Etranacogene Dezaparvovec “Transformative” for Patients With Hemophilia B

Updated follow-up data from the phase 3 HOPE-B trial (NCT03569891) have continued to demonstrate durable factor 9 (FIX) expression in people with moderate to severe hemophilia B treated with etranacogene dezaparvovec (Hemgenix; CSL Behring, UniQure), previously known as EtranaDez. The data were presented by Steven Pipe, MD, professor, pediatric hematology/oncology at CS Mott Children’s Hospital, at the 64th American Society of Hematology (ASH) Annual Meeting, held December 10-12, 2022, in New Orleans, Louisiana. Hemgenix was approved for this indication in November 2022.

CGTLive spoke with Pipe to learn more about the new data and how it reflects the therapy’s durability. He also discussed other positive, and surprising, findings.

CGTLive: Can you outline the HOPE-B study?

Steven Pipe, MD: We enrolled 54 participants in the trial. We didn't exclude patients who had hepatitis B or C history, although they had to have had a sustained viral response using antiviral therapies to eradicate hepatitis C, and they couldn't have an advanced form of fibrosis in their liver. All the patients participated in a lead in study for at least 6 monthswhere they continued their standard of care FIX replacement therapy, and we found an annualized bleed rate of 4 bleeds per year requiring treatment.

EtranaDez was dosed in a single, outpatient infusion over about 1 to 3 hours and was generally well tolerated, and we followed up patients for months afterwards. Withadeno-associated virus (AAV)-mediated, liver-directed, gene therapy we always have to watch for evidence of an immune response to the AAV capsid. If patients experience these elevations in liver enzymes and have no intervention, they risk losing their FIX expression, presumably this immune response leads to loss of those cells and loss of the transgene and no expression. So, we monitor expression and enzyme levels carefully.

Can you discuss the outcomes of the study?

Pipe: Going into the trial, 40% of the individuals recruited had neutralizing antibodies to AAV5. During post-dose follow-up, that didn’t appear to affect the immune response. Nor did it seem to impact the overall expression, so that was a really positive finding. Only 9 men actually showed the transaminase elevations and triggered the immunomodulation that we use in these trials. The levels went back to normal; we weaned them off, and they were able to sustain their FIX expression. Everyone came off steroids and had normal liver enzymes by the 6-month point. From month 7 through 18, the ABR dropped to 1.5. and the mean FIX levels have settled in just shy of that non hemophilic range.

Everybody was able to stop the prophylaxis, and the vast majority of individuals are not bleeding. One patient had a very high level of neutralizing antibodies who did not respond so theremay be a threshold where very high antibodies may impact the efficacy, which is probably above the 90th percentile of what you would find in the in the global population. Another individual had symptoms and signs of an infusion reaction and stopped the infusion after receiving only 10% of the dose, so he did not respond. All other participants were able to come off routine prophylaxis and sustained good bleed control.

What was the new long-term outcome data presented?

Pipe: After month 18 to month 24 we're seeing stable FIX expression and no new adverse events. This has confirmed the positive data and I think bodes well for the future that 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 can be durable for hopefully their lifespan.

There are some other surprising findings in this trial, mainly the enthusiasm the patients have expressed about how their life has changed after going through this treatment.It’sreally exciting to see them come to clinic, and I hear about the activities that they're involved in that they couldn’t do before; I hear them expressing that they have a sense that they're not bound to their infusion protocol anymore. They're making decisions withouthaving to think about when their last infusion was and what their FIX levels are likely to be at any point and if it’s it safe to do an activity. A lot of them come to clinic now and say, “when I used to have hemophilia,” which I think is really cool. It shows that at a psychosocial and mental health level, that this is transformative, even beyond what we're achieving with the bleed control. And that’s great to hear.

Transcript edited for clarity.

REFERENCE

Pipe SW, Leebeek FWG, Recht M, et al. Adults with severe or moderately severe hemophilia B receiving etranacogenedezaparvovec 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. Presented at: 64th ASH Annual Meeting, December 10-12, 2022, in New Orleans, Louisiana. Abstract #2141