My name is Kelly. I'm a member of the Biotechnology Research team at Jefferies, and it is my great pleasure to do a fireside chat with President and CEO of Prime Medicine. Thank you very much for doing this. My pleasure. To begin with, could you please provide a quick overview of Prime and its differentiated gene editing platform? Sure. So when we talk about—Sorry, this seems very loud, actually, in the back. Is it okay? Very loud? No. Okay. It just seems very loud to me. It seems to be coming over my shoulder. In practice, Prime, when we talk about the technology, which spun out of David Liu's lab at the Broad, in 2019, and has greatly improved since then, we talk about four attributes. One is versatility, one is precision, one is effectiveness, and one is breadth. The versatility really represents the fact of the, of the edits that we can do when we do gene editing. So when you think of rare genetic diseases, and it's important to point out, Prime is not only working in rare genetic diseases, but it's really the paradigm for where we work, we can correct any kind of mutational mismatches that occur. For base pairs of DNA, 12 types of mismatch, we can correct all of them, as compared to, say, base editing, which can correct 4 of them. We can edit, we can correct, we can destroy, we can change. We can do pretty much of anything, and as a matter of fact, I think one of the critical elements to the versatility is that we actually correct genes. We put them back to normal. Our aim is to do genetic cures for patients overall. We can also do small mutations that are small deletional mutations and correct them, insertional mutations and correct them. In a later stage of Prime Editing, Prime Editing is moved fast. Later means 6-12 months later from when the company spun up. We were able to deal with hotspot, stretches of DNA, 100 or 150 base pairs in length, where we could lay down just a perfect replacement of that hotspot and thereby cover multiple mutations at one time, no matter whether you had mutation number 1 and you had mutation number 7, we would lay down a perfect genetic wild-type sequence at that particular point. More recently, we've been able to show, for example, we can precisely remove very large stretches of DNA, and the best example of that, that we've had, is working in repeat expansion or triplet diseases like Huntington's. We can literally take out just the pathologic repeats and leave the normal number of repeats. It's as if we went in with a scalpel, cut the DNA, put it back together again. Of course, not that, it's not the mechanism by which we do it, but it's literally a genetic cure there as well, and we've shown that in seven repeat expansion diseases of the fifty or so that exist. This year, we started talking about a technique that we've been working on for more than three years in the laboratory and in Prime, called PASSIGE, and that's the ability to precisely put very large kilobase-size, multiple kilobase-size pieces of DNA, precisely at a particular spot in the genome. And of course, today, we can get DNA into the genome. We do that with lentivirus, but it's very, very random. This is precisely targeted to a specific spot as well. So that's versatility. Precision refers to the fact that it appears as if we have little, minimal, or no off-target activity, and that's very, very important, obviously, from a safety point of view. In practice, we know that part of that reason that we have such low levels is because we don't cause double-stranded breaks, which really cause a lot of indel formation, whether they land at the target site or elsewhere in the genome. But the other reason is that Prime Editing is a three-stage process, and at each stage, there's a separate annealing step that must occur before you move to the next, and the next, and the next stage. So in practice, if a Prime Editor lands on a wrong spot, three separate annealing reactions have to occur before the edit is complete, and that seems to keep the level of off-target editing really minimal. As a matter of fact, in our, one of our lead programs, chronic granulomatous disease, where we've said we intend to file an IND next year, in that program, to date, using what I call IND-ready assays, really comprehensive studies, we haven't found a single detectable example of off-target editing. I'm sure that'll change as we continue to go through programs, but it's just a marker of how low our off-target activity is. The third thing really is just effectiveness. So of course, some of the effectiveness is for a once and done type of approach. Some of it is once we make the change, it goes to all of the daughter cells. Some of the effectiveness is that we do it in situ, exactly where the gene is, so it stays under the normal control. But it's also important to point out that there have been rumors since Prime Editing came forward, that the editing efficiency is very, very low. But in practice, if one optimizes the Prime Editors in our clinical programs for moving forward, we routinely get 70%, 80%, 90% precise editing, more than enough to get a therapeutic effect. And last but not least, is the breadth of Prime Editing. We look at pathogenic mutations. The NIH has a database of more than 75,000 known pathogenic mutations. We can literally look at them and check them off. When we did that with the first version of Prime Editing, we're already over 90% of the known pathological edits we could correct. And now that we have newer techniques and improvements to Prime Editing, we know that the number is much larger. So in many ways, this technology was designed to look at all the gaps in other approaches to Prime Editing and to really fill them overall. Sorry, can't help but gush a little enthusiastic when I talk about the technology. ... Thank you very much, Keith. And as Prime is making a transition to the clinical regulatory side of the preclinical development, we understand that Prime currently has about 250 full-time employees. I was wondering if you could please discuss, you know, further areas of expansion? Yeah, so this question is about where we might expand Prime Medicine these days as we start to move towards the clinic. And, you know, companies undergo this routine evolution as they go forward. In our case, it's gonna be a little bit complex because we have so much to do in the preclinical and, you know, pre-IND space. Plus, of course, what we have to do is to move many of these programs to the clinic. Right now, Prime Medicine is just under 250 people in size. The majority, well over 90% or so, are literally on the front lines, people who are adding value to the company each day. As we start to go forward, we certainly expect we'll be adding more and more to the clinical and the regulatory groups as we go into the clinic. But it's important to realize we have a very, very large pipeline, at least 18 programs. To be honest with you, we have 100 additional programs that we'd love to do. It's one of the advantages, or one of the excitements of Prime Editing, is you can do just so many things. But of course, as many of you would expect, it's also a challenge because companies our size can't do that. So we'll be talking maybe a little later about some of our business development activities as well. So we'll also be investing in sort of the relationship-type approaches, the things that will let us work very well with partners as well. I think clinical reg and sort of relationships with partners are going to be two of the important areas that will continue to grow. Thank you. And so for the immediate targets indications, Prime has various, target tissues, including the blood, liver, eye, ear, et cetera. Could you please discuss how these indications, have been chosen and the criteria that Prime has employed in selecting, indications, development candidate, development indications? Sure. So we get asked a lot, how do we pick the indications? Because if you look at our pipeline, you can see we're working in 6 or 7 different tissues. We're using 3 different delivery modalities, et cetera. The reason we did it originally, which no longer holds up, is when we started, the idea was to really explore where Prime Editing would work well. With any new technology, what you expect to find is the glitches or the problems or the issues as you go forward. We picked a broad pipeline, expecting that we would look at many different organs. We just mentioned just 4 of them, but there are actually 1 or 2 others as well. We picked 3 different delivery methods, ex vivo, LNP delivery, and as well as AAV delivery, in addition. We picked different kinds of cells, terminally differentiated and rapidly dividing, and everything in between. The purpose were to find out where Prime Editing work well and where were the places that were more technically challenging. I tell the story, I tell it often. My CSO came in when we put that pipeline together, into my office. That point when we set the pipeline of 18 programs, I don't think we actually had 18 employees at that point, so it just gives you an idea of our ambitions overall. But he said to me, "I can't possibly do this." I said: Look, I'm an old hand. I've been doing drug development for 35 years, including almost two decades at Merck. You start preclinical programs, half of them are gonna be gone in a year or two. They may not be gone forever, but they'll hit technical bumps or hitches as you're going forward, and it'll be a little bit of a slower path. Don't worry, in a year, it'll be closer to 9. Well, it's 3 years later, every single one of our programs is still moving towards the clinic. I can't say rapidly for each one because it's too much bandwidth for a company our size. But almost all those programs we could do in a moment if we wished, and in practice, there are many others that we've been thinking about potentially adding to our pipeline through BD activities. We picked half our pipeline for a straight, clear path to the clinic. When you think about eye, ear, liver, and ex vivo approaches, everybody knows exactly how to do it. Doesn't mean there aren't technical challenges along the way, and there have been. It's the fact that you actually know exactly the technology, what it's gonna use for delivery. In many cases, there's already somewhat of a regulatory path going forward. These were organs that you could deliver, in some cases, locally. People really understood how to do it. It was more a matter of a Gantt chart, and we've been moving those programs forward, and they were chosen specifically for those reasons. Because we do feel a really important step is to show that Prime Editing works in humans, not as a scientific demonstration, but really derisks people's concerns about how this would work. And of course, only in humans can you confirm that all the lack of off-target activity in all of the animal and other species, in fact, translates into humans. It was very important for us to get them into humans very, very rapidly, and that's really the path we've been doing. We clearly have liver, ex vivo, eye, and ear programs that are moving rapidly to the clinic. But some of the best programs are the ones that really are in the second half of our pipeline. These are things where we do things that no one else can do. To my knowledge, there's no one else, except people who are essentially using Prime Editing, and in fact, most of those people who are essentially using Prime Editing, we believe, are actually using Prime Editing, regardless of what they call it. No one without using that technique, for example, can go into repeat expansion diseases and just remove the pathological repeats, show that that completely corrects the biochemistry, restores the natural expression and proteins, in that particular disease, and has phenotypic effects, first in the test tube, and then in the, you know, and then in animals. That's essentially a genetic cure, and there are many approaches that people are taking to some of those diseases. The repeat expansion disease is just one example, but it's a place where we think we can do something absolutely no one else can do. And those places are gonna follow a little bit more slowly because delivery in those approaches is not a fully solved problem. ... All right, and with the first IND expected to be filed in 2024 for the lead indication in CGD, could you please discuss the status, and what's needed in order to file the IND? And given the ultra-rare indication with high unmet needs, could you please discuss the likely regulatory requirements for approval and expectations for gene editing levels for clinical benefits? Sure. Before we start, let me just explain, we didn't pick CGD, chronic granulomatous disease to be the lead program. It chose itself. As I mentioned, we picked a lot of different areas we thought Prime Editing could work. All of those areas are moving forward, eye or liver, and ex vivo. But the ex vivo just went as smooth as can be in many ways. It was one of those places where everything we tried, while hard, and I have to give credit to our teams, but literally everything worked as we were going forward. So it declared itself as sort of our leading program at that point, that we'd like to think of waves of programs coming forward. We're very happy it declared itself in some ways. It's a really, it's a program with incredibly high unmet need. The only curative treatment today is an allogeneic bone marrow transplant. An autologous bone marrow transplant that's curative, which is what we're offering in this particular case, seems quite good in comparison. All the patients are clustered in well-known centers, and there's enough of those patients that it'll be important to the company. It isn't a great commercial opportunity, but it's going to bring in revenues, and it'll be relatively quick, we hope, to help fund the company, much sooner than some of the other indications that we're looking at, that are gonna have more elaborate clinical programs. At least that's in our estimation. So what's left to do? We declared a development candidate in the first quarter of 2023. That means we fixed all the machinery of the Prime Editor that's gonna go into humans. At the end of this year, we intend to be in IND-enabling studies, totally confident that we'll be able to hit that milestone. That requires making GLP material, as well as doing GLP tox studies, and we know exactly what's required for ex vivo studies as well. The other parts that one needs to do to file an IND, besides making the material, GLP, but remember, you have to follow that up with GMP material as well, okay? It's the tox study, of course. It's preclinical studies that support for the FDA that one, in fact, is likely to have a therapeutic effect. We've already presented that data on numerous occasions to investors in the scientific meetings. It's a very robust off-target or lack of off-target program, and we just presented some of that data at ASGCT, but we hope we'll give a full update later this year so people can see it. But as I mentioned, our off-target data looks great. And last but not least, you have to have a clinical program that the FDA agrees is suitable for an introduction in humans. We certainly believe that we understand what is gonna be necessary, and we're certainly confident that we're gonna file a very robust IND. It's helpful the number of other companies, for better or for worse, that have run into hiccups with the FDA. It tells us a lot about what we need to do when our IND comes forward. But it's the other reason, in fact, I like going with chronic granulomatous disease. It's an ex vivo indication, and the requirements are a little bit less. But I don't want you to think that, boy, isn't that great? Prime doesn't have to really hit the hard stuff. Keep in mind, 90% of what you file for an ex vivo or an in vivo are exactly the same. And until this recent hubbub about the off-target, almost every IND that got held up primarily was because of a CMC manufacturing point of view. So in practice, I'm not talking in gene editing, I'm talking across all areas. Believe me, I know I personally have filed more than 200 INDs in my career to date. In practice, in fact, what we'll do is we'll be checking off 90% of the hard stuff, and when we do our first in vivo study, of course, we have to deal with that other 10% that is, shall we say, held up other companies. We have better guideposts for what we need to do with a little bit of time to get ready for it. Can't say that's gonna be trivial, but this is a great way to start. We're essentially clearing all sorts of things, our assays, our in vivo approaches, our preclinical, our tox. We're gonna get that in place, and I'm certainly feeling confident with the FDA, though anybody would be a fool these days to say they fully understand what the FDA is gonna do at the time of IND. It's important to emphasize, we're also putting in CTAs in other countries exactly for that reason. We just feel that getting FDA feedback and putting in an IND is a rite of passage for every gene editing company. No matter how much you might wanna hold it off, it's probably better to hear the bad news early, so you can begin jumping in it and really addressing. All right, and in terms of blood indications, with the recently established collaboration with Cimeio Therapeutics, I was wondering if you could please discuss how this collaboration would further benefit Prime's blood target indications? Sure, I'll be happy to. So this is a shielding approach. Prime isn't the only company, nor is Cimeio, that uses the shielding approach. Beam has one. Other companies have talked about such approaches. The idea really originally started with, could we do more less toxic bone marrow transplants instead of using things like busulfan? Could we use an antibody to clean out the bone marrow cells when you put another in? That probably is an idea that, you know, may still be useful, but shielding goes beyond that. And what it really says is, can we actually develop an antibody approach that would take the HSC cells that one no longer wants in the bone marrow away?... but protect the new HSC cells that you edit into the body. So this isn't exactly how it happened, but roughly what happened is Cimeio came to us and said, "We have a great antibody. We've discovered how that antibody can attack CD117, an absolutely necessary antigen on hematopoietic stem cells, and we have found an edit that actually doesn't abrogate the function of CD117, but it protects those cells from our antibody. And the only way to do that edit is with Prime Editing. We'd like to really license it for our programs." What they weren't really aware of is we can multiplex edit in Prime Editing. As a matter of fact, it's one of our advantages, 'cause if you don't have off-target activity, you don't have bystander editing. When we do multiplex editing, the amount of off-target activity is incredibly low, which is one of the limitations to true multiplex editing with CRISPR technologies. So in practice, what we said to them back is, "Let us work in our areas. You work in your areas. What we're gonna do is, together, we're gonna develop this. So we're gonna do a shielding edit, as well as a therapeutic edit. And when we do both of them, we can use the antibody to clear out the bad, old cells, and we can put the new ones in that are protected, as well as have the therapeutic edit." It's just a beautiful idea. And in practice, we believe Cimeio's antibody is among the best out there, and that antibody puts certain constraints on the types of edits one could do. Since we can do just about every type of edit, we're a great partner for that in many ways as well. Of course, the real promise of this isn't for ex vivo approaches, though that's a wonderful way to do it. The real promise is for in vivo approaches, because editing HSC cells in vivo today is almost impossible. It could only occur at very, very low levels in anybody's hands that I'm aware of. But if you have an antibody that you could use to select, and Cimeio-generated data that actually shows this, one can repeatedly treat people and enrich for the cells that have both the therapeutic edit as well as the shielding edit, and increase the number of cells in the bone marrow that actually are, in fact, the therapeutic cure. It's just a great idea, and frankly, if one stops and thinks about where you would edit HSC cells, if you didn't have to do a toxic bone marrow transplant, we may have a list of 50 or 100 places where we could start tomorrow. So we certainly are very excited about this. All right, aside from ex vivo editing, could you talk about the other delivery strategies that Prime is working on? Sure. So we're working with, with AAV and with LNP, and let me just say a word about it, a brief word about AAV. In general, we have to think really carefully about AAV for Prime Editing because we're a once-and-done technology, right? We would like to get our machinery there, have it work for a week or two, some cases, even days or hours, and then we would like it to end, okay? And so after that, an AAV vector sticking around is a detriment, it has no positive value to us. But on the other hand, we've clearly made a decision, a strategic decision, in places today we couldn't get to without AAV. Eye is a good example. We are going to use AAV in order to, to get to that spot. Some of the new and most exciting things that are happening in targeted delivery are happening in AAV, so we may be in that situation for a number of years. We take two AAV to fit our machinery, and many people have asked us, "Does... Is that a problem? If you have two AAVs, just how much does that decrease the efficiency?" If anyone would like to see in our deck that's on our website, we do a specific experiment to look at that, where we use two AAV to deliver to the brain. We put some dual AAV into the CSF of a mouse. We allow it to infect the cortex. We get about 50% of the cells are transduced by at least one AAV. What we do is we isolate those cells, and we ask, how many of them got the second AAV? They expressed the machinery, the two pieces found each other, and they did the edit. And that experiment was well over 90% completed the edit. Makes absolutely no intuitive sense, but in practice, if you're able to take up one AAV, you seem to be able to take up the other cell, find the pieces, and do the edit with remarkable efficiency. And we've done that experiment multiple times. It's been done with base editing as well by Beam, by David Liu's laboratory. Two versus one AAV, almost no drop-off in editing efficiency. Now, that doesn't mean the AAVs, the ones using today, are really what I would like to have happen, and I'm expecting that we're gonna have to work, and we are working and improving them. I think the place, though, that we're really most excited is our LNP delivery. A lot of people have come to us and said, "You know, so you can do LNP delivery. You can do what Verve is doing, for example, or, you know, Intellia. You know, what kind of gene-editing company are you?" It's a very fair comment. Of course, they've been working on those things for 3 or 4 or 5 more years than we have. You know, what can I say? But we've built up our own LNP shop from soup to nuts, literally from discovery all the way through to making GLP material. As a matter of fact, in our proprietary lipid library today, we have probably 700 proprietary lipids, and we're probably gonna be close to 1,000 by the end of the year or early next year. Keep in mind, that's about the size of the library I understand that Beam bought when they bought Guide Therapeutics for $200 million, and we've done that really organically as well.... We will, we have promised people that we will show in vivo editing, proof of concept in one of, or more of our programs later in the year. We are very happy with the progress we're making, and I certainly hope that we will be able to announce where and what scientific presentation we are going to present the data sometime in the near future. But I think it's a real tribute to the LNP work that's been done by our group. Also, keep in mind, as part of our collaboration with Beam, we have access to Beam's LNP delivery as well. So we have many routes to actually get to LNP delivery, and we certainly think that's a very promising route, both for the liver, but we also think it has promise outside of the liver as well. And that's a place where Prime Editing really fits well with the machinery, just like base editing and just like CRISPR. Understood. Based on Prime's expectations for several proof of concepts data in 2023 and early 2024, could you please discuss on what the next pipeline updates might be? So I can't say much today because we really haven't shared that publicly, but what I can say is we expect there'll be a number of presentations before the end of this year, early into next year at scientific meetings. Primarily, where we're going to put out some of our data. Some of it'll be about our programs that are closest to clinic, some of them will be some of our exploratory programs. Some of the exploratory programs, such as repeat expansion disease, cystic fibrosis, DMD, etc. These are places where we're also making extraordinary progress as well. So we hope to be able to share that more on delivery, certainly more on off-target activity and/or the lack thereof. So we're really looking for a fairly broad sharing of scientific data in this year into next year. In general, that's our approach. We should be presenting things primarily at scientific meetings and really letting the scientific community see what we're gonna do. And I hope we'll convince people, again, of the progress. Keep in mind that, you know, four years from today, when we do our IND, you know, this was a technique that was being studied in one laboratory, special laboratory, David Liu, but one laboratory in the whole world. We've gone from that single laboratory, industrialized this, and developed our pipeline, and, you know, frankly, we'll be going to submission of an IND in a four-year period. It's pretty extraordinary progress. We very much look forward to seeing the data this year and next year. Thank you very much, Keith, for joining us today. Thank you very much, and thank you, everybody, for your patience. Bye-bye.