Prime Medicine, Inc. ($PRME)

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?

1 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?

1 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.

0 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. .

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

Thank you, appreciate it. Thanks for having us.