preheader BJH 1

Gene therapy with etranacogene dezaparvovec in moderate to severe haemophilia B with pre-existing anti-capsid neutralising antibodies

The phase III, single-dose, HOPE-B trial assessed the efficacy and safety of etranacogene dezaparvovec, a gene therapy containing the Padua factor IX (FIX) variant, delivered by the adeno-associated virus serotype 5 (AAV5) viral vector, in severe and moderately-severe male haemophilia B patients. By week 26 post-dose, the majority of patients had a mean FIX activity of 37.2%. At a single-dose of etranacogene dezaparvovec, FIX activity increased to a level comparable to a mild-to-normal range by week 26, irrespective of pre-existing anti-capsid neutralising antibodies (anti-AAV5 NAbs). As a result, patients were able to discontinue prophylactic treatment while the incidence of bleeding was significantly reduced in the majority of patients.


Historically, the treatment for haemophilia B has been limited to regular prophylactic intravenous infusions of factor IX concentrate. Etranacogene dezaparvovec is a gene therapy developed from the combination of the adeno-associated virus serotype 5 (AAV5) viral vector with the Padua factor IX (FIX) variant, that includes a liver-specific promoter. AAV5 has been assessed previously in phase 1 studies, demonstrating stable expression of FIX at 4.5-5 years without any late safety signals. In a subsequent phase 2b study, a single dose of etranacogene dezaparvovec conveyed a FIX activity of 41% at the time of the 1-year post-dose follow-up. HOPE-B is an ongoing, open-label, single-dose, single-arm, multi-national phase III trial assessing the efficacy and safety of etranacogene dezaparvovec in male patients with severe or moderately-severe haemophilia B with pre-existing titres of anti-AAV5 neutralizing antibodies (NAbs). Participants were adult males with a baseline FIX activity of ≤2%, who had previously been on continuous prophylaxis for at least 2 months. Patients were screened for bleeding and FIX activity during a 6-month lead-in period, after which, participants were given a single intravenous dose of etranacogene dezaparvovec equal to 2x1013 gc/kg. Patients were excluded if they had been exposed to FIX inhibitors, or had an active hepatitis B/C or HIV infection. Co-primary endpoints of this study included FIX activity at 26 and 52 weeks after dosing, and 52wk annualised bleeding rate, compared to the lead-in phase. Secondary endpoints included rates of bleeding, FIX consumption, safety and correlation of FIX activity levels with pre-AMT-061 anti-AAV5 Ab titre over 26 weeks follow up.


Of the 75 patients screened, 67 entered the lead-in period, with 54 patients actually being dosed and completing 26 weeks of follow-up. The mean age of these patients (±SD) was 41.5 (±15.8) yrs. Over 80% of participants had severe haemophilia B (FIX activity <1%) and more than half of participants had a prior hepatitis B or C infection. In total, 38 (70.4%) patients experienced bleeds (n=123) during the lead-in phase despite prophylaxis and 23 (42.6%) patients had NAbs to AAV5 at baseline (max titre: 3212.3). By week 26, FIX activity had increased to a mean (±SD; low, high) of 37.2% (±19.6; 1.0, 97.1), representing a change from baseline of 36.0% (±19.7; 0, 96.1, p<0.0001). Similar results were observed in follow-up past week 26, with one patient displaying a similar level of FIX activity at 18 months. Interestingly, no correlation was found between pre-existing NAbs and FIX activity, up to a titre of 678.2 (R2 = 0.078), although one patient, who had a NAb titre of 3212.3 did not respond to treatment. Overall, 39 (72.2%) patients reported 0 bleeds in the first 26 weeks post-treatment, with the remaining 15 patients reporting 21 bleeds in total. Relative to the lead-in period, by 26 weeks of follow-up, total bleeds had decreased by 83% and treated bleeds had decreased by 91%, allowing 96.3% of patients to successfully discontinue routine prophylaxis. Secondary endpoints were also favourable, with mean (SD) annualised FIX consumption (IU/yr/pt) decreasing from 292,304 (±171,079) during lead-in to 12,622 (±36,466) at week 26, representing a 96% reduction. Overall, 37 (68.5%) patients had any-grade treatment-related adverse events, post treatment, the majority of which were mild (81.5%). The most common treatment-related AEs were influenza-like illness (13.0%) and headache (13.0%). No inhibitors to FIX were reported, and no relationship was seen between the safety profile and the NAb titre. No deaths occurred and no treatment-related serious AEs were reported. Infusion-related reactions occurred in 7 patients, with one subsequent discontinuation. Overall, 9 patients developed treatment-related elevations in liver-enzymes and received steroids, per protocol. All patients stopped receiving steroids before week 26 and FIX activity was preserved in the mild range.  


Following a single-dose of etranacogene dezaparvovec, FIX activity increased to a level comparable to a mild-to-normal range by 26 weeks, without the need for immunosuppression. This included patients with titres of pre-existing anti-AAV5 NAbs. As a result, patients were able to discontinue prophylactic treatment and the incidence of bleeding was reduced significantly in the majority of patients. Finally, the safety profile observed in this study was consistent with early phase AAV5 studies.


Pipe SW et al., First Data from the Phase 3 HOPE-B Gene Therapy Trial: Efficacy and Safety of Etranacogene Dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in Adults with Severe or Moderate-Severe Hemophilia B Treated Irrespective of Pre-Existing Anti-Capsid Neutralizing Antibodies. Presented at ASH 2020; Abstract LBA-6.

Speaker Steven Pipe

Steven W. Pipe

Steven W. Pipe, MD, University of Michigan, Ann Arbor, Michigan, United States


See: Keyslides


Back to Top