Adults with Severe or Moderately Severe Hemophilia B Receiving Etranacogene Dezaparvovec in the HOPE-B Phase 3 Clinical Trial Continue to Experience a Stable Increase in Mean Factor IX Activity Levels and Durable Hemostatic Protection after 24 Months’ Follow-up

Abstract

Introduction: Etranacogene dezaparvovec (formerly AMT-061), an investigational gene therapy for hemophilia B, 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 a liver-specific promoter. The Phase 3 HOPE-B clinical trial (NCT03569891) of etranacogene dezaparvovec met its primary efficacy endpoint, providing hemostatic protection superior to standard of care FIX prophylaxis over 52 weeks of follow-up after stable FIX Padua expression (defined as Months 7-18). However, the potential for liver-directed AAV to sustain long-term clotting factor expression remains unknown, with most human experience derived from early phase clinical trials. Aim: Efficacy and safety data is provided from the pivotal Phase 3 HOPE-B clinical trial over a period of 24 months of gene expression. Methods: In this open-label, single-arm study, adult male participants with severe or moderately severe hemophilia B (FIX≤2%), with or without pre-existing AAV5 neutralizing antibodies (NAbs), were infused with a single dose of etranacogene dezaparvovec (2x1013 gc/kg), following a ≥6-month lead-in period receiving FIX prophylaxis. FIX activity, annualized bleed rate (ABR), and FIX infusions were assessed frequently during the lead-in and first 12 months after receiving etranacogene dezaparvovec, then every 6 months during the long-term follow-up (Years 2-5). Adverse events (AEs) were recorded continuously. Results: Of the 54 participants who received etranacogene dezaparvovec, 53 participants received the full dose and 52 completed 24 months of follow-up. At 464 days (~15 months) following infusion, one 75-year-old participant died from cardiogenic shock, preceded by a urinary tract infection, which was considered unrelated to treatment. Of the 54 participants, 52 (96.3%) discontinued and remained free of continuous FIX prophylaxis from Day 21 to Month 24, including 20 participants with baseline AAV5 NAb titers up to 1:700. One participant with a markedly higher AAV5 NAbs titer (1:3212) and one participant who received only a partial vector dose (due to an infusion-related reaction) did not express FIX Padua or discontinue FIX prophylaxis. Compared with the ≥6-month lead-in period (mean ABR 4.18), mean ABR for all bleeds during Months 7-24 post-treatment was significantly reduced by 64% (mean ABR 1.51; p=0.0002), sustaining the same bleed reduction that satisfied the primary endpoint of the trial during Months 7-18. The mean ABR for all other bleed types was also substantially reduced (Figure 1). The mean FIX activity level of participants was 39.0 IU/dL (standard deviation [SD]: ±18.7; min-max: 8.2-97.1) at Month 6 (n=51) and sustained at 36.7 IU/dL (±19.0; 4.7-99.2) at Month 24 post-treatment (n=50; Figure 2). There was an overall 96% reduction in mean unadjusted annualized FIX consumption from the lead-in period (257,339 IU/year/participant) to Months 19-24 (9751 IU/year/participant; p<0.0001). During the 24 months post-dose, all participants experienced at least one treatment-emergent AE (TEAE); of the 557 events, 424 (76%) were mild, 115 (21%) were moderate, and 18 (3%) were severe. A total of 38 participants (70.4%) experienced 93 treatment-related TEAEs, with only one occurring during Months 18-24. There was an increase in alanine transaminase (with or without increased aspartate transaminase) in eleven participants (20.4%). Nine participants (16.7%) received supportive care with reactive corticosteroids for a mean duration of 79.8 days (SD: 26.6; range: 51-130 days). There were no serious AEs related to treatment; a serious AE of hepatocellular carcinoma was determined by independent molecular genomic and integration analysis to be unrelated to treatment. Conclusions: Demonstrating durability of disease correction with acceptable safety is the next major hurdle for gene therapy in people with hemophilia B. After 24 months’ follow-up, single-dose etranacogene dezaparvovec resulted in stable FIX Padua expression in participants with AAV NAb undetected or <1:700 titer; reduction in ABR remained durable and superior to FIX prophylaxis. This outcome was achieved with limited early reactive corticosteroid exposure in a minority of participants, allowing all participants who discontinued prophylaxis to remain off prophylaxis at Month 24. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal