Good afternoon, everyone. Welcome back to the Cantor Healthcare Conference, day two. We've got our last session of the day. I think everyone will be well rewarded for sticking with us through the company tracks. Of course, we do have some topical panels just after this. It's my pleasure, and I'm sorry, my name is Eric Schmidt. I'm one of the Biotechnology Analysts at the firm. It's my pleasure to welcome back to the conference, Editas. We're thrilled to have with us Gilmore O'Neill, the company's President and Chief Executive Officer, and also Amy Parison, the company's Chief Financial Officer. Gilmore, Amy, thanks for being here. Maybe just to start, high level, what's the company like today? Yeah. So, thanks very much, first, Eric. Great to be here. Where the company is today is Editas Medicine really has completed its focus on being an in vivo therapeutics company that uses and leverages CRISPR editing to create therapeutics. Philosophically and operationally, we're aligned in that we choose to develop medicines that really transform the standard of care. They have to make a meaningful change, and that's efficacy-driven change to the standard of care. Secondly, they have to be mechanistically differentiated. We leverage the unique capabilities of CRISPR editing, and what that means is that we don't use it to do things that other modalities can do. A very good example is that we really focus on creating gain-of-function edits that basically increase the levels of disease-mitigating proteins. Third, we are very careful in choosing the diseases that we will actually bring those medicines into, in that we will focus on diseases in which there is a biomarker that we can readily measure and lead to rapid decision-making around dose selection. Then finally, and this is an important part of the pivot that we've completed being a fully baked in vivo company, is that we're very much focused on creating easy-to-use, single infusion or injection, low cost of goods, durable medicines that can be accessible to patients that need them. And that philosophy is epitomized in our lead program, EDIT-401, which essentially is differentiated or has the potential to be differentiated in efficacy by achieving a 90% reduction in LDL cholesterol, as we've demonstrated across non-human primates, along with other atherogenic lipoproteins, including Lp(a) and ApoB. It is simple to use, requiring a single infusion, and it generates the effect by creating or mimicking a gain-of-function variant that increases levels of LDLR, which exceed those that have been seen with other approaches. Gilmore, if we are sitting here 12 months from now, and it has been a successful year, what will you have accomplished? Well, we will have accomplished a number of things that we can stage over the next 12 months. The first is that we will dose patients this year, and we are tracking well for that, having submitted documentation to the HREC in Australia and being in dialogue with them. We continue to stay on schedule for dosing this year. In the first quarter of next year, we will share safety data from the first cohort patients. Then later in 2027, we will share top-line data that includes safety and efficacy across multiple dose cohorts. Okay. Gene editing comes in a bunch of different varieties. How do you look at your basic gene editing tools and stack them up versus the field? I think tools are very important, but how you use the tool is also important. Our key technology, using CRISPR-Cas9 and CRISPR-Cas12, essentially has the potential to create edits or even deletions. We leverage that in a way, I was saying earlier, that is unique to gene editing. One of the things that you cannot really do very well with a monoclonal antibody, an antisense, or an siRNA, with certain very rare exceptions, is increase the levels of protein. We are actually using our editing technology, or indel technology, to essentially create or mimic naturally occurring gain-of-function variants that increase levels of protein. That really is at the core of our philosophy, is how we use the tool. We're certainly going to talk about your lead program, 401, but how many opportunities for gain-of-function biology have you identified? We've already identified, and really, I would say at the beginning of that journey, several gain-of-function potential targets. We have disclosed two of those. One is our EDIT-401, which we'll discuss later, and the other is our in vivo HSC-targeting therapy with the potential for sickle cell and thalassemia, which we have kept in discovery because of our entire focus of bandwidth and resource to advancing 401. But we continue to optimize that, and as I said, we have several other targets. Then actually, we continue to explore and search for additional gain-of-function variants. But the truth is, we expect to find others. Why haven't others gone after this gain-of-function approach, do you think? Well, I think there are probably several reasons. In many ways, they had enough to pioneer. I think our peers have done a really magnificent job of pioneering in vivo editing. Kudos to Intellia for betting on LNPs before COVID. I don't know if you remember, before the pandemic, LNPs had not been validated across billions of human beings. So, they did all that pioneering work and are highly committed to indel, and the same for other therapeutics companies. We did the pivot a little later, and it gave us an opportunity to sit back and say, "Okay, how do we differentiate, or what additional things can we contribute to the field?" I think this idea of leveraging an indel tool to focus on a gain-of-function was a clear area that we could actually really contribute and expand into. Okay. As part of the pivot that you did make toward in vivo applications- Yes. -from ex vivo, you did require an LNP delivery technology. Why don't you tell us about that component? Yes. We have, I would say, two platforms, if you will. We have our in vivo liver delivery platform, which we have licensed from our partner, Genevant, and that is the formulation that we're certainly using to advance our lead EDIT-401 into the liver. In addition, we have our own wholly owned, homegrown targeting LNP, whose chemistry enables us to de-target the liver, and to which we can conjugate different binders to target different cell types. Obviously, what I would say in discovery, it's early, but the lead asset there is our HSC program. What do we know about the lipid from Genevant in terms of its experience? Yeah. So, it is a unique formulation for us. However, most of the components of that lipid nanoparticle have been in human trials before. Also very importantly, recently, we have completed a large number of GLP tox studies that really have demonstrated a very good profile for that lipid nanoparticle as we move into the clinic this year. Any economics of that relationship that you'd like to talk about? Sure. The economics at this point for LNP Technology are fairly standard, so I kind of like to think of those as kind of off the shelf as we sort of think about the costs. Okay. Royalties? Yes, that is certainly part of it, yeah. Amy, staying with you, from an investor perspective, what do you think is most underappreciated about the Editas story today? I think Gilmore touched on this. We are using our CRISPR technology in a way that others are not right now, and EDIT-401 is the program where we are really starting to show where that impact can be made. So, I think it is the upregulation the way that we are using CRISPR. If I may add, if you do not mind. Sure. We've actually had an opportunity, and Amy has been part in these conversations, that we meet a lot of investors where there's a light bulb moment, where they kind of say, "Well, yeah, you're doing cholesterol, but it's a very busy, competitive space." We say, "But when you actually look across the space, a lot of different companies are using multiple modalities, base editing, epigenetic silencing, small molecules, monoclonal antibodies, to target PCSK9." What has been demonstrated really consistently across the non-clinical and clinical translational space is there appears to be a ceiling or cap effect with a 50% - 60% reduction, which by the way, don't get me wrong, transformative, has transformed the field. But again, to our point, we are trying to do better than that. When they hear that we're actually driving through a different mechanism, an even greater upregulation of LDL receptor, and achieving mean reductions of 90% LDL, it's kind of like a light bulb goes off, and they say, "Oh, now I understand." I think if I was to say what's underappreciated, it is that there's a distinction between the efficacy and the mechanism that we're getting together. Great translation or great transition into EDIT-401. So, with regard to that PCSK9 dependent cap of 50%, 60% LDL reduction- Yeah. What do you think biologically is happening there? Do we know? Yeah. Well, we have a very good sense. One of the key things that's happening first is that we certainly, when we look at our non-clinical experiments, we're achieving very high levels of LDL receptor. The LDL receptor is expressed on the surface of the liver, and it is the key cleaner, if you will. It cleans LDL cholesterol, which is the bad cholesterol, put it in crude terms, and it pulls it out of the circulation, with obviously well-validated benefit. How do we get that LDLR upregulation? First of all, we're seeing in our monkey studies at least a sixfold increase in LDL receptor expression in the liver, which is certainly at least a multiple or two greater than what has been seen with PCSK9s. How are we actually be able to achieve that when they keep bumping against that? We think it's because we are directly increasing the level of LDLR receptor expression. That's because we're duplicating a gain-of-function variant or mimicking a gain-of-function variant that was described in an Icelandic kindred. Before I get there, the key point is that that variant essentially alters a regulatory domain in the gene, which when transcribed into a messenger RNA, prolongs the half-life of that messenger RNA, and we believe enables many more copies of the LDLR protein to be copied off that message. Why doesn't that happen in PCSK9? Basically, PCSK9 inhibition, even if you max it out, you're actually maxing out inhibition of degradation of the LDL receptor that's synthesized by the cell. Even if you max it out, you can only get to a maximum LDLR level that's made by the cell, and I think that's maybe what the ceiling is. By essentially going directly to the source, we believe that we're achieving that effect, and therefore driving the- Cleaner shot on goal. Yeah. Tell us about the genetics of this population and how they inform- Yeah -this variant. This population was very much a case study of what our philosophy, which is looking for human naturally occurring gain-of-function variants. In fact, as we were doing this work, we are not just looking at databases but looking at papers. deCODE genetics had published a paper about three years ago describing an Icelandic kindred in which seven members had very low LDL cholesterols. When they actually characterized them genetically, they found that they had a 2.5 kb deletion in the three-prime untranslated region of the LDLR gene, which actually resulted in the removal of several microRNA binding sites. microRNA, as you know, is critical to regulating RNA by binding and targeting the messenger RNA for degradation. By removing that, you reduce the rate of degradation of the RNA, increase its half-life, and therefore enable more copies of the protein to be made. These are not patients. That is the key point. They are not patients. These people have done very well and live with LDL cholesterol levels of between 13 mg and 60 mg per deciliter. You are mimicking that exact situation. We are mimicking. It is not a perfect duplicate. We basically walked across that deletion with a series of exploratory guide RNA pairs and find one that was actually even more potent. That is what we brought forward into EDIT-401. Okay. You mentioned the phenotype, healthy otherwise patients. Yes. Just LDL super low. Yes. Nothing else. Nothing else. That is one strand of evidence that give us confidence about driving LDL cholesterol low. Obviously, a lot of KOLs we have talked to say, well, they actually regard LDL as a toxin. Opinion is great, but I like to see and we like to see scientific data as we consider moving forward with this. Additional strands to the Icelandic kindred is there is a more recently published French kindred, which has a similar phenotype. When you look at families or individuals in families who are homozygous for loss of function of PCSK9, many of these family members have LDL cholesterol levels in single or very low double digits. So that is another piece of evidence. Then finally, if you look at the interventional side, multiple studies, and more recently, PCSK9s, have actually characterized and done post hoc analyses determining that some subjects in the trials actually do achieve very low cholesterols in, again, low single or low double digits. By the way, low single digit is below the limit of detection and do very well. Not only do they actually get an enhanced benefit compared to people who achieve higher targets, but they actually do very well in that substudies looking at cognitive function. The EBBINGHAUS, for example, substudy of FOURIER, has demonstrated they cognitively are no different over time compared to their peers. Also looking at homeostasis for sterol vitamins and hormones also are intact. Lower the better? Yes. To no lower limit? That's- What is the unmet need in a PCSK9 world? Yeah. Including potential oral therapies, how many patients are not getting to goal? A substantial. Even if we sort of, let's look at the patients who people are trying to get to target, because there's also still an evolving education in the preventative cardiology field to get people to more aggressively treat. The guidances were only recently updated, and even before they're updated, many physicians, and I completely understand what the concerns and the challenges for them, were struggling even to get patients to guidance levels, the 2020 or 2019 guidance levels. The levels now recently updated are even more aggressive. Just in that real world, there's that element. But just let's look at this sort of refined world of clinical trials. In recent PCSK9 clinical trials, and I go to cite the Coral Reefs study for Merck's inclisiran, 90% of the patients randomized to inclisiran received at least one other medicine, lower cholesterol-lowering medicine. 2/3 were on a statin plus inclisiran. The other third were on a statin plus another medicine plus inclisiran, either by ezetimibe or bempedoic acid. Even then, 50% of those patients were not getting to less than 40 mg per deciliter, which is really the target you want for patients with very high risk. What does that turn into from a patient number point of view? If you look across the totality of HeFH and patients with established cardiovascular disease in that very high risk category, not getting target, that could be around 9 million -1 0 million patients in the U.S. alone. Okay. I would say that in that Coral Reef study, of course, these patients are being heavily monitored and supported. They are adhering to the medical regime. Obviously, you go into the real world, that is going to be more challenging. Okay. I think you referenced the CTN that has been submitted in Australia. Is that correct? Where are we in the process? Yeah. We are in the process where the HREC has been submitted. We are actually now interacting with the HREC, answering queries, and that is really right on the schedule that we expected. And what type of queries or back and forth needs to- Well, the kind of queries that we get are things like modifications to the informed consent form and some questions and discussion around the starting dose. Okay. That was my next question. But before we get there, when do you think you will be able to clear these HREC questions and have a green light to proceed? I think we are guiding towards, and I think we are optimistic that we will actually be dosing this year. The exact timing, I wouldn't actually commit to until I don't want to say it until they actually say yes, thumbs up. But I think we feel confident that we are staying on track. If you were to get HREC clearance and recommendation- Yes- -to proceed tomorrow, how long would it take, ballpark, to dose the first patient? Well, obviously there's site activations and so on, so we're probably talking about a couple of months. A couple months. Okay. Starting dose, where do you think you're likely to end up? Or how close to maybe I know where I would like to end up, Eric, and then I also know that the HREC may agree or disagree. I feel much more comfortable answering a question like that when I actually have the thumbs up in saying, "This is the dose you are starting at." Obviously, I think everybody appreciates that where you start tells you how many cohorts you are going to have to send. Let me pause for a second because I did not tell you what the study looks like. Sure. My apologies. We are basically doing a two-part phase I/phase II study. Part one is a serial dose escalating cohort study. Each cohort will occur at a higher dose. We are looking at at least three patients per cohort, a 3+3 design, which many of you will be familiar with, and then at least four cohorts. What we would like to get to is a human equivalent dose that we think lines up with that efficacy we saw in non-human primates, about 0.6 mgs per kg. We based it on scaling from a monkey from 1.5 to 0.6 as kind of a crude three-to-one scaling, which really stands up to scrutiny across multiple translations for gene editing in the last couple of years. Obviously, we obviously want to choose a dose, and we have chosen a dose where we believe that it is safe, because obviously subject safety is the most important thing we think about. Obviously, we want to also get to a dose that is meaningful as soon as possible for patients. Another piece is obviously considering that no matter what dose you give a patient, you are creating an edit, and that is a genome edit and it is permanent. We wanted to get as close to something that would enable them to get some potential, any benefit, or even some of them to get some benefit. That is how we are thinking about the dose. Obviously, the interaction with the HREC will actually finalize where they agree with us on that. Okay. If I can unpack a little bit of that. Sure. Gilmore, just first, the targeted dose in humans of 0.6 mg per kg equivalent to the NHP dose, is that equivalent to the NHP dose that gave you that 90% Yes. LDL lowering? Yes. That's really not just a target. That should be fully efficacious. That's where we anticipate seeing it. It might be a little higher or lower. Sure. We will have to find out. I think you just referenced this, but the starting dose would have to have some equipoise in it in terms of having a benefit to the patient. You could not gene edit a patient- Yeah. -without thinking that there would be some level of benefit. Yeah. So, I would like to think that. Yeah. Ethics are really, I think, a compromise of competing moralities. I'm getting philosophical now, but I would like to think that. I would have to say that in the precedent, in previous studies, people have sometimes started, and I think reasonably, certainly as the pioneers, lower. I think we're in a position now where the field has evolved. There's a lot more understanding, so I think we have the opportunity to really move into that area, as you're talking about, where if you're creating a permanent edit, there might be some chance of benefit. Obviously, the argument there is not quite as strong or potent as it would be for AAV, for example, where when you dose somebody with AAV, you've permanently immunized them against that AAV, so you really have to give them some benefit and be sure that you can. Here it's a little different. Even so, a permanent edit is not the same as a transient exposure to some other kind of medicine. Is there a precedent in Australia for being able to start at a certain level? I think the precedent to date has been relatively conservative, but obviously they've had a lot of experience. What determines that precedent? Is it your preclinical package or safety? I think it is going to be a combination of preclinical. I think the collective experience that has grown, remembering that in vivo editing was a thing of science fiction as recent as four years ago. Now we have actually generated a lot more data. I think all of that helps us move that forward. Last question on this topic. Once you do have your starting dose and you are going through your 3:3 escalation, how quickly can you escalate? What we are hoping for, at least in each cohort, is it might be just sufficient to have three alone. The three plus three, the additional three might be if we want to sort of tease out some additional question. What we anticipate is there will be a sentinel period of follow-up. The patients are followed for a few weeks, then we have basically created an infrastructure that enables a very rapid collecting of data. Obviously, the focus is on safety and certain safety markers, to enable us then to have a safety review committee and then actually authorize the escalation to the next dose cohort. Can that escalation be double the dose, or what factor increase? We haven't sort of gone into details, but there's kind of a doubling or sort of Fibonacci type sequence approach. Okay. It's de facto a doubling. Okay, how does this, what we just discussed, Gilmore, all come together in terms of your ability to show us both safety- Yeah -in the early part of next year, then potentially some efficacy in the back half? The starting dose in that first cohort will certainly be a significant de-risking event from just looking at that LNP and its exposure in humans for the first time. I think whatever way we start, that enables to that. Where the starting dose, we finally agree, it will probably determine when, at which cohort, we will get to the target dose of 0.6. But overall, what it enables us to do is still deliver on those milestones of a Q1 safety disclosure for the first cohort of patients, then top-line data for the following cohorts with both efficacy and safety later in 2027. Almost regardless of where you are in the second half of the year. Yeah. You will give us whatever- Yes. -efficacy results you have. Yes. That is the plan. Yes. Hopefully, you will be at close to 0.6. Yes. Okay. How do we think about the steps beyond the SAD study? Yeah. The steps past that is we basically go into Part two. In the Part one study, we select a dose, we confirm a dose with sort of an ideal benefit risk. We will use that dose and bring it into Part two, and we would expand the number of patients exposed at that dose. That, we would anticipate completing enroll by the end of 2028. With those data, and this will be determined by what we see happening in the real world now, there are others in this space right now, we would plan to interact with regulators and start talking about a pivotal. What kind of expansion is appropriate for a gene editing therapy of this nature? Well, if we look across the space, what we've seen is expansions to maybe an additional 25, 30 patients. Okay. Then, beyond that, this is an LDL- Yes. -driven drug. An LDL drug. Beyond that, certainly, we're a small company. The HeFH patient population has significant unmet need. It's certainly at a scale that we could actually develop. The precedent suggests that you can get an approval with an LDLC outcome in a couple of hundred patients. Obviously, that is subject to agreements with regulators here and around the world. That's certainly a path that we could certainly pursue independently. As you expand beyond, and we obviously think that, as I've already alluded to, there is a substantial unmet need, we believe, in not just HeFH, but patients with established cardiovascular disease who can't get to target. As you expand there, that scale gets to a point where a partner would certainly help us in maximizing the value. Okay. How do you think about when it's appropriate to pursue a development partner? Obviously, we're at the point where we want to really get to the human POC. We would really like to get there. I think that really is a significant de-risking moment for us, for patients and clinical trialists, and obviously for a potential partner. That really sort of lays out where we'd want to go for a POC. The good news is that we're well-funded to get us there. Well, that's another good transition. Yes. Amy, you can come in and talk to us about your current cash balance and how long it does take you. Sure. We have cash into the second half of 2028. As Gilmore just discussed, our development plan for EDIT-401, that allows us to progress through the phase I/phase II, Part one, and into Part two. So, we're well capitalized, as you were just discussing, to be able to generate value to really show human proof of concept for EDIT-401. The cash balance, at quarter end or with the recent balance? Yeah. As of the second quarter of this year, it was $212 million. Okay. We have talked briefly about the HSC program. Yeah. I know it has been, to some extent, backburnered. Yeah. Given your focus on EDIT-401, that seemed like a wise decision, but you did bring in some capital. Are we doing anything right now to resource that program? Well, as you well know, and you definitely know because you had to pay them in a previous life, discovery scientists love to tweak and improve. We have that ongoing, and you can do that at relatively low cost. Yes. As you also well know. That is happening. Okay. Obviously, at the appropriate point, really our use of proceeds and our focus is really on getting EDIT-401 going forward. At an appropriate inflection point, we could actually then direct some more capital just to move it forward. But we can leverage many of the learnings that we are now getting with our in vivo. Okay. Is there a milestone that might be announceable based on the discovery work that is happening? Is there a proof of concept that you hope to achieve at some point? Yeah. We haven't actually set out to or have laid out plans yet to disclose any critical milestone, but that's something that we're actually working through. Work going on in the background. Yeah. Okay. Well, that, I think, covers most of what's going on at the company. Have I forgotten anything? No, I think you actually touched on everything. We basically have our lead asset, which epitomized or characterize our philosophy of differentiation, our pipeline with a very high level, and obviously our ability to fund through to critical value inflection and data points. And obviously, as always, we are completely focused on helping patients and making sure that we appreciate the sacrifice they make in enduring our trials and look after them. And we are spot on time. Thank you, Amy Parison and Gilmore O'Neill. We look forward to an eventful 2027. Thank you. And we appreciate you being here. Thank you very much. Thank you. Great. Thank you.