OC 02.3 - Etranacogene dezaparvovec hemophilia B gene therapy phase 2b trial final results: stable and durable FIX level expression over 5 years

Background: Etranacogene dezaparvovec is the first approved gene therapy for hemophilia B (HB). It is a recombinant adeno-associated virus serotype 5 (AAV5) vector comprising a codon-optimized FIX Padua variant transgene under the control of a liver-specific promoter, differing by 2 nucleotides from its predecessor (AMT-060).

Aims: To investigate FIX levels following etranacogene dezaparvovec treatment in adults with HB (FIX levels ≤2%).

Methods: Phase 2b, open-label, multi-center trial (NCT03489291) in which 3 HB patients on routine prophylaxis received a single intravenous dose of etranacogene dezaparvovec (2×1013 gc/kg) and were followed for 5 years. Informed consent was obtained and the study was approved by the institutional review board/ethic committee at each center. Secondary endpoints included laboratory parameters, bleeding rates and adverse events.

Results: All 3 participants had neutralizing antibodies (NAbs) to AAV5 at mean titer of 25 at dosing. Mean aPTT-based FIX activity remained stable throughout the trial duration: from Year 1 (40.7%) to Year 5 (46.7%). At Year 5 post-dose, FIX activity measured 46.8%, 39.0% and 51.2% in the 3 participants, respectively. Mean and median ABR for the cumulative follow-up period Years 0–5 was 0.14 and 0, respectively, for all bleeds. One participant experienced 2 bleeds (1 traumatic and 1 spontaneous muscle bleed, both treated with on-demand FIX) during Year 1 post-dose and none thereafter, and 2 participants were free from any bleeds over 5 years. Consequently, no patients returned to FIX prophylaxis. Safety profile was favorable throughout study follow-up: there were no treatment-related serious adverse events, clinically significant liver enzyme elevations, FIX inhibitor development or thromboembolic events.

Conclusion(s): Sustained and stable FIX activity post-etranacogene dezaparvovec administration was observed over 5 years, enabling discontinuation of routine prophylaxis, irrespective of anti-AAV5 NAbs at baseline. Patients have been offered to enroll in the extension study (NCT05962398) for an additional 10-year follow-up.