Five years after a single infusion of etranacogene dezaparvovec, the majority of patients in the HOPE-B trial maintained near-normal factor IX activity and experienced a significant reduction in bleeding events. Data presented at the International Society on Thrombosis and Haemostasis (ISTH) 2026 Congress confirmed that for most men with severe or moderately severe hemophilia B, the gene therapy successfully replaced the need for routine prophylaxis.
Long-term Efficacy and Factor IX Stability
The HOPE-B trial followed 54 men who received a single dose of the AAV5-vectored gene therapy, which carries the hyperactive factor IX Padua variant. According to the study results, 50 participants completed the full five-year monitoring period. Researchers observed that endogenous factor IX activity remained remarkably stable, moving from a mean level of 39.0 IU/dL at six months to 36.1 IU/dL at the five-year mark.
The therapy effectively reduced the burden of treatment for participants. Exogenous factor IX usage dropped by 98% among responders, falling from an average of 262,077 IU per year during the lead-in period to just 5,919 IU per year post-treatment.
Impact on Annualized Bleeding Rates
The clinical benefit of the therapy was measured against each patient’s own history during a lead-in prophylaxis period. The data showed a sustained decrease in bleeding episodes across all categories. Adjusted annualized bleeding rates (ABR) dropped by 82% overall, declining from 3.99 to 0.71. More specifically, joint bleeds saw a 90% reduction, falling from 2.20 to 0.23.
All reductions in spontaneous, traumatic, and factor IX–treated bleeds were statistically significant at P<0.0001. This consistency suggests that for the vast majority of trial participants, the single-infusion approach provided durable protection against the complications typically associated with hemophilia B.
Challenges in Patient Response and Immunity
While the trial demonstrated high success rates, not every participant achieved the same outcome. Two of the 54 enrolled men did not respond to the therapy. Investigators linked one failure to a high baseline AAV5-neutralizing antibody titer of 3,212.3. The second non-responder received only a fraction of the intended dose following an infusion-related reaction.
Among those who did respond, neutralizing antibody titers ranged from below 7 to 678. These findings have initiated a clinical discussion regarding patient selection: determining the exact threshold of preexisting AAV5 immunity that should disqualify a candidate from treatment remains a primary focus for future implementation.
Safety Profile and Treatment Durability
Over the five-year study period, researchers reported no serious treatment-related adverse events. There were no documented cases of oncogenicity or late-onset hepatotoxicity. While two patient deaths occurred during the trial, investigators concluded that neither was related to the gene therapy.
Durability remains a consideration for long-term care. One responder required a return to continuous prophylaxis approximately 29 months after the initial infusion, indicating that while the therapy is effective for most, it may not provide a permanent solution for every individual.
Frequently Asked Questions
What is the primary mechanism of etranacogene dezaparvovec?
It uses an adeno-associated virus serotype 5 (AAV5) vector to deliver the hyperactive factor IX Padua variant, allowing the body to produce its own factor IX.
How effective is the treatment at reducing bleeds?
The HOPE-B trial reported an 82% reduction in overall annualized bleeding rates and a 90% reduction in joint bleeds over five years among responders.
Can patients with preexisting immunity receive this therapy?
High levels of AAV5-neutralizing antibodies may interfere with the therapy. One non-responder in the trial had a high titer of 3,212.3, highlighting the need for careful patient screening.
Are there long-term safety concerns?
No serious treatment-related adverse events, oncogenicity, or late hepatotoxicity were reported throughout the five-year study duration.
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