AAV gene therapy shows durable benefit in hemophilia B

1. In this prospective cohort study, a single intravenous dose of scAAV2/8-LP1-hFIXco gene therapy in men with severe hemophilia B led to sustained factor IX expression and significantly reduced bleeding and factor IX usage over 13 years.

2. No long-term vector-related safety concerns emerged; transient liver enzyme elevations were managed effectively, and no participants developed thrombosis or chronic liver injury.

Evidence Rating Level: 3 (Average)

Study Rundown: Hemophilia B is an X-linked bleeding disorder caused by mutations in the F9 gene, resulting in deficient or dysfunctional factor IX and leading to frequent spontaneous bleeding. Gene therapy is an emerging area of interest for conditions with identified causative mutations. Accordingly, this prospective cohort study evaluated the long-term safety and efficacy of a single infusion of scAAV2/8-LP1-hFIXco gene therapy in ten adult men with severe hemophilia B. Over a median follow-up of 13 years, factor IX activity levels remained stable (median 4.8 IU/dL in the high-dose cohort), while the median annualized bleeding rate decreased nearly tenfold from 14.0 to 1.5 episodes and factor IX concentrate use dropped by a factor of 12.4. Seven participants discontinued prophylaxis. Transient elevations in liver enzymes occurred early but were managed without lasting hepatic injury. Two participants developed cancers deemed unrelated to the therapy. The small cohort size limited the generalizability of the study. Conversely, the extended follow-up period of the study and sustained clinical benefit of treatment support the long-term utility of AAV-mediated gene therapy in hemophilia B.

Click to read the study in the NEJM (New England Journal of Medicine)

In-Depth [prospective cohort]: This prospective cohort study followed ten adult men with severe hemophilia B who received a single intravenous dose of the scAAV2/8-LP1-hFIXco vector between 2010 and 2012. Participants were assigned to low (2×10¹¹ vg/kg, n=2), intermediate (6×10¹¹ vg/kg, n=2), or high (2×10¹² vg/kg, n=6) dose groups. The primary endpoints included factor IX activity, annualized bleeding rate (ABR), and factor IX concentrate use. Median follow-up duration was 13.0 years (range 11.1–13.8). Factor IX activity remained dose-dependent and stable, with mean steady-state levels of 1.7 IU/dL (low), 2.3 IU/dL (intermediate), and 4.8 IU/dL (high). The overall median ABR decreased from 14.0 to 1.5 episodes annually, a 9.7-fold reduction (IQR, 3.7 to 21.8), with the high-dose group showing a 16.4-fold reduction (IQR, 9.7 to 31.3). Median factor IX concentrate usage declined from 2613 IU/kg to 367 IU/kg, a 12.4-fold decrease. Strengths of the study include the 13-year follow-up, detailed biochemical and clinical tracking, and robust reductions in bleeding and treatment burden. Persistent factor IX expression and safety without chronic liver injury or thrombosis are particularly noteworthy. A biopsy ten years post-infusion confirmed transgene expression without fibrosis or dysplasia. However, three patients with advanced joint disease resumed prophylaxis despite transgene expression, indicating variability in clinical outcomes. Additionally, high-titer anti-AAV8 antibodies persisted, complicating future vector re-administration. Overall, this study supports the long-term benefit and safety of AAV gene therapy for hemophilia B.

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