Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B.

Etranacogene dezaparvovec (AMT-061) is a recombinant AAV5 vector including a gene cassette containing the factor IX (FIX) Padua variant under the control of a liver-specific promoter. A phase 2b study was conducted to confirm that a single dose of 2 × 1013 genome copies per kilogram of etranacogene dezaparvovec will result in FIX activity ≥5% 6 weeks after dosing. Secondary end points included FIX activity at other time points, bleed frequency, FIX replacement, and safety. Etranacogene dezaparvovec was administered as a single IV infusion to 3 adults with severe to moderately severe hemophilia B. Before treatment, participants had low levels of preexisting neutralizing antibodies to AAV5. This article reports a planned 26-week interim assessment. At week 6, mean FIX activity was 31% (23.9%-37.8%), increasing to 47% (33.2%-57.0%) at 26 weeks, with 2 subjects exhibiting sustained activity >40%. Consistent with the FIX activity, etranacogene dezaparvovec was associated with a complete bleed cessation with no need for FIX replacement therapy up to 26 weeks. Etranacogene dezaparvovec was generally well tolerated. No clinically significant elevations in levels of liver enzymes or inflammatory markers were observed, and no use of corticosteroids related to treatment was required. In individuals with severe to moderately severe hemophilia B, etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity, cessation of bleeds, and abrogation of the need for FIX replacement, despite the presence of preexisting anti-AAV5 neutralizing antibodies detected by using a highly sensitive luciferase assay. Consistency of results in the 3 participants supported an expanded evaluation of the safety/efficacy of etranacogene dezaparvovec in the HOPE-B (Health Outcomes With Padua Gene; Evaluation in Hemophilia-B) phase 3 trial. The current trial was registered at www.clinicaltrials.gov as #NCT03489291.