End-of-study analysis of the HOPE-B trial confirms the durable efficacy and safety of etranacogene dezaparvovec hemophilia b gene therapy over 5 years

Abstract Introduction: Etranacogene dezaparvovec, the first approved gene therapy for hemophilia B, is an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized, highly active factor IX (FIX) Padua transgene controlled by the liver-specific promoter LP-1. Primary analysis of the pivotal phase 3 HOPE-B clinical trial (NCT03569891) of etranacogene dezaparvovec demonstrated superior bleeding protection compared with standard-of-care FIX prophylaxis at 18 months post-gene therapy. We report end-of-study data from the HOPE-B trial, the longest duration of follow-up in a phase 3 trial of gene therapy in hemophilia B to date, evaluating long-term durability of FIX expression, efficacy, and safety over 5 years post-etranacogene dezaparvovec infusion.Methods: Adult males with severe or moderately severe hemophilia B (FIX ≤2%), with or without preexisting AAV5 neutralizing antibodies (NAbs), received a single dose (2×1013 gc/kg) of etranacogene dezaparvovec following a ≥6-month lead-in period when they received their standard-of-care FIX prophylaxis. Efficacy (adjusted annualized bleeding rates [ABR], one-stage FIX activity levels, FIX consumption) and safety data (adverse events [AEs]) over 5 years post-gene therapy are reported. Results: Of 54 etranacogene dezaparvovec recipients, 50 completed 5 years of follow-up (1 withdrew efficacy consent early, 2 died [unrelated to treatment], 1 had a liver transplant, and efficacy data collection ceased afterward). One did not complete the 60-month assessments at the 5-year post-dose visit. ABR for all bleeds during Months 7–60 post-gene therapy was significantly reduced to 1.52 vs 4.16 during the lead-in period (rate ratio 0.37 [95% CI 0.18–0.76], p=0.0035). ABRs for all bleeds were 1.33 (N=54), 0.91 (N=54), 0.83 (N=53), 0.40 (N=51), and 0.40 (N=51) at Years [Y] 1, 2, 3, 4, and 5, respectively. Spontaneous ABR (1.52 during lead in vs 0.53 during Months 7–60; p=0.0133), joint ABR (2.34 vs 0.35; p<0.0001), and traumatic ABR (2.01 vs 0.43; p<0.0001) were significantly reduced post-gene therapy. The mean endogenous FIX activity level remained stable and >36% during Years 1–5 post-gene therapy (mean ± SD: Y1, 41.5 ± 21.7%; Y2, 36.7 ± 19.0%; Y3, 38.6 ± 17.8%; Y4, 37.4 ± 16.7%; Y5, 36.1% ± 15.7; p<0.0001), with similar outcomes being observed between NAb-positive and -negative individuals. Mean annualized consumption of exogenous FIX (N=54), excluding exogenous FIX use for invasive procedures, decreased by 96% from 257,339 IU/year during lead-in to 10,924 IU/year during Months 7 to 60 post-gene therapy (p<0.0001). Two individuals did not express endogenous FIX following gene therapy (non-responders) and continued FIX prophylaxis (1 had the highest baseline NAb titer of 3212; 1 received ~10% of the planned dose [previously reported]). Over 5 years post-gene therapy, only 1 (1.9%) participant eventually resumed FIX prophylaxis (at 30 months post-gene therapy [previously reported]), following decrease of their FIX activity to 2–5% and the occurrence of spontaneous bleeding events. During 5 years post-etranacogene dezaparvovec infusion, a total of 100 treatment-related AEs (TRAEs) occurred in 39 participants. Most of these occurred during the first 4 months post-gene therapy; only 5 occurred between Y4 and Y5. The most frequent TRAE was early (<6 months post-gene therapy) alanine aminotransferase elevation (n=10 participants); 9 individuals received corticosteroids for a mean (SD) of 81.4 (28.6) days (range: 51–130 days). Molecular analysis of incident cases of hepatocellular carcinoma, CNS schwannoma, and myelodysplastic syndrome (all previously reported) established unrelatedness to AAV genotoxicity. No long-term hepatotoxicity or AAV-related oncogenicity was observed. Conclusion: The completed 5-year HOPE-B trial conclusively demonstrated that a single dose of etranacogene dezaparvovec delivers sustained, robust, endogenous FIX Padua expression, significantly reducing bleeding rates and the need for exogenous hemostatic support in most participants with severe or moderately severe hemophilia B. This gene therapy showed a favorable safety profile, with no late-onset AAV-related oncogenicity or hepatotoxicity observed. The positive benefit/risk ratio reported here highlights etranacogene dezaparvovec as a transformative therapy for individuals with hemophilia B. Consenting HOPE-B participants will be monitored long-term until 15 years post-treatment in the IX-TEND 3003 study.