All right. What's that? Yeah. Okay. Great. Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's a great pleasure that I'd like to welcome Allan Reine, the CFO of Prime Medicine. Thanks so much for joining us today, Allan. Oh, thanks for having us here. I appreciate it. We're going to do fireside chat format. Maybe for those who are new to the story, if you want to give a one-minute intro to Prime and what the company does? Yeah, it's hard to do Prime in a minute, but I'll do my best, so Prime Medicine, it's named after our gene editing technology, which is called Prime Editing. This is a technology that was founded out of David Liu's lab, so the company really got started in about 2020, and I think in a very short period of time, we've really developed this technology to be what I think is the most versatile way to edit the genome today, and given some of the safety parameters, I think the safest way to do it as well, so happy to tell you more about the technology, but really excited from where the company is today and how we'll evolve over the next few years. Our first program, we had an IND accepted back in April of this year. Our second IND will be in the first half of 2026. Things are progressing well. Got it. Yeah, I think that's a great overview and maybe talk a little bit more about the Prime Editing technology and how that compares to other approaches out there? Yeah, so I think about sort of the evolution of gene editing. So you had sort of the CRISPR-Cas9 technologies, some of the differentiations there just for people's awareness, which I'm sure many of you are aware of that technology. But you're making sort of double-stranded breaks in the DNA. As a result of that, you'll have a lot of potential off-target complications that you get with that type of technology. And they do what we call sort of that search-and-replace really well. So they're able to find the right place in the DNA that they want to cut. And they're really good at sort of knocking genes out, right? But you can't do a lot of sort of rewriting or putting in new genetic code. There's been some additional technologies. One's called base editing, where you can do a little bit of that. You can change one base pair to another, but you're limited by four base pairs that you can switch, so not the full 12. And those are really just on those sort of specific transition mutations that you can target. With Prime Editing, you can do all different types of gene editing. So I'll give you a few examples. So one is we can do deletions, just like any typical CRISPR-Cas9, if we want to knock something out. We can do insertions, so correct mutations, like a frame shift mutation, like we do with our CGD program. We can obviously correct point mutations and not just erase what's there, but put in the right base pair as well, so like we do for our Wilson's disease program. We have something that's called hotspot correction. So we can do, what I'd say, larger edits. So let's say it's a 50 base pair that covers a few different mutations of a disease. We can go after all of those with one editor. We can excise large segments of DNA. So for an example, repeat expansion diseases, which can sometimes have thousands of base pairs, you can excise those out. And using our PASSIGE technology, we can do large gene insertions, so multi-kilobase base pair insertions at a very precise location within DNA. But I think it's important whenever you're thinking about a gene editing company, we're not just gene editing companies. Every gene editing company is also a gene editing delivery company. And that's a very important part of our platform as well. From the delivery side, we've developed for the liver a universal LNP proprietary to Prime that we'll take forward with our Wilson's program and other liver programs as well. For our ex vivo programs, we use electroporation to essentially get the editors into those cells, and for some of our other programs that we've paused, that we're looking to potentially partner, we've used AAV as well. Got it. In your third quarter update, you announced reprioritization of your pipeline. Maybe talk a little bit about that and just where you're focusing at now and how investors should think about that? Yeah, so we went through what we call a value framework exercise throughout this year that really started. I joined the company back in January. We started the evaluation soon after that. If you had seen our pipeline previously, I think there were about 18 programs or probably were even a couple more than that. So we knew we weren't going to take all of those forward. And if you think about it, the company is pretty young, and it still is pretty young. So it makes sense when you start a company. I kind of think about it like the hourglass shape. You really want to figure out everywhere that this technology might work. I think as the company was evaluating that, they expected there to be a little bit more natural attrition than there was. So I call this more forced attrition, which took place. And so we evaluated all of these programs, really understanding what is the commercial opportunity, is there an unmet need, what does competition look like, are there standards of care that do a pretty adequate job today, what are we competing against in that market, are there other gene therapies, gene editing therapies that are in development. We spent a lot of time thinking about clinical tractability. Are these programs that we think can be de-risked in the clinic in a reasonable period of time? Are there studies that we can do to get to registration in a reasonable period of time? We looked at technical feasibility. For example, we had a number of neuro programs, and I think, and I hope we're going to be back investing in that in the future, but I think delivery to the brain is still something that is sort of a to-be solved, not completely solved today. And so in looking at sort of all the programs that we had, we wanted to sort of go down and can we check all of those boxes as we think about the right capital allocation strategy. The pipeline that you see today, we've got obviously the BMS transaction, which I know we'll talk about later, for ex vivo CAR T cells. We've got our chronic granulomatous disease going after two different types of mutations there. And then Wilson's disease, I think, is a great example where large market, we think there's not a lot of competitive, there's not a lot of competition there. We think we can really own that market when we get there. And we think it's something that most physicians would use in almost all of their patients. So it really checked all of those boxes, and we have a great delivery vehicle. Our ocular program, GSD1b, another liver program, we weren't able to check those boxes. And for ocular, it was a clinical tractability question. For GSD1b, it's really looking at market size and our cost of capital today and just making the right capital allocation decisions today. Got it. Makes sense. And so you had your original pipeline. Theoretically, the Prime Editing technology could work in all of those different settings, but based on just figuring out which ones made the most sense strategically, that's how you kind of funneled it down? Yeah, and just maybe to add to that, because I think you're bringing up a good point, which is we were actually, it was working in these areas that we paused. We actually had great data. We had two INDs. We could have filed late next year, early 2026. And frankly, deprioritizing programs like that is really hard. It's really hard. We don't love it for patients. We don't love it for the scientists to love it. But we have to look at our cost of capital. And everything that we're doing within the company today is an eye towards value and is an eye towards lowering our cost of capital in a reasonable time frame. And if we do that, and we do that well, it's my belief we can get more Prime Editing drug products out to more patients over time. Got it. And you mentioned the Bristol deal. Let's talk about that. I definitely want to jump into the clinical program where there's a lot of interest. But for the Bristol deal, there was a pretty big upfront that came along with that. What does that say about the technology, the validation for the technology? And maybe talk about the deal terms and what both companies get out of the partnership? Yeah, so I mean, I do think it's our first, I'd say, major strategic deal. The other thing I'd say is there haven't been a lot. There were a few years ago, but there haven't been a lot of big gene editing strategic deals that we've seen in the last couple of years. So I think to see something of this size in this field, I think, is important, not just for Prime, but I think for the sector in general. And one day, the market will reflect that. So maybe to talk first about the deal terms. So we got $110 million upfront. But I think an important part of this is, obviously, there's all the biobucks we talk about, but there's actually a lot of milestones sort of before the, we'll call it sort of commercial biobucks kick in. So it's $185 million in preclinical milestones. So it's a pretty sizable number for capital that you can get pretty early in that development. There's $1.2 billion in development milestones. So even before you get to those sort of quote-unquote biobucks, it's a pretty significant potential funding vehicle to Prime. I think if you look at BMS, who are one of the leaders in sort of CAR T therapy, they're thinking out to the future. I mean, I maybe don't want to speak for them, but this is what I believe is they're looking out to the future and trying to think, how do they remain one of the leaders in this field? And I think having a therapy, a CAR T therapy that can really capitalize on sort of that, a fully non-viral system where you don't have random integration. The great thing about Prime Editing is you don't get these sort of. We can do very high-efficiency editing in these T cells without these off-target events. And I think that's something that was probably really important to them. We can do getting this high efficiency while multiplexing is another thing that I think is a big advantage for this type of technology there. So it's for an unspecified number of targets, but for each target, CAR T target, you can have a number of different knock-ins and knock-outs as well to create sort of this optimal product. So we'll be working with them to obviously provide these editors to use in those CAR T therapies. We'll also be helping them out with optimization, some of the off-target work and other things that we can bring to the table in this collaboration. Got it. Makes sense. And with the pipeline reprioritization, you have potential to partner out other assets with the company. How has the deal with BMS changed conversations with other potential BD partners? And does that deal set the floor or ceiling for what future BD deals could look like? Yeah, so I mean, I think we've been in conversations with a lot of different companies that are still ongoing. I think the BMS deal, you can definitely see things pick up a little bit post that. But again, I think we're talking to a lot of the major players anyways. But I do think people do perk up when they see you kind of do your first deal, and definitely a deal of that size. In terms of setting a floor or ceiling, it just depends on what we partner, right? There are going to be some assets, like some of our deprioritized assets that are maybe smaller in scope. And for some of those, I wouldn't use this deal as what to gauge this another deal against. There might be other deals that are similar to this where it's maybe out of scope in what we're doing today, but something where we can bring sort of our novel technology to the table for what someone else is working on, and maybe this can set a floor or a reasonable range of kind of how we'd think about transacting there, but there's, and again, I just want to be clear, we never promised BD. These things are never done until they're done. If anyone's worked in pharma, you know these things can take a while, but what I would say is there's a lot of positive conversations, and we're hopeful that the BMS deal is, it might be our first deal, but it's going to be far from our last deal. I think for a company like ours, it'll be an important funding mechanism going forward and not just a funding mechanism, but a way to get Prime Editing out to more patients ultimately. Got it. Makes sense, and so let's jump to CGD. You got the IND cleared for this program, which was a big step in the space with having the first Prime Editing technology move into the clinic. Maybe provide a status update on the study. I know you can't talk a lot about where you're at with screening and enrolling patients, but what can you say about where you're at right now with the phase I? Yeah, so well, we can't talk about screening and enrollment, so I can't really give any updates beyond that. But what I'll say is we have continued to guide to data next year. So that guidance is still in place. We haven't commented on when in 2025 because it's another question that people ask. So we decided before the trial started, we're not going to sort of do the constant enrollment updates because once you do it once, you kind of have to keep doing it all along. And frankly, when we enroll a patient within a few months, we'll know both if we had successful engraftment, we'll know if we're seeing positive biomarker data, which for this is a true proof of concept. And we still are going to figure out if we're going to come out with one patient worth of data, a few patients worth of data. We prefer to just come out with it when we come out with it. Got it. Okay. And so. The other thing I'd add, though, is you can go to ClinicalTrials.gov. It'll show you what sites are involved in the study, so you can get updates there as well. Got it. And so this would be one to three adult patients that you would be treating initially. Would you announce when you dose the first patient, when you treat the first patient, or? No. Yeah, so it's two to three patients, I think, is what we've said, two minimum in a cohort. For what would be in the data update? Oh, for the data update. Yeah. So we haven't said how many patients will be in the first update. And we won't comment when we enroll. Because again, once we comment on that, you'll kind of know exactly when that data will be. And we prefer to just come out with it when we come out with it. Got it. Okay. And is there anything more you can say about just what the gating factors are in the process for enrolling a patient and treating that patient and what types of patients you would include or exclude? Yeah, so I mean, I'll start with inclusion and exclusion. So obviously, they have to have the mutation type that we're looking to treat. So that has to be obviously confirmed. You'll have to make sure they obviously don't have the biomarker DHR, which if they have that mutation, they shouldn't have a lot of cells expressing that DHR. They can't initially have recent or ongoing infections or inflammatory complications. We hope in the future we'll amend that and potentially enroll some of those patients. But we think it's right to start off with excluding these patients at the outset. And so there was a second part to your question, which was. Yeah, inclusion, exclusion, and just gating factors. Yeah, gating factors. So if you think about the trial, you have to screen, enroll a patient, then you need to mobilize them, so you do your apheresis. Then there's obviously manufacturing and then all the release testing. Then there's the conditioning, the myeloablation you have to do for these patients, and then ultimately dosing. So it is a prolonged timeline for getting that first patient ultimately screened, enrolled, and dosed. That could take even up to six months to go through all of those steps. The good thing is once we kind of do that for the first patient, we can start the second patient. So patients subsequent to that can potentially go a lot faster if we do a lot of those steps upfront, except for obviously the conditioning and dosing. Got it. And we've talked a little bit about what you'd want to show on DHR. Maybe talk about your latest views on what the bar is and what FDA would want to see to enable you to do a smaller expansion that would qualify for approval. Yeah, so I kind of looked to allogeneic transplant, and there's a lot of data there which shows with allotransplant, if you have a degree of chimerism, you have at least, I think it's even at least 10% DHR positive cells, I think, but definitely 15%, you call it somewhere in the 10%-20% range, you should have a significant benefit, if not ultimately cure for these patients. So we believe that level of editing is sufficient to ultimately get to what you would hope for these patients would be normally functioning neutrophils. In our preclinical data, we're showing DHR positive cell levels of like 80%. So we're getting very, very high numbers, well above what we think we need for an ultimate normal functioning cells for these patients. Ultimately, what happens, we'll see, but our expectation is that can be used as an endpoint in a registrational trial. We have not, obviously, talked to the FDA about that yet. That would happen once we generate our initial data. But our expectation, again, this is our expectation, is that we can do this with a fairly small number of patients. So think of a registrational trial of hopefully 20 patients or less. We hope that's even closer to 10 patients. But again, we'll wait and see. Got it. And maybe briefly talk about X-CGD, where that could potentially be included under the same IND. Yep. And also just kind of how that could set precedent for additional expansion. We're going to move into Wilson's. Maybe that's kind of a good segue? Yeah. So I think for X-CGD, it's a bit of a different approach in that for p47, we're fixing a specific frame shift mutation. For X-CGD, it's one, it's an intron or, sorry, exons like 2 to 13. We're sort of replacing that full amount of DNA. So here, we're using our PASSIGE technology. So you put in a landing pad so that you're inserting this DNA in a very precise place where those exons exist. So as you think about that, it's slightly different. Now, all of that being said, there might be a few different assays that are different. Obviously, you have a DNA donor here. So there's a little bit, things are slightly modified. But we do believe this is something that should be able to get done under one IND and get done together. So we, again, no agreement on that. We'll have to push this program to that point before we have that conversation, but feel pretty good about that. Got it. Okay. And for Wilson's, talk about the strategy there, what the first steps are going to be. And you recently reported some data at ESGCT as well. Maybe talk about that? Yeah, so as we think about Wilson's disease, we're moving into IND-enabling activities this quarter, so that's happening now. We're doing some final, I would say, tweaks in terms of lead optimization. The strategy there would be then to file an IND in the first half of 2026, and we're still evaluating the right endpoints and everything else and the clinical trial design, but feel we're in a pretty good place, and there's some precedent there on kind of how to run these trials as well with some of the gene therapies that have gone into the clinic. We did present some data, so this is the first time we've presented any actually in vivo data for this program at ESGCT. And we called it interim, which is sort of a weird thing to say for preclinical data, but interim because the editors that we showed there are not our sort of final drug candidates. We'll show sort of what that final data looks like probably over the next few months. But what we showed there is sort of looking at three different optimizations and sort of the level of editing going from 30% of hepatocytes up to close to 80% of hepatocytes. We've got editors today that are even above that, I would say. And then looking at one of the less optimized editors. So I think it was optimization two, which had about 50% editing in human hepatocytes and mice, showed copper reduction. That was getting pretty close to kind of maxing that out. Not quite there, but almost there. We think our final drug candidate is going to essentially you'll look at, we believe, normalizing copper levels, having very high efficiency editing. We showed some NHP data also showing good translation from what I would call in vitro to in vivo, seeing pretty comparable levels of editing to show that we've got good bioavailability in a large animal as well. This program is moving along great. It's really almost caught up to GSD1b, which was going to be our first liver program prior to our prioritization exercise. Got it. And you're going to have some data at AASLD as well. Is it going to be similar data, or could there be some of the other optimized? Yeah, I think there'll be some incremental data there. But I think some of the sort of final drug candidates and copper data might take a little bit longer. I'm not sure when we'll end up coming out with that. But some of the copper studies will take about four weeks if you're going to look at sort of comparable data to what we've shown. You can see some data in a week and see if you're trending to get to essentially what we think would be normalized copper or maxing out copper reductions in these animal models. But there'll be some incremental data there, and then we'll share the data, additional data as we get it. Got it. And for Wilson's disease, this could be a pretty big market opportunity based on the number of patients out there. Maybe talk about the strategy going from the initial mutation with the H1069Q to adding on additional patient populations. So the H1069Q mutation, the estimates range from about, excuse me, 30%-50% of the Caucasian population. So as I think about Wilson's predominantly in the US, we're looking at about 30%-50% of the 10,000, which is sort of the low end. So you're looking at 3,000-5,000 patients for the initial mutation. The second mutation we're working on is one called R778. That is a mutation that in the U.S. population, I think is somewhere in the 5%-10% range. So as we think about layering that on top, in the US, it gets you to call it 35% on the low end to call it 60% on the high end. But in the Asian population, that's a very prevalent mutation that I think is present in 20%, 30%, or 40% of patients. So there might be a strategy to either do that on our own in Asian markets. There is a place to develop that in U.S. markets, and ultimately, we'll have to decide if we want to take that forward on our own or if it makes more sense to partner that in Asia-Pac. Got it. Makes sense. And when could we learn more about just the additional progress with optimizing the editors? Is that something you'd share next year? Yeah, either later this year or sometime next year. We'll definitely show what our sort of PE editors are showing. But are you talking about for 778 specifically or just either one? For either one. Yeah. I mean, hopefully, we'll get to some R778 data next year. But in general, I think we're essentially there with the data we've showed. It's just doing some final tweaks. And I think the data we even have today could be a drug candidate, but we've got even better drug candidates that we've developed. Got it. Well, there are a couple of other things we didn't get a chance to talk about. But maybe in closing, if you want to highlight anything we forgot, and then talk about cash position and what investors should be focused on over the next 12 months. Yeah, so our cash position is around $245 million as of September 30th. That gets us into the first half of 2026. I think you look to next year. We talked about obviously Wilson's getting into IND-enabling studies at the end of this year, but then moving towards that IND in early 2026 and sometime in the first half of 2026. For CGD, obviously, it's getting initial data this year, but not just initial data. We'll continue to have updates as we progress there, updates potentially on X-CGD. We didn't talk about cystic fibrosis today, but that's another, I think, important program that we're moving through in preclinical studies. Hope to have some additional data in that program as well next year. And always the potential as we talked about for more business development. Great. Thanks so much for joining us today, Allan. Thank you for having us.