All right, everyone. I think we'll go ahead and get started. Thank you for joining us on day 3 of TD Cowen's 46th Annual Healthcare Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen. It is my pleasure to have with me today the team from Prime Medicine. Up here with me, we have the CEO, Allan Reine. Maybe just to kick things off, before we go into the individual programs, if you wanna 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.
Yeah, sure. First off, Joe, thanks for having us, at your conference this year. Sort of state of the company, this is a really important year for Prime. you know, I couldn't be sort of more excited to be in the seat that I'm in today, kinda watching, one, all the progress that has been made last year as we really get ready to put, our first two in vivo liver-directed programs into the clinic, and that's gonna be Wilson disease, and alpha-1 antitrypsin deficiency. We have both regulatory IND/CTAs, going in, we said for Wilson disease, the first half of this year. For alpha-1 antitrypsin deficiency, we said middle of this year. Both of those are coming soon. Ultimately getting those into patients and generating some clinical data.
We continue to make progress across the company. Our cystic fibrosis program, which is being, you know, predominantly funded by the Cystic Fibrosis Foundation, making good progress there. Hoping to get to some preclinical proof of concept data this year. With our collaborators at BMS, moving forward with our ex vivo CAR T therapies. I think beyond that, we announced yesterday that we are planning to file a BLA for our Chronic Granulomatous Disease program.
We've treated two patients to date and believe we've seen data that has been published in the New England Journal of Medicine back in December, but really, you know, I think transformed the lives of these two patients, and we think this could be a very important therapy for that disease.
Perfect. Maybe we'll start there, 'cause obviously after the first two patient data, you know, you suggested that you wouldn't really take this one forward on your own. I guess what with the FDA recently and any sort of communications or guidance from them kinda led to this decision? Is this something that I guess that you would launch, or would you still look for a partner to kinda commercialize it?
A couple things I'll say there. 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? If you think about CGD, there's maybe 1,000-2,000 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, call it 250 patients. The majority of them have actually had allogeneic transplant. That might leave 50 ± patients left to treat. 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-$100 million as you think about the CMC requirements, clinical requirements, the people that are needed to do that. We made that decision, unfortunately, and it was unfortunate 'cause 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, with that type of procedure.
You know, 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, you know, these ultra kind of rare indications and offering more flexibility. As we kind of listened 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, you know, great data. We believe that should be supportive of taking something like this forward.
Yeah, 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, you know, they're supportive of us taking that forward. You know, there's still some other things. There's manufacturing, other things that we still wanna get final alignment on, but, you know, in every scenario, we feel like there is a path forward here that makes sense from a, from a spend standpoint, where it's, you know, somewhat minimal spend, and ultimately we can get this important drug to patients.
Maybe if you could just let us know what's next? I guess, have you requested a pre-BLA meeting? Kinda what's the next we'll hear maybe on, you know, the next steps for CGD?
Yeah. I mean, we've already had conversations, so there's always, you know, formal, informal conversations that obviously go on. You know, we haven't kinda commented what the next communication will be. We'll kind of update people as we go. I think I just wanna make clear, we are going to file this BLA. You know, I still think we're still figuring out timing, so whether that's something that happens this year or at some time in the first half of next year will depend on a couple of things, but this is going to happen. It's just a question of when.
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?
I mean, look, when you think about Prime Editing, you know, I come at it from. You know, there's two ways to come at it. One, can I get high levels of editing efficiency in the cell type that I'm trying to target? 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. What we've shown in HSCs is we can get very high levels of editing efficiency, and that high level of editing efficiency is translating into clinical studies into humans. It also becomes about delivery, right? This is always gonna be a delivery question when you're talking about gene editing.
You know, we always say we've got the best cargo, you also need the best delivery vehicle to get that cargo to the tissue type. 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, so lipid nanoparticles, that target the liver. To me, it's we've sort of de-risked 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, we've got to show that translation as well ultimately.
Great. Maybe we'll jump over to the other programs, 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?
Yeah. I think what's underappreciated for Wilson disease is really how high that unmet need is. I think there's 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, you know, 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. If you think about Wilson disease, this is a disease of impaired copper metabolism, so copper builds up in the liver. It 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. It's the, you know, 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. So it's a high burden to the patient, even on those medications. Even if you're well controlled, you know, you are still not metabolizing copper normally in your liver. 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. Compliance on these medications tends to be very low. It's about maybe, you know, I think a third or more of patients tend to be non-compliant with their medication. Again, this is a high unmet need, and this is something where we can really transform the lives of these patients. I think the idea here is obviously we're gonna 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 in, you know, 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. You know, we at least have shown preclinically we have less off target than some of these technologies, so there might be, you know, additional things that we maybe don't have to show in a sense. I think in general, it's, you know, we're not kinda giving the play-by-play, I guess, on all the IND and regulatory preparedness, but I would say we're well on track with our guidance of, you know, IND/CTA for Wilson in the first half.
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?
Yeah. If you think about what dose escalation looks like here, you know, typically companies have done, I'll say what they've done in the past, like cut two to three patients per cohort. The number of cohorts is gonna depend on a couple of things. One, what's your starting dose, and how high is your starting dose to your optimal biologic dose? You know, you hope to start at a minimum at a biologically active dose. Assuming we can start at a biologically active dose, you know, there'll be some number of cohorts to 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 gonna look at a number of different biomarkers, but one that I think is gonna be really important and can give us a really early read of preclinical, or sorry, clinical proof of concept, is looking at a radiolabeled copper PET study. What we do here is we're gonna, we're gonna do this study in patients before they get the treatment, and you'll be able to see the amount of copper that's kind of loaded into the liver. Do they have impaired or now are they gonna 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 gonna load with radiolabeled 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. 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 'cause they're not excreting copper through the normal route, through the fecal route, 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, be able to show that they have sort of normal copper.
Do you think in these patients, obviously, it's gonna be a liver-directed therapy, but you indicated some of the CNS neuropsych, you know, 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? Or how do we think about that?
Yeah, I mean, the answer is yes. You'd expect to see improvements in both. I think there are some neuropsychiatric deficits that are unrecoverable. 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. One of the downsides of standard of care is you can actually get an increase in neuropsychiatric symptomatology at the start of treatment. 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.
I think, you know, as I think about it, like, once you have sort of neurons that, you know, neurons that are essentially dead, those aren't necessarily gonna come back, but I think you can improve or at least halt the brain disease.
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 gonna need kind of a more traditional pivotal study looking at some of these endpoints?
Yeah, I mean, I think for Wilson disease, you know, there haven't been drugs really approved in a very long time, I think in, you know, a decade or more in the disease, and those have been sort of copper chelators, very different mechanisms. You know, I think it's gonna 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, you know, 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 kinda what you're doing. You know, think about copper PET as an example. We'll see what that looks like when we ultimately get to the clinic.
If you see incredibly strong data across, you know, a number of patients with copper PET, could that be something you could use, you know, as an endpoint? You know, I think ultimately, you know, I think about this as removing standard of care 'cause that's gonna be your goal here. You wanna get these patients off standard of care and show that they have normal copper metabolism off standard of care. Whether you're showing that at, you know, 3 months, 6 months, 12 months will probably be the negotiation with the FDA. I think that could serve as the basis for an approval.
Can you talk a little bit about the proportion of patients with Wilson's that you can address using this specific therapy? If you do see success here, are there other mutations that you can address or kind of how do we think about that?
Yeah. We kinda break it down based on different populations. If we think about the US, 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%-50% of that population. We'll go after additional editors that target different mutations. 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? That will really be, you know, sort of a commercial question that we'll have to ask at that time. I've sort of guided people to about 60% of the population.
When we go into different regions, so if we think about Asia and we think about Japan, it's actually a bit of a higher prevalence there, and the mutational backdrop is a little bit different. There, the first mutation we're going after is the most prevalent. It's called R778L. That's about, you know, again, 40+% of patients, and we think a handful of editors there, you know, can maybe get us to even 70% of patients.
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, you know, so the liver and lung manifestations. What's the ideal here?
Yeah, I mean, there's still nothing really new that's been approved yet, right? There's a lot of development and drug development in the space. The standard of care is still replacement therapy, you know, 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? 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, you know, 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 gene, normal protein. 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 three 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 to 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. You know, 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. There's a little bit of a litigation going on. I guess, what are the differential components between your therapy and theirs? What are sort of the next steps in that dispute?
The dispute there. It's not a litigation, it's an arbitration. The dispute there is we are doing Prime Editing, and Beam has rights to do Prime Editing for transition-only edits. You know, that's something that's sort of written in the contract that's public and how it says it. We believe our approach is sort of well within our rights. They're contesting that. We expect to have a resolution of the arbitration in the first half of this year.
Perfect. 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?
Yeah. I mean, I think for this program, it's, you know, a little bit different than Wilson disease, where here you've got a very clear biomarker that you can look at. You're looking at levels of AAT in the blood, and you can look at levels of mutated protein versus normal protein in the blood. These are measurements you can take. You can take them frequently. They're easy to get. You can see what it looks like at one week, two weeks, four weeks, you know, where you should have a, you know, maximal, starting to get to that sort of maximal effect. You'll know very early what this looks like. You hope to get, you know, patients as close to or into the normal range as you can.
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? What are things that you're gonna be looking for, just given some, you know, developments across the genetic medicine space?
Yeah. I mean, you can for some of these. You know, so once it's a one-time therapy, but you can give, you know, there's some medications you give to tamp down inflammation, et cetera, which I don't know the final protocol yet, but there are, you know, things that you can do. You know, that being said, we've got a very strong, you know, 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 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. We see that, again, this could have a wider safety margin. We'll have to prove that out, and time will tell.
We've seen a lot of companies sort of cap at, you know, a mg/kg or around that range. 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.
Maybe next, the company has indicated and it's gonna 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?
You know, I'll start with the unmet need. There are 10%-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. You know, even though that is a drug that has transformed the lives of a good chunk of this patient population, there is still high unmet need here. And the Cystic Fibrosis Foundation 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?
I think if you know, 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. Think about how powerful that is. Not only are we turning that back to normal, we're doing it under what we call endogenous control. The body's gonna 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. You know, this isn't a very abundant protein, so getting this under endogenous control, we think is very important. We think this is really the only treatment that can do that.
There's been a lot of approaches that use mRNA and other things that are trying to, you know, or genetic or gene therapy that are trying to get expression of CFTR in the relevant cell types. The question is, how much expression do you want? I think that's sort of an almost an unknown. Like, people are still unclear what the right amount of expression is. Are they getting too much? 'Cause you can see through some of these studies, like they're getting expression, but we're not seeing functional improvements. We don't have to ask that question because the body's already doing that for you. We're just turning that gene back to normal, letting the body decide how much CFTR should be expressed.
what's the status of the program, kind of when we'll see next preclinical or, early clinical data?
Yeah. We're making good progress there. We're in, I would say, lead optimization now. We're getting high levels of editing, and now it's really putting that together with delivery and getting the right delivery vehicle, and again, proving that we're getting to the right cell type and 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?
You've had the deal with BMS now a couple years. Maybe why were they the right partner? If you can go into the decision really to partner out the Prime Edited ex vivo CAR T product platform.
Yeah, 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 a, you know, oncology, immunology, infrastructure. But we believe, again, we've got the best cargo if you're gonna edit CAR T cells. BMS, you know, through their acquisitions is one of, well, Celgene ultimately joins one of the leaders within that field. They are, you know, an obvious partner for this. They're still investing heavily in this obviously, and think it's a very important modality as they move forward. Again, we've got the best cargo, so it's putting I think the best cargo with one of the top companies out there. You know, we're making good progress.
When you partner with a large pharma, there's not a lot that you can say.
Mm-hmm
... when you give away the program like that. I would say we're making good progress, they're great partners, and we're very happy with the status of the program.
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?
Yeah. What I could say is there are pretty significant preclinical milestones. We've said it's part of the collaboration. There's up to $185 million in preclinical milestones. You know, we haven't broken it down more than that, you can think about what preclinical means and, you know, you would think about that as, you know, call it before IND-enabling studies. You know, there are milestones that we think are very achievable. Hopefully as we get, you know, through to the first, you know, if you think about the ones that are subsequent to that, you know, once we've delivered a lot of the reagents, that could go a lot quicker as well potentially.
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. 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. What do you see outside of that?
Yeah, I think I break it down into different buckets. I think one bucket is, you know, there are certain things that we're just not gonna do ourselves. We know we're probably not gonna do ourselves, at least with our current build. 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. This is something that, you know, 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, 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 it's an area we're in, you know, 3 to 5 years from now, and I hope there are, you know, companies that are gonna be willing to kind of work within that space and take this technology forward. You know, I think beyond that, if I look at, you know, our current assets, you know, I think nothing's sacred, right? We're always open to partnering. I think it's gonna depend on what makes the most sense, you know, for Prime. We're gonna do, you know, the similar analyses and determine if, you know, 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. I think it's gonna continue to be a healthy mix of BD and other means as we think about, you know, financing this company going forward. You know, 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. You know, when I joined the companies, you know, we had like 18 plus programs 'cause we were trying to figure out where to go. You know, 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.
As we think out a year or 2 years, there's gonna be a lot more to do, right? It's I don't wanna say it's endless, but there are so many opportunities. There's always gonna be things for us to develop, and that's why nothing is sacred today.
Maybe can you talk a little bit about your current cash runway? What does that get you through for some of these catalysts? 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 kinda 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. Now that we are where we are today, we've 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. There's sort of this buried 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 January 1, 2027, we've got cash into 2027. We haven't said exactly when. As you know, our two big data events are gonna be in 2027.
You know, we're funded through obviously getting our INDs into the clinic, obviously getting through this, the arbitration that you mentioned, pushing forward with CF. When we talk about our runway, that doesn't include other things that could help fund the company. It doesn't include BD, it does not include BMS milestones, does not contemplate, you know, the CGD approval, et cetera. There's other things that can help really fund the company as we think about going forward. You know, we're at a burn rate now where the amount of money we actually need to get through 2027 is not significant. There really isn't a big, you know, funding overhang as we think about the company today, which is nice.
Awesome. Well, thank you very much for the great discussion.
Thank you.