Final Analysis of a Study of Etranacogene Dezaparvovec for Hemophilia B

BACKGROUND: Prophylactic treatment for hemophilia B necessitates lifelong, regular intravenous factor IX infusions. Gene therapy offers the possibility of a single-dose treatment that produces durable endogenous factor IX expression and disease control. Etranacogene dezaparvovec comprises an adeno-associated virus serotype 5 (AAV5) vector and the highly active Padua factor IX variant. The primary analysis of this study showed that etranacogene dezaparvovec reduced annualized bleeding rates and adverse events were mainly of low-grade severity. Final data from 5 years of follow-up are now available. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered a single infusion of etranacogene dezaparvovec in men with hemophilia B (factor IX activity level, ≤2 IU per deciliter), regardless of preexisting AAV5 neutralizing antibodies. The prespecified 5-year analyses included adjusted annualized bleeding rates (difference between the post-treatment period of months 7 through 60 after gene therapy and the lead-in period), factor IX expression, and safety outcomes. RESULTS: In the full analysis population (54 participants), the adjusted annualized bleeding rate for all bleeding events was 4.16 during the lead-in period and 1.52 during months 7 through 60 after gene therapy, a reduction of 63% (95% confidence interval, 24 to 82). During the 5-year follow-up period, endogenous factor IX expression remained stable; at 5 years, the mean (±SD) factor IX activity level was 36.1±15.7 IU per deciliter and the mean exogenous factor IX consumption for routine prophylaxis and treatment of bleeding events had decreased by 96%, from 257,339 IU per year during the lead-in period to 10,924 IU per year during months 7 through 60 after gene therapy. Efficacy did not differ substantially between participants with and those without AAV5 neutralizing antibodies at baseline. Adverse events that were possibly related to treatment were rare after month 6. CONCLUSIONS: Sustained endogenous factor IX expression and low annualized bleeding rates over a 5-year period were observed after an infusion of etranacogene dezaparvovec. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).