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Gene Therapy Offers Years of Benefit for hemophilia B, Landmark Study Shows
A single infusion of gene therapy dramatically reduces bleeding and the need for regular treatments in most patients with hemophilia B, according to long-term data presented at the 67th American Society of Hematology (ASH) Annual Meeting & exposition and published in Blood. The findings offer compelling evidence that this approach can significantly improve the lives of individuals living with this inherited bleeding disorder.
The phase 3 HOPE-B trial, led by Steven Pipe, MD, at the University of Michigan, tracked 54 adult men with severe or moderately severe hemophilia B for five years after a single infusion of etranacogene dezaparvovec, a gene therapy utilizing an adeno-associated virus serotype 5 (AAV5) vector. Researchers sought to address a critical question in the field: dose the therapeutic effect of gene therapy endure over time?
Participants in the study had limited baseline factor IX activity – 2 IU/dL or less – and were already undergoing routine prophylactic treatment to manage their condition. Following a six-month baseline period, each participant received a single intravenous infusion of the gene therapy at a dose of 2 × 10 genome copies per kilogram. The study then monitored bleeding rates, factor levels, factor usage, and safety.
The results demonstrate a significant and sustained reduction in bleeding. From seven months to five years post-infusion, the adjusted annualized bleeding rate for all bleeds was 1.52, a roughly 63% decrease compared to the 4.16 bleeds observed during the lead-in period with standard prophylaxis. This positive trend extended to both spontaneous and joint bleeds, remaining consistently lower throughout the five-year follow-up. Importantly, the data showed no indication of waning efficacy in years four and five, a crucial factor for long-term success in gene therapy.
Beyond bleeding rates, factor IX expression also remained robust. Mean endogenous activity stayed above 36% through the end of the study, shifting most patients from the severe range of the disease to levels typically associated with mild hemophilia B or even better. This translated into a remarkable 96% reduction in overall factor IX consumption. Only one patient – approximately 2% of the cohort – required a return to routine prophylaxis after experiencing a decline in factor levels and a recurrence of bleeding roughly 2.5 years after treatment.
The study also included individuals with pre-existing neutralizing antibodies to AAV5. Outcomes for these patients were generally comparable to those without detectable antibodies, suggesting the therapy can be effective even in the presence of an immune response.However, two participants did not achieve sustained factor expression, one with the highest baseline antibody titer and another who received a lower-than-intended dose.
In terms of safety, treatment-related adverse events were largely confined to the initial four months after infusion. Ten participants experienced transient elevations in alanine aminotransferase, which were successfully managed with corticosteroids. Investigators reported no evidence of delayed hepatotoxicity, malignancy, or othre late-emerging safety concerns related to etranacogene dezaparvovec over the five-year follow-up period.
These findings provide strong evidence that a single infusion of gene therapy can deliver multiyear benefits for many patients with hemophilia B. However, several key questions remain. Researchers are now planning extended follow-up, out to 15 years, to determine how long factor expression will persist. Identifying factors that predict loss of response is also a priority. Furthermore, as new non-factor therapies and long-acting products emerge, understanding how patients will weigh a one-time gene therapy treatment against more flexible options will be crucial.
For now, the HOPE-B trial significantly strengthens the argument that gene therapy can liberate patients with hemophilia B from the ongoing cycle of infusions for years to come. Whether this benefit will extend for decades remains the central question driving ongoing research.
