St. Jude Children’s Research Hospital
John DiPersio, MD, PhD, the director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine
© 2024 MJH Life Sciences

All rights reserved.