Study Confirms Long-Term Safety and Efficacy of AAV Gene Therapy in Hemophilia B
Adeno-associated virus (AAV)–mediated gene therapy continues to demonstrate promise for individuals with severe hemophilia B, according to 13-year follow-up data on the scAAV2/8-LP1-hFIXco vector. The findings provide a rare long-term perspective on the durability and safety of this therapeutic approach, offering essential considerations for managed care professionals and payers evaluating coverage policies for gene therapies.
In this study, 10 adult men with severe hemophilia B received a one-time intravenous infusion of scAAV2/8-LP1-hFIXco at low (2×10¹¹ vg/kg), intermediate (6×10¹¹ vg/kg), or high (2×10¹² vg/kg) doses. Participants were followed for a median of 13.0 years (range, 11.1 to 13.8), making it one of the longest follow-ups to date in the gene therapy landscape.
Key efficacy endpoints included factor IX (FIX) activity, annualized bleeding rates (ABR), and FIX concentrate use. Safety was assessed through clinical events, liver function tests, imaging, and biopsy.
FIX activity remained stable throughout the follow-up. Mean FIX levels at 13 years were 1.7 IU/dL in the low-dose group, 2.3 IU/dL in the intermediate group, and 4.8 IU/dL in the high-dose cohort. Importantly, 7 of the 10 participants no longer required prophylactic therapy.
The median ABR dropped dramatically—from 14.0 episodes (IQR, 12.0 to 21.5) before treatment to just 1.5 episodes (IQR, 0.7 to 2.2) post-treatment, reflecting a 9.7-fold reduction. Factor IX concentrate use decreased by a factor of 12.4 (IQR, 2.2 to 27.1), underscoring the substantial reduction in treatment burden.
These findings reinforce the clinical value of gene therapy in preventing bleeds and reducing dependency on costly factor replacement therapy, which are critical elements for long-term disease management and health care resource allocation.
Safety outcomes over 13 years were favorable. A total of 15 vector-related adverse events were documented, mainly consisting of transient aminotransferase elevations. Notably, no participants developed FIX inhibitors, thrombosis, or chronic liver injury.
Two cancer cases emerged during the follow-up period but were determined to be unrelated to the gene therapy vector by both investigators and an expert multidisciplinary panel. A liver biopsy performed 10 years post-infusion revealed healthy hepatocyte transgene expression, without signs of fibrosis or dysplasia. Importantly, high levels of neutralizing antibodies to AAV8 persisted in all participants, highlighting potential challenges to vector re-administration.
The sustained clinical efficacy and absence of late-onset safety concerns over 13 years position scAAV2/8-LP1-hFIXco as a durable treatment for severe hemophilia B. From a managed care perspective, the dramatic reduction in bleeding events and factor concentrate use translates to potential long-term cost offsets, improved quality of life, and reduced utilization of acute care services.
However, the persistence of AAV8-neutralizing antibodies and current limitations on re-administration require thoughtful policy development around patient eligibility and timing of therapy.
Reference
Reiss UM, Davidoff AM, Tuddenham EGD, et al. N Engl J Med. 2025;392(22):2226-2234. doi:10.1056/NEJMoa2414783
