ASH 2020 | HOPE-B trial: etranacogene dezaparvovec shows promise in hemophilia B

There’s really three key takeaways from this late breaking abstract. The first is that this is the largest cohort of gene therapy patients treated with an AV-mediated liver-directed gene therapy. It’s the first data from any phase III trial to get patients through what ends up being a first co-primary endpoint of 26 weeks of follow-up. So that’s the first key takeaway.

Second key takeaway is that this is the only trial for using this AV platform in hemophilia that did not exclude patients based on having pre-existing neutralizing anti-AAV capsid antibodies. This has been the single biggest exclusion criteria for bringing patients with hemophilia to gene therapy trials, anywhere depending on the capsid subtype, anywhere up to 40 to over 50% of patients will screen out of these trials due to neutralizing antibodies. We did collect that data in this study, but we treated irrespective of their neutralizing antibodies and the results from the trial support that that was the right approach as there did not appear to be any correlation in both safety and efficacy measures for almost all of the participants in the trial, regardless of their antibody status.

The third key takeaway, in my opinion, is one of the other key adverse events that occurs in the course of AV-mediated liver-directed gene therapy is what we believe is an immune response to the capsid, which leads to a paddle cellular cytotoxic immune response. This is manifested in the trials by an elevation in transaminases, things like the ALT or AST. And if we don’t intervene, when we see this liver toxicity we risk losing those transduced cells from the liver, and then we lose the expression from the trans gene.

What’s been done in previous trials is to do a short course of oral corticosteroids as soon as we see the elevation of the liver transaminases, and this has been shown in other trials to be able to salvage the expression and resolve the transaminitis. It turns out of the 54 subjects that were dosed in this trial, only nine of them had evidence of this liver toxicity and all responded to the oral corticosteroids. They were all able to come off of steroids before week 26 of follow-up, and all eight were able to maintain their factor nine expression within the mild range. I think this is a good outcome from this well-described side effect of this type of gene therapy.