Research Summary

5-Year HOPE-B Data Support Durable Hemophilia B Gene Therapy

Edited by:
Ashton L. Stahl

Key Highlights

  • In 54 participants, adjusted annualized bleeding rates fell 63% from lead-in prophylaxis to months 7 through 60 after gene therapy.
  • Mean factor IX activity remained stable at 36.1 IU/dL at 5 years, with 96% of participants showing endogenous expression.
  • Exogenous factor IX use decreased 96%, and 94% of participants discontinued continuous prophylaxis without restarting.
  • Most treatment-related adverse events occurred within 6 months; none of the serious adverse events were considered treatment-related.

A final 5-year analysis of the phase 3 HOPE-B study found that a single infusion of etranacogene dezaparvovec was associated with sustained endogenous factor IX expression, reduced bleeding, and markedly lower factor IX use in men with severe or moderately severe hemophilia B, according to findings published in The New England Journal of Medicine.

This open-label international study enrolled 54 adult men with hemophilia B and baseline factor IX activity of 2 IU/dL or less. After a lead-in period of at least 6 months on stable factor IX prophylaxis, participants received a single intravenous dose of etranacogene dezaparvovec at 2×10^13 genome copies/kg. Prespecified 5-year analyses compared adjusted annualized bleeding rates during months 7 through 60 after infusion with the lead-in period and also assessed factor IX expression, factor IX consumption, and safety. Participants with preexisting AAV5 neutralizing antibodies were eligible for enrollment.

Study Findings

In the full analysis population, the adjusted annualized bleeding rate for all bleeding events declined from 4.16 during the lead-in period to 1.52 during months 7 through 60 after treatment, representing a 63% reduction (95% CI, 24 to 82). The adjusted annualized bleeding rate also decreased by 65% for spontaneous bleeding (1.52 to 0.53), 85% for joint bleeding (2.34 to 0.35), and 78% for traumatic bleeding (2.01 to 0.43). Out of 54 participants, 50 (93%) completed 5 years of follow-up.

Endogenous transgene-derived factor IX expression was observed in 52 participants (96%). At 5 years, the mean factor IX activity level was 36.1±15.7 IU/dL, and 80% of participants had a factor IX activity level of at least 12 IU/dL. Factor IX expression remained above 30 IU/dL on average throughout years 1 through 5. Efficacy did not differ substantially between participants with and without baseline AAV5 neutralizing antibodies, although factor IX activity was somewhat lower in antibody-positive participants.

Use of exogenous factor IX fell from a mean of 257,339 IU per year during lead-in to 10,924 IU per year during months 7 through 60, a 96% reduction. Continuous prophylaxis was discontinued and not restarted in 51 participants (94%). Among the 52 participants who responded, 51 maintained durable protection against bleeding from months 7 through 60.

Clinical Implications

According to the study authors, etranacogene dezaparvovec provided sustained clinical benefit over 5 years, with durable endogenous factor IX expression and low bleeding rates. Most treatment-related adverse events occurred within 6 months, and no factor IX inhibitors or thrombotic events were reported. Although neoplasms were reported during follow-up, independent molecular analyses found no evidence that they were related to treatment. The authors noted that interindividual variability in factor IX activity remains an important consideration.

Expert Commentary

“The increased factor IX expression was associated with reductions in annualized bleeding rates and exogenous factor IX consumption. In addition, after the treatment with etranacogene dezaparvovec, no evidence of oncogenicity, of long-term toxic effects on the liver, or of any substantial toxic effects was observed after the first 6 months,” the researchers concluded.

Reference

Pipe SW, Miesbach W, Recht M, Leebeek FWG, Key NS, Castaman G, et al; HOPE-B Study Group Investigators. Final analysis of a study of etranacogene dezaparvovec for hemophilia B. N Engl J Med. 2026;394(5):463-474. doi:10.1056/NEJMoa2514332