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Significant improvement in mean factor IX activity with etranacogene dezaparvovec for haemophilia B

In a previous phase IIb study, etranacogene dezaparvovec was found to induce a mean factor IX (FIX) activity of 44.2% at two years in haemophilia B patients after a single infusion. Presented at EHA 2021, the phase III HOPE-B trial reports a mean FIX activity of 37.2% at 26 weeks in the largest gene therapy cohort to date, eliminating the need for bleeding prophylaxis.

Haemophilia B (HB) is a disease characterised by factor IX (FIX) deficiency, resulting in a lifetime risk of spontaneous bleeding, typically into the joints of the body. Although continuous prophylaxis can improve symptoms and reduce risk, breakthrough bleeding may still occur and negatively impact the patients’ quality of life. To eliminate the need for continuous prophylaxis, gene therapy is being investigated in this setting. Etranacogene dezaparvovec is an adeno-associated virus serotype 5 (AAV5) vector, containing a codon-optimised Padua wild-type FIX gene with a liver-specific promoter. Phase I/II trials have demonstrated the efficacy and safety of this therapy, with data suggesting that anti-AAV5 neutralising antibodies (NAbs) do not preclude successful transduction. With the largest gene therapy cohort to date, 26-week follow-up data of the phase III HOPE-B were presented recently at the EHA 2021 meeting.

HOPE-B study design

HOPE-B is a phase III, open-label, single-dose, single-arm, multinational study that enrolled 67 male patients with moderate-severe HB (FIX≤ 2%). After a 6-month lead-in period, 54 patients were given a single intravenous dose of etranacogene dezaparvovec (2x1013 genome copies/kg) without prophylactic immunosuppression. All patients were required to be on FIX prophylaxis for at least two months prior to treatment. Pre-existing anti-AAV5 NAbs were assessed at baseline but were not used as an exclusion criteria of this trial. The co-primary endpoints of this trial were change in FIX activity at 26 weeks and 52 weeks as well as a 52-week annualised bleeding rate compared to the lead-in period.

Statistically significant increase in FIX activity at 26 weeks

The mean age of this cohort was 41.5 years, with 81.5% of patients having severe HB (FIX <1%). Overall, 42.6% of patients had detectable NAbs at baseline. After a single infusion, FIX activity rose rapidly, to a 26-week mean of 37.2%, representing a mean change from baseline of 36.0% (p< 0.0001). In patients with follow-up longer than 26 weeks, comparable FIX activity persisted up to the longest follow-up of 18 months. No correlation was observed between pre-existing NAbs concentrations and FIX activity, up to a titre of 678. One patient had a NAb titre of  3,212 and subsequently did not respond. A total of 123 cumulative bleeds were reported during the lead-in period, which reduced to 21 bleeds over weeks 0-26 post-infusion. Conversely, the number of patients with zero bleeds increased from 16 during the lead-in to 39 during weeks 0-26. Total and treated bleeds, relative to lead-in, decreased by respectively 83% and 91%. In the per-protocol population, 98% of patients were able to discontinue prophylaxis and remain prophylaxis-free. The mean annualised FIX usage decreased from 290,769 IU during the lead-in period to 12,537 by week 26.

In total, 88 treatment-related AEs (TRAEs) occurred in 37 patients, with 79.6% of these being classified as mild. Nine patients required steroid treatment due to elevation of transaminase, although all patients had discontinued these steroids prior to week 26. Furthermore, FIX activity was preserved in the mild range (8-39%). Infusion-related reactions were experienced by seven patients, resulting in discontinuation of infusion in one patient. The remaining six patients were able to complete their infusion. Importantly, no inhibitors to FIX were observed, and no relationship between NAb titre and safety was found.


After a single infusion with etranacogene dezaparvovec, mean FIX activity significantly increased to near-normal levels at 26 weeks. Importantly, this analysis included patients with an anti-AAV5 NAb titre up to 678. As a result of the received gene therapy, the vast majority of patients were also able to discontinue prophylaxis and bleeding was abolished in the majority of patients throughout the 26 weeks. The majority of AEs were mild and were manageable with corticosteroids, supporting the safety profile observed in earlier studies. A final analysis is planned at 1 year.


Miesback W, et al. 26 week efficacy and safety of etranacogene dezaparvovec (AAV5-PADUA HFIX VARIANT; AMT-016) in adults with severe or moderate-severe haemophilia B treated in the phase 3 HOPE-B clinical trial. Presented at EHA 2021; abstract S256.

Speaker Wolfgang Miesbach

Wolfgang Miesbach

Wolfgang Miesbach, MD, PhD, University Hospital Frankfurt, Frankfurt, Germany


See: Keyslides


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