Welcome back to day two of the Citi's Life Sciences Conference. My name is Silvan Tuerkcan, and I cover precision medicines at Citizens. Now it's my pleasure to host Allan Reine, CEO of Prime Medicine. Thanks so much for joining us. Yeah, thank you for having us here. Maybe just start at a high level. It seems like it's a very pivotal time for Prime. A s you move into the clinic, you've got to execute a bit, but then 2027, we could have the first human data with Prime Editing. Very exciting. Could you just walk us through kind of like the highlights and the key inflection points that you see going forward? Yeah, I mean, I think I say every year it's a pivotal year. I'm sure I'll keep saying every year is a pivotal year, but it really is a big year for the company. We are right on the precipice of getting our first two in vivo programs into the clinic for both Wilson's disease and alpha-1 antitrypsin deficiency. In terms of clinical data, you're right, like, we're on track for both those programs to get clinical data in 2027. I would say we do actually have clinical data- That's right. In patients, but that's for our ex vivo program in chronic granulomatous disease, which I know we'll also get to talking about. It is a very big year for the company in terms of getting those programs into patients. I think what both these drugs can do can be pretty revolutionary for those patient populations, and I think they are both high unmet needs. As we do that it continues to really de-risk our liver platform, as you think about it. That's from a delivery standpoint. As we think about how we can leverage that going forward, it's really gonna put us in a position to take additional programs to the clinic, to patients a lot faster and a lot cheaper. Great. Yeah, maybe talk about that one program. Recently, it was a very positive surprise for me in CGD that you're bringing it back and you're gonna try to bring it in front of the FDA and see what they say. Kind of what prompted that decision? Was it a lot of the patients or the patient community that demanded it, or was it just the attention it was getting with those first two patients? I think there are a number of factors that changed. We made this decision to deprioritize this program in May of last year. At the same time, we announced that, you know, one patient worth of data, we ultimately came out with a second patient that we had treated. At the time, as we thought about going forward towards licensure we estimated that cost, if you include all of the CMC requirements for licensure, obviously the FTEs, the employees that you need to get there, and the clinical study that would be needed to get there, even if it's a small clinical study, could cost us, you know, between $50 million and $100 million. Mm-hmm You know and take a few years. As we thought about that from a shareholder investor standpoint, there's no way that we could justify that investment. I think a lot of things have changed, and they started to change actually really soon after that May nineteenth announcement last year. Where the FDA has really shown that they can be more flexible, would like to be more flexible when it comes to programs like this, especially in indications where there is high unmet need, where there's, they'll call it plausible mechanism, but we understand the biology well, we understand the endpoints well. I think this is a program that fits perfectly within that. It's a disease that affects people at a young age. The only real treatment for these patients stays allogeneic transplant, which many of them undergo. This could be a much better option for these patients than allogeneic transplant. Importantly, a lot of patients have aged out of allogeneic transplant, and so they really have no option. This is a treatment that for the first time these patients will now have an option to really, you know, change the course of their lives. We're really excited about getting this, in to a BLA. There's still kind of a couple of steps that we're thinking about going through. You know, for one, we'll probably enroll one more patient. We do have Rare Pediatric Disease Designation here. We'll enroll probably one more pediatric patient, and the timing of enrollment will depend on, do we need data for that patient or not. Whether we kind of decide to submit a BLA this year or if it's sometime next year, and just finalizing some of the final CMC requirements. Really excited about getting this program to patients, and we think it's a really important program for Prime. Yeah, no, it really seems like the FDA has developed a sweet spot for gene editing because of, I guess, the promise of the technology. Maybe thinking about the concrete steps, you said maybe not one more patient and see how much follow-up we need there. Like, what? You will have a meeting with the FDA to discuss the BLA filing or the scope, or is that a first step, or will you just file the BLA and see? Well, what I would say at this point, you know, we're not commenting on sort of our FDA interactions. I've commented more broadly on what our plans are. What I would say is, I think we've got the data in hand today to get approval for this drug. I don't think we need additional data to get approval. I think it all comes down to the ultimate label, and do we wanna get a label? Can we get a label with the current dataset? We've treated an 18-year-old, we've treated a 57-year-old. Can we get a label that includes the pediatrics with the current dataset, or do we wanna enroll, you know, one more patient under 18 to get that label? That's still a conversation that we're going to have. On the CMC front, you know, when I talked before about it being $50 million-$100 million, now it's a small fraction of that to get this drug to approval, so it makes it a good opportunity for us to now to make that much smaller investment. From the CMC side, the FDA is also being a lot more flexible, I'd say, in sort of what the CMC requirements are. So we want some sort of final alignment there, but even what we understand could be a worst case is not a bad case for the steps that we'd have to go through, and not too costly either. Great. The financing needs from your, you know, from your balance sheet, are, you know, they're manageable. Yeah While you execute. Cash runway guidance unaffected. Okay, great. Thank you. Maybe, yeah, moving on to in vivo, which I think, you know, most people are focused on here and on this story, maybe with Wilson's disease, often it's viewed as treatable, yet you're emphasizing how big the significant unmet need here is. Can you just highlight what is underappreciated and what Prime Editing would bring to the table here? Yeah, it's a great question, and I think it's a really important one because I think there are some out there that, and we've heard this from investors at times, this is a disease that has, you know, standard of care. You can take copper chelators, you can take zinc salts. What I would encourage these people to do is kind of the work that we did, which is talk to the key opinion leaders, talk to the patients, and you'll quickly learn this is a very high unmet need. These patients are not happy on standards of care. Many of these patients can still progress, so up to 20-30% of patients, even if they're compliant with standard of care, actually can still have progressive, both liver or neurological disease. Yes, some patients, if they're adherent, may live a relatively normal life. T hey'll be on a low copper diet. These medications aren't easy to take. You have to take them multiple times a day, sometimes fasted, sometimes with food, depending on what medications you're on. It's not, you know, they argue about lifestyle, but you also don't know if you're that patient that is going to progress, is going to be more impacted even on standard of care. Again, almost half of patients or close to it are not able to be compliant on standard of care, and you can quickly get copper buildup, you can quickly get additional end organ disease. This is something where we have seen a broad desire among both physicians and patients, where I think it would be pretty universal that if they're candidates to get our Prime Editing drug, I think the majority of patients and the majority of physicians will opt for this ultimately. Great. It seems like there's a fair amount of patients that don't tolerate standard of care, and would those be predominantly you know the population for Prime Editing or would it be all of the patients? Also there's a gene therapy in development there. What would be the limitations of that versus Prime Editing? Yeah. I think, and we've asked those questions too. I mean, I think the easy low-hanging fruit are gonna be those patients that are not compliant, whether it's because of tolerability or something else. Mm-hmm. That's obviously the low-hanging fruit. When we ask the same question around patients that actually are managing, you know, to be compliant with standard of care, many of those patients, if not the majority of those patients, are also would opt for this treatment and the physicians would opt for this treatment for them. I think it's actually going to be applicable to both, like how that ramp looks in the different populations, don't know yet. We're doing some of that work now. I really believe there'll be broad acceptance of this therapy across those patients. Again, just given the fact that this, you know, chelators and zinc salts, they're not curing the disease, right? They're helping, you know, they're you know the zinc salts are helping to prevent absorption, copper chelators, 'cause the copper is going into your blood, is helping to excrete it into the urine, so it's kind of doing something a little different. That's not the normal excretion of copper, right? What we're offering is we can really fix the mutation. We can take your gene, your mutated gene back to normal. If you treat a patient early enough, they could never get disease. Like that's a pretty exciting profile as you think about a drug. What we'd ultimately like to do is say, obviously we're gonna treat that prevalence pool, but as we think about the incidence pool, how do we get in to treat patients, you know, that are 5, 6 years old, really before they develop clinical disease? Mm-hmm. Sorry, you asked about Ultragenyx too. That's right. Yeah. I do wanna answer that question as well. Yeah, gene therapy and gene editing therapies, you know, there's a lot of differences. I'll just tell you what the differences are from the competing gene therapies out there. One, they're using a truncated version of the protein, so it's not the full length protein. Yes, it does contain the active site, but you know, as people know in protein biology, the truncated protein might have slightly different activity than the full length protein. Two, hepatocytes turnover, they don't turn over as quickly as epithelial cells or other cells in your body, but they turn over, whether it's every six months, a year, et cetera. There'll be a dilution of effect because, you know, half the daughter cells will have the maintain that gene expression and half won't. We're again fixing that mutation in the DNA, so every daughter cell is going to have that correction. That this should be a... We've shown this in longer term studies, as have others. These gene editing therapies tend to be very, well, they are very durable. Those are, you know, two of the key differences. Obviously, they deliver through AAV, so there is required, I think, significantly more immunosuppression as you give that drug, which you don't have to do when you think about an LNP to the same degree. I think there's a lot of important differences and, you know, I think ultimately that'll play out in the clinical data. Great. What are the remaining steps to get to IND or CTA and what is the timeframe that, if you'll remind me of that? Yeah. We haven't given sort of the play-by-play. Mm-hmm I can remind you what our guidance is. Our guidance for Wilson disease is a regulatory filing in the first half of this year. It's what, March eleventh. The first half of this year has three and little months yet. Three and some months left, so you can imagine kind of where we are there. And the alpha-1 program, we have guided to a mid 2026 regulatory filing, and you know, I'd say we're only a couple months behind Wilson disease as you think about Alpha-1. Right. In Wilson's disease, looking at your phase 1 trial or design, what would they look like? What are some of the endpoints you would measure? Maybe we'll ask about the efficacy bar later, but yeah. Yeah. It'll be a, you know, dose escalation study. We haven't said how many patients, but usually, you know, companies will typically do, you know, two to three patients per cohort. You know, you hope to start at a biologically active dose. We think we've got a pretty potent molecule here, so we don't expect there to be, you know, a significant number of dose cohorts to get to the optimal biologic dose. We'll have to see what happens when you get into humans. The things that we're gonna measure that I think are gonna be really important in the study, so one is a radiolabeled copper PET study. What we'll do, and we have, if people wanna pull up our presentation, you can see the radiolabeled copper PET study that we did in mice. Mm-hmm. What you can show at least pre-clinically is what it looks like in a wild-type mouse, a mutated mouse, and then a mutated mouse that has our treatment. What you could see is complete normalization of copper metabolism in a Prime-edited mouse that has the mutation for Wilson disease. We're gonna do that same study in humans. We are gonna do a baseline study before they get treated, and then we're going to do a six to eight week study as well. We're not gonna mandate this in every patient, but we're gonna be doing this at sites that can do it in the majority of patients. We should be able to see a pretty early read of proof of concept if we can translate what we see preclinically to clinical, of normalization of copper metabolism or copper or, you know, very improved, I'd say, copper metabolism. We'll look at other measures. We'll look at urinary copper, that is, you know, significantly elevated and mutated in Wilson disease patients. Once we treat them effectively, that should be, you know, reduced down, hopefully closer to normal levels. In some of these patients, you can get liver biopsy that you can look at, liver copper, in addition to, you know, percent of the hepatocytes that have been edited. Again, we're not gonna mandate that in every patient, but we should get that in some patients. We'll look at ceruloplasmin, which is another enzyme that you can measure that is very low in patients that have Wilson disease, which you can see go back up to normal levels on treatment. I think ultimately, you also wanna look at how do these patients do if you remove standard of care. If we can show that these patients do not require standard of care, you can remove that standard of care, and they still have normal copper metabolism or normal copper levels, you know, then you could show you've, you know, effectively, at least genetically, hopefully cured or greatly improved these patients. Great. Without, you know, obviously going too much into details here, but like what is your read at this point from your animal work of where we can get to? Will it be a cure? The metabolism, is it rectified in all patients, a portion of the patients? Like, can you lay out, like, where do we get to? Is this like where? Yeah. the intelligence getting to an HIE or is it? Look, it's a great question. This is how I'll answer it. I'll say, again, preclinically, we, you know, at pretty and I'll say reasonable levels of editing. Mm-hmm We can get to normalization of copper metabolism. How that translates clinically, if that translates clinically, then you'd expect to at least, I would call it, genetically cure these patients. Why do I call it a genetic cure, and I'm hesitant to sometimes use the word cure? You know, if a patient has neurologic or psychiatric disease, patients with Wilson's disease, they'll get both liver disease, but they can also get neurologic or psychiatric disease as well. Some of those symptoms, like if you have neuronal cell death, you're not necessarily going to reverse that. Some of those symptoms can reverse, but some might not reverse. I would hesitate to call that a cure. We could definitely halt that disease getting worse, but you know, you won't necessarily cure a patient that has really deteriorated. I think the same goes for liver disease. We, you know, I think we've seen significant improvements even in patients that have, you know, grade three, even grade four liver disease. Once there's enough fibrosis, once there's enough cirrhosis, you know, we'll have to see, you know, how much you can reverse that. I think what we've seen and what's been a positive, if you transplant these patients and they get a third of a liver, that's gonna regenerate, and you're gonna have, you know, almost normal level liver function, and you can help with the neurologic and psychiatric symptoms too, which leads us to believe we can have a pretty significant impact, and it gets back to what I said earlier. If we can treat early, then I believe this can be a cure. Great. What about the regulatory pathway, and the endpoints? Is that pretty much figured out by the gene therapy, so ahead of you, or is there some uncertainty? I think this is something where I hope we're trailblazers. I think it's all gonna always be data dependent. The better the data is, the more flexibility there may be, and the more, I think both sides are gonna try and figure out how to expedite a therapy to patients. We have some ideas in mind on how to get to, I would say, faster endpoints in a sort of registrational setting. I f the data plays out how we believe it will, we don't think these will have to be large studies. We think these can be relatively small studies. I think it's a little too early to comment on specific endpoints for registrational study. All right, great. Maybe last question on this topic. Obviously, you cover some mutations. There are some outside of the range of what you can target, what's kind of your long-term path on getting to all the patients in Wilson's? Yeah. To break down the mutational background here, if you think about U.S. and Europe and the predominantly the Caucasian population, the first mutation we're going after is called the H1069Q mutation. That affects about we say somewhere between 30%-50% of that population. It's the most prevalent mutation in the Caucasian population. C all it 40%. Then with a handful of other editors, we think we can get to somewhere around 60%. We're probably not gonna be treating, you know, we're not gonna be treating 100% of these patients. We think we can treat 60%, you know, hopefully, you know, it might make sense to even, you know, develop a few editors and do even more. The importance there is all we really need to do is swap out the guides, right? Everything else stays the same LNP, same mRNA. We can do these all under one IND, and so it should be pretty rapid as you get additional mutations into the clinic and just getting to proof of concept there, and ultimately, we hope to licensure. Now as we go outside of the U.S. and Europe, and you go into the Asian population, there, the most predominant mutation is called R778L. That mutation affects maybe even up to, you know, 50% of that population or more, and then a handful of editors might even get you to 70% of the population there. So this is a global disease. W e'll have plans to pursue this globally, and it's, you know, an unmet need on a global basis. Right We'll continue to pursue multiple mutations. Nice. Yeah, moving on to AATD, alpha-1 antitrypsin deficiency, it comes up a lot. Like, there's a lot of excitement around it, a lot of people jumping in. Maybe if you can tell us where Prime Editing fits in there with all the other modalities that are out there and what you hope to bring to the table. Yeah. I mean, look, it is. It's a competitive field. We know there's a lot of people working in the space. I think the reason for that is if you think about genetic diseases, this is a genetic disease where 98%-99% of patients have the same mutation. If you think about an editor and whether it's an RNA editor or a gene editor, it's sort of the perfect disease for that reason. It's also, there's an unmet need, right? Mm-hmm. There's replacement therapy. It's questionable on how effective the replacement therapy is. This also is a disease where I think patients and physicians also are looking for better options. As we think about Prime Editing, and I'm not gonna go through all the different modalities, what I would say is the Prime Editing is the only modality that offers taking a patient back to wild-type protein. We are fixing the mutation at the DNA level, right? Mm-hmm. We are fixing it at its source. What does that mean? That means the patient is under that gene is under endogenous control. Your body is dictating how much alpha-1 protein you need and when you need that protein. In my opinion, that's a huge benefit to Prime Editing over other technologies. No other technology can do that. You know, the RNA editors work, you know, obviously at the RNA level, and there's gonna be limitations there versus, again, fixing this in as a one and done therapy at the source. Base editing, you know, there's bystander edits and other things that can happen. Again, I think this is sort of the perfect application for a Prime Editing approach. Nice. Maybe in terms of clinical development, would you just follow the footsteps of base editing in terms of patient population, endpoints, duration, everything, etcetera, or is there anything that you would change? Yeah. I think the clinical path there has been somewhat simplified. I don't know that there's anything more that we need to do. There's a lot of patients out there. There's a great biomarker. Mm-hmm that we can look at, just looking at AAT levels. You can see that impact very early, right? Probably see 'em in a couple weeks and have, you know, optimal effect at, you know, 4 weeks, 6 weeks. There's kind of no reason to reinvent the wheel there. I think we've got a really good framework to how to think about studying that disease. Mm-hmm with a gene editing approach. Great. Maybe zooming out a little bit across your in vivo programs, safety and delivery are obviously central themes here, right? We, when we talk to investors, we sometimes get pushbacks across all CRISPR therapies or gene editing about the irreversibility of it and maybe off targets, and what, you know, why that will be holding back the field. Just can you talk about what gives you confidence in your LNP approach and, you know, the therapeutic index you've achieved to date? Yeah. I'll talk about the LNP, but I also want to address sort of the off target and other things that are not LNP related. As we think about LNP specifically, we have an LNP, this will be the first time that it's going into the clinic. We have benchmarked this LNP against multiple other LNPs that have both gone into the clinic and others that we know others are bringing into the clinic. I'd say when you look at liver function tests, when you look at cytokines, when you look at coagulation markers, at least from what we've seen pre-clinically, we seem to have a much wider therapeutic index. That gives us, you know, hope as we go into the clinic that again, we're not devising drugs that we need to necessarily dose higher. We're looking for drugs that you can dose under 1 mg per kg, but it's nice to know that you might have the ability to go, you know, well above that if needed in the clinic. You know, that'll play out as we get to that data set. I think when you think about the technology, that's the beauty of Prime Editing. We really don't see a lot of off-target impacts with this technology. You know, or on-target impact as we think about indels and other things. You know, it really creates, I think, a technology and a platform that can really overcome some of the limitations of other approaches. Great. Well, thank you, Allan. Thanks for joining us today. Thank you. Yeah, I look forward to seeing your programs in the clinic. Great. Thanks, Silvan.