Abstract
BACKGROUND: Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) is the first phase 3 trial of adeno-associated virus (AAV) serotype 5 vector-based gene therapy for hemophilia B to have enrolled participants with neutralizing antibodies (NAbs) to the viral vector. OBJECTIVES: Evaluate the efficacy and safety of etranacogene dezaparvovec in a post hoc subgroup of participants with preexisting AAV5 NAbs 4 years posttherapy. METHODS: After a ≥6-month lead-in period on continuous prophylaxis, people with moderately severe/severe hemophilia B (factor [F]IX ≤ 2%) received a single infusion of etranacogene dezaparvovec. AAV5 NAb status prior to infusion was determined. FIX activity, annualized bleeding rates (ABRs), and safety were evaluated in participants with preexisting AAV5 NAbs. RESULTS: A total of 21/54 participants had detectable preexisting AAV5 NAbs (titer: 8.5-678, n = 20; titer: 3212, n = 1). Two participants did not respond to treatment (high titer: 3212, n = 1; received partial dose, n = 1). The mean FIX activity was 36 IU/dL (SD, 18) at 1 year (n = 18) and 34 IU/dL (SD, 16) at 4 years (n = 15) posttreatment. Unadjusted ABRs for all bleeds (treated and untreated) decreased by 74.4% from 4.64 during lead-in to 1.18 during months 7 to 48 (n = 21). ABRs for spontaneous and joint bleeds decreased by 79% and 82%, respectively. The mean FIX consumption decreased from 245,476 IU/y (SD, 144,497) during lead-in to 23,975 IU/y (SD, 48.928) during years 1 to 4 (P < .0001). The most frequent treatment-related adverse events were infusion-related reactions (23.8%) and transient alanine aminotransferase elevations (14.3%). No late hepatotoxicity was observed. CONCLUSION: Etranacogene dezaparvovec demonstrated long-term efficacy and safety in individuals with preexisting AAV5 NAb titers ≤ 678, expanding eligibility for gene therapy to a broader hemophilia B population.