Okay, good morning, and welcome back to day two of the Cantor Conference. My name is Eric Schmidt. I'm one of the biotechnology analysts at the firm, and I'm delighted to host our next session with Editas. We're gonna be doing a fireside chat with Gilmore O'Neill, the President and CEO, as well as Erick Lucera, SVP and CFO. So thanks, guys. A very timely chat it is, coming off some news earlier this week. But maybe before we get to the very latest on your product development plans, Gilmore, just give us a quick overview of where Editas stands, including your cash, your cash burn, etc. Yeah. Thanks very much, Eric. Great to be here. So Editas is actually nicely positioned. We have made significant progress in completing our pivot to being a fully, in vivo, CRISPR editing company. Over the last year, we had planned or outlined that we would advance a number of programs in our portfolio, at mid-year make a selection for a prioritized program, but in additionally, you know, also announce near the end of the year a third tissue, building on our targeted LNP platform technology. As you know, earlier this week, probably coincidentally leading into the investor conference season, we announced that we had selected EDIT-401, our as our lead asset that will go into the clinic. It is an LDLR-targeting program that substantially and to an unprecedented level of 90% reduces LDL cholesterol, and it enables us to get to human POC in a meaningful timeframe and generate human value by the end of 2026 within our current cash runway, and our cash runway extends into Q2 2027. Well said, yes. Okay, well, let's talk. Let's maybe just high-level back up to how we got here. What Editas has been around now for many years as a gene-editing pioneer. What is special about your gene-editing technology? And now obviously you're applying it in a different direction, but from a core principle standpoint- Yeah Why is Editas differentiated? I think, let me start with one point, which is, I think CRISPR editing is differentiated from all other therapeutic technologies in that it has demonstrated a probability of technical success in translating from the pre-clinic to the clinic at a level that's not been seen for other platforms, worth saying. Then within that context, what differentiates Editas is a know-how that we have consciously built around mechanistically differentiating how we use CRISPR to functionally upregulate or increase the levels of proteins that have therapeutic benefit. And I think that is a critical part of our secret sauce. I think the other thing is that philosophically, sort of at a corporate level, we have determined from an early stage that while CRISPR can do many things, we should really focus and choose to go after areas with an efficient use of capital that will get to human or demonstrate human value as quickly as possible. Okay, two points in there, I guess. One is the decision to go after upregulation of biology, and the second is the decision to maybe go in vivo. So let's tease apart those two. In terms of upregulation of biology, why is this not intuitive or maybe a little bit off the beaten path relative to other CRISPR companies? And how many scenarios have you looked at where you identified biology that can be upregulated? I think that what differentiates it, or rather what enables it, is that we live in 2025, and that means that we don't have to go back and say, "Well, has this target been pharmacologically validated?" We now have the luxury of working with very well-curated, large data sets that have genotype data and phenotype data in sort of large populations from around the world, and that enables us to substantially de-risk targets using human genetic data as opposed to pharmacologic data. That immediately opens up the possibility that you can do things that no other technology can do, so I think that's how we kind of went to say, "Well, how can we be different from others?" and so that's how we managed to do that while de-risking it. I think EDIT-401 is a nice example of that because it leverages a genetic human experiment, and we'll come back to that in a second. I know you want to talk about it- No, no, don't worry, don't worry. No, no, but I think that was the... I think that was the important point. I think you had... There was a second part- What about in vivo? Why in vivo? Oh, yes, and why in vivo? So I think the in vivo approach really is demonstrated, again, by many of the issues we've learned from dealing with cell, and particularly autologous cell therapies. The cost of goods is high, and the cost of development use is high, and the complexity of use is high. Going to in vivo means basically taking our machinery, delivering it directly to the human cell of interest through a simple infusion. So the idea is, and what we're all trying to drive to now, is a point where a patient can go in and have an infusion, and maybe spends, you know, two hours and $10 in the hospital parking, which is important these days, and enables them to actually then get a meaningful and lifelong and durable benefit from that simple infusion, which is totally different from having cells collected, then going through a transplant and spending a month in a high dependency or ICU situation to recover from transplant. That's the first thing, and that's kind of obvious, even within the United States, but it also means that we can ubiquitously use this technology around the world because it's much simpler and easier to use. The cost of manufacturing is much lower, the margins are better, and ultimately, it's going to be easier for healthcare systems to really understand how to use these. And I think very importantly, and I want to summarize, we have found, we believe, an economic model whereby with that scalability, with that ease of use, and with the durable lifelong benefits provided, you can actually create substantial benefit for patients, meaningful savings for healthcare systems and payers, but also ultimately also create value for our shareholders. So putting the two together, Gilmore, upregulation of genes with an in vivo targeted approach. Anyone else doing that? I don't think so. You know, I want to be always careful about that. I'm not, I'm not aware either. I think we're aware. How many different applications or opportunities have you identified where that strategy could make sense? If I was just to say within the space of the liver, because that's very rich, we've identified you know in excess of five and more potential opportunities there. I would say higher end for a point of view of just technical opportunities. We haven't really explored with as much rigor as we will in the future, looking at other tissues, but even within the liver, we actually see you know significant opportunity there. Okay, we can get to 401 now. Okay. So you recently unveiled this as your lead program, EDIT-401. Yeah, just why don't you walk us through what it is and why it's of interest? We're interested because we think that it basically can transform the hyperlipidemia treatment paradigm, not least because we've seen robust preclinical efficacy, with 90% reduction in LDL cholesterol across not just non-human primates, which have demonstrated a high positive predictive value in translating interventional cholesterol-lowering studies from the preclinical space to the clinical space. But we've actually also seen it across multiple models, including models with high baseline LDL-C, and that was a mouse model with a high-fat diet, and we've actually also seen it in a model of heterozygosity for the LDLR mutation, which essentially reflects, and is a good reflection of the heterozygous familial hypercholesterolemia genotype in humans. So that's, I mean, the first thing from an efficacy point of view. And why does that matter? I have a slide later, but point is, it is an unprecedented level of reduction that hasn't been seen and doesn't exist in the current standard of care. As I've already alluded to, with an in vivo delivery, it's a potential one-time treatment. You go in for your two hours, you have your infusion, you go home, and you don't have to worry about taking an injection or a pill for the rest of your life. The market potential is sizable. There are multiple segments within that market, from refractory heterozygous familial hypercholesterolemias, to high-risk patients with existing cholesterol or high levels of cholesterol who are not meeting targets, and then beyond. I've already alluded to the economics and how that would benefit, but the business model is further enhanced by the scalability off-the-shelf nature of the LNP, which means we get to margins that can actually create meaningful value for us, while enabling healthcare systems to realize the savings that should accrue from such a clinical benefit. And I think the final thing is that, again, with that positive predictive value in non-human primate and our ability to move into the clinic, quickly, we could get to human proof of concept by end of 2026. So, for those who wanna go a little bit deeper in the science, how does the upregulation occur, and what's sort of the genetic- Yeah basis that supports this approach? So an Icelandic kindred was identified some years ago. Seven members of that family across three generations had very low LDL cholesterols of about 17-30 milligrams per deciliter, which is equivalent to about 0.4-0.5 millimoles per liter for those in the SI world. And this was associated with, you know, excellent health outcomes. It was determined or identified that they had a large two-and-a-half kilobase deletion in the 3' untranslated region. And we were able to look at that target and say, "Okay, how can we optimize around that?" So we actually... Our discovery team basically did a massive optimization mapping experiment, and essentially identified a deletion that they could create, which spans a number of regulatory domains, which ultimately results in the production of a messenger RNA that is more stable and allows the increased synthesis of large levels of LDL receptors. So we're seeing at least six x or sixfold increase in LDLR levels at the doses we've treated or tested to date in non-human primates, and indeed have seen higher levels of upregulation in murine models as well. So the genetic association that pointed you in this direction was just out there in the public domain, and you guys- It was in the- Yeah It was in the public domain, but again, it was a nice validation of something we've leveraged before in that we used the hereditary persistence of fetal hemoglobin to determine we should go after the HBG1/2 promoter. I think the other thing it validated was a strategy we have internally of working with existing databases and indeed identifying non-publicly disclosed targets with this same natural variant. There are additional variants of the same nature that are not publicly disclosed beyond this cohort of seven? Is that what you're saying- Sorry, I thank you for correcting- Sorry, yeah because I realize how that could be misconstrued. I wasn't talking about hypercholesterolemia. I'm talking about the general- more on our general strategy for identifying natural variants that would point to targets that can functionally upregulate. Okay, so, just remind us of the development path and milestones going forward? On 401. So the key elements that will have to be executed, and we're focused on, is to continue the process, opt- or not the process optimization, but the development process for GMP manufacturing, a formal dose range finding study, which by the way, we will also leverage to further look at lower doses, 'cause we have yet to determine a minimally efficacious dose in the non-human primate, and obviously, we are actually well advanced in developing our off-target editing package, which looks good to date, and by the way, sits in the hands of a very seasoned group that has built previous off-target editing packages for... that have met the needs of regulators. So those are the things we have to get through, and that drives us towards a human-... IND/CTA in the middle of 2026. I would say, by the way, we're already looking at and exploring countries, and sites, where we can find the patients for our phase I. Is the next announceable event the filing of that submission, CTA or IND submission? That is possible, but obviously, we are sharing more non-clinical data in between those now and then. We have a number of scientific meetings that we will present, and obviously we'll share the venues and dates at a time that is allowed to us. Okay. So you spoke to a 90% reduction in non-human primates- Yeah Of, LDL-C. Just put that into context relative to other therapies that are out there, and why is lower better? Yes. So first, and this is highly illustrative, we've taken out the numbers, for various reasons, just to keep it simple. But, you know, the current highest standard of care would be the mean reductions of 60% seen with PCSK9 inhibition, either through the use of monoclonal antibodies, or an antisense approach. We are substantially higher. So what does that mean in real terms? Well, a lot of genetic studies, and importantly, interventional long-term outcome studies have demonstrated that a reduction of 40 milligrams per deciliter or 1 millimole per liter of LDL cholesterol is associated with a 20% reduction in cardiovascular risk at 5 years. So when you actually look at the onset of action, of time for us, and the 90% reduction, that translates into meaningful differences. I just use illustratively, that's not to say anything about the type of patient, but just for illustrative reasons. If you think of a patient with a LDL of 180 milligrams per deciliter, a 90% reduction in that translates into multiples of that 40 mg reduction, and it appears those multiples do translate into risk reduction. So that matters from the efficacy point of view. From a safety point of view, you know, I think this sort of leads to the next question, well, is there a floor to how far you can go? Is LDL cholesterol, is it like a cigarette, where there's no amount that's good for you? Or is it like blood pressure, where you need a minimal... There's a floor that you need that is compatible with a good health, even if there is a ceiling that is way too high. And we would say that the, the genetic, data and experience to date, and, subgroups with very low LDL cholesterols, you know, the order of, medians of 25 milligrams per deciliter in long-term, interventional studies, outcome studies like, FOURIER or ODYSSEY, would all point to the idea that there is no floor yet identified for LDL cholesterol. And it is important to say, we're not removing LDL, we're not removing cholesterol. Cholesterol exists and circulates in many, forms and in many particles of different densities. Remind us, when you look at your 90% reduction relative to baseline, that's independent of where baseline starts in terms of your higher fat or lower fat models? Yes, it is, and thanks for, you know, reminding me of that. We have demonstrated that across multiple levels. So the healthy non-human primates had relatively low levels of LDL-C, 90% reduction. In mouse models where we had high-fat diet, or they were heterozygous for LDL cholesterol and had high baseline LDL-Cs, they saw a similar reduction. So I assume your initial commercial strategy would be directed at patient groups that have higher baseline LDL-C? I think our development and early commercial strategy, and I think it's worth highlighting that, from a commercial point of view, and even at a full development point of view, there are subpopulations, within the hyperlipidemia, you know, blanket population that we could actually develop to ourselves. Obviously, as our ambition for public health impact increases, we could expand the size of this population. That would require larger studies, longer outcome studies, and would necessitate partnerships. From a commercial development point of view, starting with that, starting with those refractory, HeFH patients, certainly a very viable path, and frankly, also even commercially would create meaningful value for us. Obviously, maximizing value is what we want to do, and that might necessitate partnering. What does proof of concept look like? I know you've got it to that by the end of next year. Yeah. So proof of concept means that we will see substantial reductions in the LDL cholesterol. The wonderful thing... And might I should say, the wonderful thing about this space is that, you know, the LDL cholesterol biomarker has been very well validated, over the years. It has a regulatory precedent as well, not just for use of advancing into, larger studies, but frankly, for regulatory approvals. I will say that one of the ways that we chose diseases to prioritize was not just mechanistic differentiation, efficacy differentiation, but actually also translatability to humans, including the use of, rapid readout, easily accessible biomarkers. So the LDL-C biomarker really gives us that opportunity. From the point of view of the size of the study, you know, when we look at what I would say the precedent that's been demonstrated by CRISPR editing, you see large outcomes in small numbers of patients. With the effect size that we're seeing here in the non-human primate, with the early onset of action, we're seeing at forty-eight hours post-infusion, these levels, you can anticipate how you can work out and think about how that effect size can translate into smaller numbers of patients required to see the signal, as well as, you know, a shorter follow-up to see that signal. Is there a cohort, size-wise that you'd like to have read out by the end of next year? I haven't locked that down yet. We're actually thinking very actively about that, but, you know, there is, you know, a good set of precedents we've already seen within the PCSK9 development space across monoclonals right through to CRISPR editing, and I think that points to a number of things and highlights a number of things. First of all, the point I've made about effect size and the size of the cohorts. The second is about where dose exploration is likely to go, and the third is that there is a well-validated path from a regulatory point of view in a number of jurisdictions, and frankly, it also highlights that those particular patients, refractory patients, are readily available, and it actually also, I'd say, validates the timelines that we're talking about. You, you mentioned earlier you hadn't yet found a lower limit of activity. Yeah. Is there a lower dose cohort that you expect to begin at or have targeted? We haven't identified that yet. What I will tell you that the precedent to date and the FDA guidance suggests that when you're scaling an in vivo CRISPR formulation in an LNP from non-human primate to humans, you basically reduce by about two-thirds or divide by three. Indeed, the precedent we've seen to date would put you there. I also want to emphasize that we haven't identified a lower starting dose because we haven't found the minimally efficacious dose yet. We will continue to explore downwards. Okay, so there'll be additional preclinical data that we would be seeing- Yes You would expect even before you start these studies? We will be generating more, yes. What would be the forum for those preclinical results to be shared? We haven't determined that yet. Some of the preclinical data that we already have is in upcoming scientific meetings, and obviously, as that data evolves, as we select more meetings, we will keep people informed, keep you all informed at the appropriate time. Could it be as early as this year? We will give timelines and venues at, you know, as, you know, soon before those meetings. Okay. Maybe let's shift to commercialization or commercial considerations for EDIT-401. You're moving from an area, sickle cell disease, where you would have expected to be charging millions of dollars per patient to one in which the standard of care is a few thousand dollars per patient. Yeah. So how do you think about the commercial cost considerations here? Yeah, so we've been, you know, doing a lot of work to understand sort of the pricing paradigms that sit around here. I think there are a couple of things. First of all, we see a substantial change in the effect size. We think that creates value. We have a durable effect as well, which doesn't require redosing or certainly lifetime use. And so that also creates value. That combination, along with the fact that we have an off-the-shelf scaled manufacturing process that gets margins and cost of goods much, much lower than what people have seen to date with cell therapies, et cetera, basically puts us in a place where we can actually create you know, a competitive pricing and access paradigm or agreements with payers while maintaining value for ourselves. You've talked about pharmaceutical margins. Yes. What does that mean? What that basically means is that we're not talking about a cost of goods of $600,000 per patient. What it basically means is that you go into a world where, you know, much of your cost will reflect what you've done or what you're realizing and returning for your development and IP, as opposed to sinking it into manufacturing for individual patients. Correct me if I'm wrong, but I think the anti-PCSK9 drugs are, on an annual basis, somewhere in the $5,000-$6,000 per year range today? Is that ballpark accurate? I think their list is higher, and I think they're probably effective-l ist de facto is about that, yes, so. So you think you've got a more potent effect that deserves a bit of a premium, and then you think, of course, you're gonna capture a multiyear. Yeah. Yes. Yes. I don't want to put words in your mouth, but- Yeah, no, we can capture a multiyear, and I think the other thing I just want to say is that as payers look at this, and by the way, we have had some preliminary discussions with payers, they are excited by and acknowledge and recognize the potential transformational nature of these data, should it be replicated in humans, and they've already identified patient populations which they feel that this would be very appropriate to use upfront. I think the final thing I want to say is that as we think about payers, the payer spectrum is different around the world, but what we believe is, with what I've outlined from a manufacturing cost, from a potency, durability, and from an effect size cost, we can deliver two different timeframes, the savings they want in the near term. You know, some payers in the United States have to worry about cycling of patients, so they need to see a near-term benefit, but obviously, then we have to have long-term and durable benefit, and with that and with our margins, we believe that we can actually realize those value propositions for those different payer needs and requirements while actually giving ourselves value. Okay, so bear with me while I do some math. Sure. You've got the cost of a PCSK9, and again, $5,000. So per year, and you've got a better drug, so we'll give you twice that value. We'll give you $10,000 a year, and as you say, payers want to get a fairly rapid return on their investments. So four years' time, we would expect a payer to want to recoup the cost of therapy. If you're charging $40,000, four years times $10,000 of benefit per year- Can you have pharmaceutical margins? Without committing to a price, I would actually say that you actually have got ourselves in the margin. Your calculation would put us in the margin. Pharmaceutical. Yes. What else needs to happen to scale to that level? Are you needing to put in place any manufacturing considerations or any facilities or brick-and-mortar or anything like that? Actually, so a great question. These are things we'll always consider. I think the good thing about the state of the LNP manufacturing space is that owing to unfortunate events five years ago and the pandemic, you know, the ability, the bricks-and-mortar, et cetera, and sort of, I would say, generic process for manufacturing LNP at, you know, very reasonable costs, has actually been done. We're basically able to leverage off that substantial experience, and dare I say, almost commoditized supply chain. Same with, the RNA component as well? Largely so, yes. Yeah. Yeah, okay. So we know that you back-burnered to some extent... Well, I shouldn't, I don't want to put words. Let us know what happened to your in vivo sickle cell program. How would you communicate the status of that? Yeah, so the status of that is that, you know, we had achieved, again, reached a point where it was achieving more than the minimum product profile that we had set, a threshold of efficacy that was meaningful. Any of you who have worked in the clinical development space or have sat with discovery researchers always know that they do not want to hand that child over just yet because there's one more thing they can do to make it better. And so what we are actually doing, and we have that critical mass in our discovery, is to enable and allow, and exploit this opportunity of, dare I say, the pause, or rather the non-advancement to high cost and spend to development to further optimize the asset, and the program. So it's still getting resources? So it is getting resources to, for optimization, yes. What would you be trying to further optimize? Well, you can always do better, as they say. And so we can actually work across the gamut of, there are some elements of the payload that could be tweaked or some elements of the targeting and delivery that can be tweaked. I mean, the challenge here, I assume, would be delivery to stem cells as a- Yeah What I would say from a profile point of view, we've been very happy to where we've gotten to date. Okay. you know, frankly, if we had the luxury and the assets to do both, we would advance, you know. Is this now a partnership candidate, or are you active in discussions, or do you want to do the further optimization prior to investigating this? Yeah, I think we're agnostic, you know, frankly. As I say, the perfect can be the enemy of the good, but when an opportunity arises to optimize something, you take it. And so I think we're in a very good place from the point of view of any of those options. Okay. And what's the outlook for a potential partnership? Are folks interested in this opportunity, more broadly speaking? Without going into specifics, what I would say is that this is the space for targeting LNPs is actually has been getting more and more exciting. Is that interest driven by business development transactions we've seen or, anything in particular? Yeah, I think one can look at what's happened in the business development space to sort of really get a sense of that excitement. Okay, and then just remind us again, the cash and cash burn that we're looking at between here and the end of next year. I know this is of excruciating importance to investors. Yes. Yeah. So to reiterate, we have cash into Q2 of 2027. As Gilmore mentioned, you know, we're excited to be able to fund EDIT-401 through to human POC and beyond with our cash runway. Our cash runway, you know, we ended Q2 with $179 million of cash, which is a good, you know, measure of how the math kind of works to get us to Q2 2027, so. And in addition to EDIT-401's progress, you're funding modest investment preclinically or even research-wise into sickle cell. Anything else getting funded? So we're excited about our pipeline. We've announced that we'll have an additional target by the end of this year. So we know we do have some funding allocated to some discovery work, both as we optimize the HSC program and for this additional target tissue. That's a liver target, I assume. We haven't said. Yeah, we haven't said. What we did actually guide to at the beginning of this year is that we would talk, have a third tissue. So we have liver, we have HSC, and we would announce the third target tissue. So the third target will not be liver or HSC? It's a target tissue. It's a tissue. Tissue, yes. It's not... It is a tissue. Yes. Yes. Yes. Yes. Okay. Yes. Great. We are out of time. Thank you very much, team. Thank you. Appreciate the updates. Thank you. Thanks very much, Eric.