Hello, everyone. My name is Mitchell Kapoor. I'm a senior biotech analyst at H.C. Wainwright. It's my pleasure to welcome you to the Genetic Medicines Conference. Today, I have Editas with me. I have the pleasure of welcoming Gilmore O'Neill, the CEO, and Amy Parison, the CFO. Thank you both for joining us today. It's great to be with you, Mitch. Thanks for the time. Thanks friend. Absolutely. Just to kick us off, maybe you can give us a little bit of an overview of Editas, where we are today. The story has changed a little bit so just catch people up to speed who may need to have a refresher, and we can kind of dive in from the questions from there. Absolutely. Happy to. So essentially, we are an in vivo gene editing company that is focused on developing simple-to-use, highly effective, differentiated, and frankly, cheap medicines, or relatively cheap medicines that can actually give a transformative benefit to patients. And we are driving, with a laser focus, on moving our EDIT-401 LDLR program, which basically drives a 90% reduction in LDLC to human proof -of- concept, targeting those data at the end of next year. Great. So just thinking about the 90% LDLC reduction you all have seen, very impressive, and then over 6x LDLR upregulation with your lead candidate, 401. What thresholds in humans would confirm the effective translation of what you're seeing preclinically? Well, I think the very interesting point is that as we want to be transformative, we want to differentiate from other medicines. And currently, statins achieve about a 40% reduction. PCSK9 inhibition, through whatever modality is used, is achieving around 60%. Exceeding that, we think, actually, is meaningfully differentiated. Obviously, I think a key point to remember is that in the recent history, we have seen that non-human primate data has demonstrated high predictivity, or is highly predictable for the human effect size, both for gene editing, or CRISPR gene editing specifically, translating into humans for CRISPR editing of the liver. And we've actually seen similar effect size equivalents from non-human primate to human for cholesterol-lowering approaches across the different modalities. So that differentiation is important to us. And so you get a sense of that threshold. Great, and you've got it to an IND or CTA by mid-2026 for this program. Which tox or durability data sets or gating factors are determining that timeline, and could regulatory feedback alter that at all? I think the key thing is that we have a very clear path to that CTA. The good news is that the experience for regulators globally has now significantly increased over the last few years. And so their comfort, and I should say the confidence with which we can actually present a plan to them is really enabled by that. Obviously, regulators and IRBs may have views, and we will have a clear, more clear view of where they are on that. But I think we have to say that we remain very confident, largely because of that growing experience that the regulators have in moving LNP formulated mRNA CRISPR editing therapies for the liver from the preclinical to the clinical space. OK, great. And you've got it also to human proof-of-concept data by year-end 2026. Will that mean some LDLC reduction in addition to safety updates? And I imagine we'll have a few months of follow-up by that point, since the IND or CTA would be mid-2026. Just maybe kind of set up that readout for us, what we can expect and what investors should be looking for there. Yeah. So I say with that 90% reduction, we're very excited about that. We want to look to safety. And the beauty of this program is that the LDL cholesterol readout is a very simple assay to run from humans. It's actually important to highlight that the assay we used in non-human primates is actually a human assay. And so you can actually see the ease of translation in humans. So we anticipate having LDLC reduction and safety parameters with a particular focus on the liver, because that is an area which is of particular interest to all of us as we dose humans with LNPs. OK, great. And what level of LDLC reduction and what kind of safety profile would define a best-in-class scenario and a shift to a standard of care for certain subgroups of patients? So not only are we mechanistically differentiated, but as you can see, and if I actually try this, yes, not only mechanistically differentiated by driving increases of LDLR by direct editing of regulatory elements of its genetics, but we actually have an efficacy differentiation here, and if you actually look at the current standard of care, which ranges from 40%-60% reduction of LDLC, exceeding that is where we want to go, and I think, as I said a little earlier, the non-human primate effect size translates very well to humans, both at the editing space and for cholesterol-lowering, and then from a safety profile, obviously, we are giving a single dose of the medicine. We anticipate maybe minor changes and temporary changes in liver function, but that is all we would expect to see, and that would give us a very superior profile. Got it. Makes sense, and between that 60% and 90%, there's quite a bit of room there for a meaningfully better therapy, but also, maybe you could speak to kind of the adherence advantages of a one-time solution. Absolutely. Happy to. Yeah. Obviously, there are others who are using a knockdown approach for PCSK9 and have really made very compelling arguments for the challenges for patients. To reduce your risk, you have to control your LDLC and get it down to a meaningful target for life. First of all, that's very hard. Indeed, 75% of treated patients fail to get to the target or maintain that target, and in order to achieve that target, they have to maintain chronic therapy for life, and that therapy may include more than one modality to get to target, so with a single dose durable therapy like a CRISPR edit, and that tied to what we believe is a best-in-class efficacy, we can see significant advantages for rapid risk reduction for patients who actually use this medicine. Yeah, that's a big thing we think about, too, is the one-time versus the one-time in a clinical setting, clinical trial setting versus the clinical trial data that others have generated, which is not permanent. There will be a real-world difference for these patients. I think it'd be very real, yes, very real, and I think, at the risk of boring people with this, sorry, excuse me, this slide, I think it's important not just to look at the effect size, but the onset of action time, and so in the real world, that onset of action time means that that risk reduction potential really kicks in very early, and that is actually meaningful to patients, obviously. Right, absolutely. And so as we look at the landscape, others trying to enter the cardiovascular space with a one-time gene edit, we're thinking about Verve, Lily, and CRISPR. Could you just set up kind of how LDLR differentiates from ANGPTL3 and PCSK9 knockouts? And how do you weigh the differences there? Yeah. So one key thing first about upregulation is that's at the core of the differentiation strategy for Editas as sort of from a scientific strategy point of view. We set out to use CRISPR in a way that was unique and could not be replicated by any other technology like Antisense or siRNA. So that was the first thing. The second thing is by using an upregulation strategy, in this case, by upregulating LDL receptor, we are basically directly editing regulators of LDL protein production. By doing that, we're actually increasing LDL receptor levels by at least sixfold, as you can see here in the non-human primate. In contrast, PCSK9 knockdown or inhibition essentially modestly increases LDL receptor because it actually stops degradation of the LDL receptor. However, in that case, you really run up against a ceiling, because in the end, there's a fixed amount of protein. By us increasing the level of proteins by using an upregulation strategy, it enables us to achieve significantly higher levels. And that is what we believe drives this differentiated effect size with a 90% reduction in LDL cholesterol. OK, great. And how will their readouts influence your path and anything about the trial design? And what are you watching for there as a fast follower in that sense? I mean, in many ways, we see certainly with the PCSK9, because ANGPTL3 is kind of targeting something slightly different. They're also going after hyperelevated triglycerides as opposed to LDL cholesterol, but those trials are very much influenced by the trials that have been developed over the last 10 years, and we see a very clear and robust path to proof of concept and beyond with the work we're doing. Obviously, we're particularly interested in the effect size they see, but to date, we've seen or see a very clear translation from non-human primate to human in regard to effect size, and obviously, we will obviously monitor safety and, very importantly, obviously, durability data. And in fact, we were very excited yesterday to see Intellia's durability data, because I think that actually is a significant validation for the durability of CRISPR-based editing of the liver when it comes to the durable efficacy. And it's important to note that we are using a similar CRISPR enzyme, Cas9, for that. So I think that really increases the overall confidence for the durability. So with durability, obviously, gene editing is much more permanent than gene therapy. So how long of follow-up do you think is needed to say, this is permanent, and this is working, and it's safe, and patients should feel comfortable coming on to therapy? Well, I think that the first thing we can say is that our confidence for durability is increasing, not just based on the non-clinical data. And obviously, we're generating that non-clinical data. Others have done that in the past. I think what's very important to understand is that as the CRISPR space expands, we're actually going to be able to, I believe, extrapolate durability data across the field. And so I think in a really very short period of time, we can actually feel very confident, certainly in our case, because we will have, how should I say, precedent already set by other therapies that are editing other targets within the liver. I think we feel confident about that as well for the very simple reason that by editing the genome, in contrast to an AAV delivered transgene, that edit will be copied into daughter cells every time a cell divides, in contrast to AAV, where an episome or a little mini chromosome sitting in the nucleus will go to one or other daughter cells when a cell divides, but it's not actually copied into both cells. So editing has a fundamental opportunity to be durable mechanistically in contrast to how maybe an AAV delivered transgene would. Great. And so you all have shared the Icelandic data for LDLR upregulation and how that relates to your strategy. How much weight do regulators place on these human genetics? And could it accelerate any regulatory timelines? Or how do you think that that affects your discussion with the FDA? I think human genetic data has really demonstrated increasing importance in the data sets and the evidence that regulators weigh. That's certainly been my experience over the last 20 years as a drug developer. The Icelandic data set is one compelling piece and certainly helped guide us to our editing strategy for LDLR upregulation. It is also important to point out that there is more than just that evidence. There are other pedigrees that have demonstrated very low, or should I say, when I say pedigrees, I mean kindreds or families of patients with genetically driven very low LDL levels who do very well and have actually demonstrated significant reductions in risk of cardiovascular disease. Indeed, there are what I would call super responders or patients in long-term outcome studies over the last decade or so who have again demonstrated very low LDLCs, who have done extraordinarily well, both from a risk reduction point of view, but actually also tolerating with no evidence of adverse effects on cognition, endocrine, or any other physiological systems. Okay. And moving just to the safety aspect, transient expression is key here. Can you expand on the mRNA persistence, enzyme clearance, and transaminase dynamics that support your favorable safety profile? Sure. So just to be clear, we obviously, the edit is durable and will be lifelong. The transient, really, nature is you want the editor, the actual machinery that edits and makes that edit to be transient. And to date, we feel very good. And others, I think, are seeing similar effects where the payload, the messenger RNA and the guide RNAs clear very rapidly after that initial injection and delivery to the liver and perform the editing function. So they seem to clear very quickly. We also see the same with lipid nanoparticles. And I believe, again, that's not just our experience. That's the experience of others. That's very compelling because you don't need the editing machinery to stick around once it's made the edit. But that edit itself, once made, will persist. OK. And on the commercial side, how do you see this playing out in terms of the first target market? You've highlighted the 70 million U.S. hyperlipidemia patients. Which subsegments define the initial launch focus for you all, of the strategy? Yeah. No, it's a very important question because obviously, as you bring a new modality into the clinical paradigm, it's very important to get the appropriate balance of benefit risk and the appropriate size of population that actually is using this new technology. So while our data are generalizable across the broad swath of hypercholesterolemia patients, we can see an initial segment around refractory heterozygous familial hypercholesterolemia patients being a very good place to start. More importantly, or not more importantly, but equally importantly, there's actually a compelling business case there because that is actually a sustainable initial population. As we grow, as we, the community, the editing community, and the health care community characterizes the long-term safety profile, obviously, we can expand into other populations. Indeed, we actually can see that there are patients with high risks of arteriosclerotic cardiovascular disease in the primary and secondary area that is, who have no complications or have already had an MI or stroke, into whom you could expand sooner. Ultimately, as I say, as we characterize the full safety, we can see a substantial upside, both in a public health impact and in value to investors. Okay, great. And on the cost of therapy in this type of an indication, it's quite a large indication you'd be going after with gene editing. Can you talk about the benefits you are providing for a one-time cure versus how you're weighing the cost over the lifetime of a patient and how you think about that? Obviously, Verve had a strategy that was to make it a really inexpensive therapy. Is that how you're thinking about it as well? The beauty of using lipid nanoparticles in contrast to other modalities of delivery, such as cell-based or vector, viral vector-based therapies, is that the cost of goods is substantial. I mean, it's a fraction, a tiny fraction of that. It's also highly scalable and very much off the shelf. That actually means the overall cost very manageable. That, combined with the rapid onset of action and the very large effect size, enables us to really anticipate a significant benefit to patients in the very near term. That matters not just to patients, but it actually also matters to payers, particularly those who may have a sort of more short-term view counted in three to five years, as well as those who actually are concerned about the lifetime durability of the therapy. So I think that enables us to both create significant savings in the near term and the long term, depending on the view of the payers, but with a cost base that creates value for them, but actually also creates substantial value for our investors, even as we, I think, significantly impact patients' lives and give them significant benefit. Got it. Okay. And I wanted to touch upon the HSC program. You had very impressive data there with your tLNP platform. Obviously, the focus has shifted a bit. But how do you see that folding back into the mix? When does that development reaccelerate? And how do you see that program fitting into Editas' pipeline? So we don't actually see that as a shift. From a strategic point of view, we are an in vivo editing company. This is what I would say more a pragmatic tactical shift in the markets in which we find ourselves today. We had telegraphed over the last year that while we were advancing two programs, our two assets, that we would make a choice in the middle of the year about, one, to drive to POC and, very importantly, drive it in a meaningful short time frame within our current capital or cash runway. And that was the reason we advanced the EDIT-401 LDLR program. Nevertheless, one thing I've always known is that scientists never saw something they didn't want to improve. So our scientists, our discovery group, has the opportunity to continue to optimize our HSC program. Obviously, as we create value, as the markets change, we could actually then move the HSC program forward for development. Okay, and what about the development so far of Editas' pipeline today? Risk mitigants 401. so what prior work have you done now that investors can look at and say, hey, this has added risk mitigation for 401 because of the translatability of your development in other areas? That's a great question because it actually is the underpinning of our strategy around in vivo editing with upregulation. A couple of things we've done to substantially de-risk this program pre-clinically is, one, use the power of human genetics to identify targets and use that human genetics to essentially identify a naturally occurring variant, like the Icelandic kindred, which pointed us to this area to edit in the regulatory genetics that control LDL receptor. Having that variant, having the history of those patients, also then drawing down on the long-term outcomes in other genetic kindreds with very low LDLC and indeed interventional studies, all that de-risks from an efficacy and safety point of view. Our partnership with Genevant to use their hepatic LNP technology is also significantly de-risking because they have substantial experience in this space and, more importantly, experience in that space translating into humans. So that actually is a significant de-risking event. I think finally, the fact that we are using the non-human primate and its high positive predictive value is incredibly de-risking too. I did say finally, but of course, again, in the context of the environment and the CRISPR gene editing of the liver space, we're seeing, first of all, an unprecedented level of technical success in translating from the non-human to the human. I would say that CRISPR editing in translation to the human has had an unprecedented probability of success. And that is de-risking. And obviously, as the experience of durability and long-term safety generates, that also continues to de-risk. So we feel that even in this pre-clinical space, we have de-risked substantially. And that really is at the core of our strategy. All very great points. Finally, just wanted to open up to you all to just discuss the next 12-18 months for Editas, as well as anything we didn't get to touch upon today that you think might be helpful for investors to consider. Well, thank you for that opportunity. The key thing from an execution point of view, as we telegraphed at the beginning of this year, was that we have essentially delivered today to all our objectives. We have a remaining objective we telegraphed this year, is to select a third tissue because it's important to remember that even as we advance the EDIT-401 asset, we are, obviously, in a very regulated manner, enabling and building our platform for delivery, as well as our payload, and that delivery enables both liver-targeted LNPs, but also non-liver-targeted LNPs, the lead obviously being for hematopoietic stem cells, so that is an important part of what we're going to do. But next year, the real focus, again, with laser focus on EDIT-401, is to have that CTA IND filed in the middle of the year and to have human POC by the end of 2026. And I just add, from an investor standpoint, we have cash into Q2 2027. So we're well funded to achieve both the IND CTA filing as well as the human POC and beyond. Excellent. We're looking forward to all of that. Really appreciate both of your time. Also, I want to send a special thank you to all the investors that dialed in. Yes, well, thanks to you all, and thank you, Mitch. Thank you. Take care. Bye. Take care.