Natural history of preexisting AAV5 antibodies in adults with hemophilia B during the lead-in of the etranacogene dezaparvovec phase 3 study

Testing for binding or neutralizing antibodies (NAbs) to adeno-associated virus (AAV) is part of the laboratory assessment of people with hemophilia considering AAV-based gene therapy. We evaluated the natural history of NAb titers to AAV serotype 5 (AAV5) in adult males ≥18 years old with hemophilia B (factor IX ≤ 2%) during the lead-in period of a phase 3 trial prior to the infusion of etranacogene dezaparvovec to characterize NAb in addition to immunoglobulin G (IgG) and immunoglobulin M (IgM) anti-AAV5 binding antibody changes over time. At screening, 48% (32/67) of enrolled participants had detectable NAbs (NAb+) with a median titer of 58 (range: 9–3,440). Participant-specific lead-in periods differed and included discontinuers (median duration: 240 days; range: 1–360). The median intra-participant coefficient of variation of NAb titer over time was 25% (range: 2%–154%). NAb seropositivity was associated with older age (p = 0.0065). For participants with detectable anti-AAV5 NAbs and IgG, there was a high correlation of titers at each visit (median r = 0.96; range: 0.92–0.99). IgM anti-AAV5 antibodies were detectable in only 9% of participants, and seroconversion was infrequent. In conclusion, AAV5 NAb test results were consistent over 6 months, which informs the timing of NAb screening when considering gene therapy for hemophilia B.