Single-dose gene therapy ‘pretty transformative’ for patients with hemophilia B
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The gene therapy etranacogene dezaparvovec conferred a substantial decrease in bleeding events among patients with moderate or severe hemophilia B, according to preliminary data presented at the virtual ASH Annual Meeting and Exposition.
Patients demonstrated clinically meaningful increases in factor IX production regardless of whether they exhibited anti-capsid neutralizing antibodies prior to therapy, and nearly all patients (98%) discontinued use of factor IX replacement after receiving the single-dose treatment, according to the researchers.
Etranacogene dezaparvovec (AMT-061; uniQure/CSL Behring) is an investigational gene therapy comprising an adeno-associated virus serotype 5 (AAV5) vector with the naturally occurring Padua human factor IX variant gene containing a liver-specific promoter.
“The HOPE-B trial is the first phase 3 study of hemophilia B and has the largest cohort of gene therapy reported to date,” Steven W. Pipe, MD, professor of pediatrics and pathology at University of Michigan, Ann Arbor, said during a presentation.
“The results show functionally curative levels, which means that patients should no longer be bleeding into joints on a regular basis,” Pipe told Healio. “The patients that I follow in this trial tell me that they don't have to think about their hemophilia anymore, so this is pretty transformative for patients.”
The HOPE-B study enrolled 67 patients, including 54 (mean age, 41.5 years; range, 16-75) who received a single infusion of etranacogene dezaparvovec at a dose of 2 × 1013 genome copies/kg and were eligible for analysis after 26 weeks of follow-up. Most patients (81.5%) had severe hemophilia B at the time of diagnosis, and half had previous hepatitis C infection.
Twenty-three patients (42.6%) had detectable neutralizing antibodies at baseline (maximum titer, 3,212.3).
Pipe said other AAV-mediated, liver-directed gene therapy trials to date have excluded patients with preexisting neutralizing antibodies, based on preclinical work suggesting that transduction of the therapy would be impaired. However, he said phase 1 and phase 2 studies showed patients who had evidence of neutralizing antibodies maintained good transduction after infusion.
Primary endpoints included factor IX activity 26 weeks after treatment, factor IX activity 1 year after treatment and 1-year annualized bleeding rate compared with the lead-in period. Secondary endpoints included factor IX consumption, bleeding rates and safety measurements.
Results showed “robust” factor IX expression by week 3 after infusion, according to Pipe. Mean factor IX activity increased by 37.2% (± 19.6) at 26-week follow-up, which equates to a 36.01% (± 19.69) increase from baseline factor IX levels (P < .0001).
Pipe said the “dramatic results” demonstrate the treatment’s durability thus far, as it abolished bleeding among the majority of patients during the first 26 weeks after therapy.
Patients had a total of 123 cumulative bleeding events in the lead-in period before therapy, compared with 21 cumulative bleeding events after therapy. Sixteen patients (30%) in the study group had no bleeding events during the lead-in period, whereas 39 patients (72%) had no bleeding events after therapy.
Overall, bleeding events in the study group decreased by 83% and the number of bleeds requiring treatment decreased by 91%.
Mean factor IX levels increased to near-normal levels by 26 weeks, according to Pipe.
All study patients required factor IX replacement therapy during the lead-in period, compared with two patients (4%) after receiving etranacogene dezaparvovec. Nearly all patients (98%) in the study’s per-protocol population discontinued factor IX prophylaxis after therapy and remained prophylaxis-free at 26 weeks.
Thirty-seven patients experienced at least one treatment-related adverse event, 76.2% of which were mild. The most common adverse events included flu-like illness (13%), headache (13%) and increase in alanine transaminase levels (13%). Seven patients had infusion-related reactions and one patient stopped therapy during infusion and received approximately 10% of the total dose.
Pipe said the results thus far showed that the presence of neutralizing antibodies had no effect on factor IX expression, with only one patient with neutralizing antibodies unresponsive to therapy.
“It's kind of a game-changer by not having to screen out patients with neutralizing antibodies,” Pipe told Healio.
“The study may tell us that there may be a threshold where antibody levels are high enough that they block transduction,” he said, adding that additional data are required to determine if there is a cutoff point where antibody levels could block transduction.
The biggest impact of this research is that it provides patients with hemophilia B with an effective choice at any point after their diagnosis, according to Pipe.
“We had subjects from age 19 years all the way up to age 75 years, so there is no real optimal age where this therapy could become an option,” he told Healio. “If this therapy ends up being approved in the future, then it’s a real choice any patient could make during their adult lifetime.”
Perspective
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Robert A. Brodsky, MD
Pipe and colleagues found that the majority of patients who received this gene therapy have been producing their own factor IX for at least 6 months, and the results may open the door for patients not previously included in other gene therapy trials.
What is notable about this study is that there was concern about naturally occurring antibodies with these vectors, and this study did not exclude patients with naturally occurring antibodies.
The results seen thus far with etranacogene dezaparvovec are extremely exciting. The ability to have a single infusion that allows patients to forget about their hemophilia for a period is the type of treatment we have always been looking for. Nevertheless, there is still a lot that we have yet to learn about gene therapies, including issues around late toxicities and choosing the best candidates for therapy.
Despite the need for longer-term follow-up, this gene therapy is a major advance, and we should all be excited that there are now great options for patients with hemophilia. This treatment has practice-changing potential.
Perspective
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Eric Grabowski, MD, ScD
This is the first phase 3 trial to show the feasibility of gene therapy for severe and moderately severe hemophilia B.
Etranacogene dezaparvovec incorporates an AAV5 vector containing a codon-optimized Padua variant human factor IX and a liver promoter. Although 23 patients were included who had a preexisting neutralizing antibody to the capsid serotype, only two had a definite or partial response failure.
Pipe and colleagues observed efficacy in terms of reduced bleeding rates and an absence of severe adverse events. The levels of factor IX in this study are exciting, with most but likely not all patients having levels above 5%, although the range of factor IX levels achieved remains quite large.
I’m looking forward to seeing the results at 52 weeks, which are still pending.
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Pipe SW, et al. Abstract LBA-6. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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