All right, let's get started. Good afternoon. Is this on? Good afternoon. I'm Geulah Livshits, a biotech analyst at Chardan, and it's now my pleasure to introduce Dr. Keith Gottesdiener, our President and CEO, and Allan Reine, CFO of Prime Medicine. The format for this session is a fireside chat, which we'll open to audience Q&A if there's time. And Keith will also be participating, along with Brian Thomas from Metagenomi, in a mini panel later this afternoon to dive into gene insertion a bit more. Thank you both for joining us today, so to begin with, can you give us a brief overview of Prime and also touch on the collaboration and pipeline updates you announced this morning? Sure, I would be happy to, and that'll fill the whole 25 minutes if Geulah doesn't cut me off. So Prime Medicine is a gene editing company, uses Prime... Sorry, Prime Medicine uses prime editing, which is really a genetic therapy or genetic editing approach that came out of the laboratory of David Liu at the Broad Institute. It really is a generation or two generations past CRISPR technology. We can go into cells, we can go into animals, and we can make all sorts of corrections of many different types, really extending the type of gene editing that one can do. Over the past four years, since this technology has come out of the laboratory and we've really industrialized it, really tested it, and moved it forward, we're very happy to say that our first program in chronic granulomatous disease was accepted for an IND, as well as CTAs in other countries, and there's a global trial now ongoing in that disease, which will be the first test of Prime editing technology. So really, the company is moving forward. Today, we actually made two announcements, and I'll mention them briefly, despite my joke earlier. The first is we signed a collaboration deal, a very broad and strategic deal with Bristol Myers Squibb, BMS, to really use Prime editing technology to advance new and innovative CAR T products in the field of ex vivo T cells. The purpose of that deal, as we hope, is to really use our strong and we think, very distinctive and novel editing techniques to really help BMS to use some of their ideas to really bring a new generation of CAR T programs forward in both oncology, immunology, hematology, and autoimmune diseases. So we're very, very excited about that part as well, and that was a deal that was very substantial to Prime in terms of the financials. We could certainly come back to that a little later. The second thing that we announced today was really a refocusing prioritization of our pipeline. Prime Medicine has suffered from the fact that... Well, I don't know if suffered is the right word. Everything that we've actually tried to do in a therapeutic setting, to all intents and purposes, is working. So we started out with a pipeline of 18 programs when the company was formed, with the assumption, which we thought was very reasonable, that some of those particular programs might be quite hard to do, even with a very powerful technology, or there might be technical issues along the way. Four years later, each and every one of those programs could advance forward. Over the last couple of years, of course, we've been making some under-the-radar decisions about where to put our priorities as we've really focused people and resources on one program or the other. But it became clear as we were starting to get closer to the clinic and the cost for some of the programs began to increase. But just as importantly, it became clear to us that it made more sense to take some of our resources and put them into specific areas to move specific programs forward faster, that the time had come really to share some of our thoughts about prioritization. And so we've done what we call a value framework. I'm sure many other companies have done that as well, but the idea really was to use a variety of different parameters. Allan can go into details in a few minutes, if you'd like, to really talk about what were those programs that had the highest value to both patients and to us, and to really make sure the priorities that we set and the resources really came down. And so this way, we're a much more focused company. Very hard decision to make because we are really deprioritizing a number of programs that really are doing extraordinarily well, but we really did think it was gonna be more important to move a group of those programs forward well and fast to the clinic and into patients than it might be to really deal with a broad swath of possibilities. Mm-hmm. So maybe let's expand on this now. Can you talk a little bit more about the decision regarding which programs you decided to prioritize versus which ones were deprioritized and how you went about making those decisions? Sure. Alan? Sure, yeah. So we, you know, really, and we've been doing this obviously, so we announced it today, but it's something that we've been, you know, working on for months. Mm-hmm. And, you know, just so we wanted to kind of announce this with the other news today to kind of show the market, kinda how we're thinking about capital allocation going forward. But how we made these decisions, you know, it's really trying to understand, you know, through a different, you know, a bunch of different parameters, you know, how do we wanna invest towards value, right? Really thinking about, how are we gonna build equity value, how do we think about return on invested capital? I like to say, like, it's unfortunate when you can't bring a medicine forward that's working to patients today. But I like to tell people in the company is, the more equity value we can build, the more Prime medicines we're gonna be able to bring to patients over time. And so I do hope a lot of these programs that Keith talked about, we'll be able to get back to. But in terms of what parameters we looked at to think about prioritization, obviously, you know, we have to understand is there a real commercial opportunity here? And is there something at the current cost of capital and what that investment will take to get there that we think is obviously a very positive net present value or NPV for the company? What is the competitive dynamic look like within a certain disease area? One of the, I'd say, a very important parameter is thinking about what's the clinical tractability of a program that we wanna go after. When we think about clinical tractability, what does that mean? Is this something where we think we can get to a true value inflection within one to two or after going into the clinic? Or is this gonna be truly a, you know, five-plus-year study to really get to a value inflection point within a certain disease area? You know, obviously, there's, you know, technical feasibility, delivery as part of that technical feasibility, where I think, you know, obviously, we've got our own universal LNP, where we think we can deliver very safely and effectively to the liver. You know, obviously, with the BMS deal and our CGD programs, we've shown that we can do ex vivo therapies very well. But then, you know, thinking about as we think about delivery to the brain, that's something we think that will ultimately get solved in the future, and we hope we'll, you know, ultimately be doing something in neuro in the future. But, you know, obviously, the feasibility there, or probably success in terms of delivery, is not where it is for liver, so those are kind of some of the parameters and how we've, you know, what went into our thinking about what to prioritize, and it really, you know, as we think about it, we know we can't push all of these programs into IND-enabling studies today, but we hope that some of these will be partnered, and others we potentially will work on in the future. Got it, and then on the BMS deal, can you talk a little bit about that? What made it attractive, and you know, how it evolves your spend projections? Yeah, so if you think about the $110 million upfront, so the pro forma number for the last reported was June thirtieth. It's about $286 million. So previously, we had talked about cash that gets us to about mid-year next year, so it's pretty significant runway extension from that into the first half of 2026. And you know, obviously, that's inclusive of some of the savings and that we get from sort of that focus pipeline. And maybe in terms of, I think you said BMS, like, what was attractive about it. Yeah. Beyond that, maybe I'll let Keith answer that. Yeah, I mean, I think there were a couple of things that were attractive. Number one is we were looking for one of our first deals to be a broad, strategic sort of collaboration. Mm-hmm. Something that would really validate, you know, interest in Prime Medicine, but also really could allow us and allow our partner to really demonstrate the, that value as we went forward. I think BMS, first of all, number one, is a great partner. They're clearly one of the leaders, if not the leaders, in CAR T therapy in general. They had some very innovative ideas about what they wanted to do and really needed a technique like ours to make them happen. In many ways, it was a match made in heaven between their creative impulses that they didn't really quite know how to manifest, or at least that's how, that's what I believe was driving it forward, because I didn't really ask them that question. Mm-hmm. But, you know, in general, they really have this commitment to let's bring CAR Ts to the next stage. They built up a huge infrastructure, and they really wanted to develop that, and we were ready to meet them and to develop the reagents, the tools, the editing, approaches that they needed to make it successful in next generations of a CAR T therapy. I have to say, the teams have worked very, very closely together. BMS spent a lot of time, shall we say, testing us as we went forward, you know, checking and testing. And, you know, in a lot of ways, they were very, you know, they had to be very reassured before we got to the end, and they were, and we're happy we're able to sign the deal. We did to sign the deal in a way that included upfront, of course. Mm-hmm. Just as important to us are very early milestones. Mm-hmm. We have $185 million worth of preclinical milestones- Mm-hmm. -and almost $1.2 billion of development milestones. So our hope is as this goes forward, that we will be having incremental infusions from those particular milestones- Mm-hmm. As we go forward as well. So we have a real incentive to make these programs work. Mm-hmm. Got it. And in terms of your role in the collaboration going forward, can you expand a little bit about what that will look like? Only to a very limited degree. There's no question that the primary leader of all the programs going forward is BMS. Mm-hmm. What we will be doing is helping to make the reagents that are necessary to develop these individual things- Mm-hmm. the individual CAR Ts. Of course, we'll be playing a bigger role in all of that preclinical development and even the regulatory interactions, but BMS is primarily working with us to help make these creative edits possible. Mm-hmm. Got it. Anything else you wanted to highlight about the news from today?... that we haven't touched on already? I think this is probably a good start. All right. We might come back to this, but I did wanna make sure we talk about your clinical stage program. Okay. So you mentioned that it's received IND clearance. The study's up on clinicaltrials.gov. Very exciting. Can you walk us through the product and how that trial is designed and what we see there? Sure. So chronic granulomatous disease is a disease where children, young adults, can't fight off infections 'cause their white cells essentially can't produce important substance that actually kill bacteria and other... and fungi as well, and so in the particular case that we're dealing with, which is a form or one form of chronic granulomatous disease, in practice, there is a mutation called P47, and that mutation prevents the white cells from being able to kill bacteria. We specifically can correct that particular mutation and restore normal function, and you can tell that by using a test that literally measures the enzymatic activity in the white cells to move things, you know, to be able to kill the bacteria per se. That test is called DHR. We've been able, in our animal models, over and over again, to show very high levels of correction, engraftment, and quick return of function overall, and that's what we're hoping to show in the near future in the clinic. We put it in an IND to the FDA and also to other countries. This is a global trial. It's been accepted as a clinical trial in numerous countries, but in that global trial, the regulatory agencies accepted our IND in 30 days. I think we're the first gene-editing company where the FDA hasn't at least put a company on pause before they've been able to go forward with their trials. A real testament to the fact that our team spent enormous amount of time generating the data the FDA wanted, and really, the robustness of prime editing in general. The trial, which is starting, is one where we will do autologous bone marrow transplants to patients, who will take out their stem cells, mobilize them, edit them, and put them back into them, and when they're done, if it works the way it has in our animal models, it'll essentially be a lifelong cure from that point. Mm-hmm. And you've said that you'd use or you hope to use DHR as a surrogate marker. Can you expand a little bit on that and talk about what a good result would look like for that metric? Sure. Well, let me talk a little bit more broadly, including DHR, if I can. In practice, when you do these kind of trials, there are three things you'd like to see. The first is that after you've edited the cells, they're viable, and they engraft robustly. So that's the number one point, and there have been a company or two that have struggled with actually getting full engraftment as the products go into human beings. Based on everything we've seen so far, the cells tolerate extremely well prime editing. The second thing you'd like to see is high levels of editing efficiency. So far in our animal models, we're getting 80%, 90%, sometimes 95% precise correction. So prime editing is incredibly efficient in making those corrections overall. And I should point out that's very reassuring 'cause these animal models are where we take human stem cells, edit them, and then just put them into an animal model to allow them to populate the marrow. So we're actually editing the same human stem cells that we would in a patient. So high levels of editing. But I should point out that there's very good human data that shows that only low levels are enough to cure. So the robustness is 'cause, frankly, we're overachievers, so we like to get to very, very high levels in humans, but it's pretty clear that very low levels, 10% or 15% of the cells edited, is more than enough to actually, shall we call it, cure the disease. The third part is the return of the enzymatic function, that the white cells with this correction, in fact, produce the gene, it comes together, and it actually produces the enzymatic activity that kills the bacteria, and that's the DHR test. That, that's a test that's been used for a couple of decades. It's how the disease is diagnosed, it's how the disease is followed, and it directly measures what's missing in those patients that we know is the cause of the inability to fight off infection. So we believe this will be a very good surrogate marker, potentially not only in phase I trials, but also potentially- Mm ... we would argue with the FDA and regulatory agencies going forward. Mm-hmm. And in terms of the regulatory interactions, I mean, obviously, you've received the IND clearance. Can you comment on your off-target analysis strategy? Yeah, so, our off-target strategy is based on the fact that so far in our programs, we can't find off-targets at all. I don't want to suggest they couldn't be there at very, very low levels, but based upon the types of assays and the levels of sensitivity the FDA felt very comfortable with for our INDs, we can't detect that in any of the programs moving towards our clinic. So prime editing, in general, probably has the potential to be among the safest of gene-editing approaches. So we've made that a major focus overall. Our discussions with the FDA found them incredibly knowledgeable about that. I don't think they sounded quite so knowledgeable at the advisory committee meeting for CRISPR Vertex, where there was a lot of confusion, I think, overall on the- Mm ... on the off-target. But believe me, if we had any thoughts that that was the case, when we sat down with them, we talked about it, they made it very, very clear. This was an area they felt was extremely important, and they knew everything about it. We talked through what we needed to do with them. They probably pushed us a little bit harder than they have the CRISPR companies because it's a new technique, and we just delivered what they asked, and frankly, the data looked wonderful, and essentially there were few, if any, questions about any of the data that we submitted. Got it. Great. Oh, maybe just one more thing. Mm-hmm. These same editing techniques are gonna be useful for every prime editing program. So it doesn't matter which organ, which technique, what type of prime editing you're doing, the same set of suite of assays is gonna be the same. So now that we've gone through all the process of validating them and sharing that with the FDA, it's gonna be really increase the ability for us to move forward more rapidly with our next programs. Mm-hmm. And on the topic of other programs, I think you also announced another program in CGD, the X-CGD program- Correct. -which I think we didn't touch on yet. Can you expand on why that was, exciting? It was exciting for a couple of reasons. So X-CGD represents about two-thirds of the patients. The type of CGD we're talking about is probably about a quarter, so it's a much bigger population overall. But what's important is we get to leverage all the things that we've done. To all intents and purposes, the clinical trial's the same, the path to an IND is the same, the animal models that we use are the same. We hope the surrogate markers could be the same. As a matter of fact, I'm kind of hoping to eventually put the second type of CGD into the same clinical trial as the first, which is an amazing step forward for those of you who have ever tried to set up clinical trials in multiple countries across multiple sites. So there's a tremendous amount of synergies ongoing, and it actually increases the patient population by probably two to three-fold as well. Mm-hmm. Got it. And if I'm not mistaken, that program will use the PASSIGE technology? It will. Okay, so that's... Mm-hmm, so it's not going to be a precise, gene correction, but rather than an insertion, a strategy to address more patients? Yeah, so I probably should take one minute to describe the PASSIGE technology. Prime editing can make small, medium size, and large edits. One of the larger edits is a PASSIGE technology, where we can put in a gene-size piece, up to five or 10 kilobases, very precisely into a specific location, and if you do that, you can, for example, in a place like X-linked CGD, where there are no prominent mutations or not many, you can correct just about every mutation by putting in a gene-size piece. Think of it as gene therapy or, you know, on steroids, in the sense that you can put it in exactly the right place. You can put it under the endogenous control, and you can correct all of the mutations, so we will be using the PASSIGE technology for that. We're using PASSIGE today, very important part of our BMS collaboration. Mm-hmm. Right. Mm-hmm. Right. This is probably the second place we'll be using it, but we're also using it in our program for cystic fibrosis as well. Mm-hmm. And on the in vivo programs, we have a few minutes left, but, Allan, you already talked about the kind of rationale for what was prioritized, what was deprioritized. But, you know, any highlights on Wilson’s disease and cystic fibrosis in terms of what we should expect going forward? Yeah, sure, so in terms of Wilson's disease, you know, we will have data coming up during the fourth quarter. We'll be at both ESGCT and AASLD. We've shared some in vitro data in the past, but we really haven't shared any in vivo data for that program, so I think we're really excited to unveil that data for the first time. We have shared, you know, previously, some data around our universal LNP at some conferences- Mm-hmm. As well, so this is sort of putting that all together that can show you kind of, you know, why we're so excited about bringing that program to the clinic, to patients, and cystic fibrosis, I don't think we've commented on when we'll update data there. I think I can say we continue to make good progress within that program, but we haven't, you know, talked about when we're gonna update that and at what conferences. Yeah, we're kind of excited about cystic fibrosis as an indication. I mean, there are a lot of reasons to be excited, but probably the one of the most important scientifically and possibly clinically related is cystic fibrosis is one of those places where you really want expression in certain genes, and you don't want it in others. You want the levels of expression to be set by physiological levels. Mm-hmm. Any kind of exogenous delivery has intrinsically the problems of getting the right cells to express and at the right levels. Mm-hmm. If we can solve all the problems we need to, and we're certainly making progress, you're in the situation where the endogenous control can say, "This cell really shouldn't express the CFTR. This cell should express it at a high level. This cell should be going up and down, depending on whether you're living in Arizona or, you know, in Alaska, hot or cold, or whether you've just come back from, you know, a marathon or other kinds of things." That kind of physiological control is one of the major advantages. Mm-hmm ... of the type of prime editing that we do, and we think it'll be particularly important in cystic fibrosis. Mm-hmm. Great. So in the last minute or so, I wanted to ask what you think the market might be missing about Prime Medicine? I'll go first, maybe. I think the market still is lumping gene editing companies together, and they're lumping gene editing companies with very early preclinical companies. I might point out we're not a preclinical company anymore, but I'll feel better when I actually have clinical data in hand, and I can really look people in the eye and say that, but I think that's part of it, and I also think to this point, people haven't differentiated among these different gene-editing companies. I mean, obviously, we're biased, but we think really we have an extraordinary technology that can do things others cannot, and we expect that if we keep executing, that people will recognize it someday. Allan, do you have anything to add? Yeah, look, I think it's, you know, it's obviously, you know, I've been doing this for over twenty years, and I've seen a lot of different market cycles, and things go up and down. You know, everyone was jumping over themselves to get involved in gene editing, you know, three, four, or five years ago, and, you know, the tide turns a little bit in terms of sentiment, and I expect that to turn back. As I look at, you know, Prime Medicine, the reason I joined this company, I think it is by far and away the best gene-editing technology that exists. We continue to make great progress within the company. I think as we can kind of continue to deliver on that, present more data, as we get some of these drugs closer to patients, and obviously ultimately to commercialization, I think that that value will accrete. So I think there's a lot of interest, both from obviously you know what we did with BMS- Mm-hmm ... but other pharma partners, but there, you know, still remains a lot of investor interest as well- Mm-hmm ... and I expect that to continue. Yep. Fantastic. I think that brings us to the end of the session. Thank you both. That was great. No, thank you. Thanks. Thank you, everybody.