ESC 2026 | Insights into the potential of CRISPR-based gene editing in ATTR-CM

So when we think about it, TTR amyloidosis in some ways is the perfect condition to treat with CRISPR, with gene editing, because the disease is clearly driven by expression of a single protein, TTR. And so if we knock down that protein, we know from other studies that have used other mechanisms to knock down the protein, you can achieve better outcomes. So it makes a lot of theoretical sense. Now, what’s exciting for patients when I talk to them about clinical trials and what gets them excited more than anything is that it’s a single one-time intravenous therapy. So the alternatives are taking pills every day or subcutaneous injections that currently range from every four weeks to every three months. So the idea, it’s a one and done. You get the intravenous infusion and permanently it is knocked down. That’s attractive to many patients. Now, what we’ve learned so far from Phase I data is that quite clearly that single dose of intravenous therapy will knock down levels by about 90%, and they do not come back up. And there’s sustained data now, and it shows there’s not even a hint that it comes back up. So we’ve learned that. We also know from the Phase III clinical trial, of course, we don’t have data from it, and It’s still enrolling. We do know there was a safety concern. So there were about 1% of patients after the first few hundred were enrolled who had significant rises in their liver function tests. Thankfully, in all but one case, they self-resolved, but in one person, it proceeded to more frank liver failure, and that patient ultimately was hospitalized and died. And so the study was put on hold for a few months while it was investigated and there were new safety protocols put in place and then aligned with the regulatory agencies and has since restarted. So that’s important and it’s important for potential subjects for the trial to understand that low but not zero risk. But it remains a very exciting therapy because of, again, the potential to knock it down so much with a single therapy. The first question, of course, is will the Phase III clinical trial show improved outcomes? Because it can make all the sense in the world mechanistically. It can be safe. But if it can’t hit a primary endpoint in an efficacy trial, it’s going to be a moot point. But assuming that it does achieve that, then it’s exactly the things that were highlighted. So safety, of course, is going to be super important. One thing that we are very fortunate with in the ATTR amyloidosis space is that the therapies we have not only are quite efficacious, but are tremendously safe and well tolerated. And so if you had any substantial number of patients with safety concerns, that would, I think, really hinder the uptake of the use of this and I think would appropriately give patients pause. If not, then I think that as long as the efficacy is at least as good as the other agents that we have, and there aren’t safety concerns, then it’s much more about logistics, having the setup to be able to administer it, comfort level, both from the place where the infusion is happening, but also among the patients. You know, I live in California, in Silicon Valley. The patient population I see tends to be very excited about this sort of cutting edge gene therapy. That’s not true everywhere. And when people hear about getting a therapy that’s going to actually change their genetic code, there is some understandable hesitancy from some people. That’s okay, even if it does get approved for patients who are hesitant to use that, we do have obviously very good alternative therapies. But I think those will be some of the factors that drive its ultimate uptake, assuming it’s ultimately approved.

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