Prime Medicine Aktie

Hi, good morning, everyone. My name is Chris Yu. I'm on Terrence Flynn's team covering biopharma and biotech companies. I'm delighted to host Allan Reine, CEO of Prime Medicine. Before we start, for important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. So, Allan, thank you for joining us.

Thank you for having me here.

Maybe we start with some high-level questions about the company. In the past two decades, we have all witnessed the amazing evolution of gene editing technologies. And you guys are at the forefront of that. So maybe talk about how Prime Editing is different versus kind of the earlier generations of gene editing technologies.

Yes, and I think you said it right. It really is a revolution. I think we're all very lucky to kind of, be alive to see these technologies and others as they advance. I know they're just incredible as you think of where we were 20 years ago and where we are today. So I always think about the evolution of CRISPR, kind of, nuclease-based editing kind of, to Prime Editing. And nuclease-based editing, we're looking at Nobel-winning technology, really incredible for the first time. You could, with very high efficiency, go to a very specific point in the DNA and with a double-stranded break really make that cut. And the result being very effective at knocking out targets, very effective at knocking out proteins or changing regulatory elements like they do in sickle cell, and an incredible technology. We have an approved drug now. We have others that are likely looking like they're close to approval.

So this is becoming sort of that dream of 10-plus years ago is now becoming a reality for patients today, which is obviously what this is all about. That nuclease-based editing with double-strand breaks, there are some liabilities there obviously. Some of the both on-target but also off-target consequences that can happen, chromosome rearrangements, translocations, some off-target editing that can occur. But in general, really, really promising technology.

And then out of David Liu's lab came another type of gene editing called base editing. And now for the first time you can not just knock something out, but with high efficiency actually correct something, right? Make a change to the genome, a very specific change. And with base editing they use what's called a deaminase enzyme. And you can change kind of, 1 base pair to another. So you can do an A to a G, G to an A, C to a T, T to a C. Those are the 4 base changes that you can make with base editing. And very effective for certain diseases where you have that very specific type of mutation, but limited to really only correcting those types of mutations, or like CRISPR, you can use that to knock things out as well.

It also uses, instead of a double-stranded break, you're using what we call kind of, a Cas9 nickase, which is creating a single-stranded break, which is a lot gentler on these cells and ultimately doesn't lead to the same rate of chromosomal rearrangements, translocations, and other off-target issues. So a nice step forward in doing things that nuclease-based editing could not do. With Prime Editing, we can do everything that the kind of, first-gen genetic technologies can do. We can do everything that base editing can do, but not just those 4 base changes. We can do all 12 changes, but we can also do so much more.

So, we have the ability to, instead of using a deaminase, also out of David Liu's lab, he came up with the idea of, well, let's use a -- him and Andrew Anzalone, who are scientific co-founders, came up with, we can now use a reverse transcriptase and actually create a template that goes right into the guide. That gets transcribed right into your DNA. So instead of changing 1 base pair, we think about this as a word processor. Instead of it going after 1 letter, we can put in whole new sentences. So the first time we can make very much larger kind of, full insertions of anything from, you know, 10 to 15 base pairs. But with our PASSIGE technology, we can actually do almost full gene insertions.

So it's a really powerful technology. I like to say it's the most versatile gene editing technology that exists, given the number of different changes we can make. But it's also the safest as you think about the limited kind of, off-target, on-target, and other consequences that you see with some of these other technologies.

That's a great way to start this conversation. Certainly there are a lot of potentials for Prime Editing based on what you just described. The way I see it, like with gene editing, a lot of efforts have been focused on delivering to the liver. Can you kind of, talk about what are the remaining hurdles to kind of, expand the technology kind of, outside the liver to other organs and other diseases?

Yes, so you're asking the $1 billion, $100 billion question. You know, I think the initial promise as we looked at gene editing was there are just so many different diseases, both genetic and non-genetic, that would benefit from this type of technology. And it was just a matter of, okay, let's get the delivery technology towards all of these different tissue types. Well, that's proved, I think, a lot more challenging than probably initially thought. And I think today we've shown that these, and it's not just gene editing, it's other technologies too that are RNA-based that require delivery. But I think we can very effectively today get delivery into the liver for gene editing. We've seen that proof of concept for both nuclease-based editing, base editing and soon to be Prime Editing.

We've obviously seen this done with these technologies, both prime-based and nuclease-based editing, ex vivo, so it can obviously be done in cells. We've shown that with chronic in our Chronic Granulomatous Disease program. Obviously, it's been shown in sickle cell with those two other technologies. But as you go beyond that, it gets more challenging. I think we've seen good delivery to the eye. And I know Editas had an earlier program where they could at least effectively deliver, and we've got some early preclinical data showing that we got really good eye delivery as well. We think we can get delivery to the ear. So it becomes like are there real opportunities there to go after from a commercial standpoint.

But where I see kind of, the biggest opportunity for Prime Editing would be if we can get successful delivery to the brain. I think there are a couple of maybe AAV-based approaches today that may work, but I don't think there's anything today that we've said that we've seen to say we think this is a solved issue. I would say we continue to scour the world for advancements in these types of delivery. Because I do strongly believe this is a case of when, not if. But I don't know if that when is in 1 to 2 years or in 5 to 10 years. But as soon as that gets solved, we are going to be there to explore those areas because again there's a tremendous amount of unmet need in the brain where Prime Editing can make significant impacts in the lives of patients. And if in 5 to 10 years I hope to be treating many of those diseases with Prime Editing.

And then beyond that obviously there's heart, there's muscle, there's kidneys, there's other organs that we'd like to get to as well. And there's varying levels of advancement. Again, we're staying very close attention to those so that when we do see something that looks promising, we can jump right on it. I think the lung would be a good example. Where in collaboration obviously with the Cystic Fibrosis Foundation here, we've got programs in cystic fibrosis that we're developing where we think lung delivery looks very promising. We've seen AAV. We've seen HSV with other companies. And we've seen LNP be successful, at least in delivering that cargo. And we think Prime Editing has the potential to be a best-in-class therapy as we think about cystic fibrosis.

So that's an area we think, you know, is in the process of being solved, where others we think are probably more in the future. But again tons of opportunities that delivery question gets solved. But it's a great question and one we spend a lot of time talking about and thinking about.

Yes, that sounds good. And recognizing that in the past year, there has been a lot of changes at the FDA. And now I think we have seen some stability there. Just how supportive in general is the FDA on gene editing? That's part 1. And then second is, like, how has your interaction been with them recently?

Yes, I mean, I think in general the FDA, and I know that we've all been through a lot over the last year, in terms of kind of, what's gone on there. But I think even over that entire period of time, even with all the changes, it's been in the right direction, I think, when it's at least come to cell and gene therapy for the most part, especially when it's come to, I think, gene editing. They seem very supportive. There's a lot of different measures and endeavors going on at the FDA. Where they're trying to help these companies create more products for patients in need, especially when you go down to the rare and ultra-rare indications. And so I think that's going to continue.

And these efforts are both on the CMC side, the ease of getting to the clinic. I mean, for us, I mean, we went and the FDA, you know, essentially gave us alignment that we can file for approval on two patients' worth of data. I mean, that's incredible flexibility. Obviously, it's an unmet need. We showed a really strong data set in curing two patients. But that's showing a lot of flexibility in that real desire to get these drugs to patients in need. In terms of recent conversations, like we don't comment, you know, on specifics on our dialogue with the FDA. What I would say is we continue to have constructive conversations across the board with the FDA. And for the most part it seems like business as usual. I think it's nice that we have leaders that are not interim that are now in place at CBER, well, for us CBER but also CDER. I think Karim is going to do a fantastic job there. And we're sort of excited that whole agency can now go in the right direction going forward.

That's great. So let's kind of, talk about the specific programs that you are running right now. Wilson's disease is your most advanced in vivo program, and the IND recently got cleared. Can you kind of, walk us through the phase 1-2 design specifically and then kind of, what are the key biomarkers that you would be measuring?

Yes, so the IND was cleared back in July. We also had a CTA cleared back in New Zealand in June. This is going to be a global study, so we'll be enrolling in other geographies ultimately as well. The design of the study is going to be a dose escalation. We'll be looking at a few, call it initially planning for 3 cohorts. You can always add cohorts if needed. We'll be looking at 3 different dose levels. The lowest dose is potentially a biologically active dose as we start to get to the second and third dose levels. There could be a lot of biologic activity if the preclinical data translates well to the clinical data.

And I think from everything that we've seen from other programs across different gene editing approaches, we've seen fairly good translation as you kind of look even just mouse to human. And so we'll, within those studies, we'll obviously be assessing safety. I think safety is paramount. We, with our LNP, and this will be the first time this LNP has gone into the clinic, we've got, appear to have a very wide therapeutic index, much wider than some of the LNPs that have gone into the clinic that we've actually benchmarked doing experiments internally. So excited about the prospect there then obviously looking at efficacy. I think the good thing with gene editing if you're in the right indication is and if you have a good biomarker, you can get a really early read.

Right, if you're making that precise correction and you're doing it with high enough efficiency and you have a good biomarker you know pretty early if your drug is working for Alpha-1, which I'm sure we'll talk about with which investors are very familiar with because there's a number of programs out there. Obviously you can look at, very simply look at, blood levels of AAT and look at the differential between M-AAT and Z in the systemic circulation. Wilson doesn't have a biomarker that's that easy because most of these patients are on standard of care so we can't just look at copper. But what we can do, another way to do that, is we're going to be doing radiolabeled copper PET scans. We'll be doing those scans both at baseline and then about six to eight weeks after treatment.

And we have really nice images that are in our deck that I encourage people to go look at, which are these mouse models showing what the copper PET looks like. And in a diseased mouse, which you'd expect to see similar in a diseased human, and there's some publications that actually kind of, show what this looks like in a human as well, you could see these livers completely lit up with copper because they lack the enzyme and the ability to effectively shuttle it into the bile for normal fecal excretion. If you look at what a wild type mouse or human would look like, you have very normal copper metabolism. You don't see that copper lighting up in the liver because it's been normally metabolized.

And if you look at even just a lower dose of 0.4 mg/kg and a somewhat higher dose of 0.8 mg/kg, if you look at the images that we have, we look very much like that wild type mouse. And completely normalizing copper metabolism. And you really only need to get to a heterozygote level. You only have to get to that level, a heterozygote level, within a copper PET study, which isn't quite normalized copper metabolism, but those patients don't have disease. So even if you can get to that level, you could feel very comfortable removing standard of care and knowing that these patients won't have a copper burden that is going to continue to add to their disease.

So just to follow up on that point. I mean, obviously, everything is going to depend on the data. But is it reasonable to assume that if the data looks good, the kind of, the radiolabeled copper biomarker could potentially serve as an endpoint for accelerated approval? Or it's still early to say?

Yes, I think it's still early to say. I always like to say things, it's always dependent on, everything's always data dependent, and the better your data, the more flexibility that might get awarded to you. I kind of, use a base case as, hey, let's get patients off of standard of care for some period of time as a potential registrational endpoint. If your data looked incredible, that you're getting all these patients to vastly improve copper metabolism, and that's very predictive of getting patients off standard of care, there's always an upside scenario where the FDA can be a little bit more flexible there. But we're kind of, using our base case as some period of time off standard of care ultimately for registration. And depending on strength of data, there could be upside to that. Okay.

And just maybe two other things to add. The other things we'll look at, it's not just the radiolabeled copper PET, but we'll look about at an enzyme called ceruloplasmin, which is very low in patients with Wilson's disease. It's something that kind of, helps to bind the copper and shuttles it through the circulation, in the absence of this ATP7B enzyme that's mutated. That doesn't occur and that ceruloplasmin degrades very rapidly. So as you treat these patients and you have normalized enzyme function, you should see those levels of ceruloplasmin go up. We'll also be looking at urinary copper, which in disease patients is very high, because the main mode in disease patients of copper excretion is through the urine, not through the feces. So and these patients will also test if you see that urinary copper come down. So there's a mix of different endpoints that we can look at, not just the radiolabeled copper PET, and they should all start to point in the right direction if we're having the right impact.

OK, sounds good. And then you guided proof of concept clinical data in 2027. So what kind of, initial clinical data do you expect to disclose and like do you know how many patients that you would disclose those data for?

Yes, I mean, I think we'd be looking at, at a minimum we'll be looking at those kind of, 3 key endpoints that I talked about, radiolabeled copper PETs, ceruloplasmin and urinary copper, safety obviously as well. You know, this is kind of, standard where you do a few patients per cohort. You know, we've talked about, you know, at least 3 cohorts. So you can kind of, do the math on what a potential, you know, first data set could look like. You always have the ability to backfill in certain cohorts if you feel like you're at a good dose level. So we'll wait and see kind of, where we are. If things translate well, then you'd expect somewhere between 6, 9, 12 patients essentially to get to that first data set.

Great. Great, thanks. And then with that POC data that you're going to get in 2027, what kind of, data will be sufficient to give you the confidence to move the program forward?

Yes, I mean, I think what we're going to want to see to gain, so I think at a minimum, are you improving copper metabolism? Like, that's the bare minimum, right? If we're not improving, and if we're making that edit, you should be improving copper metabolism. So, are we able to achieve the level of editing efficiency that we've seen preclinically, or even some level? That's similar to that, which is not that high to see a really strong effect, right? Even at high 20s whole liver editing, we're getting to almost normalization of liver copper metabolism in a mouse model. So as long as we can see vastly improved copper metabolism and these other markers are going the right way, we know we have a drug.

And then I think the secondary question to that is, is this something that is effective in every person? Is there any reason why we're not getting kind of, widespread efficacy, which is the expectation based off animal models? And so, you know, if you have like 1 of 6 people responding, then, you know, you know you can have a response, but there's something wrong there. So you'll want to see pretty consistent responses across the majority of patients. And I think if you have that, that tells you you've got a drug.

Okay, yes, that makes a lot of sense. And for Wilson's disease, your current candidate only covers 1 mutation. I think it's the H1069Q mutation. There are other mutations for Wilson's disease. So kind of talk about how you're going to broaden that program into to cover other mutations in a timeline to do so.

Yes, so the H1069Q mutation covers about, we say, 30% to 50% in the Caucasian population. So we think about predominantly the U.S. and European populations. Other numbers we've looked at, maybe that's closer to 40%, 45%, but somewhere within that range. We think ultimately with a handful of additional editors, we can get to about 60% of the population in the U.S. and Europe. And the ability to get those studied is we know, or at least we have alignment that we can do additional mutations under the same IND and we can leverage all the information, the majority of the information that we have from the first mutation for subsequent mutations. So it's a lot faster and it's a lot cheaper to do each additional mutation.

And hopefully given genotype to phenotype is pretty similar across Wilson disease, there's not a lot of, you know, not significant difference. Hopefully it's going to be a small number of patients that need to be studied as well to ultimately get those to licensure. As we go into Asia, it's a little bit different. The mutational backdrop's a little bit different. The prevalence actually seems to be a little bit higher. And the most prominent mutation there R778L is even potentially 40%, 45%, or even more percent of those patients. And with a handful of editors, we might even be able to get to like 70% of that population.

So we think we can pretty quickly get to the next mutations. Our R778L is pretty close to ready to go. There's some additional off-target and other work we'd have to do to get ultimately to the IND, but we've got a pretty good editor right now, you know, and we're trying to determine the right time to kind of layer that in to this current study, even though it's a prominent mutation in Asia. There are patients we've identified in the U.S. that do have that mutation. So you could start studying that outside of Asia first before you go into Japan. But that would be the plan for that program.

Got it. A competitor is developing a gene therapy for Wilson's disease. What are you watching in this space when it comes to gene therapy?

Yeah, I mean, look, I think first off, you know, I mentioned that we're probably going after 60% in these geographies and 70% in Asian geographies. So there's a market beyond what we're doing. So there is a place for other therapies to play. We think a gene therapy and a gene editing approach are very different. You know, a gene therapy, they're using a, you know, you can't fit the full gene in an AAV, so it's a truncated version of that gene, which, you know, can or can't have the exact same type of functionality. It's something that's not under endogenous control, so you're under the regulatory controls of the AAV that you're putting in there, when we're making a permanent change at that mutation location at that gene in that genome, so you're under the normal endogenous or the, you know, normal regulation of that gene.

So we always say, like, you don't want 0 copper, right? It's always going to be some balance that you're trying to get with many of these things. And being under endogenous control is the right answer. The other thing is every daughter cell that has the correction is going to have that correction. So this is something that's durable and gets maintained over time. Some data suggests that you even have a positive selection bias over time. But even without that, this is something that's a durable fix. For gene therapy, that, you know, hepatocytes, you're not dividing like, you know, epithelial cells, but they do divide over time. And so it is something that will get diluted out over years because every daughter cell, only 1 of the daughter cells will have that vector.

So there's a durability, long-term durability question there, too. So I really feel for this specific disease or most diseases where you're going after the liver, a gene editing approach where available is a better approach than a gene therapy approach. But, yeah, and we'll hopefully that we'll see data to validate that.

That makes sense. I would like to talk about AATD now. It's another very important program of yours. So recently, the arbitration panel ruled in favor of you guys, so now you can move ahead with your program. I think Beam said that that decision was somewhat narrow. They still have some rights in developing AATD with Prime Editing. So just can you help us square away what each party's rights are in this space?

Sorry, what?

Each party's right and your right and their right.

So we've never contested whether Beam has rights to Prime Editing in Alpha-1. So as part of the collaboration agreement that we did with Beam back in 2019, they have rights to Prime Editing for doing certain types of edits, which are transition-only edits, essentially what you can do with base editing. What I think this decision, and we always felt, okay, we're operating under the prime field where we're not just doing transition-only edits, we're also doing non-transition edits. What this decision says is it clearly defines what the Beam field is and what the prime field is, which is, again, back to what we believe the Beam field and the prime field were before. And so as long as we're operating within the prime field, which means we are doing non-transition edits as well, then again, that has a material impact that's within the prime field.

Okay, that makes sense.

It's a clear definition across the fields.

Okay. So AATD is a somewhat crowded field for gene editing, and for good reasons, just because there's a really high unmet need and there's a large patient population. So there are two companies that already have some clinical data for AATD. So where do you think your candidate can potentially differentiate from those two?

Yes, so there's two base editing companies that have had data. You know, Beam's got probably the largest collection of data to date, and I think they're showing somewhere in the, you know, mid-teens level of systemic levels of Alpha-1, which is kind of right square into what you'd expect for a potential heterozygote patient, which typically don't get disease. And I think it seems, looking at kind of MZ levels, that they're probably near levels of saturation. With that other company out of China, they've released a few patients' worth of data. I think the first patient, which had a higher baseline, that looked much higher. And I think the next two patients that came out kind of look maybe in a similar range to where Beam is, maybe a touch higher. So it looks like the data that we've seen to date from those two companies look very similar from what I'm told.

The company out of China, YolTech, has a lot less bystander edited protein than Beam has, which we can debate if there's some theoretical potential risks there. But it seems like everyone's kind of getting to saturating levels and then potentially getting to kind of similar levels of Alpha-1. I think what becomes really important as you go out is not just what levels of Alpha-1 you're getting to, but also it's going to be safety. How safe is your LNP? It's one thing to dose 5 patients, 10 patients, even 30 patients, what are things going to look like when you've dosed 100 patients, 200 patients, 300 patients, and again, you know, we think we've got a LNP that is a pretty wide therapeutic index, and from a safety standpoint, we think we're going to be in a good place.

And then from an efficacy standpoint, yeah, I think we're going to have to wait and see. I mean, we still, I still believe a Prime Editing approach where you're taking a patient back to wild type protein, where there's no bystander edits or anything else going on that you're fully at wild type protein, to me, it should be the sort of preferred therapy here. And even though we're not first, I think there's still the potential to be best for that reason. We'll see how all the data, you know, plays out over the next couple of years. And as you said, it's a crowded space, but it's a large market and there's a lot of patients to treat out there.

Yes, that makes sense. And is the LNP used in the AATD program the same as the one used in the Wilson's disease?

It is. A lot of what we did in Wilson's to Alpha-1. And for future liver indications, we think we can, you know, take that to another level, leverage even more, scale even more, et cetera.

Okay, that's great. I know you guys are working on an IND right now for AATD. What are the remaining gating factors in there?

We are still reiterating our guidance of a regulatory filing this quarter.

All right, so soon. So similar to what I asked about Wilson's program, you expect to provide initial proof of concept data in 2027. Again, like, what kind of data will you provide from how many patients?

Yes, I don't know patient numbers yet for that, but what I would say is, you know, we've kind of seen from others you can get pretty quick read out. Looking at serum Alpha-1 levels and percentage M versus percentage Z and you could see that as early as, you know, a week to two weeks so you get pretty quick readouts there. And so, you know, again, probably not dissimilar to Wilson as we think about patient numbers potentially, depending on how many cohorts we need to get to the right dose level. But yes, expect to have that data sometime next year as well.

Okay. And then similarly, what kind of proof of concept data would give you the confidence to move the program forward?

Yes, I mean, I think, you know, we're not kind of recreating things here. I think we've seen what other companies have been able to do. I think similar types of development paths are likely for all of us. We're going to do some small number of patients. As long as you're seeing pretty consistent levels, response rate in these patients and levels, that you can very quickly transition to a registrational trial for accelerated approval where you're using, you know, serum levels as your kind of main endpoint.

Now I want to switch to your CGD program, your ex vivo program that you had two patient data. We have all read in the news how those two patients are doing so much better thanks to your drug. So kudos to you guys. So in June you talk about that FDA is willing to kind of accept those two patient data as a filing package. Where is that conversation now? Can I have any update on the timing?

Yes, so we're planning for a filing sometime in the first half of next year. There is just some small kind of CMC requirements that are needed and that's kind of what's gating to that filing. So yes, we think we're in a good position there.

And if it's approved, what is your commercial strategy there?

Yeah. I mean, there's not a lot of patients out there with the disease. It's an important therapy, so we want to make sure it's available. You know, we're not looking at this as some massive commercial opportunity for us. But we think with a very kind of minimal amount of expense, we can get this drug to the patients in need.

Okay, great. In the last two minutes, I want to touch upon the other programs that you have in your portfolio. Cystic fibrosis, you talked about that earlier. Maybe talk about just an overview of the status of that program right now.

Yes, so we're continuing to make good progress there. We're, that's an area where we're looking at predominantly LNP as the delivery technology to the lung. We've gotten to a number of editors that look like we're getting high efficiency editing definitely seeing really high efficiency editing as we look at ALI cultures and other things that kind of people look at to try and de-risk this. You know, next step is to really getting to really good in vivo data and getting to a drug candidate to ultimately hopefully get this into the clinic in the next couple of years.

And you touched upon this earlier, like delivery to the lung, it has been a challenge for the industry. So, like, can you talk about your progress there and like what have you seen so far in that area?

Yes, we're evaluating both external and internal LNPs. But as you look at LNP to the lung, I think that, and there's some mRNA and other therapies and gene therapies, that is more been HSV or AAV, but there's been some therapies where I think you can get the drugs delivered, right? Then it's a question of do you have the right cargo? Are you getting the right amount of expression of the CFTR gene in the right cells? And so there's a couple of different approaches here as I think about cystic fibrosis. There's one, can we get enough editing in the right cell type and sort of those basal, basal lung cells that are going to give you that sort of that long-term benefit, and that would be sort of a great result.

But this is also an indication where, even if you can hit those bronchial epithelial cells, that are going to turn over at some rate, this could be a possibility of, hey, maybe I have a little bit more frequent dosing and I'm dosing this every twice a year or a few times a year instead of a once and done. So I think there are different approaches here that can ultimately lead to success and I think we'll probably test a number of them and figure out what's best for these patients. Because we can go after all the patients that really are not amenable to Trikafta and other treatments. Because of the mutation set that they have. But there's no reason we also can't go after that F508del population in the future as well.

Right, yes, that makes sense. And so when should we expect to see some preclinical data in that area?

Yes, I think we'd hope to share some additional data, you know, later this year or sometime next year as we get to proof of concept.

Time is up. So, Allan, thank you so much.

Yes, thank you. Great questions, and thank you for having us.

Good morning, everyone, and thank you for joining us. And it's my pleasure to introduce Prime here. And with us, we have Dr. Allan Ryan, CEO of the company. Alan, to start here, can you provide a high-level overview of where the company stands today and what updates we can anticipate as we look to the second half of this year and beyond?

Yes. So where we stand today is, if you think about the company was founded 5, 6 years ago, really to carry forward this great technology, which is Prime Editing. We've now successfully taken our first program into the clinic. It's for a disease called chronic granulomas disease, where we've effectively at least genetically cured 2 patients.

So this is a program that's -- or a technology that's real now where we've seen real impact, and that's an ex vivo cell therapy. And for our first 2 in Vivo Programs, we're approaching the clinic for those programs. So it's a very exciting year, both for Prime Medicine and also, I believe, for the patients that we're going to be treating in the near future.

As we think about over the next upcoming milestones and what to expect over the next year, obviously, importantly, getting our 2 in vivo programs, as I said, into the clinic and ultimately, clinical data, that's both in Wilson disease and alpha-1 antitrypsin deficiency. We have guided to data for both of those programs in 2027. For our CGD program, -- we are marching towards a BLA filing. So hopefully getting that drug approved on the market and treating those patients that have that devastating disease. And beyond those programs, we're really excited about our cystic fibrosis program that we're working on with the Cystic Fibrosis Foundation.

There, we're guiding to this year. We have a number of other, I would say, when you think about the liver targeted therapies given the -- what we think is a very leverageable platform now towards liver disease. And there's a number of very interesting, I would say, diseases, a lot larger even than Wilson Alpha-1 that we're looking at there. And then there's a lot of other, what I would say, promising areas to look at when you think about Prime Editing.

I think about sort of 2 components, right? You've got -- can we edit cells effectively in different tissues and then can you deliver to these different tissue types. So when we think about cell therapy, when we think about the liver and even to the lung, there's been clinical data that I think has derisked delivery of those tissues with either gene therapy or gene editing approaches. For other tissues, as the delivery technology starts to -- sort of those problems get solved as we think about brain delivery and others, there'll be an incredible amount of opportunity for this technology. And we're also pushing forward, making good progress with our collaboration with BMS, Bristol-Myers. That's for ex vivo CAR-T cell therapy.

Maybe just to level set here. You're the original and kind of the lead on Prime editing here. And -- given the unique features and based on the work you've done now to this point, what is your view on the optimal application for this technology versus the other gene editing approaches?

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Yes, that's a good question. So as we think about the -- well, as I think about Prime Editing and how it's differentiated. So we're making a single-stranded break, not a double-stranded break. We really limit off-target edits, chromosomal translocations, et cetera. So I think there's a lot of advantages from a safety standpoint as you think about other gene editing approaches.

In addition to that, we can also do any type of edit. So we can do everything that CRISPR/Cas9 can do. We can do everything that base editing can do, but we can also do so much more. So as I think about optimal applications, the answer is there are so many areas where this technology can get used. I think that's evident by -- when I joined the company, we had a pipeline of 18 programs. Yes, that's too many programs for a younger company to go into potentially.

But what I would say is the reason there were so many programs is there's so many exciting areas to take this technology. And I think that's sort of the right thing to do for a young company to some extent because you're really just exploring where things are going to work. And again, it comes back to delivery.

We know we can get great editing at different cell types. And as delivery gets solved, we just think there's going to be a tremendous amount of opportunity over the coming years to develop this in many other places beyond the liver, the lung and the ex Vivo setting.

And you're employing a proprietary modular LNP here when you -- with regard to delivery using a single formulation for both liver programs. Can you speak to this technology and its differentiation?

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Yes. So as we think about our liver-directed LNP because obviously, we have a lung-directed LNP program as well with cystic fibrosis, as we think about the liver-directed LNP program, we've done a lot of preclinical work on our LNP delivery. And we see, at least as we compare to some of the other LNPs that have been in the clinic, we see a very favorable toxicity profile when we look at liver function tests, markers of inflammation and markers of coagulation. So -- if that translates to the clinic, it's possible that we're going to have a wider therapeutic index than some of the lipids that have gone into the clinic. And obviously, we have to prove that out with clinical data, but we're excited about what we're taking into the clinic.

And you also have a technology that could introduce lot of genomic inserts via passage. Can you provide an overview of that in the clinical applications?

Yes. So Passage is a large insert. We can do thousands of base pairs versus a Prime editing template where, yes, maybe you can edit up to 100 base pairs, but really thinking about very large either probably genes, if they're small genes, but full introns, et cetera. So the benefit of that is, I guess, twofold.

One, you can treat the majority of mutations just with one large insertion for a disease. And the second benefit is you could also, if you wanted to put in a gene to express a certain protein. So there's really good use cases for this technology.

As you think about what Passage is and why it's, I think, differentiated from other technologies out there that are doing large insertions is we're actually using a Prime edit to put in what we call a landing pad. So -- and that landing pad is where that DNA or that DNA donor is going to be inserted into the genome. And why that's important is with lenti and other technologies, you're really getting random insertion. So what that means is you're often going to be reliant on the promoter of where you get inserted or the regulatory elements of where you get inserted. So for us, we can ensure that we're inserting in the same place every time under whatever regulatory elements for that gene that we want to ensure we're getting the right amount of expression. So it's a very exciting technology.

It's the basis for the collaboration we did with BMS. We'll do additional non-passage edits, but getting sort of passage and the insertion of the CAR is what's used for that technology. And again, we think it's a very differentiated technology to anything else as you think about CAR-T cell therapy.

There are other areas we think -- where we think passage can be useful as well. In vivo, as an example, it's not the sort of lead approach for cystic fibrosis, but it's something else we're looking at there where we can do large insertions potentially in the lung.

In vivo, there's a little bit more of a -- you're really solving for that DNA donor. So it is a little bit more complicated as you think about ex Vivo, but we think there are some potentially promising technologies from the in vivo setting as well where we're looking to get some proof of concept there as well.

And can you just provide an overview on the IP portfolio? What's covered there and how you think about the arbitration that's going on?

Yes. And so the arbitration is a little separate from the IP portfolio, and I'll get into that. But from an IP standpoint, we have -- we hold 10 U.S. patents and 19 ex U.S. patents. We cover any construct or what I would say is combination or permutation of a CRISPR-Cas enzyme, a template guide RNA and a reverse transcriptase, that is owned by Prime Editing. In addition to that, we have patents that cover our specific drugs sequences -- patents on our drugs and patents on our delivery system. We have very broad portfolio, we think we're the only company that's really an issued any [indiscernible] IP as you think about Prime Editing. In the future there absolutely a lot of company that we see out there, at least a few that are pushing forward with Prime Editing approaches.

And we think at the right time we're going to be collecting a lot of milestones, money, royalties attaches from this company. When it comes to arbitration, that's not an IP question its a contractual question, that thing answered there. And that's over our alpha-1 antitrypsin deficiency program and that's arbitration with [indiscernible] therapeutics. We expect the decision on the arbitration sometime by the latter half of July or earlier potentially. And what we said is we feel very confident that we're operating within the prime field and not within the beam field. And we hope and expect that the arbitrators see it that way, and we'll announce when we get that decision.

Let's move over to the clinical program here. So for Wilson's disease, an IND for your program 577 is expected. Should we expect here in the near term?

Yes. So we -- guidance still holds for a regulatory filing for the first half of this year. We would typically announce once that is accepted. As we think about clinical translation, I think about that as what do we expect to see in the study and when will we see that data. So we do expect data in 2027.

So that guidance is maintained. As we think about clinical translation, there's a number of ways we think we can show that as we get to the clinic. One thing that we're doing in this study is something called the radio labeled copper PET study, and we'll be doing these studies both at baseline and the 6 to 8 weeks in patients in the study. And that will enable us to see -- and you can look at our preclinical data, and we have some of this included in our presentation on our website. And you could see that even at doses as low as 0.4 milligrams per kilogram, we're getting essentially normalized copper metabolism. The livers look essentially look like what you'd -- wild type, and you can see a wild-type mouse in that experiment.

So if that data can translate, we can show what I think is very compelling data to prove out that we're getting to normalized copper metabolism, the editor is doing what it's supposed to do. And even in that 0.4 milligram per kilogram group, we're seeing editing levels of hepatocytes below 50% that's getting us there.

So even at what is that 25-ish percent bulk liver editing, we're getting near normalization of copper metabolism. And I'd say rates -- I think if you look at those livers, it's probably you're seeing even better than you're getting, let's say, a heterozygous patient has. So if you think about that and heterozygous patients don't have disease. So it's -- if we can recapitulate that data in the clinic, we think we could at least genetically cure these patients.

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In the context of that data, though, what level of editing do you expect to see or need in humans in order to see clinical...

Yes. So to see -- I mean, I think to see -- if you think about -- that's assuming the mouse translates 1:1, but oftentimes, we've seen similar translation with other gene editing approaches, whether it's CRISPR or base editing approaches. So if that translates the same way other editing approaches have translated, then it's absolutely possible at similar dose levels, we could see that level of editing. Obviously, there could be some differences. Maybe you see -- as you go to -- you never know until you get to the clinic, and it's always possible you get better editing at lower doses or even higher doses depending on how it translates. But I think what that means is even at low doses, we can expect to see efficacy.

The good news is, as I said before, we think we've got a fairly wide therapeutic index. So if we have to dose higher, we think we've got a really nice window to be able to explore higher doses if necessary. From an editing efficiency standpoint, again, it comes back to even 25% bulk liver editing can get you very effective data.

We've seen as high as -- well, I'm kind of going between bulk and hepatocyte editing. So let's just stick to hepatocyte editing. So at 45-ish percent hepatocyte editing, we're getting really compelling data. We can get up to -- we've shown data 80%, even up to 90% hepatocyte editing as well. So the ability to go higher is there. Again, we might only need a certain percentage, but we have the ability to edit the vast majority of hepatocytes.

And you've emphasized PM577 modularity where post approval, you could quickly target additional Wilsons mutations here to expand upon the opportunity. How quickly could you add mutations beyond this and incorporate them into the existing regulatory filings?

Yes. So we think we're going to be able to leverage multiple components here. So one is a lot of the IND-enabling work. We think we'll -- we can rely on a lot of the IND-enabling work that's been done for the Wilson program, but also for the alpha-1 program as we think about all the GLP tox studies, biodistribution studies because that's all really looking at the lipid more than anything else.

In terms of the editor, what we think will be required for additional mutations is really some of the off-target work, and it might be a smaller off-target package, but some off-target work, which is not a huge lift. So you can do those things relatively quickly. And then it's really getting to high levels of editing, showing that you're getting good editing in preclinical models. The second mutation we're likely going to go into is called our778L. It's the most prominent mutation in the Asian population. And we've already shown very high levels, 80%, 90% editing in preclinical models for that editor. If we see really good in Vitro to in Vivo translation, you can also argue for future mutations because you even jump from in Vitro or just do one small in Vivo model to go into the clinic. So we think these will be much smaller regulatory packages and ultimately can get into the same IND.

We'll do these all under one IND. And there's also leverageability as we think about manufacturing because we're using the same LNP, likely the same mRNA. So you're really thinking about changes to the guide and potentially the nicking guide if we're using that in these constructs.

On PM-647 in Alpha-1 antitrypsin deficiency, you're also submitting an IND here in mid-'26. Could you provide an update on time lines here and the IND-enabling study progress and what proof-of-concept data points would lend confidence to this program? I mean, given we've seen what's played out with some of the others.

Yes. So again, sticking to our time lines there. So no change to guidance for a midyear regulatory filing for alpha-1 -- for the Alpha-1 program. As we look to proof of concept here, this is a little different than Wilson disease. For Wilson disease, there's a couple of companies doing some different -- have some different approaches there, but there's no other gene editing approaches that we know of. that are going towards the clinic for Wilson disease.

For Alpha-1, there's a number of RNA editors, base editors and prime editors actually going toward either in or going towards the clinic. So we've seen a lot of studies there. There's a very reliable biomarker there when we think about just looking at Alpha-1 protein and you could look at blood levels. So you've got a very reliable early biomarker that can really tell you if you're getting to levels which are deemed protective in patients.

And we saw some early data, I mean, as you cited from some of these competitors, there's a Chinese competitor, JolTEC, where one patient at the higher dose saw AAT levels increase to normal range and then corrected MAAT levels or MAAT increasing to greater than 95%. So that appears interesting and differentiated versus B. Maybe talk to how to put these data sets in context.

Yes. I mean it's interesting what they did. They -- so Alpha-1 is really sort of an Eastern European disease, right? So it's a disease that really affects the Caucasian population, doesn't affect -- I don't think it really exists in the Asian population. So what they did was they took 2 patients from Germany, flew them to China to treat them as part of a study, and those are the 2 patients that we're seeing that data from. I think that data looks really interesting. But I always caveat, I don't think 2 patients' worth of data is enough to draw conclusions. If they can show that data in more patients, then -- and I know they have an open U.S. IND now, so we'll get some U.S. data as well. That will be something that's interesting.

They do, I think, still have a bystander edit. I don't think the percentage of bystander edited protein is similar to beams, which is the majority of the protein that gets edited has the bystander edit. They've commented -- I don't know if they've shown data, but they've commented that it's much lower.

So I think that's better because more of that protein is wild type, but it's not 100%. So I still think there's a place for Prime Editing because I think if you just kind of look at the 2 technologies, if you have a technology that can take you essentially back to wild-type protein, I still think that could be the preferred approach to a base editing approach. So we'll see what their data shows as they develop more of it.

Can you elaborate on that bystander edit?

For -- Yes. So with base editing, that can cause -- they can cause what are called bystander edits. And what that means is within the editing window, I mean, they're just changing one base pair to another base pair.

So let's say you're converting like A to Gs. So every A within that editing window has the potential to be converted to a G, right? So you'll have the corrective edit that you want, which is that A to G. But if there's another A and that's converted to a G, that's called a bystander edit, right, because it's -- call it an undesired edit.

And sometimes these undesired edits, even changing base pair, if it changes the amino acid sequence, I mean, if you just think about Alpha-1 disease, it's a single base pair that's mutated that causes the disease. So the question is, what do these other edits do? I think they've shown it's still functional protein.

They have some early data that suggests it may on some liver trafficking. But again, it's not as functional as wild-type protein. And I think we'd still want to see a lot more gain in terms of liver trafficking.

Great. On your CGD program, you had previously intended to partner the asset for further development. Walk us through your process here and what changed in the regulatory competitive landscape to warrant commercialization?

Yes. I don't think we ever talked about necessarily partnering the asset. I think when we announced about a year ago, we came out with our initial data. And at the time, made the decision to actually discontinue the program. And at the time, we said we're discontinuing it, but yes, we were open if someone wants to take it on as a partner or if there's another way to get this to patients.

What happened subsequent to that, there were a lot of changes within the FDA and a lot of, I would say, an FDA that's become a lot more flexible and has really tried to put an infrastructure in place where some of these therapies, especially when you're looking at smaller populations in the gene and cell therapy area can get developed because in many ways, the requirements for these diseases can be the same for a large disease.

So the cost of getting these therapies even to approval can be pretty significant. So we kind of did 2 things. So on one side, we saw the CMC requirements, they were starting to talk about more flexibility. They put out some guidances, and there is a lot more flexibility now on the CMC side. So we feel really good about our CMC plan in terms of taking this ultimately towards approval.

And initially, the cost would have just been exorbitant and not something that we could have done for this program. But now it's really a fraction of what that would be. And we think we've got a good CMC plan as we think about taking this forward to approval, where we have general alignment on sort of what's required for approval, and it's something that's well within our resources to be able to do. When it comes to the patient number is also, well, if we have to go and enroll, call it, 10 or 20 patients to get this to approval, that can cost -- I'm just throwing numbers out there, but let's call it, north of $20 million, even more than 2 million of patients just to get them into these studies.

That's a pretty significant number where given there may only be 50 to 100 patients to treat in the U.S., it's very hard to think about getting a return on that investment that would justify it. And so we went to the FDA to really ask the question, look, we've got 2 patients. These 2 patients, we've transformed their lives really by genetically curing them and they don't have new -- not getting any new symptoms.

They have active neutrophils. They should be protected against infections. I mean this is really revolutionary for these patients. is this something that you would think is approvable even just based on 2 patients' worth of data? And I would say even frankly, to my surprise, the FDA was fully on board with that data package being sufficient from a patient standpoint to get to approval.

On the cystic fibrosis program here, just provide an overview of the partnership and the development program here and what really stood out as -- with regard to this disease as an optimal indication for Prime Editing. And would you have to do it on a mutational basis? Or could you go beyond?

Yes. So for CF, the reason that I think Prime Editing could be the optimal approach here is, well, first off, you've got a population of patients, call it, 10% to 15% that are, for whatever reason, can't take standard of care. Some of them have mutations, something called nonsense mutations where the correctors just don't work.

And there are patients out there that really can't tolerate standard of care. So even though CF has become a disease where -- I mean, it's just incredible what's happened in that space, where people could live into their teens or 20s now can live much more normal lives, with much more normal life expectancy.

I mean that's an incredible advancement in that disease. But there are these patients that are left behind. And with Prime Editing, if you take some of these nonsense mutations, we can go in and just correct that mutation and really normalize CFTR expression within those cells. And we think even getting to 30-ish percent editing, we hope we can see a really strong clinical benefit in those patients. There's really no -- I know there's been some gene therapy approaches, some mRNA approaches. The problem with the mRNA approach is you have to dose them very frequently. And I think that's going to be something that's difficult when you're taking anything to the lung like that over a long period of time from a safety standpoint. And we know I think one company out there did announce that from a safety standpoint, they couldn't move forward.

CFTR is also a gene that's sort of you want the right amount expressed at the right time and you kind of don't have as much control. And so if you have too much expression or too little expression, that might not be optimal as well. We're correcting the gene at the locus under normal, so it will be under normal physiologic control. So you're getting the right amount of CFTR expressed at the right time. So we really think this is the optimal therapy for CF.

We are initially going to go after specific mutations. So we call this our hotspot editing approach. What we mean by that is one editor. If there's 2 mutations and like this is patient to patient. So if one patient has mutation A and the other patient has mutation B, which is very close to that mutation within a number of base pairs, editor can actually correct both mutations. So that helps where you don't have to develop multiple editors for a couple, 2 or 3 mutations. So with a number of hotspot editors, we can get at a lot of these nonsense mutations.

But one example is there's Del 508 and there's a 507 mutation. So one of those mutations we're going to go after is 507. With that, we'll also be able to go after the Del 508 patients. So the goal here isn't to just go after those 10% to 15%. That's the initial goal where there's an initial mutation that we're going after. But ultimately, we think we can treat the vast majority of this population, and we do think there'll be a benefit even over corrector therapy.

So I'm not saying they necessarily need to go off that therapy because there's also manifestations outside the lung, but something we could treat as well. In terms of the collaboration, I think about it more as the work we're doing with the CF Foundation, we're doing the work, but they're essentially funding that work.

They're a very well-capitalized foundation, thanks to Vertex and the IP that they had and the royalties that they sold. And they are a very committed organization to ensuring that no patient is left behind. So they are very focused on getting that 10% to 15% of patients treatments that can essentially do what Trikafta and others have done for this disease. So we've got a very good relationship with them. At least they tell us that this is one of the most promising therapies that they see within the space, and they're essentially helping to really fund this program going forward.

Where do the competitor gene editing program stand currently?

I don't know -- and there could be things out there that I haven't seen, but I don't know that I've seen any gene editing companies that have been developing in CF. I think there's maybe one collaboration I saw, but I don't know that, that program went anywhere. So we don't see much in terms of gene editing competition right now in that space.

Is there anything more you want to touch on with regard to the Bristol partnership here on the passage technology in ex vivo T cell therapies?

Yes. I mean continue to make good progress with our partners. Obviously, when you're partnered with big pharma, you can't really comment on where you are. You give that up when you partner, but given the financials, that's worth it, I would say. There are pretty significant milestones as part of that collaboration. We've, I think, commented $185 million in potential even just preclinical milestones, which we think are achievable, at least the first 1 or 2 over -- we're not commenting exactly on time period, but in the near to medium term.

So that continues to move forward well. We think BMS is very excited about that approach, that allogeneic ex Vivo CAR-T approach and continue to make good progress there.

Great. A last question here, AlIan. Just remind us of your cash runway in the context of these programs that you're running?

Yes. So we have about $150 million that was last reported as of March 30. That takes us somewhere into 2027. In terms of from a program standpoint, we said data in '27. So we haven't said exactly kind of does cash get you fully through data or not. That obviously depends on a few different factors. But I would say is, again, we think about BMS, that doesn't include any milestones from BMS.

It doesn't include, obviously, if we're able to monetize CGD in some way and it doesn't include additional BD. So at this point, additional capital required to get through '27 is not what I would call significant. So we think we're in a really good place today.

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Great. Well, with that, thank you so much.

Thank you, appreciate it. Thanks for having us.

Hi, everyone. My name is Maury Raycroft and I'm one of the biotech analysts at Jefferies. I'd like to welcome Allan Reine, CEO of Prime Medicine. Thanks so much for joining us today, Allan.

Thanks for having us here.

And we're doing a fireside chat format. So maybe for those who are new to the story, if you can give a brief intro to the company.

Yes. So Prime Medicine is a company that's focused on progressing our technology, which is Prime Editing. This is a revolutionary gene editing technology, sort of the 1-minute pitch without going into all the details around the technology is think about this as the way I like to say it is it's the safest way to edit the genome versus any other type of gene editing technology that's come before this, but it's also the most versatile way to edit the genome.

So think of Prime Editing as we can do any type of edit that any other technology can do, but we can also do so much more, right? So we can do large insertions. We can do -- fix all these different types of edits that other technologies can't do. For example, in Wilson disease, going after what are called transversion edits, et cetera. So again, the most versatile and the safest gene editing technology, we think that exists out there.

Got it. Yes, it's a great intro to the company and the technology. Maybe starting off with your Wilson's disease program. You've got the Prime Editor PM577, which is entering the clinic first half of this year. You're guiding to file an IND and/or CTA first half of the year. What can you say about where you are with the submission package at this point? And what are the remaining gating factors?

Yes. So I think all we've said all along is what our guidance is, and our guidance remains the same as the regulatory filing for Wilson disease in the first half of this year. What you typically expect from us is to announce once an application has been accepted. So look to that as the next announcement there.

Got it. Okay. And is there more you can say on the strategy here? Are you only focused on getting the study going and getting to initial safety and efficacy? Or would you want to pursue a global Phase I/II and quickly try to accelerate development?

Yes. So this is -- we're planning on even this initial Phase I/II study to be a global study. So we've got a number of sites that we've already selected and are already working very closely with a number of KOLs out there. And I can tell you, there is a lot of interest. I've attended some of these KOL sessions at some of the conferences, and there's a lot of interest amongst the KOLs for the study. So this is going to be a global study.

But there's also a lot of interest from the patient standpoint as well. So a lot of patients have also reached out here. So this is an area of very high unmet need. We're hearing that from KOLs. We're hearing that from patients, and we're very excited to get the study going. And data dependent, we'll expedite this as much as we can.

Got it. And you've already -- you've enrolled an estimated approximately 30 Wilson's disease patients across 7 U.S. academic centers in a prescreening observational study. Just stopped enrolling earlier this month. How will this impact your enrollment time lines for the dose escalation and eventual expansion?

So this is U.S.-based. So it's not going to impact, obviously, our ex-U.S. sites. But for the U.S., what this allowed us to do is to really identify a number of patients -- and I think that number is a little bit over 30 now, a number of patients that we'll have genotyped to confirm that H1069Q mutation, which is the initial mutation we'll be addressing in -- for our first Wilson disease study.

And so that should help us sort of fast track getting those patients ultimately enrolled into our treatment study and hopefully help us move those cohorts along faster. But again, that's U.S. focused. So it won't impact what we're doing ex U.S., but should help us enroll faster in the U.S.

And it's observational. So some of those patients may not qualify? Or how should we think about that?

Think about that as we're trying to enroll patients into that study that we think could be good candidates for the clinical study is my understanding.

Okay. Got it. And is it fair to assume that by the end of this year, you could have sites open and potentially a few patients dosed?

That's a fair assumption.

Yes. Okay. Any more granularity on that...

We're not going to give updates on patient-by-patient enrollment into our study. But based on the time lines we've put out there, I think that's a reasonable assumption.

Got it. Okay. And at the ASGCT meeting recently, you showed preclinical data at 0.4 mg per kg and 0.8 mg per kg doses, suggesting approximately 45% hepatocyte editing is the threshold for near normal liver copper in mice. How many dose cohorts? Should we expect an escalation in your clinical study? And based on your human-equivalent dose modeling, are you starting at a dose where a functional cure is achievable?

So that depends on, obviously, the question you're asking what your starting dose is, right? You're going to go in with a starting dose that you'd like to go at and then the regulatory jurisdiction where you're going into has to agree on that starting dose. So you can't necessarily answer that question until you know exactly what your starting dose is.

That being said, we're very encouraged by what we see even at 0.4 mg per kilogram. Even at that dose, where if you think about bulk liver editing, that's somewhere in the 20s, right? So hepatocyte editing in the, call it, 40% to 45% range, we're seeing almost complete normalization of copper metabolism preclinically. So that suggests that at that fairly low dose level in patients, we could potentially see normalization.

Normalization might not even be where you need to get to because remember, a heterozygote, so a person that has one mutation but doesn't have that second actually doesn't have disease, right? So they might have increased copper in their liver and some increased copper, but they actually don't get sort of "clinical" Wilson disease. So we're very encouraged by that data, and it suggests a dose of 0.4 or potentially even lower, if the preclinical data translates well, could be very effective in these patients.

If you look at where other companies have started in the clinic, that suggests we could be at a dose that's not too far below that. So you may not be at your optimal dose when you start out, but the goal is to be at a biologically-active dose when you start out, and we do expect to be there. And the better the data translates, hopefully, the closer we are to that optimal biologic dose.

Got it. And so based on what you said, can you put finer points on just the amount of editing efficiency you need in order to get efficacy in the clinic?

Yes. Again, this all comes down to preclinical to clinical translation. So I think preclinically at fairly what I would call low editing rates, like below maybe at 40% hepatocyte editing or maybe even as low as 20% bulk liver editing, maybe even lower, you might get to levels that are equivalent to essentially where a heterozygote is in terms of copper load in the liver. We'll see ultimately what that looks like clinically, but at least suggests you can be at lower levels of editing to derive benefit.

That being said, we're at very high levels of editing, right? So if you look at where we're getting to at 0.8 and even slightly above that, we're getting to levels of 70-plus percent editing, and we've even shown data getting to 80%, 90% editing. And we think we've got an LNP that at least looks to us could have a good wide therapeutic index here. So the ability to dose higher is there. We're not saying it's necessary. But at least what we've seen preclinically, we're very encouraged about that dataset.

Got it. Makes sense. And you're leveraging traditional Wilson's biomarkers like ceruloplasmin...

I can never say that word either. Ceruloplasmin.

And serum copper, urinary copper and the fecal copper, what threshold or magnitude of change versus baseline would you consider sufficient to demonstrate functional cure restoration?

Yes. I don't know that those numbers are sort of understood, right? I don't think there's sort of an exact number to say what a functional cure is when you're looking at serum copper, urinary copper, fecal copper.

So the way I like to think about it is the way that copper is normally excreted, it's down to an enzyme in the liver, it's excreted through the bile, so ultimately through the feces. That's normal copper metabolism and excretion. In a Wilson disease patient, they lack that enzyme that's able to normally metabolize that copper. And so you don't get that fecal excretion. That copper builds up in the liver. It ultimately spills out into the bloodstream. It collects in different tissues in the body. So you obviously get that liver disease, but you can get pretty severe neuro and psychiatric disease because of the buildup of copper in the brain. And ultimately, that copper gets excreted predominantly through the urine -- through the kidneys and through the urine. So that's sort of abnormal copper excretion.

So when you treat, what we see preclinically is we can fully normalize fecal copper, we can fully normalize urinary copper. We're not going to have necessarily like a baseline measure on these patients, but you'll see what sort of that normal range is. And the expectation is that we can get these patients, if we get to a high enough level of impact, we can get them into that normal range. But I can't sort of off the top of my head, quantify exactly what those numbers are.

Got it. So it sounds like the urinary copper that's going to be something that you're highly focused on.

I think -- as I think about the endpoints that we're looking at, if the copper PET data translates well preclinically to the clinical setting, that should be the most compelling data because we'll be doing a baseline measure and then we'll be doing a measure 6 to 8 weeks after that patient is dosed. And that should show you have you -- do you have a significant improvement in the way that copper is being metabolized because you actually take these patients off of standard of care for those few days before they get the radiolabeled copper. So you're seeing the sort of true copper metabolism when they have full disease and after they've been edited.

I think things like urinary copper, fecal copper, there are some other measures of ceruloplasmin and ceruloplasmin-like measures something called NCC, that you can look at, those will also all be very helpful measures to sort of gauge where you are in terms of disease improvement.

Got it. And for the radiolabeled copper, is that going to be included in the initial study? And how important is that going to be for regulators?

So that will be included in the initial study. So yes, it's actually -- it's not a large effort, but it is actually a separate IND you have to do for that -- for the radiolabel copper assessment. So that's something that's in progress as well, but that will be included in the initial study.

From a regulatory standpoint, there are other companies that have included this in their study. It's relatively new, I would say, but there are a couple of companies in Wilson disease that have started to include this as part of their studies. So it's possible they have some experience with that now. I think the better the data looks, the more likely the FDA will allow us to use this as a good measure of, one, hopefully, removing standard of care and showing that these patients remain sort of -- have normalized copper once you've removed standard of care. But there's also the possibility of could this be something that's used as an endpoint in a registrational trial.

I'm not sitting here today saying that's the case. Like I think the base case is always going to be can you remove standard of care and show that these patients are maintained. But as we always say, the stronger your dataset, I think the more flexibility the FDA could have.

Got it. Makes sense. And you're enrolling patients with moderate liver disease. How are you thinking about the safety in that population, particularly in the context of prior liver safety signals seen with other gene editing approaches? And are you incorporating steroid prophylaxis or more frequent liver monitoring in the study?

Yes. So we are -- we do have some prophylactic or some drugs that are given to sort of right -- kind of just before you treat. So that does exist here, but you don't have to do significant steroid loads or anything like that.

From a safety standpoint, we can just look at what we've done preclinically, and we have benchmarked our lipid against some of the other lipids that have gone into the clinic. And we do see improved measures when we compare across liver function tests, we compare across some of the inflammatory markers and we compare across some of the coagulation markers that you see.

So if that plays out as we go from sort of the preclinical setting to the clinical setting, it's possible that you do have a wider therapeutic index. And as you're going into patients that are going to have some element of liver disease, it's moderate liver disease here, we hope that therapeutic index is something that hopefully plays in here, and this is very safe in that population.

Yes. That makes sense. And as you look ahead to initial data expected in 2027, what do you plan to report? Will there be an opportunity to show proof of concept in an early cohort? Or would you want to wait for more mature and complete dataset?

Yes. I mean I'll never say never to anything. I mean I think everything is kind of always on the table with this stuff. I think we -- I mean, obviously, with CGD, we came out with 1 patient and then a second patient. We ultimately only dosed 2 patients. And then in the end, we're actually going to be filing for a BLA just on 2 patients' worth of data. But I think in general, it's better to put out a more fulsome dataset where investors can really and physicians and patients can really understand what that data is. I don't love the idea of you throw out one patient, you've got proof of concept and then that second patient doesn't validate what you did in the first patient.

So I always find more data is better. But when we feel like we have a dataset that we think is validating, and it's the right time to share that dataset publicly, we'll do that. And I think if it's important to share for patients and for others, when we have a dataset we feel is ready, we'll report it.

Got it. Okay. Let's shift gears and talk about alpha-1. For this program, you're going to file an IND or CTA in the middle of this year and then show initial data in 2027. Maybe just starting off, what's the latest you're seeing on the status of the filing and what are remaining gating factors there?

Yes. So same thing at Wilson. I'll sort of not answer the question in the same way and just say same -- no change to guidance at this time.

Okay. I guess for both programs, is there anything critical that you're waiting on?

Again, just refer you to our guidance.

Okay. And for the Phase I, do you plan for your Phase I to follow a similar staggered Part A and Part B structure as Beam, where you separate lung and liver patients to establish LNP safety? Or is there an opportunity for cohorts to enroll concurrently to accelerate development time lines?

Yes, it's a good question. Wilson is a little bit ahead of alpha-1. Whether that's going to sort of play into -- in terms of when we dose, if we can leverage one to the other, don't know, right? If one was very far ahead, then you could potentially leverage safety as you think about dosing in your alpha-1 study. But I think they're close enough at this standpoint. I don't know if that's something that's going to be sort of meaningful here.

I think for now, I think about it as probably going into different cohorts, not so much from a safety standpoint. I actually think it more so from a -- just efficacy standpoint. I think seeing efficacy for lung disease, you're really just kind of looking at levels, right? I think seeing sort of an improvement in liver disease is a little bit different in terms of the biomarkers or what you want to look at to get some comfort there. You're just going to get a much faster read likely as you think about lung disease versus liver disease, although there's a few things you can look at in liver that can get you there. So my expectation is we'll start off similarly with lung disease, but the goal will be to pivot to liver disease patients as well.

Got it. And how are you thinking about biomarker endpoints relative to Beam? And is there anything you're planning to do differently that could allow you to better understand or demonstrate impact on functional measures?

Well, I think early on, you're really looking at biomarkers, and it's really hard to get a read on functional measures. I think functional measures is something that's going to take a much longer period of time. Some companies, and this is more sort of luck of the draw, if you get a patient that's undergoing some type of inflammatory response to infection and you see elevated CRP, et cetera, yes, you can show -- or am I getting the biomarker increase, that response there.

But in terms of a functional benefit, those are longer-term studies. And I think what we've seen today, most companies are going to be going forward, looking at biomarkers, predominantly AAT. There might be another couple of things that you get to include in there as well as a basis for an accelerated approval, but there'll be confirmatory studies where there'll be some different measures that we'll have to look at as well.

Got it. And kind of a similar question to the Wilson's one earlier. Just based on your preclinical data for alpha-1 in the mouse model, you've got 2 dose levels that restore AAT above the normal human range. Can you confirm if you're starting the dose escalation at an equivalent dose or below those doses [ validated ] in mice? And with your data and others' data, what are the key things to know about your dose range strategy?

Yes. I mean I'll caveat this in the same way, right? Until you have sort of what you agreed upon dose level is, it's -- you can say you want to start at a certain dose, but you don't have that go-ahead yet. In terms of thinking about those dose levels, if I think about the lower dose level there, if we're successful starting where we want to start in that specific study, that should be fairly close to that lower dose level.

Got it. Okay. And should we expect a more comprehensive preclinical update for your AATD program at a medical conference in 2026?

I don't think so. I mean I think we've put out a lot of our data already. I think we've got a really strong profile as we're moving forward. We do have some additional data internally. But frankly, I think we've got a really good profile from what we've seen. So not to say that we're not going to share any additional data, but I don't know that we have any plans at this time to share any additional data.

Got it. Okay. And you're currently in arbitration with Beam related to your AATD program and previously guided a resolution by first half of this year. What is the status and latest you're seeing on time lines for potential resolution?

Yes. So we've refined that somewhat. So now we've said so the first half of this year, we expect a decision by the end of July. It could come sooner, but we have a date that we know there's a commitment to get us a decision by. So by that date or before. So we're within, call it, 7, 8 weeks of having a decision or, again, it could come earlier.

Got it. Okay. And can you talk more about how PM647 clearly falls within Prime's retained field under the collaboration agreement? For example, does PM647's Prime Editing mechanism introduce edits beyond direct correction of the E342K mutation that impacts hepatic secretion and functional restoration?

Yes. So what Prime's editor does is we have a number of measures when we think about improving editing efficiency that impacts something called mismatch repair. So when you think about a Prime editor and not to go too far into the cellular biology, but you're always fighting against mismatch repair. We're always trying to do things that can kind of tamp down that sort of mismatch repair.

And so we have a number of tools and one of those tools is doing something that we call synonymous editing, where we make some additional edits that don't -- they impact -- they impact the sequence, the coding sequence, but they don't impact the amino acid sequence because the redundancy built -- that's built into that translation. And so when we do those additional synonymous edits, that's sort of one of the tools that can impact mismatch repair. And so that's something that we do here. So there's additional edits there that really get us to the product that we have and to the editing efficiency that we're able to achieve.

Got it. And so that basically should be very independent from the collaboration agreement.

Yes. I mean if you read the language of the collaboration agreement and you read across what it says in terms of the Beam field and the Prime field, at least we believe it's pretty clear that anything that is a -- does a transition-only edit that falls within the Beam field. Anything that does a transition-only edit and -- does a transition edit and a non-transition edit, clearly falls within the Prime field. This is not an agreement that was separated based on disease. The one disease that is called out is sickle cell disease and Beam has rights to sickle cell disease for Prime Editing, and we don't contend that.

Got it. Okay. Grifols is going to report pivotal AATD data second half of this year using PD15 to measure emphysema progression at 2 different doses. What are you looking for in the data? And what type of read-through will it have to Prime?

Yes. So this is another -- this is a replacement therapy?

Yes.

Yes. We haven't seen a lot of great data as we think about sort of functional data with replacement therapy. So I think it's important to see something that can really validate kind of what they're doing. I don't see that as having a real impact in terms of will patients, will KOLs opt for this one-and-done therapy if they have that option.

I -- let's see what the data shows. But even a very positive data event there, I still think a lot of this market would be willing and will prefer to go to a sort of once-and-done gene editing treatment. But let's see what that data shows. I -- for patient's sake, honestly, I hope it's good data. I hope patients have options that actually work because they're getting these therapies today. I still think we all question on are they really having a strong benefit.

Yes. Okay. Makes sense. And for cystic fibrosis, moving on with your pipeline to cystic fibrosis, what are the specific hurdles in optimizing LNP versus AAV delivery to basal cells? And what exactly do you need to show in your anticipated 2026 in-vivo proof-of-concept data to advance into IND-enabling studies?

Yes. So there's a couple of different approaches here. So I think we're focusing more on LNP versus AAV for probably just in the 5 minutes, I won't go into it. Probably for obvious reasons to a lot of people, I think LNP would be a preferable approach here.

And among -- and thinking about that approach, there's also different target product profiles that we're thinking about. So one is how do you get to those basal cells? Because if you can get to those basal cells, you can truly have a once and done or treat a few times and you're done kind of therapy in cystic fibrosis. And that would be a huge win for patients. But another huge win for patients could be, what if I could get to the secretory cells. And they make it some of those -- that basal cell population. So over time, I can dose less frequently. But if I can get to those secretory cells that are turning over every month, 2 months, 3 months or even longer potentially, depending on that could be different for a cystic fibrosis patient.

So maybe there's actually a drug I can dose with a Prime Editor that is dosed, I don't know, twice a year or 3 times a year, even 4 times a year. We know some of these drugs with LNPs have been dosed daily. And there's been some tox daily, but we know others that have been dosed even 3 times a week where we haven't seen high tox burden. So this is something that can be dosed. And if you can dose it a lot less frequently and have this be very efficacious, maybe you don't have to get to those basal cells.

So there's different sort of profiles I think we're looking at here, and I think there's a number of different ways to win. This is a very important population of patients where, call it, 10% to 15% of patients that, for whatever reason, either because of their mutation or because of tolerability just can't take current standard of care. These are drugs that have revolutionized the treatment for CF, right? This has dramatically changed the lives of these patients. But the Cystic Fibrosis Foundation is looking at these patients, as are we, and saying, there's a number of patients that have been left behind. How do we treat those patients effectively? And that's what we're working really hard internally and with the Cystic Fibrosis Foundation to really try and figure out. And we're hopeful that we're going to get to some real proof-of-concept data this year preclinically that we can really get towards a DC and ultimately get to IND-enabling studies here because we see this as a really, really important population to treat.

We're also not going to stop there. So even one of the mutations we're going after is very close to del 508, the same editor could address both that 507 and 508 mutation. And I think this could be a very desirable solution for patients that are also on TRIKAFTA that are treated for -- that have the del 508 and it could be in addition to their correctors, this could be something that's very beneficial to those patients as well. So we're not just going to stop at that one population. We know that's a very important population to target first, but we also are thinking broadly about the CF population.

Got it. And for the 507, 508, just out of curiosity, is that a pan-genotype editor there or...

So what we do -- so if you think about the editing window, like usually, we're covering -- I don't know, we could do longer base pair edits, but you can very easily do 10, 15, 20 base pairs. And so you can cover -- if 2 mutations are sort of right beside each other and think about it as one editor can really cover both of those mutations. We call this hotspot editing when one editor could do multiple mutations. But I'm not talking about hundreds of base pairs where you're editing amongst that. It's sort of like if you have 1 or 2 or 3 mutations that are very close together, then one editor can address all of those.

Got it. And you've got technology that could address pan-genotype PASSIGE technology...

Oh, PASSIGE, yes. Sorry, I didn't know that's where you're going. Yes. So PASSIGE would be if we're -- whole genes maybe are -- maybe it's not a whole gene, but you can do pretty significant almost whole introns. So there, you can do, yes, pan, large insertions, you can cover the majority of mutations essentially with one large insertion. That's something we are also working on with the CF Foundation. That is just when you're doing a whole or a very large multi-kilobase insertion, that's going to be a more complex problem to solve with lung delivery. I hope we get there, and we're working on that as well. But I think we've got a great approach just looking at the current Prime Editors. And if we can get there with PASSIGE, that's going to be a great pan solution as well.

Got it. And you've highlighted potential to expand into larger liver-based indications and know the development plans are still being finalized. When should we expect more clarity on that?

We would hope to provide more clarity on that as we kind of get through the year. There's a lot of really interesting indications where I think Prime Editing is uniquely suited for. Indications that are, frankly, a lot larger even than Wilson disease and alpha-1 antitrypsin deficiency. And so hopefully, we have more to say on that as we move along there.

Got it. Any update on the collaboration with Bristol?

No, continues to progress well. A lot of big preclinical milestones there. So continue to make good progress there. There's only -- they don't let us say anything, so not more I can say there, but good progress.

Good. Okay. So we're pretty much out of time. Maybe just to close up, if you can recap key catalysts ahead over the next 6 to 12 months that investors should be focused on.

Yes. So obviously, you mentioned the arbitration, we'll have that coming very soon, getting these 2 programs ultimately into the clinic, getting to data and what I think is going to be proof-of-concept data from our first 2 in-vivo clinical programs in 2027. And I think importantly, we didn't talk much about CGD, but filing a BLA for CGD, hopefully sometime later this year, sometime in the first half of next year and getting that important medicine to patients as well.

Got it. Allan, thanks so much for joining us today.

All right. Thank you.

All right. Welcome back to day 2 of the Citizens Life Science 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.

Yes. Thank you for having us here.

Maybe to start at a high level, it seems like it's a very pivotal time for Prime. As you move into the clinic, you've got to execute a bit, but then 2027, we could have the first-in-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?

Yes. I mean I think I say every year, it's a pivotal year. And 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 disease and Alpha-1 Antitrypsin Deficiency. In terms of clinical data, you're right, like we're on track for both of those programs to get clinical data in 2027. But I would say we do actually have clinical data in patients, but that's -- and for our ex vivo program in chronic granulomas disease, which I know we'll also get to talking about. So it is a very big year for the company in terms of getting those programs into patients. I think what these -- both these drugs can do can be pretty revolutionary for those patient populations, and they are both high unmet needs. And as we do that, it continues to really derisk the -- our liver platform, as you think about it. And that's from a delivery standpoint. And as we think about how we can leverage that going forward, it's really going to put us in a position to take additional programs to the clinic to patients a lot faster and a lot cheaper.

Great. And yes, maybe talking about that one program. So recently, it was a very positive surprise for me in CGD that you're bringing it back, and you're going to 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 the first two patients?

Yes. So I think it's -- there are a number of factors that changed. So we made this decision to deprioritize this program in May of last year. At the same time, we announced that one patient worth of data, we ultimately came out with a second patient that we had treated. And 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 between $50 million and $100 million and take a few years. So 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 19 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, I'll call it, plausible mechanism, but we understand the biology well. We understand the endpoints well. And I think this is a program that fits perfectly within that. It's a disease that affects people at a young age. And so the only real treatment for these patients today is allogeneic transplant with many of them undergo. This could be a much better option for these patients in allogeneic transplant. But importantly, a lot of patients have aged out of allogeneic transplant, and so they really have no option. And this is a treatment that for the first time, these patients will now have an option to really change the course of their lives. So we're really excited about getting this to a BLA. There's still kind of a couple of steps that we're thinking about going through. For one, we'll probably enroll one more patient. We do have rare pediatric 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. So 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. So really excited about getting this program to patients, and we think it's a really important program for Prime.

Yes. 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. But like what -- so you'll have a meeting with the FDA to discuss the BLA filing or the scope. Or -- is that a first step, or will you just be...

What I would say at this point, we're not commenting on sort of our FDA interactions. I 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 want to get a label? Can we get a label with the current data set? We've treated an 18-year-old, we've treated 57-year-old, can we get a label for -- that includes pediatrics with the current data set? Or do we want to enroll one more patient under 18 to get that label. And that's still a conversation that we're going to have. And on the CMC front, when I talked before about it being $50 million to $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. So the financing needs from your balance sheet are the manageable while you execute.

Yes. Cash runway guidance unaffected.

Okay. Great. Thank you. Maybe moving on to in vivo, which I think most people are focused on here on the story. Maybe with Wilson's disease, often it's viewed as treatable. Yet you're emphasizing how significant the unmet need here is. Can you just highlight what is underappreciated, and what Prime Editing will bring to the table here?

Yes. 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 standard of care. You can take copper chelators, you can take zinc salt. 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 of liver or neurological disease. So yes, some patients, if they're adherent, may live a relatively normal life. They'll be in a low copper diet. These medications aren't easy to take. You have to take them multiple times a day, sometimes fast, sometimes with food, depending on what medications you're on. So it's not -- 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. And again, almost half of patients or close to it are not able to be compliant on standard of care. You can quickly get copper buildup, you can quickly get additional end organ disease. So this is something where we have seen a broad desire amongst 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. So it seems like there's a fair amount of patients that don't tolerate standard of care. And would those be predominantly the population for Prime Editing, or would it be all of the patients? And also, there is a gene therapy in development there. What would be the limitations of that versus Prime Editing?

Yes. So I think -- and we've asked those questions, too. I mean, I think the easy low-hanging fruit are going to be those patients that are not compliant, whether it's because of tolerability or something else. That's obviously the low-hanging fruit. But when we ask the same question around patients that actually are managing 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. So 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. But I really believe there'll be broad acceptance of this therapy across those patients. Again, just given the fact that this chelators and zinc salt, they're not curing the disease, right? They're helping their -- zinc salts are helping to prevent absorption, copper chelators because the copper is going to 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. And what we'd ultimately like to do is say, obviously, we're going to treat that prevalence pool. But as we think about the incidence pool, how do we get in to treat patients that are 5, 6 years old really before they develop clinical disease. Sorry, you asked about Ultragenyx. I do you want to answer that question as well. Yes, gene therapy and gene editing therapies, there's a lot of differences. So I'll just tell you what the differences are from the competing gene therapies out there. So 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 as people know, in protein biology, the truncated protein might have slightly different activity than the full-length protein. Two, hepatocytes turn over. They don't turn over as quickly as epithelial cells or other cells in your body, but they turn over, whether it's over 6 months, a year, et cetera. So there'll be a dilution of effect because 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. So this should be a -- and we've shown this in longer-term studies as some others, these gene editing therapies tend to be very -- well, they are very durable. So that -- those are 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. So I think there's a lot of important differences. And I think ultimately, that will play out in the clinical data.

Great. And what are the remaining steps to get to IND or CTA? And what's kind of the time frame that -- if you remind me of that?

Yes. So we haven't given sort of the play by play, but I can remind you what our guidance is. So our guidance for Wilson disease is a regulatory filing in the first half of this year. It's, what, March 11. So the first half of this year has a -- 3 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 I'd say we're only a couple of months behind Wilson disease as you think about Alpha-1.

Right. And Wilson's disease, looking at your Phase I trial design, what would they look like? What are some of the endpoints you would measure? And maybe I'll ask about the efficacy bar later, but...

Yes. So it will be a dose escalation study. We haven't said how many patients, but usually companies will typically do 2 to 3 patients per cohort. 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 a significant number of dose cohorts to get to the optimal biologic dose, but we'll have to see what happens when you get into humans. The things that we're going to measure that I think are going to be really important in the study. So one is a radiolabeled copper PET study. So what we'll do and we have -- if people want to pull up our presentation, you can see the radiolabel copper PET study that we did in mice. And what you can show at least preclinically is what it looks like in a wild-type mouse, mutated mouse and then a mutated mouse that has our treatment. And what you could see is a complete normalization of copper metabolism in a Prime Edited mouse that has the mutation for Wilson disease. So we're going to do that same study in humans. We are going to do a baseline study before they get treated, and then we're going to do a 6- to 8-week study as well. We're not going to mandate this in every patient, but we're going to be doing this at sites that can do it in the majority of patients. So 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 very improved, I'd say, copper metabolism. We'll look at other measures. We'll look at urinary copper that is significantly elevated in mutated in Wilson disease patients. Once we -- if we treat them effectively, that should be reduced down, hopefully closer to normal levels. In some of these patients, you can get liver biopsy, you can look at liver copper in addition to a percent of hepatocytes that have been edited. Again, we're not going to mandate that in every patient, but we should get that in some patients. And then we'll look at seroplasmin, 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. And I think ultimately, you also want to look at how do these patients do if you remove standard of care. So 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, then you can show you've effectively, at least genetically, hopefully cured or greatly improved these patients.

Great. And without obviously going too much into the 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 someone rectified in all patients, a portion of the patients? Like can you lay out like where do we get to? Is this like where the [indiscernible] is getting to an [ HAV ] or is it...

Look, it's a great question. I'll -- this is how I'll answer it. I'll say, again, preclinically, we -- at pre and, I'll say, reasonable levels of editing, we can get to normalization of copper metabolism. How that translate 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. If a patient has neurologic or psychiatric disease, so patients with Wilson disease will get both liver disease, they can also get neurologic 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. So I would hesitate to call that a cure. I could -- we could definitely halt that disease getting worse, but you won't necessarily cure a patient that has really deteriorated. I think the same goes for liver disease. We -- I think we've seen significant improvements even in patients that have grade 3, even grade 4 liver disease. But once there's enough fibrosis, once there's enough cirrhosis, we'll have to see 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 1/3 of the liver, that's going to regenerate, and you're going to have almost normal liver function, and you can help with the neurologic and psychiatric too, which leads us to believe that we 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 therapies that are ahead of you, or is there some uncertainty?

I think this is something where I hope we're trailblazers. I think it's all going to always be data dependent. The better the data is, the more flexibility there may be, and the more I think both sides are going to try and figure out how to expedite a therapy to patients. So we have some ideas in mind on how to get to, I would say, faster endpoints in a sort of registrational setting. If the data plays out how we believe it will, we don't think these will have to be large studies. We think this can be relatively small studies. But I think it's a little too early to comment on specific endpoints for registrational study.

All right. Great. And then 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 Wilsons?

Yes. So to break down the mutational background here, if you think about U.S. and Europe and predominantly the Caucasian population, the first mutation we're going after is called H1069Q mutation. That affects about -- we say somewhere between 30% to 50% of that population. So it's the most prevalent mutation in the Caucasian population. So call it, 40%. And then with a handful of other editors, we think we can get to somewhere around 60%. So we're probably not going to be treating -- we're not going to be treating 100% of these patients. We think we can treat 60%. Hopefully, it might make sense to even develop a few editors and do even more. And the importance there is all we really need to do is swap out the guides, right? Everything else stays the same, 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 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. We'll have plans to pursue this globally. And it's an unmet need on a global basis. So we'll continue to pursue multiple mutations.

Yes, 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?

Yes, I mean, look, 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. So 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? There's replacement therapy. It's questionable on how effective the replacement therapy is. So 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 going to go through all the different modalities. What I would say is the -- what -- 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? We are fixing it at its source. So 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. That's -- in my opinion, that's a huge benefit to Prime Editing over other technologies. No other technology can do that. The RNA editors work obviously, at the RNA level, and there's going to be limitations there versus, again, fixing this as a one-done therapy at the source. Base editing, there's bystander edits and other things that can happen. So again, I think this is sort of the perfect application for a Prime Editing approach.

Maybe in terms of clinical development, would you just follow the footsteps of base editing in terms of patient population, endpoints, duration, everything, et cetera, or is there anything that you would change?

Yes. I think the clinical path there is -- 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 that we can look at, just looking at AAT levels. You can see that impact very early, right? You probably see in a couple of weeks and have optimal effect at 4 weeks, 6 weeks. So you've -- 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 with a gene editing approach.

Great. And then maybe zooming out a little bit across your in vivo programs, safety and delivery are obviously central themes here, right? And we -- when we talk to investors, we sometimes get pushback across all CRISPR therapies or gene editing about the irreversibility of it and maybe off targets and what -- why that will be holding back the field. Just can you talk about what gives you confidence to your LNP approach and the therapeutic index you've achieved to date?

Yes. So 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. So as we think about LNP specifically, we have an LNP. This will be the first time that's going into the clinic. We have benchmarked this LNP against multiple other LNPs that have gone into the clinic and others that we know others are bringing into the clinic. And 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 preclinically, we seem to have a much wider therapeutic index. So that gives us 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 well above that, if needed in the clinic. So -- and that will play out as we get to that data set. And 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. And so -- or on-target impact as we think about indel and other things. So 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. And yes, I look forward to seeing your programs in the clinic.

Great. Thanks.

All right. I think we'll go ahead and get started. Thank you for joining us on day 3 of TD Cowen 46th Annual Healthcare Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen, and it is my pleasure to have with me today the team from Prime Medicine. And up here with me, we have the CEO, Allan Reine.

And maybe just to kick things off before we go into the individual programs, if you want to provide just a brief kind of state of the company overview, recent progress and maybe what should investors be looking at for the rest of 2026?

Yes, sure. And first off, Joe, thanks for having us at your conference this year. So sort of state of the company, this is a really important year for Prime. I couldn't be sort of more excited to be in the seat that I'm in today, kind of watching, one, all the progress that has been made last year as we really get ready to put our first 2 in vivo liver-directed programs into the clinic, and that's going to be Wilson disease and alpha-1 antitrypsin deficiency. And we have both regulatory IND/CTAs going in. We said for Wilson disease, the first half of this year. And for alpha-1 antitrypsin deficiency, we said middle of this year. So both of those are coming soon.

So ultimately getting those into patients and generating some clinical data. We continue to make progress across the company. So our cystic fibrosis program, which is being predominantly funded by the Cystic Fibrosis Foundation, making good progress there. Hoping to get to some preclinical proof-of-concept data this year and then with our collaborators at BMS moving forward with our ex vivo CAR-T therapies.

I think beyond that, we announced yesterday that we are going to -- we are planning to file a BLA for our chronic granulomatous disease program. We've treated 2 patients to date and believe we've seen data that's been published in the New England Journal of Medicine back in December that really, I think, transformed the lives of these 2 patients, and we think this could be a very important therapy for that disease.

Perfect. And maybe we'll start there because obviously, after the first 2 patient data, you suggested that you wouldn't really take this one forward on your own. So I guess, what would the FDA recently and any sort of communications or guidance from them kind of led to this decision? And then is this something that, I guess, that you would launch? Or would you still look for a partner to kind of commercialize it?

Yes. So a couple of things I'll say there. So we announced the decision to discontinue the program back in May of last year. At that time, as we thought about taking that program through commercialization, what's the cost of getting there? And then what's the commercial opportunity? So if you think about CGD, there's maybe 1,000 to 2,000 patients in the U.S., let's just take the low end of that, say 1,000 patients.

About 25% have the mutation that we're targeting with this product, so call it 250 patients. But the majority of them have actually had allogeneic transplant. So that might leave 50 plus or minus patients left to treat. So it's hard to make a great commercial argument to bring that forward, especially given what the cost is to get a therapy like that to approval. It could cost you $50 million to $100 million as you think about the CMC requirements, clinical requirements, the people that are needed to do that. So we made that decision, unfortunately.

And it was unfortunate because we have really strong data. It's really exciting data, and we would love to get this to these patients that -- where there is a really strong unmet need. These are either patients that can't get an allo transplant, so they really have no other option. And if they can get an allo transplant and they're a younger patient, this is a therapy that is a much better option than an allogeneic transplant where you don't have graft versus host and other issues that come with that type of procedure.

So I think what changed is we were listening to all of the FDA rhetoric over the summer. They talk about plausible mechanism. They talk about faster path to approval where there's unmet needs or high unmet needs. They talk about these ultra kind of rare indications and offering more flexibility. So as we kind of listen to that, it was like, all right, well, maybe it would cost us a very small fraction of what we thought before to actually get this through to licensure.

We've got great data. We believe that should be supportive of taking something like this forward. And yes, so we don't talk about maybe specific conversations or FDA dialogue. But what I can say is on the sort of clinical side, as we think about 2 patients worth of data, they're supportive of us taking that forward. There's still some other things. There's manufacturing, other things that we still want to get final alignment on. But in every scenario, we feel like there is a path forward here that makes sense from a spend standpoint where it's somewhat minimal spend. And ultimately, we can get this important drug to patients.

And maybe if you could just let us know what's next? I guess, have you requested a pre-BLA meeting, kind of what's the next we'll hear maybe on the next steps for CGD?

Yes. I mean we've already had conversations. So there's always formal informal conversations that obviously go on. We haven't kind of commented what the next communication will be. We'll kind of update people as we go. But I think I just want to make clear, we are going to file this BLA. I think we're still figuring out timing. So whether that's something that happens this year or sometime in the first half of next year will depend on a couple of things. But this is -- it's going to happen. It's just a question of when.

And maybe just based on the data, we don't have to go into the individual details of the data. But I guess, what did you see overall in reference to kind of how that could reflect on the broader Prime platform?

Yes. I mean, look, when you think about Prime Editing, I come at it from -- there's 2 ways to come at it. So one, can I get high levels of editing efficiency in the cell type that I'm trying to target, so this is can I get to high levels of editing efficiency in HSCs and hepatocytes and all these different cell types that we've looked at going after certain tissues. And so what we've shown in HSCs is we can get very, very high levels of editing efficiency.

And that high level of editing efficiency is translating into clinical studies into humans. It then also becomes about delivery, right? And this is always going to be a delivery question when you're talking about gene editing. We always say we've got the best cargo, but you also need the best delivery vehicle to get that cargo to the tissue type. So for our ex vivo HSC program, we actually use electroporation to get the editing machinery into the cell.

For our liver-directed programs, we'll be using LNPs -- lipid nanoparticles that target the liver. So to me, it's -- we've sort of derisked, can we edit at very high efficiency in human cells. We've answered that question. We've got great preclinical data now when we go to in vivo, and we've got to show that translation as well ultimately.

Great. Maybe we'll jump over to 2 of the other programs, but maybe we'll hit on Wilson's first. Maybe just what is sort of the unmet need in Wilson's? Why would a prime editor candidate be specifically applicable here?

Yes. So I think what's underappreciated for Wilson disease is really how high that unmet need is. I think there are some other companies that are working in this area that have done a little bit of work for us and kind of shown people how high that unmet need is. There's actually a recent patient-centered FDA meeting where you can actually get the transcript. And these are patient testimonials so you can get an understanding of the need for a therapy like this, how it could really transform these patients' lives.

So if you think about Wilson's disease, this is a disease of impaired copper metabolism. So copper builds up in the liver, ultimately spills out into the bloodstream. You get copper accumulation in the eyes, in the brain. The main symptomatology tends to be around neuropsychiatric disease and predominantly liver disease. And it's the liver disease that can ultimately lead to liver failure, and it's one of the most common reasons for a liver transplant. There are copper chelators and zinc salts that patients can take as standards of care. These are difficult medications to take.

They have to take them either some are fasted, some are with food, you have to take them multiple times a day. They have very short half-lives. And so it's a high burden to the patient even on those medications, even if you're well controlled, you are still not metabolizing liver -- copper normally in your liver. So you can still progress even on those standards of care. You can still have a shortened life expectancy. You also have to be on a very low copper diet, another kind of difficult thing for these patients to kind of go through.

So compliance on these medications tends to be very low. It's about maybe I think 1/3 or more of patients tend to be noncompliant with their medication. So again, this is a high unmet need, and this is something where we can really transform the lives of these patients. And I think the idea here is, obviously, we're going to treat any age to start, but how do we get to these patients early? How do we get to them so they never develop any symptoms or any consequences from this disease.

Can you kind of walk us through what remains to be done before submitting the initial IND or CTA? And any specific considerations, I guess, related to an in vivo prime editor versus either other in vivo gene editor approach or ex vivo?

No, I don't think there's other considerations when you're thinking about a prime editor versus a base editor versus CRISPR. We at least have shown preclinically, we have less off-target than some of these technologies. So there might be additional things that we maybe don't have to show in a sense. But I think in general, it's we're not kind of giving the play by play, I guess, on all the IND and regulatory preparedness. But I would say we're well on track to -- we're well on track with our guidance of IND/CTA for Wilson in the first half.

And what would an initial trial look like? You've guided to data in 2027. What would that, I guess, data package kind of include from a number of patients address perspective?

Yes. So if you think about what dose escalation looks like here, typically, companies have done, I'll say what they've done in the past, like 2 to 3 patients per cohort. The number of cohorts is going to depend on a couple of things. So one, what's your starting dose and how high is your starting dose to your optimal biologic dose. So you hope to start at a minimum at a biologically active dose.

So assuming we can start at a biologically active dose, there'll be some number of cohorts of that optimal biologic dose. Once you get there, you'll likely expand that out and treat more patients at that dose or sometimes you'll select a couple of different dose levels. In this initial study, we're going to look at a number of different biomarkers. But one that I think is going to be really important and give us a really early read of preclinical -- or sorry, clinical proof-of-concept is looking at a radio labeled copper PET study.

So what we do here is we're going to do this study in patients before they get the treatment, and you'll be able to see the amount of copper that's being -- that's kind of loaded into the liver. So they have impaired or now are they going to have normal copper metabolism. We have some really, I would say, striking images you can look in our investor deck on our website where you can see a liver that has the mutation that you're going to load with radiolabel copper, that is just bright yellow, right? That liver -- that copper is staying there. It's not being metabolized.

If you kind of look at a similar animal mouse that's had our treatment that's gotten our prime editor, they're back to completely normal copper metabolism. It looks just like wild type. You can see those images in the deck. And so we'll be able to get -- if we can recapitulate that in our clinical study, we can get a pretty early read looking at proof-of-concept.

In addition to that, we'll look at other measures. We'll look at urinary copper, which is really elevated in patients that have Wilson disease because they're not excreting copper through the normal route through the fecal route. So you can really see urinary copper come down if our therapy is effective. You could look at different enzymes as well. Ultimately, you can take patients off standard of care and be able to show that they have sort of normal copper.

And do you think in these patients, obviously, it's going to be a liver-directed therapy, but you indicated some of the CNS neuropsych kind of complications of the disease. I guess is that an expectation that you'll be able to see benefit on some of those along with the reduction in copper? How do we think about that?

Yes. I mean the answer is yes. So you'd expect to see improvements in both. I think there are some neuropsychiatric deficits that are unrecoverable. And I think that's just the reality of the disease. That's why you want to get in and treat these patients earlier. So they never get these neuropsychiatric issues. And one of the downsides of standard of care is you can actually get an increase in neuropsychiatric symptomatology at the start of treatment.

So this is obviously something that we think you can avoid. There's also some data. You can look at liver transplant data that can show some improvement in neuropsychiatric disease. So fixing the liver disease can fix the brain disease, so to speak. But I think when you -- as I think about it, like once you have sort of neurons that are essentially dead, those can't -- aren't necessarily going to come back, but I think you can improve or at least halt the brain disease.

And how clear is the registration path for Wilson's or the approvable endpoints? Is this a situation where an accelerated approval based on some of the biomarkers that you're looking at, obviously, not next year, but would be an avenue to pursue? Or do you think you're going to need kind of a more traditional pivotal study looking at some of these endpoints?

Yes. I mean I think for Wilson disease, there haven't been drugs really approved in a very long time, I think, in a decade or more in the disease. And those have been sort of copper chelators, very different mechanisms. I think there -- it's going to really depend on the strength of the data, right? The stronger your data, the more consistent the data is amongst the patients that you're treating. I think the more amenable a regulatory body might be towards an accelerated approval and endpoints that can be maybe novel or where you're trailblazing kind of what you're doing. Think about copper PET as an example.

We'll see what that looks like when we ultimately get to the clinic. But if you see incredibly strong data across a number of patients with copper PET, could that be something you could use as an endpoint. I think ultimately, I think about this as removing standard of care because that's going to be your goal here. You want to get these patients off standard of care and show that they have normal copper metabolism on standard of care. And whether you're showing that at 3 months, 6 months, 12 months will probably be the negotiation with the FDA. But I think that could serve as the basis for an approval.

And can you talk a little bit about the proportion of patients with Wilson's that you can address using this specific therapy? And if you do see success here, are there other mutations that you can address? Or kind of how do we think about that?

Yes. So we kind of break it down based on different populations. So if we think about the U.S., Europe, Canada, Australia and New Zealand, we think about the Caucasian population, the first editor we're going after targets a mutation called H1069Q. That's about 30% to 50% of that population. We'll go after additional editors that target different mutations. So we think about it as maybe a handful of editors will get us to 60% of the population.

We'll have to then decide, does it make sense to make investments to go after some of the smaller segments, and that will really be sort of a commercial question that we'll have to ask at that time. But I've sort of guided people to about 60% of the population. When we go into different regions, so if we think about Asia, we think about Japan, it's actually a bit of a higher prevalence there and the mutational backdrop is a little bit different. So there, the first mutation we're going after is the most prevalent. It's called R778L. That's about, again, 40-plus percent of patients, and we think a handful of editors there can maybe get us to even 70% of patients.

And maybe we'll jump over to AATD, the next program. The space has heated up a little bit in AATD over the past several years. I guess, where do you see your therapy kind of fitting in? Obviously, there's the liver and lung manifestations. What's the ideal here?

Yes. I mean there's still nothing really new that's been approved yet, right? So there's a lot of development and drug development in the space. The standard of care is still replacement therapy, which I think is still questionable in terms of what is the benefit of that therapy. And there's some different reasons we can talk about. I'm sure it does something, but how much is it doing to really protect these patients.

And so there's a lot of different approaches. There's the RNA editing approach. There's the gene editing approach. There are base editors, there are prime editors. When I look at this disease, I believe patients, physicians are going to want to take these patients back to wild-type protein back to normal protein. The best technology to do that is Prime Editing, right? It's taking a normal mutated gene and taking it back to just wild-type normal -- normal gene normal protein. So given that this is the best technology to do that, I really believe a Prime Editing approach has the ability to be a best-in-class here.

There are 3 companies that I know of that are including us that have Prime Editing approaches. We're one of those companies. There's another company that just got into the clinic and another that's going into the clinic middle of this year. Again, we believe we've got a very strong patent estate. We believe we've got great foundational IP, and these companies are all going to be infringing that IP, and we can deal with that at a later date. But we think we're going to own the space one way or another.

Maybe on that latter point, just to kind of address it. Obviously, Beam is approaching this as well, and there's a little bit of a litigation going on. I guess, what are the differential components between your therapy and theirs? And what are sort of the next steps in that dispute?

Yes. So the dispute there -- and it's not a litigation, it's an arbitration. And the dispute there is we are doing Prime Editing and Beam has rights to do Prime Editing for transition-only edits. That's something that's sort of written in the contract that's public and how it says it. And so we believe our approach is sort of well within our rights. They're contesting that, and we expect to have a resolution of the arbitration in the first half of this year.

Perfect. And then when we think about initial clinical data for this program as well, you have also guided to having some initial results in 2027. What are sort of the outcomes here that you are guiding towards?

Yes. I mean I think for this program, it's a little bit different than Wilson, where here, you've got a very clear biomarker that you can look at. So you're looking at AAT -- levels of AAT in the blood and you can look at levels of mutated protein versus normal protein in the blood. So these are measurements you can take. You can take them frequently. They're easy to get. So you can see what it looks like at 1 week, 2 weeks, 4 weeks, where you should have a maximum starting to get to that sort of maximal effect. You'll know very early what this looks like. You hope to get patients as close to or into the normal range as you can.

And can you talk a little bit about safety for both of these programs? What sort of preconditioning do you think these patients will need, if any? And what are things that you're going to be looking for just given some developments across the genetic medicine space?

Yes. I mean there's -- you can for some of these -- it's a onetime therapy, but you can give -- there are some medications you give to tamp down inflammation, et cetera, which I don't know the final protocol yet, but there are things that you can do. That being said, we've got a very strong preclinical profile. We believe that we may have a wider therapeutic index as we think about our LNP formulation and our ionizable lipid.

We've benchmarked to many other lipids that have been in the clinic and even lipids that we think others are using that haven't been in the clinic. And we see that, again, this could have a wider safety margin. We'll have to prove that out and time will tell. But we've seen a lot of companies sort of cap at mg per kg or around that range. And I'm not saying we need to go above that, and we definitely develop drug candidates where we can dose below that, but it's always nice to have that flexibility if you do want to go higher.

And maybe next, the company has indicated that it's going to start work on -- or has started work on an in vivo therapy for cystic fibrosis. I guess, why is cystic fibrosis an attractive target, maybe particularly for Prime Editing?

So I'll start with the unmet need. There are 10% to 15% of patients that have cystic fibrosis that, for whatever reason, can't take standard of care, they can't take TRIKAFTA, either they have mutations that can't respond to that therapy or for whatever reason, they can't tolerate the therapy. So even though that is a drug that has transformed the lives of a good chunk of this patient population, there is still a high unmet need here.

And the cystic fibrosis donation is very focused on how do we cure these patients, right? What's happened for these other patients is incredible, but how do we really get to something that can cure or really improve the lives of those patients. And I think if you -- if you think about what we're trying to do, we're trying to get to the right cell types, and we're trying to convert that mutated protein back to normal. And so think about how powerful that is. And not only are we turning that back to normal, we're doing it under what we call endogenous control.

So the body is going to make the right amount of CFTR -- you don't want the body to make too much and you don't want the body to make too little. And this isn't a very abundant protein. So getting this under endogenous control, we think, is very important. And we think this is really the only treatment that can do that. So there's been a lot of approaches that use mRNA and other things that are trying to -- genetic or gene therapy that are trying to get expression of CFTR in the relevant cell types. But then the question is how much expression do you want?

And I think that's sort of almost an unknown, like people are still unclear what the right amount of expression is. Are they getting too much? Because you can see through some of these studies like they're getting expression, but we're not seeing functional improvements. Well, we don't have to ask that question because the body is already doing that for you. So we're just turning that gene back to normal, let the body decide how much CFTR should be expressed.

And what's the status of the program? Kind of when we'll see next preclinical or early clinical data?

Yes. So we're making good progress there. We're in, I would say, lead optimization now. We're getting high levels of, I would say, editing, and now it's really putting that together with delivery, getting the right delivery vehicle and again, proving that we're getting to the right cell type in the right models. I think once we get there, then it's like how do we move this as quickly as we can to a DC and IND-enabling studies.

And you've had the deal with BMS now a couple of years. Maybe why were they the right partner? And if you can go into the decision really to partner up the Prime Edited ex vivo CAR-T product platform?

Yes. I mean I think that's a platform that we weren't necessarily working on towards developing a clinical candidate ourselves. The goal at that time at least was never to build an oncology, immunology infrastructure. But we believe, again, we've got the best cargo if you're going to edit CAR-T cells. BMS through their acquisitions is one of -- Celgene ultimately is one of the leaders within that field.

And so they are an obvious partner for this. They're still investing heavily in this, obviously, and I think it's a very important modalities as they move forward. And again, we've got the best cargo. So it's putting, I think, the best cargo with one of the top companies out there. And we're making good progress. There's -- when you partner with a large pharma, there's not a lot that you can say when you give away the program like that. But I would say we're making good progress. They're great partners, and we're very happy with the status of the program.

And maybe can you talk about any milestones coming your way in relation to that or at least kind of maybe what they're tied to, whether it's candidate identification, entry into the clinic? Anything that would be helpful.

Yes. So what I could say is there are pretty significant preclinical milestones. We said as part of the collaboration, there's up to $185 million in preclinical milestones. We haven't broken it down more than that, but you can think about what preclinical means. And you would think about that as call it, before you get into IND-enabling studies. So there are milestones that we think are very achievable. And hopefully, as we get through to the first, if you think about the ones that are subsequent to that, once we've delivered a lot of the reagents that could go a lot quicker as well potentially.

And how do you think about partnerships in general? Obviously, the company has a lot of different areas where Prime Editing could be effective and over the years has kind of streamlined the initial pipeline. But how do you see what you want to keep internally versus working with a partner? Obviously, the ex vivo CAR-T was clear. I guess, but what do you see outside of that?

Yes. I think I'd break it down into different buckets. So I think one bucket is there are certain things that we're just not going to do ourselves. We know we're probably not going to do ourselves, at least with our current build. And so I think about cell therapy. And there's a lot that can be done in cell therapy. I think Prime Editing could be one of the best technologies that you take to different types of cell therapy. So this is something that I'd love to see in someone else's hands.

I think another area would be in neuro. I think there's probably the greatest opportunities as I think about a genetic disease standpoint within neurological disease. I think there's still some delivery challenges and other things. So I don't think it's necessarily the best use of our capital today. I hope -- but I hope it's an area we're in 3 to 5 years from now. And I hope there are companies that are going to be willing to kind of work within that space and take this technology forward.

And then I think beyond that, if I look at our current assets, I think nothing is sacred, right? We're always open to partnering. I think it's going to depend on what makes the most sense for Prime. We're going to do the similar analysis and determine if based on terms, if it's better to keep something or it's better to work with a partner. We think we've got an incredible technology, and it's what's the right way to sort of shepherd that forward. And I think it's going to continue to be a healthy mix of BD and other means as we think about financing this company going forward.

I think lastly, I'll just say there's so much opportunity. I mean what's great at being at a platform company like Prime is there are so many different places we can go. When I joined the company, as you know, we had like 18-plus programs because we were trying to figure out where to go. We've shrunk that down, and I think we're focusing on the right things today, and we're focusing on places we really believe can generate a ton of value for the company. But as we think out a year or 2 years, there's going to be a lot more to do, right? It's -- I don't want to say it's endless, but there are so many opportunities. So there's always going to be things for us to develop, and that's why nothing is sacred today.

And maybe can you talk a little bit about your current cash runway? What does that get you through for some of these catalysts? And obviously, time and money is maybe particularly a focus in genetic medicines. Is there sort of an inherent pay to play to be in the genetic medicine space? Or how do you think about how much you have the actual ability to kind of cut when you can?

I'd hate to be a gene editing company starting out today from scratch. I think the reality is it's been capital intensive to get where we are today. But now that we are where we are today, we have built so much institutional knowledge. We've built so much value in terms of what we can do within this platform and pipeline today. That's very hard to replicate. So there's sort of this barrier to entry now that I think we and others might have.

When we think about our current runway, we've got cash, we've said into 2027. It's not Jan 1, '27, but we've got cash into '27. We haven't said exactly when. As you know, our 2 big data events are going to be in '27. So we're funded through obviously getting our INDs into the clinic, obviously, getting through the arbitration that you mentioned, pushing forward with CF. And when we talk about a runway, that doesn't include other things that could help fund the company.

So it doesn't include BD. It does not include BMS milestones, does not contemplate the CGD approval, et cetera. So there's other things that can help really fund the company as we think about going forward. And the -- we're at a burn rate now where the amount of money we actually need to get through '27 is not significant. So there really isn't a big funding overhang as we think about the company today, which is nice.

Awesome. Well, thank you very much for the great discussion.

Thank you.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. Our next presenting company is Prime Medicine, and presenting on behalf of the company, we have CEO, Allan Reine. Allan, over to you.

Thank you, and thank you for having us at the conference today. Today, I'll be making some forward-looking statements. So please see our documents on file with the SEC.

So I'm very excited to be here today to talk about Prime Medicine, our technology Prime Editing I believe, has the potential to impact millions of patients' lives as we think about going into the future. This is based on a couple of things. One, I believe gene editing, which is really an early technology as we think about it, is going to be a very important tool as we look to human disease even today, but as we look out into the years to come. And Prime Editing really is the most versatile way to manipulate the genome. So this technology can do everything that any other gene editing technology can do, but also many other additional types of edits. That's because we can really write into the genome, any sequence that we'd choose. So with that, we can do large incisions. We can do large insertions. We can do what we call hotspot editing, missense mutations, transversion mutations. So it's really an endless possibility of the types of diseases that we can ultimately treat with this technology.

It's not only the most versatile way to edit the genome, but it's also the safest way to edit the genome. So we don't cause a lot of the consequences that you get with earlier gene editing approaches. We think there's a lot of important changes that are happening on the regulatory framework that we see today. So we think there'll be the ability to really move these therapies, both faster and cheaper as we go into the clinic and ultimately to commercialization. We've got an extremely strong IP position around this technology that we've won exclusively in-licensed from the broad and that we've expanded on internally as a company.

And we've already shown some clinical data that we put out last year that I'll share again with you today to show this really has curative potential in patients. So today, we're really strategically delivering on the promise of this. So how are we doing that?

We're very focused today on our in vivo programs. So we have our liver franchise, and we're really executing on both Wilson disease and alpha-1 antitrypsin deficiency. And we have INDs for both programs coming this year. We have initial efforts underway. How do we expand beyond just these programs within our liver franchise, I think there's a lot of exciting, very large indications, even nonorphan indications, where Prime Editing offers a very differentiated approach that we can think about, and we hope to share more about that as we get throughout the year.

BD is going to be a very important component on how we think about this therapy. So as we think about delivering on the promise here, how do we get this into more patients. We're not going to be able to do all of this alone, so doing more business development deals is going to help to expand the reach of this very important technology.

Now this is going to be an important year for the company as we think about 2026 and 2027. So the name of the game right now is focus. Let's get our programs into the clinic, and let's get towards proof-of-concept clinical data. So for Wilson disease, we're planning for an IND or CTA in the first half of this year, and clinical data for that program, proof-of-concept clinical data for that program in 2027. For our second liver franchise program alpha-1 antitrypsin disease, we're planning for an IND and/or CTA in the middle of this year, again, with proof-of-concept clinical data coming in 2027.

Our third program is in cystic fibrosis. That program, we continue to make good progress. There's a tremendous unmet need in patients that either can't tolerate or are not amenable to current standards of care that will be the initial low-hanging fruit that we plan to go after here. Ultimately, we believe we can treat the majority of that population, and we hope to share some additional in vivo proof-of-concept data for that program in 2026.

As you look at our pipeline today, what you see is a pipeline really focused on high-value programs. So what defines a high-value program for Prime Medicine? A high-value program is a program where we think there's a high probability of success, high probability of technical success. There's a near-term clinical endpoint that can show a proof of concept in that disease, and there's a large addressable market. Large, I'll put in quotations, but it's relatively large as we think about orphan diseases, and I'll go into the patient populations here and explain why these are multibillion-dollar opportunities.

So that's where our focus is today, but again, the plan is to expand that as we build this company and think about other areas where we can get a lot of synergy into what we want to do next.

We're continuing to make good progress as well with our BMS collaboration. There, we collaborated -- we signed a collaboration deal in the -- at the end of the third quarter in 2024. That's based on ex vivo CAR-T therapies for both oncology, hematology and immunology. There's some pretty significant, also preclinical milestones that come as part of that transaction, and there was $110 million upfront when we signed that deal. So that's sort of one deal that we're doing, but there's going to be -- we hope to be more as well. And again, the idea is how do we expand the reach of this really important technology.

Here's the clinical data that I alluded to earlier. So this is in a disease called chronic granulomatous disease. And we've shared this data. It's in the New England Journal of Medicine now, which was published late last year, and essentially is showing you that we functionally cured 2 patients. This is an ex vivo therapy. So we're manipulating hematopoietic stem cells and then giving those sort of back to the patient, they're engrafting, it is very quick engraftment, and you're seeing a very impressive set of data here. And we are in discussions, and we're trying to figure out a way to bring this to patients and potentially more to come there.

As we think about the off target, what I alluded to before in terms of what differentiates this technology even beyond the versatility and what we can do with it is the safety. So this is some of the data that we had generated as part of our CGD program, and you can see here, we have no detectable double-strand breaks. We have no detectable off-target edits, no detectable bystander edits as you shouldn't expect that with Prime Editing. We don't see detectable deletions, chromosomal rearrangements. And oftentimes, we actually use CRISPR-Cas as a positive control here. And we've recapitulated this data for a number of -- for really a number of all of our lead programs as well.

So this is, again, I'll emphasize, the safest way we believe to edit the genome. Now we're building this platform to really optimize modularity. So how can we quickly go from program to program, how can we quickly go from mutation to mutation even within the same disease. And I want to hone in here on a couple of things. So one is the regulatory frameworks. So how has that changed over the last 6 months to a year. Well, it's the ability, and I think we've heard the FDA or other companies state this, the ability to do multiple mutations with the same disease under one IND, and I think we have received some feedback that we believe will allow that to go forward.

I even think the European regulators are also starting to pay more attention here, and we hope we see some progress there where there's an allowance there as well. We recently received some feedback that we're going to be able to leverage some of our IND-enabling studies for Wilson disease for alpha-1 antitrypsin program. And why is that? So as you think about drug product and we look at our liver-directed programs, we're using the same lipid nano particle. So the only things that are really changing here are slight changes to the sort of cargo, as we think about these 3 squiggly lines you see in the middle, right? The majority of that drug product stays the same. And that is really what likely is going to dictate safety and other things. So the ability to kind of leverage from one program to the next, again, is a tremendous amount of savings and time as we think about going from mutation to mutation within the disease, going from disease to disease within the same tissue, and again, this is an incredible amount of synergy, and we're really excited to be able to leverage there.

And I do want to talk a little bit about our intellectual property that we have around this technology. So just to make it clear, any combination or permutation of a CRISPR Cas enzyme, a template guide RNA with the reverse transcriptase is Prime Editing full stop. You can call it something else. You can put a fancy name to it, that's still Prime Editing. And I can assure you, we're going to very vigorously defend and enforce our intellectual property at the right time.

So turning to our liver franchise. So I mentioned before, these are large opportunities for orphan indications. They're 2 of the largest genetic diseases. For Wilson disease, we believe there's about 10,000 patients in each of the U.S. in the EU. Japan actually potentially is a higher prevalence rate, so there could be 7,500 patients plus. So as we think about this disease globally, there's a significant number of patients and a significant commercial opportunity. We're not going to go after 100% of these patients because we can't go after every mutation. So as we think about the U.S. European market, we think with a handful of editors, we can probably get to about or in the U.S., Europe and Japan, we can probably get to about 25,000 or so patients just with 6 editors or the 6 most common mutations.

There's also potentially an incidence rate here of 300 patients per year. So it's not just kind of treat that area under the curve, but the question is, how do you actually build a long-term business here as you think about some of these indications? So -- and then for alpha-1 antitrypsin disease, that's a population of about 10,000 to 15,000 patients as you think about the U.S. and Europe, so call it, 20,000 to 30,000 patients within those geographies. That tends to be more of a sort of Caucasian disease. So there's not as much of a global opportunity, but again, 99% of those patients are going to have the same mutation, so you can essentially go after all of those patients with one drug product with one editor.

So to talk a little bit about our data in Wilson disease. So this is showing on the left panel here. Our two lead mutations that we're going after. So the first one we plan to bring to the clinic in the first half of this year is the H1069 editor. You can see we're getting very high levels of editing efficiency here. We're getting similar high levels of editing efficiency with our second mutation, we're planning to progress, which is the most prominent mutation in the Asian population. And there again, we're getting well above 80% editing efficiency.

You could see here, as I mentioned before, we don't see any off-target editing in any of our programs. And you could see that here on the right, where we're really only editing that dot you see above the gene that we're trying to edit. We're not seeing anything from an off-target standpoint.

From a preclinical phenotypic side, so what happens when we actually make this edit with high efficiency? Well, on -- as you look at the middle panel here, the left is wild type. The middle shows what an untreated mouse looks like that has the 1069 mutation. And on the right, that is a mouse with that 1069 mutation that has then been treated with our editor.

So on the left and on the right, you could see we've essentially normalized hepatic copper concentration. So we are mobilizing that copper out of the liver, which is what repairing that enzyme or correcting that enzyme should do.

Copper is typically excreted through the fecal route. In patients that have these mutations get copper build-up in the liver. It ultimately goes into the blood, and you get very high urinary excretion and very low fecal excretion. We're essentially showing here that you can normalize that fecal excretion. We also have data that shows that urinary excretion also goes down, so that's being normalized as well. So it's almost a full phenotypic rescue, but as I say, sort of a picture, you could see it in a picture. And here, you can see on the left is sort of that wild-type mouse, and this is what's called a copper challenge, so radiolabeled copper challenge. So you're giving these mice radiolabeled copper. In the middle, you can see that liver, that yellow that's just lighting up. All that copper is accumulating in the liver because they don't have this enzyme to be able to excrete it normally.

And on the right is that treated mouse, which looks identical almost to wild type so you're getting almost full restoration of hepatic copper. So we are also going to be doing radiolabeled copper PET in the clinic. So this will be an important clinical endpoint in addition to a lot of other kind of biomarkers that you can look at for Wilson's disease to allow us to get to sort of proof-of-concept data again in 2027.

As we think about our clinical plan here, as I stated, we're going to start with 1069Q as sort of the first mutation. That's about 30% to 50% of the population in the U.S. and Europe. The second will be 778L, which is the most predominant Asian mutation. And then we have a handful of other editors to sort of get to those percentages of the population that I mentioned before. And this is a disease that standard of care really hasn't changed in decades. The KOLs that we've talked to, and we did a big KOL event internally at ASLD, there's a lot of excitement to get to a drug that can impact the patients' lives. They have to be on low copper diets. They've got to take lifelong therapy with iron calators and zinc salts that these docs would love to get these patients off of. So this is a very exciting therapy, and we look forward to bringing that into the clinic.

For alpha-1 antitrypsin deficiency, the goal here is to really normalize alpha-1 levels in humans. You could see here patients that have the -- that are homozygous for what we call the Z mutation, have very, very low levels of this enzyme at baseline. So the goal is how do we get these patients back to normal?

What we show here is very high levels of editing efficiency. In the middle, you see here, it shows the amount of corrected protein in the blood versus mutated protein. And you could see at the higher dose level, we're almost completely normalizing the levels of M protein in the blood and essentially taking in these mouse models all the way back to the normal range. So beyond alpha-1 and Wilson, I just want to talk a little bit about what our plan is in terms of business development, again. So I think there's a number of areas that we're looking at. So one is what can we do sort of within our core, some of the programs that we have today. And I think there's a lot of excitement as we think about our current pipeline. There are going to be things that we want to do outside of our core, and there's a lot of interesting areas to take this technology. One example is what we've done with BMS, but I think there's a lot of other ways we can capitalize on what we're doing beyond just this ex vivo CAR-T with BMS, and there's a lot of interesting things we're thinking about there.

Two examples I've listed is neuro disease and other areas within cell therapy. And there's also delivery technology. So how do we ensure as the field progresses that we're taking advantage of delivery? So as delivery to the brain advances and delivery to other tissue types, we think we've got the best cargo. So as technologies advance, we'll let other companies trailblaze there, but we wanted to ensure that we're taking full advantage of that derisking that others are doing. And hopefully, some of this we can also do with partners today.

So in closing, look, this is a big year for the company, as I've said, getting our first 2 in vivo programs into the clinic is going to be an important milestone for us and really drive towards proof-of-concept data as we look into 2027.

As I mentioned before, as we think about business development and other areas to really broaden the reach of this technology, we're really laser-focused on that execution and excited for the year. And with that, I'll sit down for some questions.

Great. Thanks, Allan, for the presentation. So I thought I would start with a little bit of a bigger picture question here. I mean I think last year, from what I understand, you had a very extensive pipeline that you were moving forward, and you've sort of refined the focus in these 2 areas. What were the kind of key pushes and pulls of making those decisions that -- and thinking that was the best path forward for the company, and then we'll dive into some specific questions.

Yes. No, that's a really good question. So I joined the company in January of '24. I actually think I came to JPMorgan, but I was joined a week later and -- but did meetings with Prime. So I think it was announced, so I was allowed to do that. But the -- and when I joined, there were about 18 programs in the pipeline. So we knew we weren't going to be able to take all of those programs forward on our own, but one of the first things that I did with the company is, let's do a full strategic review. We called it a value framework exercise, and let's evaluate every program.

We took about 3 to 4 months. We involved a lot of people across the company and really focused on some of the things I mentioned in my presentation, like what's the commercial opportunity, what's the potential chances of how do you handicap success in the clinic? What is the time frame to clinical data, right? So there were some indications like some ocular indications that we were exploring. We had really good preclinical data, but could have been 4 to 5 years before we got to a proof of clinical concept data set.

We looked at technical feasibility. So do delivery technologies exist today that we have high confidence in that we can explore, and obviously, what's the patient population, what's the unmet need? There's additional parameters beyond that, but we did work essentially on all of those and kind of ultimately, kind of what rose to the top. And from -- for liver -- for our liver franchise, we know that these -- that editors, at least we've seen it done already with CRISPR, and we've seen it done now with base editing that you can deliver safely to hepatocytes. So there, we saw there's a high probability of technical success.

There are areas where we think Prime Editing can be differentiating. So for Wilson disease, they're predominantly what are called transversion edits. So other gene editing approaches won't work there. So that's somewhere where really only Prime Editing could do. So that sort of became obvious, and for alpha-1 antitrypsin deficiency, although it's somewhat of a more competitive market, I believe that Prime Editing is the best approach for that disease, taking that patient or that gene completely back to wild type, I think, is what will win out at the end of the day there.

So that was sort of how we kind of -- those are some ideas of how we did that exercise. Cystic fibrosis is another one. So there, we're working hard on sort of delivery to the lung. And the Cystic Fibrosis Foundation is funding -- predominantly funding that program. So -- and we are making good progress there, and obviously, BMS and other things that we're doing.

So that's sort of how the exercise went and kind of where we got our focus from. And I think it's allowed us to move quickly now into the clinic soon with 2 programs and really create a company that we think can be -- create significant value for patients and for shareholders over the next couple of years.

Okay. And Allan, from a regulatory standpoint, you talked about some of your kind of key themes or key takeaways that you see for the overall space in terms of how the agencies are thinking about gene editors. We did notice this IND and/or CTA for both of your programs. Can you just help us better understand what you mean by that and why it's an and/or?

Yes. I think about it more as an and than an or. We usually use the and/or because the and/or is sort of what's going to happen first. So we're not necessarily defining that. The plan -- these are both, I was thinking about Wilson disease, and alpha-1 antitrypsin deficiency. These are going to be global studies. So this is not just going to be an IND. There's always a thought of like what's going to go first, and we haven't commented sort of which is coming first.

I would say for this, there's no reason you wouldn't do an IND before a CTA. I think this is really going to depend on where the patients, where the sites that we want to start with, et cetera, and that might dictate kind of what gets opened up first.

Okay. And can you touch a little bit on, for those that might not be familiar, the IP estate you have across the portfolio, including the foundational IP for the platform, including a number of the Prime Editing technologies?

Yes. So again, we've got, I think, 6 U.S., 12 global patents that really cover both the foundational IP many different iterations of Prime Editing because they're sort of the initial Prime Editing. There's a lot of changes that have happened along the way. And so as I think about the IP, we've got an umbrella that covers, as I said before, anything it has to do with a Cas enzyme or reverse transcriptase and a guide, right? That is Prime Editing. And anyone that's doing anything just using those components is infringing on our IP. So we've got very broad coverage there. Obviously, as you dig a level deeper, there's a lot of other innovations within Prime Editing that we also cover that others couldn't do, but even if they're just doing those -- doing something with those components, that's going to infringe on our foundational IP and then other changes they might make might infringe on other things that we also have patented.

I think that's why we've been able to receive this IP on our foundational IP on our sort of foundational technology where others have sort of tried and been able to get sort of that foundational IP issued.

Companies can often get IP issued on specific products, right? That's going to happen. They might infringe a broader patent escape, but you can get product IP that will ultimately infringe on our IP. And so there are companies out there that don't have any foundational IP behind it, but do have product, may have product IP issued or filed that may or may not get granted. And they are, we believe, will be infringing, and we will vigorously defend our IP in the future, and in force.

And just in terms of the PM 577 program, it seems like it's a huge focus for you guys in getting this into the clinic here. What are the gating factors at this point?

Yes. I mean -- we haven't -- we're not commenting on sort of where we are. We just said the filing is going to happen in the first half of this year. So if we start to talk about gating items, and we tell you exactly the playbook and where we are, what I would say is for any IND, you need to get through all your IND-enabling studies, your GMP manufacturing, and you've got to write an IND, which is no small task, which is many, many thousands of pages, and ultimately submit. So what I'd say is we remain on track, and have made good progress, and expect a regulatory submission in the first half of this year. So sorry, I can't answer it directly. That's the best answer I can.

Yes, I had to try. I had to try. Okay, And with that in mind, when do you think if all goes according to plan, you'll be able to initiate your Phase I trial and -- or Phase I/II trial, rather? And what is your latest thinking around the design?

Yes. So for initiation, as soon as the regulatory -- your regulatory submission is "accepted" then it's just getting sites up and running, and that can take a month or 2 getting through IRBs, et cetera. So typically, you'll see with most companies, enrollment will start 2 months to maybe 3 months post getting the regulatory submission accepted. So that's how I think about the start date based on when we announced that, that regulatory submission has been accepted. In terms of trial design, it's -- as you said, it's -- this is a Phase I/II trial, Phase I/II trials by design, you're going to assess safety. So it will be a dose escalation trial that's looking at safety predominantly. But this is a -- these are gene editing programs, right?

Gene editing have tended to have really strong translation as you've gone from animal to human. And so we're looking at diseases where we believe there are good biomarkers that are going to allow us to see very early on if we're having the desired effect. So you can see very early in these studies, if you -- you could see -- you can get the clinical proof of concept, I believe, very early in the diseases that we're looking at.

So for Wilson disease, that dose escalation, as I mentioned before, we're going to be doing copper PET in some of these patients. So what you visualize with those mouse that we're kind of turning around that 360, we'll be able to show that in patients that we're getting that copper clearance. And we're not going to mandate in every patient, but potentially you'll be able to see the dose -- from a dose-dependent manner kind of what happens in people.

We'll be looking at other endpoints there as well. So you can look at fecal copper urinary copper. Some of the patients will get liver biopsies, you can look at hepatic copper, you look at something called seroplasmin levels as well, which are impacted, which don't change on standard of care. And ultimately, the goal is going to be to remove standard of care and show that these patients' copper balance stays normalized even with the removal of standard of care because that's the ultimate goal for these patients.

Okay. Okay. And Allan, it sounds like as part of your kind of strategic review that you did last year, you thought about kind of like, okay, how long can you get from -- how long does it take you to get from IND or CTA to being a commercial product. So can you give me a little bit of a framework for Wilson's disease or an archetype of how you think about that from a broad strokes basis?

Yes. Look, it all -- I can give you a broad stroke basis. I think it's all data dependent. I think what gene editing drugs can do is very different than what we've seen historically. So if it translates that you can get very high levels of editing efficiency, what does that mean? Well, that means I've taken a patient that has a mutation, and let's say, I can do 100% editing efficiency. I'm not saying what we do, but let's say there's 100% editing efficiency in the cell types you wanted to get to. Well, now 100% of those cells are producing normal protein, and they're under what we call endogenous control, so normal physiologic control.

You're turning on that enzyme when it needs to be turned on, and you're getting the right amount of that enzyme produced at the right time, right? That's really powerful. It's a powerful technology that we're looking at. So I think as we think about endpoints. If this translates into humans, and we can do in animals, what we can -- if we can translate that data in animals to humans, we can get high levels of editing efficiency, then those things should be normalized. And so as you think about the regulatory paradigm and what that could look like, I think that lends itself to potentially doing smaller studies and to potentially getting to endpoints, biomarker endpoints that can really kind of dictate how these patients will do over time.

So I can't give you sort of a time frame of what we can do to commercial because it is going to be data dependent, but if it translates how we believe it will translate, I think there'll be many opportunities to move fairly fast from a Phase I/II to registration to commercial.

And what is your view of the evolving development landscape in Wilsons, anything you have an eye on? Or do you think you're really taking forward a pretty premier ideal approach here?

So I think this is a -- I think this has the potential to be a best-in-class therapy, and I haven't seen any other approaches that I think that will really compete with the profile that I think we can achieve in patients. However, I want to be clear, we're not going to be able to treat 100% of Wilson patients. So if we can get to 60-ish plus percent in the U.S. that's 40% of the patient population that can get other therapies, call it in Asia, maybe there will be 40% in the U.S. and 30% in Asia that can get other therapies. So there'll be room for other therapies. I know there's a gene therapy that's being developed, not to get into sort of what I think the differences are, but I do think a gene-editing approach could be far superior here to what a gene therapy approach can do.

I think there's some other kind of novel chelators that are coming along, which won't have a dramatic change on the disease or the course of the disease. It may offer something that's a little bit more less dosing and other things, but won't be a dramatic change to the course of the disease. So I don't see a lot of anything out there that I think can really compete with what this drug could do if it gets commercialized.

Okay. Okay. Great. And then just for the sake of time, let's maybe move to PM647 for AATD. Why you think you have an ideal approach here for the treatment of AATD and what overall product profile do you think would be compelling for a onetime prime editor and turn what could that market penetration look like, given how competitive this space is?

Yes. I mean, so the different approaches out there, there are RNA editors that have reported some data and we'll get more data and higher doses over time, and we'll see how that changes. But at least what we've seen to date I don't know that those will be competitive. They are going to be chronically delivered drugs. So they're not one-and-done therapies, but we'll see how that data develops over time with -- I think there's about -- there's 3 programs, at least, that I know of or 3 companies that are working on that. There's been with a base editing program, and I think they've demonstrated some pretty promising data showing that they can get sort of those alpha 1 levels to what I would call sort of the heterozygote level or the carrier level, which tend to be fairly -- I think those patients tend to be normal and don't have disease.

So if they can sort of maintain that, that could be a drug there. There are some differences. The base editing approach, they do have a bystander edit in the majority of the edited protein. So there's always going to be a question if that changes any of the functionality of that protein. I think what we've seen it is functional protein, but there'll always be that question that kind of hangs out there. And as we look at the Prime Editing approaches, there are 2 other companies that are doing Prime Editing. So I think as I've said before, that we believe that's Prime Editing. And I do believe Prime Editing can be the superior approach here because, again, you're taking that mutated protein exactly back to wild type. There are no other changes. It is the normal protein.

And we hope we'll be able to get to levels that can be higher within the carrier range or even within the normal range. So I do believe the Prime Editing approach will be the winning approach over time here in this disease.

Okay. And with any novel technology, there are key risks. So like Allan, what keeps you up at night about what you're doing at Prime?

I sleep pretty well for the most part, but as I look across the company, I do think there's a responsibility here in terms of this really is an incredible technology, right? I believe that. That's why I joined the company. I think this is a technology. I said at the beginning, it sounds like a provocative statement, but I really think this can impact millions of people across the world. I really believe that. And so what keeps me up at night is, are we doing the right things? Are we making the right decisions? Are we shepherding this technology in the right way to make sure it gets to enough patients, it gets to people throughout the world. That sort of what gets us excited to go to work every day, but also kind of what keeps you up at night or am I making the right decisions to doing the right things? There's no doubt in my mind the value of this technology right? So given the value of the technology, we've got to make sure it succeeds in the right way and make the right decisions to make that happen.

Okay. And you talked a little bit about how your architecture or your framework for how you think about business development for the company. It sounds like maybe something with the CGD program could be near term? Like what do you -- like what do you think is most priority for 2026?

Yes. I wouldn't think about CGD in terms of BD. I think the patient population there is too small. I think if we were going to do something with CGD, that would be something -- can Prime do something on our own to try and create some value there.

Oh, I see. And what do you mean by that exactly?

Is there a way to get even talk to regulators as a way to get approval even with a couple of patients, and how you want to think about that? Is there some way to create some value with that program internally? So that's stuff we're doing some work on. There's not more that I can share today, and we'll see how that goes. But I wouldn't think about that as anything for business development. I think it's just too small of a product.

Okay. Okay. So for 2026, the kind of the framework that you outlined had a lot of parts to it. So like what do you think 2026 is actionable this year?

Yes. I mean, look, I don't like to put time frames on anything with BD because they can -- these things can take longer or shorter, obviously, depending. So who knows when things get done. But look, I think -- again, I think this technology is now a reality, right? We've treated 2 patients. We've basically cured 2 patients. We're going to be in the clinic with in vivo therapies. We'll be derisking as we go. There are so many other areas where this technology should be developed today, that, frankly, if we had endless capital, we would think about some of those things. So doing that with partners, I think, is important. So again, I think cell therapy is really exciting. I think neurological disease is really exciting. I think there's other areas that we're excited about. I think additional liver indications is really exciting, where we see even, as I stated before, potentially very large indications. So again, we never make promises with BD, but I think given where we're going and what we're doing, I'm hopeful we'll get something done.

Okay. Okay. Great. Last question for me is just I'm actually going to ask how much cash do you have, but it looks like it's on the slide in front of me. So it sounds like $227 million. Can you just orient us to what the key milestones that allows you to get through?

Key milestones.

What. Yes. From our -- for your cash runway.

In cash runway. So I think the key milestones as we think about this year and for the -- we haven't said exactly when the cash runway is in '27. But for this year, it's getting our 2 programs into the clinic. I think those are key. We didn't talk about it. We have an arbitration going on with Beam. So we expect resolution of that sometime in the first half of this year, which I think is an important milestone to get through. For our cystic fibrosis program, it's getting to really proof-of-concept preclinical data there, I think, is important. Obviously, BD can serve as milestones as well, both new BD deals potentially, but also within our BMS collaboration. There's pretty significant milestones, $185 million in milestones.

So being able to achieve one of those as a possibility as we think about our current cash runway. And we haven't said when in 2027, we're ultimately going to have data. So I'm not going to -- I can't sit here definitively today and say this current cash runway gets us through that, although depends. But there are some of these nondilutive things that can happen as well that help us get through that.

Okay. Well, I think this might be a good place to leave it. I want to thank Allan and the Prime team so much for being here and doing this presentation with us, and thanks to all the listeners for joining as well.

Thank you. Thank you for having us.

Thank you, guys, for being here. Super excited to have an old friend join us for a new fireside chat.

Yes. Thank you for having us.

Allan, great to have you. And we all want to learn Prime Medicine and Prime Editing, but I'll let you kick things off.

Thanks, [ Omar ]. And again, thank you for having us. Pleasure to be here in Miami, escaped the weather in New York. Yes. So what can I start with just maybe tell you a little bit about Prime Editing?

I think maybe just at the outset for a lot of folks, there's gene therapy, there's gene editing, there's base editing, there's prime editing. And I think everything beyond gene therapy, folks are not quite sure what it is? How is it different? But also is it even practical? And are there -- so maybe let's start very high level and we can get into much more specifics.

Yes. So I think about just -- what is Prime Editing? Just think about it as the most versatile and the safest way to edit the genome. Now let's talk about why that is. So when I think about sort of the gene editing technology, and we start with CRISPR, which is an incredible breakthrough. Now for the first time with very, very high efficiency, you can go in and make specific changes to DNA. Like that's just an incredible, obviously, Nobel winning breakthrough. So what is CRISPR editing good at? It makes a double-stranded break, right? And so it's very good at knocking something out. You can find a very specific location in the DNA. You can make that double-stranded break, you can have that impact, and it's very good at knocking out genes or knocking out control elements if you want to maybe turn something up like you do in an example with sickle cell disease. But there's limitations to that. You can get a lot of off-target editing where you can find similar sequences where you can get additional double-stranded breaks outside of that sort of primary area where you want to edit. But you can also get what are called indels, right? So when everything kind of gets put back together after you make that double-stranded break, you'll have other base pairs that get inserted, so you can cause frame shifts and other things. So you can get proteins that get -- that can get created that are not natural that the body can then react to.

So immunogenicity?

Immunogenicity is a risk. With base editing, this is, again, an incredible discovery by David Liu's lab that now you can add a deaminase to the mix. You've added an enzyme to the mix. You've changed it from a CRISPR enzyme to a modified Cas enzyme that now makes a single-stranded break instead of that double-stranded break. And you can change one letter to another. So for the first time, you can actually rewrite the genetic code, but it's limited to one letter change to another. So you can change a purine to a purine or [ pyrimidine ] to a pyrimidine, but you can't do the reverse. So it's limited to kind of repairing or correcting 4 base pairs. You have much lower off-target editing because you're making that single stranded break, although it still does happen with base editing. And the second thing is you do get something called bystander edit. So if you're changing an A to a C as an example, and you have multiple A's within that editing window, then you can have multiple ways that get changed to C. So the protein, in some cases has additional changes. So it's not exactly wild-type like the case in their Alpha-1 program as an example.

So the exact site is not as specific as what you're saying. So there's more A's around it?

The site is specific, but in that editing window, say, that editing window where that deaminase can act might be 10 to 15 base pairs long or 7 to 10 base pairs long. If there's any additional kind of A's within that editing window, that has the potential to be converted, right, because the deaminase can act on it.

I see. Got it.

Got it. And then with Prime Editing also in David Liu's lab said, okay, well, now I'm going to add a reverse transcriptase to the mix. So I have a reverse transcriptase. And now in my guide RNA, right? So the same guide that you're using to bind to a specific sequence, I'm going to put in a DNA template, right? So DNA-based pairs that can now get written in via that reverse transcriptase right into the genome and make permanent corrections. And so you're not limited by correcting one letter. You can do actually much larger insertions, but you can correct what are called transversion mutations, transition mutations, we can fix frameshift mutations. We can do what we call hotspot editing where we can fix multiple mutations with one editor. And with our passage technology, we can do even large gene insertions or multi-kilobyte -- kilobase insertions through putting in a very specific landing pad and through a DNA donor very specifically put in where we want that DNA to be inserted, like we do with our BMS collaboration for ex vivo CAR-T cell therapies.

Got it. Got it. Okay. So that's very helpful for background. Maybe just before we proceed, is there an industry standard for off-target editing?

There -- I don't know about necessarily an industry standard. I think every company is going to come up with the assays that they're going to use to measure off-target editing. I know for Prime, we did an extremely extensive package, off-target package when it came to our first program that we took to IND for chronic granulomatous disease. And essentially, we didn't see any evidence of off-target editing. And I think from what I've seen, we have even more assays than we've seen -- even some of the other companies come out with or that we've seen. So we're doing as extensive, as an off-target analysis as we can do. And to the point of we don't see anything where the FDA is -- you don't even have to test this clinically because you don't see anything in any of your analysis.

Is it fair to say that a lot of those assays are probably more consistent between Beam and Prime, given it's the same lab where the technologies came from?

That -- I think we've all created the assays to test off-target not within that lab, but actually on our own, like that's something we've built internally. And it's something -- when we have a -- so when we nominate a lead, when we have a drug candidate that we're ultimately going to take into IND-enabling studies, we've gone through that full off-target analysis to know that, that editor does not have any off-target liability.

Got it. And so on this off-target, just so I understand it in a little more detail, this is done on an in vitro basis, obviously?

Yes. Many of these are in vitro assays, but you can do in vivo testing as well.

Has that ever been done?

Have we ever done that? Yes.

See. And just so I know how does that get done in practice in vivo? So you just...

You just do the same assays once you've done those corrections, and you can do them on multiple different cell types. So it's not only that you're looking at -- you're obviously looking at off-target within the genome, but you're also looking at off-target within different tissues. So you also want to make sure that you're also editing the right tissues.

Got it. So in vitro...

In our liver program, we want to see liver editing, but we don't want to see editing, for an example, in the [indiscernible] as and other things.

Right, right, right. Okay. Got it. And then as it relates to sort of gauging that off-target, in vitro, in vivo both have been done, but the number of target sites that's chosen, is it limited to 200, 300, 400, theoretically, it could be broader than that. So everybody has a certain defined set of target sites they're screening for.

Yes. I mean I know we go as extensive as we can. I don't know the exact number that we do. But I know it's as an extensive as an off-target analysis as we can do without knowing the full details.

Okay. Have off-target effects -- when the off-targets were seen on some of the CRISPR stuff, was the assays materially different and/or the number of target sites chosen materially different?

Not that I know of.

Okay. So they were seeing it fairly consistently in vitro, in whatever sample size they went after?

I think it depends program by program. So I don't think there's -- I don't think you can blanket statement and say like every sort of CRISPR approach is going to have off-target. We can all optimize to try and reduce or eliminate off-target. So I don't think you can blanket it. Oh yes, I think we're all using sort of similar assays, although I'm sure there's differences to kind of evaluate this.

Okay. So maybe just zooming in now on the Prime Medicine side of the story. First, maybe higher level sort of broader corporate strategy. I know there have been changes. I know you took over on the company. I think you also made some pretty significant changes on the operating structure priority list. So maybe just catch us up on what happened, what triggered that? Were you there prior to that?

Yes. So I joined the company in January of 2024. Many of these changes you're talking about happen sort of in 2 stages. So one in September of '24 and then probably again once I became CEO in May of this year. And we really focused the company on what I would call areas of where I really see value creation sort of the near- to medium term. And so when I look at kind of where our pipeline was, when I joined, we had about 18 programs in the pipeline. I think a lot of them were -- we were making a lot of great progress across the entire pipeline. Again, it's such a versatile gene editing technology that there are so many different places we could take it to. But I think in reality, there's higher -- I wanted to find places where there's high probability of technical success and there's high probability of commercial success. And sort of when we distill that all down, we've got great delivery vehicles to hepatocytes in the liver. So that's kind of where we started. Where are there true unmet needs that we can go after? And for Wilson's disease, there really is no other gene editing technology that can go after these mutations. You can't do it with CRISPR, you can't do it with base editing given these are not transition mutations. So this is something that's sort of perfect for Prime Editing. It's a high unmet need. There have not been drugs for this disease for decades. We talked to tons of KOLs and patients, and I can tell you, they are really excited for a therapy that can really change the course of this disease, which today, they're on zinc salts, they're on chelators, lifelong. They're on low copper diets. And even with that, patients can still progress. So this is something that can truly be hopefully a cure for these patients and really make a difference. For Alpha-1 Antitrypsin Deficiency, it's a competitive space for sure. But I really strongly believe that Prime Editing is the best approach for this disease because we could really take a patient back to [ what to ] true wild-type protein under endogenous control, which is important for this specific protein in the body. There are many other companies doing Prime Editing. So you saw a deal yesterday between Tessera and Regeneron as an example. Tessera, we're fairly certain is doing Prime Editing. CRISPR announced a program recently. They call it SyNThase, but it's still Prime Editing. So people can use sort of different terms for their technologies. But in these cases, they're really just sort of copying David Liu's, Andrew Anzalone's sort of [ similar ] technology and just really doing what we're doing. So again, we want to be the leader with our Prime Editing program in [indiscernible], but really believe we'll get paid one way or another, whether it's through our program or others.

And Allan, just remind me, when the cuts happened, what was cut and what was not cut? We know what was not -- was cut.

In terms of programs.

Yes.

Yes. So obviously, what we're really focusing on, again, Wilson's Alpha-1 cystic fibrosis and our ex vivo CAR-T program with BMS. The things that we deprioritize, our ocular programs, our hearing loss programs and our programs in neurological disease and other ex vivo outside of the BMS collaboration, ex vivo HSC programs. In terms of where I see a lot of value in the future because I do think a lot of these programs should go forward. We actually had a lot of success within these programs. It wasn't like we weren't -- we could have had a retinitis pigmentosa IND already, had we pushed that forward. There's another liver program that was super tiny that we didn't take.

So Are you partnering that? Or are you just kicking that [indiscernible].

We'll look to partner some of those programs. I think in some of the areas where the commercial opportunity is really small, that might be a little bit more challenging. There are other areas where the commercial opportunity is higher. I think if you think about neuro disease, so I mean, there are hundreds of different genetic diseases in the brain that we think would be amenable to Prime Editing. We've generated some really promising in vivo data when it comes to neurological disease. I think it's still a place where we've seen AAV be more successful with direct injection lately. And so we're seeing that sort of delivery problem get solved real time. I don't think we're necessarily all the way there yet, but I think we're getting there. And I'd like to see our neuro programs partnered and move forward because I think they can make a significant difference in the lives of patients if we can get that done. There's a lot of really interesting follow-on liver programs that weren't paused per se that I think can move a lot faster and cheaper as we can leverage what we've done in Wilson's and Alpha-1. So a lot of good areas to exciting areas to continue to invest in, but we have really focused the company on where we think we can build value.

Got it. So I want to sort of dial in now on the liver more specifically. And maybe let's start with the Tessera because that's what [ traits ] of a high-profile partnership. I guess maybe before we even go there, it sounds like you definitely want to develop this stand-alone and you're not looking for a partner for some of these advanced programs right now. Is that reasonable?

Yes. I mean, look, I always say there's nothing sacred, especially when you're thinking about the number of diseases that we can ultimately go after with this technology. When I think of where Prime Editing can be in 10 years, we're not going to be a one product, one disease company. That being said, I see a lot of value that we can create on our own with Wilson and even with Alpha-1. But we're -- I'm always happy to -- again, nothing sacred if there's a big enough number in front of us and the better return for shareholders to partner something, then we'll always consider that partnership. But I do see a lot of value for us in taking these programs forward. So partnering these programs would require pretty significant economics for us to do that today.

I remember last time we spoke, you mentioned your goal is double digits on efficacy for AAT programs. Where is your head at sort of on what you're looking to accomplish? And where do you think Tessera lands on some of these?

Yes. I mean it's hard to say from a competitive standpoint because everyone is using different preclinical models. So it's always -- unless you're doing apples-to-apples, true comparisons in the same model with the exact same editor and delivery system that another company uses to know exactly where everyone is. From what I've seen, at least at face value, the programs look fairly comparable across the board when you look at CRISPR, Tessera and Prime that are all again doing Prime Editing. Ultimately, it's going to depend not just on the editor -- the Prime editors being used, but it's going to depend on the delivery vehicle. At least from what we've seen preclinically, we've got an LNP that may have -- may have a wider therapeutic index from at least what we've seen initially compared to, as an example, what we've seen with maybe the Acuitas LNP that we've measured preclinically. So that could allow us to dose higher and that could be a way to differentiate. But we really have to see how these things do in the clinic.

Excellent. Okay. And what's the timing like for you versus Tessera?

Yes. So I think what they announced yesterday is they plan to be in the clinic soon. So I would take that to mean -- and I think maybe they said before year-end. So call it, we've said an IND and/or CTA mid next year. So you're about, call it, 6 months, just give or take.

Excellent. So 6 months [indiscernible].

[indiscernible] fairly close in time.

Got it. But time lines wise, it sounds like your Wilson's is ahead, correct?

Yes. So the Wilson's, we've commented on a first half IND. So that's slightly ahead, yes.

So you could have proof of concept, have data by later next year?

We're guiding to data for both programs in 2027.

Okay. Will the initial studies be on open label?

All of the studies will be open label.

Okay. So you would know theoretically later next year on where the data is tracking?

The studies will be open label. So...

Okay. Fair enough. Fair enough. And remind me again, what's the trial design for the Wilson's?

Yes. So for Wilson's disease, it will be obviously a dose escalation study. We'll be looking to find the optimal biologic dose. You're obviously going to look at safety, but we are going to test a lot of different efficacy measures initially in that trial.

Is there a certain type of Wilson's patients you're taking?

We're not going to -- at least initially, we're not going to go after patients that have decompensated liver disease, which is still a minority of the patients. So they'll be a little bit milder than --- we can go after compensated, but probably initially, we'll go even earlier. But essentially, we're just looking at patients with specific mutations, right? So the first mutation we're going after is called 1069Q, which is in about 30% to 50% of the Caucasian population. So they'll have to be genotype for that mutation. And we're looking at a number of biomarkers that can really speak to activity. So one is copper PET studies, which we're not going to mandate in every patient, but you can see the data in our deck on our website, but you can see almost complete revert and back to wild-type after these mice have been treated with our editor, PM577. You can look at -- there's an enzyme level that you can look at in the blood called ceruloplasmin, which is really low in patients even on standard of care, the ability to actually increase that once you sort of normalize these patients' enzyme levels in the liver. So there's a number of different biomarkers we can look at. Ultimately, you want to get these patients off of standard of care and show that they're really being maintained.

Got it. And Allan, just so I understand from a development perspective, is it mutation-specific editors you're making? Or could you have like a combo of multiple editors in one shot? Like how is that going to work?

So if I understand the question correctly, so we'll have -- 1069Q will be its own editor, right?

That's the IND.

That's the IND. And then we're going to have follow-on editors that we believe will go in the same IND. So the only thing changing -- the LNP is the same. The only thing changing is the guide.

So wouldn't that make a new IND then?

No, it would not.

Has that been done before by Prime on other programs?

It has not been done by Prime because this would be our first in vivo program that goes into the clinic, but we've gotten feedback that you can do multiple mutations within an IND. And we've gotten that feedback not just on this program, but we've actually had that on other programs as well that we didn't end up taking forward, but we're thinking of taking it forward.

I see. I see. so then practically speaking, just fast forwarding from -- you have proof of concept in '27, you do a quick registrational on this. So the commercial presentation looks like, what different RNA guide in the same injection without having a screen from [indiscernible].

Not the same injection. So it's a -- the mutation -- if you think about the drug product, the drug product is slightly different, right? Because you're going to have -- the guide will be different, right? And if we use a nicking guide, that will be different. Everything else is essentially the same, right? So the drug product is slightly different, but it's still the same LNP. So the expectation is, and I think the FDA, even what they put out recently in the New England Journal article, if you have a read, kind of really sort of speaks to this type of sort of plausible mechanism and a way to kind of get multiple mutations forward. So the idea would be, yes, we can prove this preclinically, whether it's an in vivo study, then ultimately take that into the clinic. The hope eventually is that we just believe there's enough in vitro to clinical translation that we don't have to even do these in vivo studies.

Excellent. Excellent. Fantastic. So unless we miss anything today, I feel like we're in good shape. So good luck. It sounds like it's a huge year coming up.

It is. No, great question. So really appreciate it.

Let's stay in close touch. Thank you again, Allan.

Thank you.

Thank you.

Good morning, everyone, and welcome to Prime Medicine's virtual event to discuss our liver disease franchise and strategy focused on Wilson disease. Our goal this morning is to provide additional detail on our strategy in Wilson disease and to explain how we are leveraging the modularity of our platform to develop Prime Editors that have the potential to offer durable cures for patients. You will hear perspectives from a key opinion leader and from our management team as we discuss the opportunity ahead of us.

Before we begin, I remind you that today's remarks will include forward-looking statements. Such statements are subject to the risks and uncertainties that could cause actual results to differ materially from those described. These risks are detailed in our SEC filings, including our most recent annual and quarterly reports. This call will be recorded, and the recording can be found under the Events section of our Investor Relations website. The slides we'll be referencing today are available within the webcast and on our website.

We are joined today by 3 speakers. First, you will hear from Allan Reine, our Chief Executive Officer, who will provide a brief introduction of Prime Medicine, contextualize Wilson disease as a cornerstone of our strategy and describe the global opportunity. Then Dr. Michael Schilsky, a hepatologist and one of the world's foremost experts in Wilson disease, will share a clinician's perspective on the disease, its presentation, diagnosis and current disease management. Finally, Dr. Mohammed Asmal, our Chief Medical Officer, will outline Prime Medicine's approach to Wilson disease, review our existing and new preclinical data presented at AASLD this past weekend and walk through our clinical development plans.

With that, it's my pleasure to turn the call over to Allan.

Thank you, Greg, and good morning, everyone. It's a pleasure to be on with you today to speak about Prime Medicine and our efforts in Wilson's disease. To quickly orient you to today's event, we've designed the agenda to provide insight into our corporate and clinical development strategy. Now we stand at a real inflection point for Prime Medicine and Prime Editing technology. Prime Editing has the potential to fundamentally transform the care and treatment of genetic diseases and beyond. Over the past 5 years, we've generated clinical and preclinical data that demonstrate the unequivocal power of Prime Editing to change patients' lives, offering potentially curative benefits in a matter of weeks.

Now our strategy is initially focused on programs targeting diseases with high unmet need, well-understood biology, clearly defined clinical and regulatory pathways and the potential for meaningful commercial impact. To that end, we are focusing initially on Wilson's disease and alpha-1 antitrypsin deficiency, cystic fibrosis and ex vivo CAR-T therapy through our BMS collaboration. And today, we are delighted to share additional details on our program for Wilson disease.

Now turning to Slide 4. Now first, our Wilson disease is an area of high unmet need. There are no curative therapies available and the current standards of care, they're highly burdensome. They can be costly, they're limited by tolerability and compliance tends to be very low. Second, Prime Editing has the potential to provide a durable cure by precisely and permanently fixing the mutation at its source and restoring normal enzyme function and subsequently, normalizing copper metabolism and halting and hopefully reversing disease.

Now as part of today's discussion, we will review new preclinical data shared for the first time at the American Association for Liver Disease Conference this past weekend, which further confirm that Prime Editing has the potential to revert a disease patient completely back to a normal phenotype. We believe this represents one of the most complete demonstrations to date of molecular correction translating into phenotypic normalization in a Wilson disease model and provides further evidence of the transformative power of our approach.

Finally, we at Prime Medicine have a deep and nuanced understanding of the opportunity in Wilson's disease and are leveraging the modularity of our platform to quickly and efficiently develop Prime Editors for the most prevalent mutations globally. While our initial efforts are focused on a mutation called H1069Q, which is the most prevalent mutation in the Caucasian population and R778L, which is the most prevalent mutation in the agent population, our ambitions are much larger. And we plan to expand rapidly into additional mutations that would allow us to address this multibillion-dollar global market in Wilson's Disease and develop fast followers in other liver-directed indications.

Now turning to Slide 5 and taking a bit of a step back, allow me to begin with a brief introduction to Prime Medicine. Now Prime Medicine was founded in David Lew's lab to harness the full potential of Prime Editing, a next-generation gene editing technology that allows us to precisely rewrite DNA. This technology is highly differentiated from other gene editing approaches. Prime Editing is the most versatile and it's the safest way to edit the genome. Other gene editing approaches have many liabilities that Prime Editing does not have. There's the potential to create neoepitopes from different indels or the body to view something as foreign.

There's the risk of chromosomal rearrangements and translocations, risk of off-target editing. And in the case of base editing, the potential for bystander edits. Now Prime Editing, again, our programs do not result in any of these. is a very highly differentiated technology, and I believe will be the primary way genes are edited in the future to target many different diseases and helping many patients across the globe.

Now why is Prime Editing different? Well, we use what's called a modified Cas9 nickase, meaning we make single-stranded breaks in DNA versus double-stranded breaks. This is very important as we think about off-target edits, chromosomal rearrangements and translocations that I mentioned before. Now this nickase Cas9 enzyme is fused to a reverse transcriptase enzyme, along with a specialized guide RNA. So we can rewrite or dictate what base pairs get written into the DNA. And this is really the only technology that can do this. And we can do this with a very high degree of precision.

We can insert we can delete or we could correct stretches of DNA, as you see in Slide 6. And we can even put in multi kilobases of DNA as well using our passage technology. So that means we can fix a wide range of disease causing mutations, including the missense transversion mutations and frame shift mutations that underlie Wilson's Disease.

On Slide 7, we're just highlighting our current pipeline. This is where we are today. And I just want to emphasize again the potential to slot in additional liver programs once we demonstrate initial success in Wilson disease and alpha-1 antitrypsin deficiency. The modular platform that we have will allow us to incur lower cost and move with higher speed as we think about additional programs. There's a great degree of synergy as we go from liver program to liver program.

There's also a lot of opportunity beyond the tissue types listed here. We believe there's a tremendous amount of potential as we think about using Prime Editing and other cell-based therapies, both ex vivo and in vivo in addition to diseases of the eye, diseases of the ear and diseases of the brain, just to name a few.

Now turning to Slide 8. From a time line perspective, our IND-enabling studies are currently ongoing for both Wilson disease and alpha-1 antitrypsin deficiency. We expect to file an IND and/or CTA for Wilson disease in the first half of '26. And for alpha-1 antitrypsin deficiency, because of the modularity of our platform, that's only a few months behind Wilson disease, and we expect to file an IND and/or CTA in the middle of 2026, with data for both programs expected in 2027.

Now on Slide 9, this slide really makes a crucial point. All of our liver programs share a common foundation, our proprietary universal lipid nanoparticle delivery. Now the drug product is composed of 8 components, including lipids, cholesterol, a targeting ligand in this instance and RNA, 6 of which are consistent across programs. Now this commonality enables us to leverage shared learnings and infrastructure such as toxicology studies, manufacturing processes, and regulatory experience, again, helping us accelerate development, reduce risk and lower costs for subsequent efforts.

This approach applies both as we transition Wilson disease to alpha-1 antitrypsin deficiency and as we call it, our march up the chromosome strategy, where we use our initial work in 1069Q mutation in Wilson disease and R778L to inform the development of fast follow-on programs for other prevalent disease driving mutations in Wilson disease.

Now turning to Slide 10 and Wilson disease and the commercial opportunity. I want to give you a brief overview of how we think about this market and why we at Prime are so excited about this program. Although Wilson is a rare disease, it's a significant market opportunity in the U.S. and globally. There are potentially 25,000 Prime Editing addressable patients in the 3 main geographies alone, U.S., Europe and Japan.

In the U.S. and Europe, there are about 11,000 Wilson disease patients in each geography. And we think with a handful of Prime Editors, we can target 60% plus of this population. And turning to Asia and the Japan market, there is a higher prevalence rate there. And based on the mutational backdrop, we believe we can potentially get up to even 70% plus of these patients, again, with a handful of prime editors. On the very low end, we think this represents a $20 billion-plus commercial opportunity. And we think this could easily be a $40 billion-plus opportunity globally.

I also think it's important to note that the incidence rate here of a few hundred patients per year. So as we think about the long-term value of Prime, stacking up incidence rates across a number of indications really creates a business model beyond treating drug prevalent populations.

Now turning to Slide 11. I want to talk specifically about Wilson's Disease. As I've explained before, it's caused by a well-characterized mutation in the ATP7D gene. There are clear biomarkers of copper metabolism, and this represents a significant unmet need that Dr. Schilsky will delve into in greater detail. Prime Editing offers the potential for a onetime curative treatment for patients suffering from Wilson disease. Our strategy begins with PM577, which targets the H1069Q mutation. We call it our anchor mutation. We've established preclinical proof of concept, which Mohammed will expand upon later and eager anticipate enrolling H1069Q patients following our regulatory filings in the first half of next year.

Now we are developing R778L as a fast follow-on. And then we have a list of a handful of other prevalent mutations that we will go after in the relevant geographies. Now because our Wilson disease programs use the same backbone, swapping out only the guide sequence, we can expand rapidly from our initial work with PM577 to develop additional Prime Editors to address other disease-causing mutations in Wilson disease. Now as I mentioned a moment ago, we've already identified our initial expansion opportunities.

With that, I'd like to hand it over to Dr. Michael Schilsky, who will provide the physician's perspective on Wilson disease.

Thank you, Allan. For those current slide deck in the next few minutes, I'm going to refer to only 4 of the slides, starting with that of the cartoon of the liver cells. A little background for you. Wilson disease is a disorder of copper transport in humans inherited in an autosomal recessive fashion. And the underlying pathology of the gene product for ATP7B that Allan has been referring to for the correction that is critical for maintenance of copper homeostasis and the liver is where this is highly expressed.

And in the liver cell, ATP7B is responsible for biliary and for the bio incorporation of copper into seruloplasmid. Now on that little cartoon, which is a simplified schema of copper handling, you'll shown on the left is the normal function and then on the right is the consequence of ATP7B dysfunction with those little dots representing copper accumulation in the liver cells due to the reduced biliary copper excretion that is in part dependent on ATP7B.

And because of the high expression and main expression of ATP7B in liver cells, the liver is really critical for copper homeostasis in the body. It's the target when ATP7B functions impaired and copper accumulates pathologically in the liver and then later in other organs as the capacity of the liver is sort of overloaded. And the main site that we concern ourselves with, although many organs, particularly the central nervous system can be affected. The proof that the targeting the liver for the correction of the genetic defect underlying Wilson disease is essential for restoration of normal copper homeostasis is provided by outcomes of liver transplantation for Wilson disease, where normal copper for the medical therapy for treating patients for copper overload is needed.

I refer next to the slide showing the relationship of time for the diagnosis of Wilson disease and patient disease expression. The diagnosis of Wilson disease is established by a matrix of clinical [Technical Difficulty] complemented by testing for pathogenic ATP7B mutations. Most asymptomatic patients or those with just liver-related signs or symptoms typically present in the second decade of life or in the late first decade, there are some. And those with neurological disease about a decade later.

Patients with neurologic or psychiatric disease typically have delays in diagnosis of 1 to 2 years as their symptoms are really thought to be other disorders initially and that those are sort of mistaken and then later on considered then they become potentially partially treatable or unfortunately, because of delays, some are left with disability for life. In practice, the current diagnosis of Wilson disease is made most often in the second and third decades of life when clinical signs and symptoms become evident.

There is a lead time bias as to what the clinical phenotype of the disease is asymptomatic and then hepatic presentations that occur in younger patients. And typically, older patients may begin developing manifestations of the central nervous system copper accumulation such as neurologic or psychiatric symptoms. And this is shown in the graph that shows the natural history of disease over time without treatment.

Now the next figure I want to refer to is that one from one of our guidances from the AASLD, and this shows the natural history of the disease on treatment and it highlights what the goals of treatment would be in different phases of disease with our current pharmacotherapy. In young patients, there are first laboratory and abnormalities before symptoms begin. And then with time, there's progressive liver damage. As you enter the second decade there's a risk of developing signs and symptoms of neurologic or psychiatric disease. And untreated, patients go on to have consequences of advanced liver failure and death is inevitable.

In a small percentage, acute liver failure develops typically in the second or third decade of life. Before the [Technical Difficulty] development of more disease and keep patients asymptomatic. Once signs and symptoms develop, the goal is to help reverse any injury, then prevent progression. And however, when severe disease is present, then rescue therapies, including liver transplant are needed.

Moving on to treatment slide. The first treatments were developed in Wilson disease in the 1950s and the first oral therapy in the 1960s with D-penicillamine and then Trientine. And these were chelators initially grabbers of copper in the circulation for excretion. And the second drug, Trientine that I mentioned was developed due to the development of both hypersensitivity reactions that occurred with early use and later toxicities, including nephritis, nephrotic syndrome, lupus-like reactions and other late dermatologic effects with the long-term use of D-penicillamine. Due to the ability to titrate the dose to increase urine copper excretion, this was typically the way we did follow patients.

Now there is an additional concern in early treatment of patients with neurological involvement with chelation therapy could be accompanied by worsening of disease and the risk of permanent disability in many of these individuals. Later on, zinc salts were introduced by Dutch investigators and then studied later on by Brewer and his colleagues at the University of Michigan. And this drug or salt -- well, I should say, elemental treatment is approved for maintenance therapy of Wilson disease.

There are really no perfect medications that are good for 100% of patients with failure rates between 10% and 20% for standard therapies and up to a 30% rate of side effects noted for chronic therapy. And most importantly, the very significant rates of nonadherence to therapy, which begs the question of whether we can achieve a curative treatment that will benefit patients with Wilson disease. While liver transplant can be curative, it comes with both surgical risk as well as the need for lifelong immune suppression. [Technical Difficulty] reserved liver transplant for rescue therapy for the 5% of patients presenting with acute liver failure and others with advanced end-stage liver disease, which are beyond the capability of rescue by pharmacotherapy.

And transplant for neurologic Wilson disease is completely prognosticate patients for this. However, there are some successes reported and particularly by our colleagues from France. Aside from symptomatic treatment for Wilson disease, for example, for tremors or anxiety depression, there is therapeutic intervention for our patients, which is dietary restriction of copper, which is another burden upon patients' quality of life. And for some, this is an extreme hardship, for example, our vegetarian patients who then have to limit their amounts of soy, legumes or other nuts and other and [Technical Difficulty] some shellfish and mushrooms.

And another issue with diet is the inability of the current to take these medications at the same time patients are eating. And therefore, most patients have to construct a daily schedule to avoid taking their medication or indeed half the time they forget and then they become less effective when taken with food.

Now there are no current treatments that have undergone human trials yet that are capable of enhancing biliary copper excretion outside of the early stage of AAV-mediated [Technical Difficulty]. And even with that as yet, no one's really demonstrated enhanced biliary copper excretion following gene transfer. Studies on tetrotimemelipate had some hopes of enhancing biliary copper excretion based on some preclinical studies. However, the PET imaging studies with radio copper showed more that it was blocking copper absorption and yet we still need to see more data as to whether it really is changing biliary excretion.

And if it is merely blocking copper, then it is really comparable to what zinc is doing as well. Therefore, if gene editing is successful and without off-target effect, this really offers the best opportunity for effectively achieving a cure for Wilson disease.

Now I'll turn the discussion back over to Dr. Mohammed Asmal.

Thank you, Dr. Schilsky. Your insights from clinical practice are greatly appreciated. Turning to Slide 18. In short, we believe Prime Editing can fundamentally change how Wilson disease is treated. Today, the standard of care is built around chronic chelation therapy and strict dietary restrictions. Patients take large pill burdens often multiple times per day under fasting conditions for the rest of their lives. Even when adherence is excellent, these regimens are only partially effective and many patients eventually progress to liver failure, where transplantation becomes the only curative option.

Our vision with Prime Editing is very different. A onetime therapy that precisely and permanently repairs the ATP7B gene restoring physiologic copper transport. By returning hepatocytes to wild-type function, we aim to normalize copper metabolism, halt disease progression and potentially provide a lifelong cure. In short, we're moving from managing copper overload to truly correcting the disease at its genetic source, a transformation in both patient experience and long-term outcome. The preclinical package supporting PM577 continues to exceed expectations and provides a very strong foundation to our IND submission.

Beginning with delivery, as we've shared before, we've engineered an optimized lipid nanoparticle specifically tuned for hepatocyte uptake. This LNP achieves high intracellular delivery efficiency with minimal innate immune activation. Regarding safety, both mouse and nonhuman primate studies have shown an encouraging safety profile. No evidence of off-target editing, no meaningful cytokine activation and only transient reversible changes in liver function tests at clinically relevant doses.

From an efficacy standpoint, we see efficient correction of both H1069Q and R778L mutations in fully humanized mouse models. And today, we are excited to review new data in a partially humanized mouse model, believed to better recapitulate the human pattern of hepatic copper trafficking and biliary excretion than the fully humanized system. These data, which we shared at AASLD this weekend, demonstrate clear phenotypic rescue, complete restoration of hepatic copper concentration in vivo and normalization of copper excretion.

In addition, using radiolabeled copper PET imaging, we can now visualize copper being rerouted through the correct biliary pathway, providing a direct noninvasive functional readout of ATP7D activity. Together, these results build a compelling case that PM577 can safely achieve durable functional correction in vivo, exactly what we want to replicate in the clinic.

We start with editing efficiency on Slide 20. The data on this slide are from previously published studies demonstrating efficient correction of the 2 most prevalent pathogenic variants in ATP7B, H1069Q and R778L, using Prime Editors delivered with our universal liver-target lipid nanoparticle. In these fully humanized homozygous mouse models, we achieved hepatocyte editing efficiencies approaching 90% following a single administration at clinically relevant doses. These data were originally presented earlier this year and have now been reproduced across multiple independent experiments.

Just as importantly, using an extensive suite of off-target assays, we have detected no off-target editing. After in silico identification of an exhaustive list of potential off-target sites, we evaluated hundreds of these sites in vitro in a patient-derived cell line. We detected no quantifiable off-target editing at any of these nominated sites. The key takeaway here is that Prime Editing can reproducibly achieve efficient and precise on-target correction across multiple ATP7B genotypes using a single LNP backbone, highlighting both the robustness and modularity of our platform.

Turning to the next slide. These data were newly presented at the 2025 AASLD meeting and represent our most advanced preclinical evaluation of PM577, our lead prime editor targeting the H1069Q mutation. Following a single systemic dose of our optimized prime editor, we observed greater than 80% hepatocyte editing. Most importantly, this level of correction was accompanied by a complete restoration of hepatic copper concentrations to wild-type levels, as shown in the middle panel. By 8 weeks post dose, hepatic copper content in the treated animals was indistinguishable from wild-type controls.

We also performed a functional copper excretion assay using radiolabeled copper chloride. At 4 weeks post treatment, treated animals demonstrated normalized biliary excretion of copper consistent with restoration of functional ATP7B protein. Taken together, these data confirm that Prime Editing not only corrected the disease-causing mutation at the DNA level, but also restored copper handling at the physiologic level. We believe this represents one of the most complete demonstrations to date of molecular correction translating into phenotypic normalization in an in vivo Wilson model.

Finally, on Slide 22, to complement the biochemical and molecular endpoints, we incorporated copper PET imaging as a noninvasive translational readout of ATP7B function. This slide summarizes findings from a PET imaging study that we also presented at AASLD 2025, using radiolabeled copper chloride to visualize copper distribution and clearance in vivo. On the left, you see wild-type mice, where copper is rapidly taken up by the liver and efficiently cleared through the biliary system into the gut within 24 hours, producing a high signal in the intestines and minimal hepatic retention.

In contrast, the middle panel shows the partially humanized ATP7B mutant animals, which when left untreated, display persistent hepatic copper retention and reduced biliary clearance, a pattern consistent with the pathophysiology of Wilson disease. The image on the right shows Prime Edited H1069Q mutant mice 4 weeks after treatment. These animals exhibit copper kinetics nearly indistinguishable from wild-type controls with loss of the hepatic signal and restoration of normal intestinal and fecal distribution within 24 hours.

This imaging modality is important because it provides a quantitative longitudinal and translatable biomarker for assessing treatment responses in humans. Liver quantification biopsy is not always feasible for all patients in clinical trials. However, copper PET imaging offers a noninvasive way to monitor copper metabolism dynamically. Collectively, the copper PET and excretion data, together with the high editing efficiency and normalization of hepatic copper levels demonstrate full restoration of ATPV7 function following Prime Editing. These results form a critical bridge between our preclinical studies and the translational strategy we will carry forward into the clinic.

Now that we've established robust preclinical proof of concept for PM577, let me briefly outline our clinical development strategy. We are advancing PM577 towards an IND and/or CTA filing in the first half of 2026, which will mark the first in-human evaluation of Prime Editing in an in vivo setting. Our planned Phase I/II study will initially enroll adult patients with Wilson disease who are maintained on standard chelation and/or zinc therapy. The primary endpoints will focus on safety and tolerability. We will also measure key efficacy biomarkers, including ceruloplasmin, serum copper and urinary copper and importantly, incorporate copper PET imaging as a noninvasive translational tool to assess restoration of ATP7B-mediated copper transport in some patients.

Over time, the study is designed to evaluate whether patients can safely reduce and eventually discontinue chelation therapy while maintaining normal copper balance. Long-term follow-up will help confirm the durability of editing and the stability of copper metabolism. We expect to initiate dosing shortly after regulatory clearance and to generate initial proof-of-concept data in 2027. Those results will represent a critical milestone for Prime Medicine, demonstrating clinical validation of in vivo Prime Editing in a systemic genetic disease and potentially enabling us to expand into additional Wilson disease populations with global impact.

With that, let me turn it back to Allan to close.

Thank you, Mohammed. As you've heard today, we believe Prime Editing offers the opportunity to deliver a durable onetime therapy that corrects the genetic defect in Wilson disease and can transform patient lives. As we transition from preclinical proof of concept to the clinic for our first in vivo program in Wilson disease, I want to close by framing what the next 18 to 24 months look like for Prime Medicine.

Now first, 2025 has been a pivotal year for the company. We had clinical proof of concept that we've already established in our first clinical program in chronic granulomatous disease. And now 2 liver programs that are advancing in parallel into the clinic, we're really entering a new era of prime editing, one defined by clinical execution and our platform modularity.

Looking ahead to 2026, our focus will be on translating these results into human studies. For PM577 in Wilson disease, we are preparing to file an IND and/or CTA in the first half of 2026, initiating our Phase I/II trial shortly thereafter. That will provide the first human data for Prime Editing in an in vivo setting with proof-of-concept efficacy data expected in 2027. In parallel, our alpha-1 antitrypsin deficiency program called PM647 is on track for a mid-2026 IND or CTA regulatory filing, positioning both liver programs to generate initial human proof-of-concept data in 2027.

For cystic fibrosis, supported by our collaboration with the CF Foundation, we plan to share additional in vivo proof-of-concept data next year as we march towards IND-enabling studies for that program. Now this coordinated execution reflects the strength of our modular platform. Each program within a given tissue builds on the same underlying Prime Editor architecture and delivery system, potentially enabling us to leverage shared toxicology, manufacturing and regulatory experience. As a result, every success compounds the next, accelerating development while reducing cost and risk.

On the business side, we continue to pursue strategic partnerships to extend our reach and reinforce our balance sheet. Our existing collaborations with Bristol-Myers Squibb in ex vivo CAR-T cell therapies and with the Cystic Fibrosis Foundation exemplify this approach. We expect to announce additional partnerships that can both accelerate pipeline progression and expand the application of Prime Editing into new therapeutic areas.

Taken together, these milestones mark the beginning of a period of sustained data generation across multiple indications. By 2027, again, we expect to have human clinical readouts for our first 2 in vivo liver programs, firmly establishing Prime Medicine as a clinical stage leader in gene editing. In short, we are moving from discovery to delivery from demonstrating what Prime Editing can do in preclinical models to showing what it can do for patients. I strongly believe today more than ever that Prime Editing is the gene editing modality of the future, and this technology will transform the lives of many people suffering from disease across the globe.

I want to thank Dr. Schilsky for sharing his clinical insights for Dr. Mohammed Asmal for dealing -- detailing our clinical approach, and I want to thank you all for joining us today.

With that, we are delighted to take your questions as time permits. Operator, please open the queue.[ id="-1" name="Operator" /> [Operator Instructions] Our first question comes from Maurice Raycroft with Jefferies.

Congrats on the progress. Maybe to start off, if you could just talk about what the bar is for functional cure in Wilson's and just the importance of demonstrating reduction or elimination in chelator or zinc use? Or is it more about normalization of copper? And yes, maybe talk more about that.

Thanks, Maurice. I think for that question, why don't we start with Dr. Schilsky, and then we can also pass it off to Mohammed to fill in as well.

Sure. That's a great question. And for sure, the 2 actually follow together. So if you can normalize the copper metabolism and reduce copper in the liver where it's pathologic, you'll also reduce it from spilling into other sites and achieve the goal of actually eliminating the need for standard of care therapy. So I think the 2 go together.

Got it. And maybe talk about just the best way to assess improvement in liver pathology in these patients. Would you be relying on Fibro scan in a clinical study? Or how would you be assessing just the improvement in these patients?

So to the first part, I mean, to know that you've achieved the reduction in copper, patients don't like to have multiple biopsies, but Mohammed Asmal referred correctly to the potential use of PET imaging, which can be noninvasively employed. There are things that are being used even in our standard clinical practice to look at how urine copper excretion is. And there's also some new development in terms of biomarkers of bioavailable copper, things like the non-ceruloplasmin copper by speciation [Technical Difficulty] that could be employed to look at the changes in the circulation that should parallel what's going on in the liver. So I think we have a much better opportunity to have a handle of using both these noninvasive surrogate markers.

You also point out the use of elastography, which is incredible we have both the use of the physical elastography, whether it's by sonographic means or MR means, but there's also use of the noninvasive testing and some of our other registry studies have been working on sort of establishing the boundaries of what the cutoffs are for disease-specific states such as Wilson disease using that. So those can all be looked at in tandem and provide us with a more global view on how the patient is doing.

Got it. And maybe last quick question. Just would you use this gene editing technology in patients with compensated cirrhosis? And what proportion of patients could have reversible liver pathology?

So the answer to that is you point out correctly in the beginning, using decompensated cirrhosis would be inadvisable for many reasons, one for safety and second is in terms of whether we can deliver product as well once you have the microcirculation of the liver disrupted. But I believe we will see, and again, this is a probability based on our knowledge of what happens with current treatment as well as in animal models that you'll see a regression of inflammation.

Over time, we do see reduction in liver stiffness and in the smaller numbers of patients that have had multiple biopsies over time, standard of care treatment can cause regression in fibrosis. So the surrogate marker of decreased liver stiffness, the parallel improvement in [Technical Difficulty] function, surrogate marker of like platelets, which also indicates the recompensation and improvement in the micro circulation, they all go together. And so I think we have an opportunity to treat a large spectrum of patients. And in the future with other tricks one can do, you can actually potentially reach even the more advanced patients. But I think you have to walk before you run.

Yes. And maybe, Mohammed, do you want to comment as well on sort of the clinical plans as we think about decompensated liver disease at the outset in the future?

Yes, certainly. I think as Dr. Schilsky pointed out, it would be ill-advised to go after individuals with decompensated cirrhosis right off the bat as they pose a higher safety risk. So our plan would be to initially go to individuals who do not have decompensated disease. Now most individuals with Wilson's Disease do have some underlying degree of liver damage. So we will need to address those individuals upfront.

I think once we have established a comprehensive safety and efficacy package in individuals with moderate liver disease, I think then we may begin to investigate individuals with more advanced disease. We are optimistic that with a safe and effective therapeutic, we may be able to establish and demonstrate some reversal even in the most advanced settings as has previously been demonstrated for individuals with viral hepatidities receiving antiviral therapy.

[ id="-1" name="Operator" /> Our next question comes from Samantha Semenkow with Citi.

I have a few for you, Dr. [Technical Difficulty] patients' journey with Wilson, do you think it does make sense for treating them? I guess I'm asking how early can you treat them? How severe do they need to be for a Prime Editing therapy? And then just building on that as well, I guess, how many of your patients do you think today, if you had this therapy would be eligible for treatment?

Okay. Well, I'll take the last part first. So in the population in the United States, 1/3 of our patients have the H1069Q mutation. So as heterozygotes in about 10% are [Technical Difficulty] that. And only we have less in the Asian population, so here in the United States. So probably only a few percent. But again, you have to look at this worldwide and in terms of which populations around the world. And also the fact that over time, you're going to [Technical Difficulty] again, editors for other mutations in the disease, whether it's going to be all single point or hotspots in the gene, that can then be expanded. But certainly, I think there is great potential to help a lot of patients here [Technical Difficulty] swipe.

Now as to when to treat, in the beginning, obviously, because you have an underlying liver disease, you probably will start with treated patients so that where you have the best safety profile and then can withdraw standard of care therapy once we know safety and efficiency, where we could potentially turn around and even go into untreated individuals that are not having any consequence of their disease. But you also have to be mindful, as I stated, that you have a background liver disease, even in asymptomatic patients, there's accumulation of copper and there can be some background inflammation.

And so you do want to -- we can take advantage of what we have currently and hopefully, even other new therapies to get the patient in the best condition to treat. So I can really see [Technical Difficulty] short of those with decompensated disease early on and eventually perhaps all patients.

Okay. That's super helpful. And just one for Allan, I guess, as well, just on strategy. As you look into the future and you're thinking about expanding the pipeline beyond this first edit for Wilson's and AATD, how do you think about balancing expanding into additional mutations for Wilson's Disease, let's say, versus adding new programs to your pipeline?

Yes. I mean, look, I think the ability is going to be there to do both. I mean, as we think about Wilsons, the cost of going -- our belief is the cost of going into additional mutations is going to be very low and very fast. There may be a world where we can even do this with in vitro data in the future if the translation is there without even getting in vivo data.

So I think the incremental cost and the benefit of even just getting to some of the patients that are even 1% or a low single-digit percentage will be a very positive sort of net present value to make that small investment, especially as we believe that gets slotted into the same IND or other regulatory filings. And hopefully, that will play out in the commercial setting as well.

At the same time, once we -- as we believe we'll establish good safety and efficacy with Wilson disease and Alpha-1, the ability to really pivot to other liver indications, especially where Prime Editing is the, we believe, the better approach. And we've got a number of diseases that we're evaluating today. Some are orphan rare diseases and some are actually much larger diseases where we're not looking at thousands of patients, but hundreds of thousands or millions of patients. So there's a lot of potential opportunity here, and I think it will be a great cost-effective way to explore both.

[ id="-1" name="Operator" /> [Operator Instructions] Our next question comes from Troy Langford with TD Cowen.

Congrats on all the progress. Maybe just one for Dr. Schilsky. Maybe just a follow-up to some of the other questions asked. I guess what percent of your H1069Q mutant patients would you say are currently not well managed or not adherent to current standard of care chelane agents or dietary therapy and might make better candidates for Prime Editing therapy for Wilson's Disease?

Well, you can look at it 2 ways. One, which people are having a lot of trouble. And again, about 30% to 50% of patients become nonadherent over the course of their time. And the second, you can look at it as enhancing quality of life of patients. If you ask patients why they want to look at curative therapies, they tell you they don't -- they believe they don't want to have to worry about timing their medicines to food. They want to eat what they want, and they want to be normal.

So it's not just a question of failing therapy, and we are good for most of our patients. But again, if you take the very long-term view, we're going to have trouble [Technical Difficulty] for patients. And then also the question becomes, as we start to understand the natural history of the disease over time, there's significant associations of depression, major depressive disorder, anxiety disorders. And these can still occur while on current standard of care [Technical Difficulty].

And so whether an early treatment or curative treatment can even give you better quality of life overall to eliminate the development of these other associated problems that we see in high frequency in patients, [Technical Difficulty] there's the potential there. And I think patients really would welcome that.

[ id="-1" name="Operator" /> Our next question comes from Salveen Richter with Goldman Sachs.

This is [ Srinath ] on for Salveen. So you've spoken a great deal about the LNP, which is the basis of your platform. What are your thoughts on AP-based therapies like the one that Ultragenyx is developing on Wilson's and how do you -- in Wilson's how do you see it being differentiated from your approach?

Yes. Thank you for the question. I can take that and others are free to add. We think this is a very differentiated approach to a gene therapy. Obviously, with Prime Editing, we're making a permanent change in the DNA. And that means essentially that all daughter cells will have that change as well. With the AAV approach, they're using a truncated version of the gene. So it's actually not the full gene. It does have the -- obviously, the catalyt complex. But as you think about different forms of the gene and tertiary structures, what that total function is, is still a little bit in question.

I think the other thing that's important is with AAV, it can wane over time as you think about years. If you think about hepatocytes, they turn over less frequently than many other cells, but we don't think they turn over every, call it, 6 months, a year or 2 years. So that effect could be diluted out over time. And there's other draw box, obviously, with AAV, can only be dosed once as one example. So we think this is a, frankly, a real cure for this disease, a onetime cure. And we think there are a lot of advantages versus other types of therapy, AAV approaches included. I don't know if anyone else wants to mention anything on that.

Yes. The other thing with AAV, once it gets in cells, first of all, you end up premedicating patients and keeping them on [Technical Difficulty] period of time. And even when you stop that, you have to watch and wait and see if they develop any more inflammatory changes, which are usually then responsive to immune suppression just to maintain those cells, but that's another risk to a patient.

[ id="-1" name="Operator" /> Our next question comes from David Nierengarten with Wedbush Securities.

I just had one on kind of thinking about the outcomes in the upcoming human study. What is the right benchmark when you think about copper reduction or copper stabilization given that the patients are likely to have some copper release early if it's working, right, the chelated copper that's in the tissues and such should be eliminated over time. So they might have an increase in copper paradoxically, right, initially at least. So just like how are you thinking about the right time points to measure these -- the biomarkers and other outcomes over time when you start treating patients?

Yes. Maybe I'll comment that if you look at our preclinical studies, we're seeing a pretty significant effect even at 2 weeks, but definitely as we look at 4 weeks, we're really almost getting to maximal copper reduction almost to normalization. So we do see that pretty rapidly. But maybe to your question, I'll pass it over to Dr. Schilsky.

Thank you. Yes. So I think the important distinction is that when you're mobilizing copper, you're not mobilizing it back in the circulation. You're pulling it out into bile, which is a [Technical Difficulty]. And that's shown beautifully in those PET studies that Mohammed Asmal told you about and shared. But I think that's a real big difference. So I don't think you're going to see any of those paradoxical changes or injuries occurring because of the pathway that the copper will be travelling.

[ id="-1" name="Operator" /> Our next question comes from Arthur He with H.C. Wainwright.

So maybe for Dr. Schilsky, I'm just curious, when you look at these different trial drug under development for orphan disease, what do you think for -- about the endpoint for an accelerated approval potentially for the agent? The only when we're looking at the copper reduction or copper center endpoint is good enough for the approval? Or do we need including some neurological improvement measurement there?

So the endpoints have to consider [Technical Difficulty] chemical endpoints and how the patient is doing. So I agree with you, you certainly don't want to cure the liver and have your patients continue to become neurologically worsened. So that would have to be the reason to follow patients very globally in this disease that has a wider [Technical Difficulty]. But again, it also depends on stage of disease that you start to treat people. So if you're able in the future to capture very early patients, whether eventually screening for the disease is universal and you find patients at very early stages, then you're only working in the preventive mode.

But I think the biochemical endpoints, ultimately, you have to show that you're restoring the natural pathway that by doing so, the parameters that we look at in terms of copper in the liver as well as copper in the circulation or excreted into urine, which is in parallel with that in circulation have improved. So it's a matrix of things that will be more convincing than just one single parameter alone. But if you look to a past example, the primary endpoint for the study for Trientine tetrachloride to [Technical Difficulty] plasmid copper. And the reason was in that in standard pharmacotherapy now you want to maintain kind of the patient where they are. And you certainly want endpoints that will point to how safe it's going to be over time because there is a lag from the changes biochemically to the time you have clinical manifestations. So you want to have things that are early and then have follow-up that allows you to say that you can maintain the patient and not have those phenotypic changes, as you point out so correctly.

[ id="-1" name="Operator" /> Our next question comes from Terence Flynn with Morgan Stanley.

This is Chris on for Terence. Thank you for doing this informative KOL call. So a question for Dr. Schilsky. Just want to understand what is the current guideline for screening for Wilson's Disease in feeders or infants? Any efforts in making that more mandatory?

Okay. So good question. The answer is there is none at this time for mandatory screening. There are exploratory programs, one beginning in the state of Washington using the peptide studies that were developed by Dr. Sehun Han on blood spots from infants, and that is in the testing mode in the state of Washington and may expand elsewhere. And around the world, there are other pilot programs looking at genomic screening. Those -- that has depending upon the ethics involved of societal acceptance for that.

In Europe, it's right now a very difficult cell. In the U.S., there are some start-up programs already beginning pilots for genetic screening. The big question separately if you follow those you find and what degree of phenotypic characterization do you have? And when do you begin safe therapy? Because if you take an infant and overtreat them, it's very different than the risk in an older patient because the young ones have growth and development to consider, especially brain development, which is copper dependent. If you look at the disease, Nike's disease, it's a great example where copper transport problems lead to neuronal significant degenerative disease. So you don't want to recreate that.

So we hope [Technical Difficulty] changes in what's acceptable as a pathogenic mutation versus a variant of uncertain significance. And those change over time as we have better tools to characterize patients. So nothing is going to be perfect, but we believe it's certainly going to find patients earlier on, which will be better.

[ id="-1" name="Operator" /> Our next question comes from Silvan Tuerkcan with Citizens.

For this informative webcast. I just have a question on the current standard of care. First of all, you mentioned that there's about 30 to 50 patients that become nonadherent to their chelators or zinc. I mean, what do these patients do once they come off? Do they just cycle up to other therapies? Or can they just live without treatment? And then on the liver transplant numbers, are they -- this to the doctor or maybe the company, are the numbers of liver transplants due to Wilson's Disease known? And how much of the Wilson's Disease patients get a transplant?

So I'll answer the second one first. The numbers of patients with 5% of the patients with Wilson disease. And those are usually 2 main indications, acute liver failure and those who present with very advanced liver disease or who stop therapy or who fail therapy and have progressive disease. And these are patients usually with very advanced [Technical Difficulty] that don't do well otherwise. So it's only a small percent of patients, and it accounts only for a small percent of patients in the larger community of patients that are transplanted.

With respect to nonadherence or complications from therapies, this is a consequential. For example, with zinc, there's a nontolerance -- gastric nontolerance and about 30% upfront. And what happens with these, especially when you get patients are left to their own is people who don't feel well and they get stomach upset after taking them, obviously stop taking the medicine. Now hopefully, patients communicate well with their providers. We try to provide them with alternatives. But sometimes those are challenging.

And often they come back much later, either after suffering for a long period of time or [Technical Difficulty] we do well most of the time, but how you define well I caution you because when you start to look in very, very carefully and follow mental health, follow neurologic function, follow liver function, there are stutterings in some of the patient course, whereas you would prefer to see, obviously, a straight line to improvement in maintenance. And so you see a lot of up and down and other issues. And not to mention the cost of therapy and monitoring that becomes challenging.

If you have patients who advance to cirrhosis, then you have to do the standard patients with cirrhosis for hepatocellular carcinoma, for variceal and you have to treat them as you would any other patient with advanced liver disease. So there are consequences and including those who stop therapy and end up with liver failure and end up transplanted [Technical Difficulty] Fortunately, not that many, but it happens.

[ id="-1" name="Operator" /> Our next question comes from Soumit Roy with Jones.

Maybe a question for Dr. Schilsky. Initial Phase I patients, I guess, they would be on copper restricted diet and on the chelators. What is the functional cure eventually, it looks like 6 months off chelators? And second one is for -- probably for Allan. Trying to get a sense -- so the IND would be just for 1069Q? Or would you also do for R778Ls because the Asian populations probably have more of that. And any overlap in those populations where some are double mutants?

So success can be measured in different ways in a Phase I. Obviously, functional cure where 6 months isn't the benchmark that we would provide it much longer term. But to be honest, if we learn in the dosing that we have a partial cure, then we've learned something in the very early phase, and we still may reduce the amount of medicine needed restriction for some of those patients or help improve their hepatic histology. So there may be benefits even if we don't get to the final endpoint. But this is why we do studies because we don't have the answer instantly. We can only give our best estimate based on those 3 studies that we hope to get to the best endpoint. I'll turn that back now, Allan or Mohammed.

Yes. I mean the initial study will be first our -- what we call our anchor mutation in 1069Q. So that will be the first regulatory filing with 778 to follow. We'll study, obviously, 778 and 1069Q likely in the U.S. and then 778 also in the U.S. and Europe. And then 778 also as we think about the agent population. But we do have a list of a handful of other editors that will be fast followers as well. And again, we expect to be able to slot these right into the same IND. So it should be very -- again, as we talked about our modularity and efficiency approach, a lot more cost effective and faster as we kind of slot in additional indications.

[ id="-1" name="Operator" /> I'm showing no further questions at this time. I would now like to turn it back to Greg Dearborn for closing remarks.

Thank you very much for attending our Wilson Disease event this morning, and we look forward to executing on our Wilson Disease strategy in the months and years to come. You may now disconnect. Good day.

[ id="-1" name="Operator" /> This concludes today's conference call. Thank you for participating. You may now disconnect.