End-of-Study Results From Hemgenix’s HOPE-B Trial

At the 67th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 6 to 9, 2025, in Orlando, Florida, end-of-study data from the pivotal phase 3 HOPE-B clinical trial (NCT03569891), which evaluated CSL Behring/uniQure’s etranacogene dezaparvovec (marketed as Hemgenix) for the treatment of severe or moderately severe hemophilia B, were reported. Hemgenix is an FDA-approved adeno-associated virus (AAV) vector-based gene therapy that is meant to impart durable factor IX (FIX) expression, bleed protection, and freedom from prophylaxis.

At the conference CGTLive® spoke to Steven W. Pipe, MD, a professor of pediatric hematology/oncology at the University of Michigan Health, who served as HOPE-B’s principal investigator, to learn more about the data. Pipe gave some background about the therapy and the trial, and then summarized the key efficacy and safety results that he presented at ASH this year.

CGTLive: Can you give some context about your presentation at ASH this year?

Steven W. Pipe, MD: This year, it was my honor to have the chance to present the end-of-study results for the HOPE-B trial. The HOPE-B trial is a study of etranacogene dezaparvovec, which is an AAV5-mediated, liver-directed gene therapy intended for adults with severe, or moderately severe, hemophilia B. This trial initially reported out its primary analysis back in 2021 and there it showed that this gene therapy was able to deliver a highly effective expression of FIX in this population of patients with hemophilia B, the majority of which were able to be liberated from prophylaxis, and really with a favorable safety profile. So at this meeting now, we've been able to follow those gentlemen now, over a total of 5 years since their original dosing, and be able to share the results with this community.

What were the key results?

When we set out to develop a gene therapy for hemophilia B, there are, I think, 4 key aspects that would define an effective therapy for this. First of all, we want to be able to have effective protection from bleeding. Secondly, we want to be able to have durable expression of FIX at meaningful clinical levels for years after a one-time treatment. Thirdly, we want to be able to show that these patients can be liberated from the need for regular FIX prophylaxis, and then finally, we want to be able to show that it's safe over the long-term.

We had 54 participants that were dosed with this trial. There were 2 individuals who were nonresponders. One individual had an infusion reaction early on and only got 10% of the dose, and the second patient had a very high titer of neutralizing antibodies against the AAV5 vector. Now this trial is unique in that it enrolled patients regardless of their neutralizing antibody status against the AAV5, and this is a differentiator from almost all other gene therapies up until this point. Other than that, all the rest of the 52 individuals had an excellent response to this therapy. Over now 5 years of follow up, there's only a single patient who did have evidence of a transaminitis following the therapy. This overall impacted his FIX expression, and then around Month 30, his level of FIX expression was just below 5%, and he had return of some of his bleeding symptoms. He's the only patient of that whole cohort who's resumed prophylaxis.

Overall, what we've observed is that we have seen impressive bleed protection. These individuals were followed in a lead-in phase for 6 months before they were dosed with the Hemgenix. That allowed us to get their background annualized bleed rate. For this cohort, it was about 4 bleeds per year. In the full follow-up phase, starting from about Month 7 all the way through now Month 60, 5 years later, the overall annualized bleed rate is reduced to 1.5, so about a 65% reduction in bleed rate compared to standard-of-care prophylaxis with FIX replacement. Then if we look actually in Year 5, it's about a 90% reduction in their bleed, so we've already met that criteria.

With regard to durable FIX expression, at the 6 month point after dosing, the mean FIX activity was in the near normal range, at 39%, and now, 5 years later, this whole cohort is still sitting at about 36% for their FIX expression. And if we look across the cohort, this looks to be very stable amongst the individual participants. This is really encouraging that we really have been able to deliver durable FIX expression over the long term.

As far as overall freedom from prophylaxis, it's 94% of the participants, including the 3 patients that I talked to you about.

Then finally, what can we learn from the safety for this program? Importantly, no FIX inhibitors and no thrombotic events. For the overall range of FIX expression, 90% of the individuals are between 5 to 100%, so we don't even have any participants who are in the super-physiologic range.

As for the treatment-related adverse events, there were 100 over the course of the trial, however 91 of these occurred within the first 6 months, and the predominant were either infusion-reactions, which were transient and manageable, or evidence of a liver toxicity related to the AAV5. This was clinically not manifest, it was just based on monitoring for transaminase elevations. Of the patients who had the transaminitis reaction, 9 out of the 54 participants, these all were treated with a course of corticosteroids. The mean number of days of exposure to corticosteroids was about 80 days. All of the transaminase elevations resolved successfully, and we were able to preserve FIX expression over the cohort.

If we look at the outcome on overall FIX expression, those who did have the transaminitis did have a lower overall expression, but notably, this didn't seem to have an impact on their bleed control, and so they still experienced good benefit from the therapy. We haven't seen any late issues related to hepatotoxicity and, importantly, no oncogenicity has been seen related to this therapy.

This transcript has been edited for clarity.

For more coverage of ASH 2025, click here.

REFERENCES
1. Pipe S, Miesbach W, Recht M, et al. End-of-study analysis of the HOPE-B trial confirms the durable efficacy and safety of etranacogene dezaparvovec hemophilia b gene therapy over 5 years. Presented at: ASH 2025 Annual Meeting. December 6-9, 2025; Orlando, FL. Abstract #538