Etranacogene Dezaparvovec Significantly Improves Hemophilia B Past 2 Years


Phase 3 data presented at ASH 2023 show the gene therapy significantly reduced annualized bleeding rates and the number of total bleeds.

Etranacogene Dezaparvovec Significantly Improves Hemophilia B Past 2 Years

Steven W. Pipe, MD

An original version of this article was published on our sister site, CGTLive.

Single-dose etranacogene dezaparvovec (EtranaDez; Hemgenix) was associated with long-term improvements demonstrating treatment efficacy compared with standard of care factor IX prophylaxis in men with severe or moderately severe hemophilia B, with or without preexisting AAV5 neutralizing antibodies (NAbs), past the 2-year mark, according to new analysis.1

In these data, which included 52 patients with factor IX ≤2% who completed 36 months of follow-up, the mean annualized bleeding rate (ABR) for all bleeds from months 7 to 36 post treatment was reduced by 64% (mean ABR, 1.52) compared with the 6-or-more-month lead-in period (mean ABR, 4.17), which was statistically significant (P = .0004). Additionally, the total bleeds (including all types)—which numbered 136 during the lead-in period—decreased to 55 during year 1, then 48 during year 2, and finally to 37 during year 3.

The median bleeds per participant decreased and remained stable from 2.0 (range, 0-10) during the lead-in period to 0.0 (range, 0-4) in the first year, remaining at 0.0 (range, 0-10) and 0.0 (range, 0-8) in the second and third years, respectively. Of note, at the 3 years post-treatment time point, 51 patients (94%) remained free of continuous factor IX prophylaxis.

The uniQure and CSL Behring gene therapy product—which was the first approved for hemophilia B in the United States—is an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized, highly active factor IX Padua R338L transgene. Previously, EntranaDez demonstrated a superiority of bleeding protection compared with standard prophylaxis for up to 24 months post-treatment—this long-term follow-up from year 2 post-administration onward is currently ongoing.

The data were presented at the American Society of Hematology (ASH) 2023 Annual Meeting in San Diego this weekend, by Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, and colleagues. “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 [of less than] 1:678, with a favorable safety profile over 3 years post-administration,” Pipe et al wrote.

Overall, the mean endogenous FIX activity level—in the absence of exogenous FIX exposure, Pipe and colleagues noted—of participants was 41.5 IU/dL (±21.7; median, 39.9; range, 5.9-113; n = 50) at year 1. This dropped to 36.7 IU/dL (±19.0; median, 33.9; range, 4.7-99.2; n = 50) at year 2, and was sustained at a level of 38.6 IU/dL (±17.8; median, 36.0; range, 4.8-80.3; n = 48) in year 3. The pharmacodynamic profile was deemed not significantly different among those individuals with undetected AA5 NAb or a titer ≤1:678, as Pipe et al wrote.

A single participant who lacked efficacy—this individual recorded their highest AAV5 NAbs titer of 1:3212—and another who received a 10% partial dose of treatment did not discontinue prophylaxis. One of those participants eventually had factor IX levels decline to a range of 2% to 5%, at which time his bleeding phenotype returned and he resumed prophylaxis per protocol at 30 months after treatment.

During the second and third years post-treatment, 37 patients (70%) and 39 patients (75%) participants received no factor IX infusion, respectively; the overall mean annualized factor IX consumption decreased by 96% (–246,763 IU/kg per participant, including those receiving FIX prophylaxis after administration of EntranaDez) over the 3 years after treatment in comparison with the lead-in period, which was also significant (P <.0001).

At ASH 2022, Pipe presented a similar dataset from HOPE B, out to 24 months of follow-up. At the time, he spoke with CGTLive, offering his perspective on the treatment’s resulting stable factor IX expression and lack of new adverse events. “This is confirming what we thought going into the trial based on earlier trial experience, and I think it bodes well for the future. Perhaps from this 1-time treatment, we will be able to achieve sustained FIX expression that is potentially transformative for the patient for bleed control and durable for, hopefully, their lifespan,” he said.

In this new analysis, the safety profile was similar, with no new deaths, no new hepatocellular carcinoma (HCC), nor any late treatment-related alanine transaminase (ALT) elevations or thromboembolic events. All participants experienced at least 1 treatment-emergent AE (AE) in the 3 years post treatment, and of the 709 AEs recorded, 541 (76%) were deemed mild, 137 (19%) moderate, and 31 (4%) severe.

No serious AEs related to treatment were recorded, though a serious AE of HCC and a death were reported previously, prior to year 2, that were deemed unrelated to EntranaDez. In total, 38 of 54 patients (70%) experienced 96 treatment-related, treatment-emergent AEs, 95% of which occurred prior to the 6-month post-treatment time point. The most common AE reported was ALT increase, for which 9 participants (16.7%) received supportive care with reactive corticosteroids (mean duration, 81.4 days; ±28.6; range, 51-130).

Additional data presented at ASH 2023 demonstrated efficacy and safety in a subset of patients with comorbid HIV treated in 2 clinical trials for the gene therapy.2 Between a phase 2b clinical trial (NCT03489291) and the HOPE-B trial, 5 of 57 total participants treated had HIV infections that were considered controlled per study protocol. The data suggest that after 36 months, the overall posttreatment annualized bleeding rate (ABR) for these 5 patients ranged from 0 to 5.0 (median, 0.64), compared with an ABR ranging from 1 to 10.4 (median, 5) prior to treatment. Of note, 2 of the 5 patients had no recorded bleeds at all in the 36 months after receiving EtranaDez. Furthermore, at 3 weeks posttreatment, 4 of the 5 patients (80%) had factor IX activity levels in the mild/normal range that were maintained going forward. Three patients had measurable factor IX levels after 3 years which was uncontaminated by any return to prophylaxis or use of on-demand replacement therapy. Of those, endogenous factor IX ranged from 31.5% to 58% (median, 32.3%).


  1. Pipe S, van der Valk P, Verhamme P, et al. 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 Severe or Moderately Severe Hemophilia B. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract 1055
  2. Pipe S, Gomez E, Hermans CR, et al. HIV comorbid infection and liver-directed AAV-based gene therapy in adults with severe and moderately severe hemophilia B: efficacy and safety results from phase 2b and the pivotal phase 3 HOPE-B trials 3 years after administration of a single dose of etranacogene dezaparvovec. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract 801
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