Good afternoon, and thank you for joining Guggenheim at our 3rd Annual Healthcare Innovations Conference. I am Debjit, one of the therapeutic analysts, and my privilege to welcome Gilmore O'Neill, President and CEO of Editas, and Amy Parison, Chief Financial Officer. Thank you both for making time for us.
It's great to be here. Thanks for having us.
Obviously, the Editas story has evolved over the last couple of years. Gilmore, why don't you just give us a rundown where you are currently, and then we can
Yeah
dial in.
Happy to. We are really at the point where we have driven or really close to complete. We have completed the evolution of Editas, where we are an entirely focused in vivo CRISPR editing company. Our lead asset, which we are on track to have patients dosed this year, really epitomizes our strategy, which is one of using the unique capabilities of CRISPR to create non-coding edits that functionally upregulate disease-mitigating proteins.
In this case, EDIT-401, our lead asset, replicates a naturally occurring human genetic variant by editing the 3' UTR of the LDLR gene, resulting in a significant upregulation, a direct increase in upregulation of that, which is associated with, in our non-human primates, a 90% reduction in LDL cholesterol, along with significant and comparable reductions in Lp(a) and ApoB. Just at AHA, the American Heart Association, two days ago, we presented an update on the data showing that those effects now are durable out to 10 months in our non-human primates.
Got it. There is plenty to unpack from the AHA, but we will get to that later. Could you help us understand, at least given the non-human primate data that we have seen from the classical PCSK9 editing approaches versus the one that you are pursuing, why does increasing the LDL receptor give you such a deeper LDLC knockdown?
Well, in all cases, they are trying to increase the LDL receptor. We believe that the reason we are able to do this with this effect size in the non-human primate, and hopefully humans, is because we are directly increasing the synthesis of the LDL receptor, whereas the PCSK9 inhibition approach is really trying to inhibit the degradation or recycling. While they are actually targeting recycling of the LDL receptor, we are directly going to the core of the issue, which is increasing synthesis of the LDL receptor.
Got it. Let's talk about the HORIZON study and implications for EDIT-401 development program. The phase I/II study is currently underway.
Yes.
Right? Given the learnings from the HORIZON study, is there a specific subset of patients that you would enroll, given you could lower Lp(a) and LDL-C? There was a signal in the
that small subset of patients who had very high LDL-C.
Yes. We've looked at the Lp(a) as what I would call is almost like a no-cost or zero-cost upside. The core central part of our thesis is the LDL-C reduction. There are a couple of takeaways from the HORIZON study. You quite rightly point out the importance of enrolling high-risk patients, and in many ways, it validates our current approach in our phase I/II to target very high-risk patients. In this case, right now, we're leading with HeFH, but we can expand to non-HeFH patients, but very high-risk patients with atherosclerotic cardiovascular disease who cannot get to target LDL cholesterol with the current standard of care. I have to say, one of the takeaways from HORIZON was it absolutely validated the critical need of getting LDL cholesterol low in these patients.
You will recall that the event rate in the HORIZON study was actually very low and is probably driven by the LDL cholesterol. But to your point about the subset of patients, those high-risk patients, those are patients who are already enrolling. We are really focused on the LDL as the selection criteria, and I think at later points, we would look at the Lp effect.
Got it. From the dose that you plan to take in the clinic or where you would like to see therapeutic activity-
help us understand the window of opportunity you have, because in the end, this is all LNP-mediated.
Yes. From the point of view of the effect size, obviously, we're going into a Part 1 of our phase I/II study is a serial cohort dose escalation study. We're starting at a non-therapeutic dose for obvious reasons, just to ensure and maximize subject safety, and then we will escalate to higher dose and get to what we think is our target efficacious dose in subsequent cohorts. Apropos the LNP delivery, I think, and I hope that I'm getting to answer the right question, in the context of HeFH, obviously, patients don't have or have an abnormal, one copy of the LDLR gene is abnormal, and therefore could impair naked LNP uptake.
Okay.
In this context, we have dressed our lipid nanoparticle with a GalNAc. That leverages, kind of enters the hepatocyte, if you like, by the back door, essentially leveraging another receptor, the ASGPR receptor family. We have very good data to show that in the context of both wild-type animals and in mice who are heterozygous for a loss of function LDLR, we are getting the same efficacy.
Got it. When we see the data at some point next year, what is your target number of patients that you hope to get to?
Yes. We essentially have designed the study with at least three patients per cohort, at least four cohorts. That is kind of the broad number. Obviously, in the context of a phase I trial, like many trials, it is a three plus 3 per cohort design in case we need to expand the patient population. But essentially, that is the overall design of the protocol.
Got it. Given that you have GalNAc, do you think, at least with LNP-mediated delivery, there is a lot more heterogeneity? Do you think GalNAc takes that out?
We think that actually does take it. In our experience, in the non-clinical setting, it has reduced heterogeneity. In fact, if you look at VERVE-102, they have also used a GalNAc, and that actually has certainly, I say, restricted, and they have a very narrow variance in heterogeneity there too.
And-
In humans.
Let us say you get to, I do not know, to that comment about at AHA, we do not have a therapy which goes above 50%. Let us say you get to that, not the 50%. What would be your target population for a registration study?
If we get to, well, frankly, we have more ambition to get more than 50%, if you will. So our target population will definitely be HeFH. We are actually considering and looking at the possibility of expanding beyond that to include also another very highly motivated population with very high risk, and those are patients with established atherosclerotic cardiovascular disease who sit in that very high-risk category where they have already had events. That actually population together in the U.S. numbers about 10 million patients.
Got it. In terms of cadence of data that we should be expecting, clearly the first dose is not going to be therapeutic. Do you wait for your full dose escalation to complete, or if you get to, I'm making up a number, 60%, you put that data out first?
Yes. The way we're thinking about it, what we've guided to is sharing, announcing safety and tolerability in Q1. That's what we're tracking to, which will be from the first cohort. Then we anticipate sharing and have guided to sharing top-level data from subsequent cohorts, which will include LDL cholesterol reductions and efficacy, along with safety and tolerability in the second half of 2027.
Got it. When you talk to physicians, what's the enthusiasm for a one-and-done approach? Because in the end, it's lower for longer.
Yes. I think I would say there are three categories of physicians. There are those who kind of say, "Well, I'd like to see how gene editing goes." There's a second category which are, would actually say, "If you have equivalent efficacy, and a gene editing approach that helps patients get down and get that area under the curve of exposure to LDL cholesterol, that's great." I think where people are really excited is with the potential offering that we have, which if we validate the non-human primate data with that 90% reduction.
We can actually help them address a need that they are wrestling to deal with, which are those patients who, despite using chronic combination aggressive standard of care, cannot get to target. As I say, that number can represent as many as 30% of patients with cardiovascular disease if you look at the clinical trial setting. Outside the clinical trial setting, that percentage or proportion of patients who cannot get to target is even higher.
Got it. Any theoretical risks of overexpressing LDL receptor?
Yeah, there are hypothetical risks which we have actually looked at very closely. I think the two key ones relate to, one, a question people said, "Is there an LDL level that is too low?" The late Gene Braunwald described LDL as a toxin. I think that position, which is shared by many of the experts we talked to, is really validated by a number of converging data points. One, the Icelandic kindred that pointed us to the LDLR variant that we are creating, where they have very low LDL cholesterol, some of them as low as 13 milligrams per deciliter. Then there are the PCSK9 homozygous knockouts, some of whom actually have single digit, which is below the level of quantification.
When we look at FOURIER and other long-term cardiovascular outcome studies, when you look at patients who have achieved the lowest targets in those studies, we have patients again in single digits. That is the first point. We believe that that can actually be done very safely. I can go into more detail if you want. From a second risk, which is a hypothetical risk, has arisen is this idea that there are some LDLR variants that if overexpressed could actually, or driven up in expression, could create an endoplasmic reticulum stress.
However, we look very closely at that, and I think one of the reasons we feel very comfortable about dismissing that hypothetical is that LDLR is actually a low-abundance protein. Where we have seen examples of high-abundance proteins which can actually cause it, you really have to be very abundant. A classic example is the alpha-1 antitrypsin, where the liver cells are producing grams of the protein every day, whereas the LDLR is in sort of the nanograms.
If there's a very high fidelity translation from the non-human primate data to humans. What does it mean for Lp(a)? Because isn't there a theoretical risk of nuance of diabetes if you go down to like single-digit Lp(a) levels?
I think it's very interesting that this diabetes story keeps coming around a lot. This is a signal that was highlighted sort of in some of the earlier cardiovascular outcome studies for the statins. What's interesting is if you look at sort of various meta-analyses, that risk is actually extraordinarily low, and in fact, may be close to, if not at background rate. Obviously, we'd keep a very close eye and monitor that, but I think in many ways that the diabetes risk has been carried forward very robustly, notwithstanding, as I say, substantial meta-analyses. If you look at The Lancet, I think The Lancet, not I don't think, The Lancet published a meta-analysis of millions of patient years of exposure, just about six months ago, and actually found that the risk had been probably over-ascertained in prior trials, and really, they toned that down quite significantly.
Got it. In terms of off-target characterizations, how much work has gone into that?
We have done a substantial amount of work. Dare I say that many of the tools that Editas created in its early days are used across multiple companies as they characterize off-target. We have done substantial amounts of in silico, which is where you start, as well as in vitro and biochemical experiments to look at this. We actually have found a very clean profile, as others have reported in this context.
Got it. Even if you were to limit EDIT-401 to the HeFH market,
Yes
it is a very large market.
It is.
Can Editas in its current form serve that market, or would you need to partner the asset?
Well, we actually believe that we could certainly do that. Indeed, one can look at one's ambition even more greatly than that when you actually look across a broader population, but certainly HeFH population is one that we could certainly service. Our intention is to actually ensure that we develop the best and optimal development package for approval to deliver value to patients and our investors, and we can do it through the HeFH, but actually, we believe that we can actually do it even with the larger, more prevalent population.
Got it. Given now this is a slightly different target than, say, PCSK9, et cetera, but the end result is still LDL-C lowering.
Yeah.
Do you think the traditional approval pathways of using LDL-C as a surrogate to reasonably predict clinical outcomes still serves as the path to approval?
Yeah. I think that's a great question. I actually think in many ways, and one has to be careful about that. Obviously, this is subject to approval with agencies and so on. First thing is that the LDLR pathway is the final common pathway for LDL-C reduction. You've got LDL-C reduction, the same final common pathway. We're directly impacting it. PCSK9 inhibitors impact the LDLR expression through inhibition of degradation, then statins impact it through other mechanisms. Overall, it's the same final common pathway. I think that the LDL precedent and path to approval actually does have a very good probability of success for us.
Indeed, you may have seen more recently, just this year, a number of programs, both recently approved, like inclisiran, and two others who had revised labels, had an indication statement that included MACE based on other people's cardiovascular outcome studies or other sponsors' CVOTs. I actually think that obviously, contingent on regulatory agreement, that the path to approval would be with LDL cholesterol, and there's ample precedent for that.
Got it. Even though if it's just an HeFH population, what kind of safety database do you think the FDA is going to ask for as opposed to more of a standard path?
Yeah. I think the precedent for HeFH approvals has centered around a couple or a few hundred patients. Obviously, that is contingent to the FDA and how they view editing. I think we will have more clarity in the next couple of years, particularly as Verve will be progressing with Lilly with their program, and we will actually have other precedents from other in vivo editors. We actually think that is a few hundred, and after that, if we go to a larger population, that will something we would have to discuss with the agency.
Got it. Earlier this year, Amy, you had a very successful round of financing. Where does that leave you? Depending upon what the feedback is from the FDA, it is going to be very different cost structures.
Yes. Thank you. We were able to raise $125 million earlier this year, and that extended our cash runway into the second half of 2028. Just to kind of piggyback on what Gilmore was saying, that will allow us to complete part one of our phase I/II trial and really progress through most enrollment in the part two. The financing really left us in a great position, as Gilmore was saying, to continue to generate value and really show the potential of EDIT-401.
I should say that, and thank you, Amy, that I probably did not do a good job of saying part one and part two. Part one is a dose escalation serial cohort, and part two is an expansion population when we select the dose from part one.
Got it. What would be your best-case outcome for the part one dose escalation before you even worry about the dose selection part?
Well, I think a best-case scenario is that we see a very robust reduction in LDL cholesterol with a good tolerability and safety profile, which we anticipate based on our non-clinical tox work, and as you highlighted, the really rather remarkable translational prediction of the non-human primate for in vivo editing. In that best-case scenario, we believe that we could then execute, design and execute a pivotal program to deliver at the very minimum HeFH, and frankly, we're interested in looking beyond that.
Is there a sweet spot that you would love to land up at? Because for most of the other editing programs, it's like getting to mid-40s would be a good outcome. But your preclinical data are so far above everything else that we've seen.
Would a number above 60% is something you would aim for, or?
Well, we would like very much to have a number that is above 60%, yes.
Got it. Well, looking forward to the data next year, and congrats on all the progress.
Thank you very much.
Thank you.
Appreciate the time.
Thank you.