Long-Term Bleeding Protection, Sustained FIX Activity, Reduction of FIX Consumption and Safety of Hemophilia B Gene Therapy: Results from the HOPE-B Trial 3 Years after Administration of a Single Dose of Etranacogene Dezaparvovec in Adult Patients with Se

Introduction: Etranacogene dezaparvovec (formerly AMT-061) is the first approved gene therapy for hemophilia B in the US and Europe. It is an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized, highly active factor IX (FIX) Padua R338L transgene under the control of the liver-specific promoter LP-1. The pivotal phase 3 HOPE-B clinical trial (NCT03569891) of etranacogene dezaparvovec demonstrated superiority of bleeding protection compared to standard of care FIX prophylaxis up to 24 months post-treatment; long-term follow-up from Year 2 post-administration onward is currently ongoing. Aim: To report long-term efficacy and safety data of etranacogene dezaparvovec from the HOPE-B trial over a period of 3 years post-treatment. Methods: In this pivotal phase 3 open-label, single-arm trial, adult male participants with severe or moderately severe hemophilia B (FIX ≤2%), with or without preexisting AAV5 neutralizing antibodies (NAbs), were infused with a single dose (2×10 13 gc/kg) of etranacogene dezaparvovec, following a ≥6-month lead-in period of receiving their usual FIX prophylaxis. Efficacy (bleeding rates, aPTT-based FIX activity levels, FIX consumption) and safety data (adverse events [AEs]) during Years 1, 2, and 3 post-treatment with etranacogene dezaparvovec are reported. Results: Of 54 participants who received etranacogene dezaparvovec, 52 completed 36 months of follow-up. Mean annualized bleeding rate (ABR) for all bleeds during Months 7-36 post-treatment was significantly reduced by 64% (mean ABR 1.52) compared with the ≥6-month lead-in period (mean ABR 4.17; P=0.0004). Total number of bleeds (all types) were 136 during the ≥6-month lead-in period and decreased to 55 during Year 1, 48 during Year 2, and 37 during Year 3 post-treatment. Median [range] bleeds per participant decreased from 2.0 [0-10] during the lead-in period and remained stable to 0.0 [0-4] during Year 1, 0.0 [0-10] during Year 2, and 0.0 [0-8] during Year 3. Superior bleeding protection was in line with the level of transgene-derived endogenous FIX expression. The mean±SD (median; range) endogenous FIX activity level (ie. in the absence of exogenous FIX exposure) of participants was 41.5 IU/dL ±21.7 (39.9; 5.9-113, n=50) at Year 1, 36.7 IU/dL ±19.0 (33.9; 4.7-99.2, n=50) at Year 2, and sustained at 38.6 IU/dL ±17.8 (36.0; 4.8-80.3, n=48) at Year 3 post-treatment. Pharmacodynamic profile was not significantly different in participants with AA5 NAb undetected or titer ≤1:678. At 3 years post-treatment, 51 (94%) remained free of continuous FIX prophylaxis. One participant who lacked efficacy (highest AAV5 NAbs titer of 1:3212) and 1 who received a 10% partial dose of treatment did not discontinue prophylaxis; 1 participant eventually had his FIX levels declined to 2-5% range; his bleeding phenotype returned, and he resumed prophylaxis per protocol at month 30 post-treatment. During Year 2 and Year 3 post-treatment, 37 (70%) and 39 (75%) participants received no FIX infusion, respectively. Overall mean annualized FIX consumption decreased by 96% over 3 years post-treatment compared to the ≥6-month lead-in period (-246,763 IU/kg/participant, including those receiving FIX prophylaxis post-treatment; P<0.0001). During the 3 years post-dose, all participants experienced at least 1 treatment-emergent AE (TEAE); of 709 events, 541 (76%) were mild, 137 (19%) were moderate, and 31 (4%) were severe. There were no serious AEs related to treatment [a serious AE of hepatocellular carcinoma (HCC) and a death were reported previously before Year 2 and determined to be unrelated to treatment]. A total of 38/54 (70%) participants experienced 96 treatment-related TEAEs, of which 95% occurred before 6 months post-treatment. The most common AE was an increase in alanine transaminase (ALT), for which 9 (16.7%) participants received supportive care with reactive corticosteroids for a mean duration of 81.4 days (SD: 28.6; range: 51-130 days). No new deaths, no new HCC, and no late treatment-related ALT elevations or thromboembolic events were reported. Conclusion: Long-term follow-up during the HOPE-B trial has shown that a single-dose of etranacogene dezaparvovec resulted in long-term endogenous FIX Padua expression and superior bleeding protection compared to FIX prophylaxis in participants without or with AAV NAb titer ≤1:678, with a favorable safety profile over 3 years post-administration.