Conference Transcript - PRME 2026-06-04

Moria Raycroft, Analyst — Jefferies

Hi, everyone. My name is Moria Raycroft and one of the biotech analysts at Jeffries. I'd like to welcome Alan Ryan, CEO of Prime Medicines. Thanks so much for joining us today, Alan. 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.

Alan Ryan, CEO

Yeah, 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 one-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's disease, going after what are called transversion edits, etc. So again, the most versatile and the safest gene editing technology we think that exists out there. Got it. Yeah, it's a great intro to the

Moria Raycroft, Analyst — Jefferies

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 submission package at this point and what are the remaining gating factors?

Alan Ryan, CEO

Yeah, so I think all we've said all along is what our guidance is, and our guidance remains the same as a 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.

Moria Raycroft, Analyst — Jefferies

And is there more you could 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 1-2 and quickly try to accelerate development?

Alan Ryan, CEO

Yeah, so this is, we're planning on even this initial phase 1-2 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 you know data dependent will expedite

Moria Raycroft, Analyst — Jefferies

this as much as we can. Got it and you've already you've enrolled an estimated approximately 30 Wilson's disease patients across seven US academic centers in a pre-screening observational study just stopped enrolling earlier this month. How will this impact your enrollment timelines for the dose escalation

Alan Ryan, CEO

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 will have genotyped to confirm that H1069Q mutation, which is the initial mutation we'll be addressing 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.

Moria Raycroft, Analyst — Jefferies

And it's observational, so some of those patients may not qualify, or how should we think about that?

Alan Ryan, CEO

think about that as we're trying to enroll patients into that study that we think could be good

Moria Raycroft, Analyst — Jefferies

candidates for the clinical studies, 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. Yeah. Okay. Any more granularity? We're not going to give

Alan Ryan, CEO

updates on, you know, patient by patient enrollment into our study, but, you know, based on the timelines we put out there, I think that's a reasonable assumption. Got it. Okay. And at the

Moria Raycroft, Analyst — Jefferies

AHGCT 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, and mice. How many dose cords should we expect in escalation in your clinical study? And based on your human-equivalent dose modeling, are you starting at a dose where a functional cure is

Alan Ryan, CEO

to you? 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, you know, 20s, right, so hepatocyte editing in the, you know, call it 40 to 45 percent range, we're seeing almost complete normalization of copper metabolism preclinically. So, that suggests that, you know, 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 quote-unquote 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, you know, that suggests, you know, 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, you know, the better the data translates, hopefully the closer we are to that optimal biologic dose.

Moria Raycroft, Analyst — Jefferies

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?

Alan Ryan, CEO

Yeah, 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 suggest 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 percent editing, and we think we've got, you know, 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, you know, at least what we've seen pre-clinically, we're very encouraged with that data set.

Moria Raycroft, Analyst — Jefferies

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

Alan Ryan, CEO

ceruloplasmin. I can never say that word either. Ceruloplasmin.

Moria Raycroft, Analyst — Jefferies

Yeah, ceruloplasmin. 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?

Alan Ryan, CEO

Yeah, 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, you know, serum copper, urinary fecal copper. So the way I like to think about it is the way that copper is normally excreted, it's bound 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 into the bloodstream. It collects in different tissues in the body, so you obviously get that liver disease, but you also 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 know, 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.

Moria Raycroft, Analyst — Jefferies

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

Alan Ryan, CEO

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 six to eight weeks after that patient's dose. And that should show 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 radio-labeled copper. So you're seeing their 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's some other measures of seroplasmin and seroplasmin-like measures, something called NCC, that you could look at. Those will also all be very helpful measures to sort of gauge where you are in terms

Moria Raycroft, Analyst — Jefferies

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

Alan Ryan, CEO

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 radiolabeled copper assessment. So that's something that's in progress as well but that will be included in the initial study from a regular 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 companies of 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 nor have normalized copper once you've removed standard of care but there's also the possibility of you know could this be something that's used as a as an endpoint in 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 that the stronger are your data set, I think the more flexibility the FDA could have. Got it. Makes sense. And

Moria Raycroft, Analyst — Jefferies

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

Alan Ryan, CEO

monitoring in the study? Yeah. So, we do have some prophylactic or some drugs that are given just sort of right, you know, kind of just before you treat. So, that does exist here. But you don't have to do, you know, significant steroid loads or anything like that. From a safety standpoint, you know, we can just look at what we've done preclinically. And we have benchmarked our lipid again, some of the other lipids that have gone into the clinic. And we do see improved measures when we compare across liver function tests, when we compare across some of the inflammatory markers, and we compare across some of the coagulation markers that you see. Well, you know, 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, you know, we hope that therapeutic index is something that hopefully plays in here, and this is very safe in that population.

Moria Raycroft, Analyst — Jefferies

Yeah, that makes sense. And as you look at 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 data set?

Alan Ryan, CEO

Yeah, I mean, I'll never say never to anything. I mean, I think everything's kind of always on the table with this stuff. I think we, I mean, obviously with CGD, we came out with one patient and then a second patient. We ultimately only dose two patients. And then in the end, we're actually going to be filing for a BLA just on two patients' worth of data. But I think in general, it's better to put out a more fulsome data set where investors can really, and physicians and patients, can really understand what that data is. You know, 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 data set that that we think is is validating and it's the right time to share that data set publicly, we'll do that. And I think if it's important to share for patients and for others, when we have a data set we feel is is ready, we'll report it.

Moria Raycroft, Analyst — Jefferies

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 saying on the status of the filing and what are remaining gate effectors there?

Alan Ryan, CEO

Yeah, so same thing at Wilson. I'll sort of not answer the question at the same point and just say, you know, same – no change to guidance at this time.

Moria Raycroft, Analyst — Jefferies

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

Alan Ryan, CEO

Again, just can refer you to our guidance.

Moria Raycroft, Analyst — Jefferies

Okay. And for the phase one, do you plan for your phase one to follow a similar staggered part A and part B structure as beam, where you separate lung and liver patients to establish LMP safety? Or is there an opportunity for cohorts to enroll concurrently to accelerate development timelines?

Alan Ryan, CEO

Yeah, it's a good question. You know, Wilson is a little bit ahead of Alpha-1. Whether that's going to sort of play into, you know, 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'd think about it as probably going into different cohorts, not so much from a safety standpoint. Actually, I think it more so from a just efficacy standpoint. I think seeing efficacy for lung disease, you know, 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 the liver that can get So my expectation is we'll start off similarly with lung disease, but, you know, the goal will be to pivot to liver disease patients as well.

Moria Raycroft, Analyst — Jefferies

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?

Alan Ryan, CEO

uh 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 long a much longer period of time you know some companies and this is more sort of luck of the draw if you get a patient that's undergoing some type of inflammatory uh response to infection um you know, and you see elevated CRP, et cetera, yes, you can show, 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 is most companies are going to be going forward looking at biomarkers, predominantly AAT. There might be another couple of things they 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

Moria Raycroft, Analyst — Jefferies

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 two 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 evaluated in mice? And with your data and others' data, what are the key things to know about your dose range strategy? Yeah, I mean, I'll caveat this

Alan Ryan, CEO

in the same way, right? Until you have sort of what your agreed upon dose level is, you know, 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, you know, if we're successful starting where we want to start in that specific study, that should be fairly close to that lower dose level.

Moria Raycroft, Analyst — Jefferies

And should we expect a more comprehensive preclinical update for your ATD program at a medical conference in 2026?

Alan Ryan, CEO

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.

Moria Raycroft, Analyst — Jefferies

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 timelines for potential resolution?

Alan Ryan, CEO

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

Moria Raycroft, Analyst — Jefferies

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

Alan Ryan, CEO

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 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 a 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

Moria Raycroft, Analyst — Jefferies

efficiency that we're able to achieve. Got it. And so that's basically should be very independent from the collaboration agreement. Yeah. I mean, if you read the language of the

Alan Ryan, CEO

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 fields. 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.

Moria Raycroft, Analyst — Jefferies

Got it. Okay. Rifles is going to report pivotal AATD data second half of this year using PD-15 to measure emphysema progression at two different doses. What are you looking for in the data, and what type of read-through will I have to prime?

Alan Ryan, CEO

Yeah, so this is the replacement therapy? Yeah, I mean, 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, you know, opt for this one-and-done therapy if they have that option. You know, 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. You know, 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, are they really having a strong benefit?

Moria Raycroft, Analyst — Jefferies

Makes sense. And for cystic fibrosis, moving on with your pipeline to cystic fibrosis, what are the specific hurdles in optimizing LMP versus AV 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?

Alan Ryan, CEO

Yeah, so there's a couple of different approaches here. So I think we're focusing more on LNP versus AAV for, you know, probably just in the five minutes I won't go into it or probably for obvious reasons to a lot of people. I think LNP would be a preferable approach here. And in thinking about that approach, you know, 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, you know, treat a few times and you're done kind of therapy and cystic fibrosis. And that would be a huge win for patients. But another huge win for patients could be, well, what if I could get to the secretory cells? Maybe I get to some of those 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, two months, three months, or even longer, potentially, depending on that could be different for a cystic fibrosis patient, though, maybe there's actually a drug I can dose with a prime editor that is dosed, I don't know, twice a year, three times a year, even four times a year. You know, we know some of these drugs with LMPs have been dosed daily. And there's been some tox daily, but we know others that have been dosed even three times a week where we haven't seen, you know, 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 you know call it 10 to 15 percent of patients that for whatever reason either because of their mutation or because of tolerability just can't take current standard of care you know 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 you know 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 uh internally and with the cystic fibrosis foundation to really try and and figure out um and we're hopeful that we're going to get to some real proof of concept data this year uh pre-clinically that we can really get towards a dc and ultimately get to ind enabling studies here because we see this is a really really important population to treat we're also not going to stop there so even you know 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 Trakafta 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

Moria Raycroft, Analyst — Jefferies

the CF population got it and for the 507 508 just just out of curiosity is that a pan genotype

Alan Ryan, CEO

uh editor there or so what we do so if you think about the editing window like usually we're covering i don't know um you know we could do longer base pair edits but you can you know very easily do 10 15 20 base pairs and so you can cover if two mutations are sort of right beside each other and think about it as one editor can really cover both of those mutation we call those hot hot spot editing when one editor can 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 one or two or three mutations that are very close together, then one editor can address all of those. Got it. And you've

Moria Raycroft, Analyst — Jefferies

got technology that could address it's pan-genotype passage technology. Oh, passage. Yes.

Alan Ryan, CEO

Sorry. I didn't know that's where you're going. Yeah.

Moria Raycroft, Analyst — Jefferies

So passage would be if we're, you know,

Alan Ryan, CEO

whole genes maybe are or maybe it's not a whole gene, but you can do pretty significant, you know, almost whole introns. So there you can do, yes, pan-large insertions. You can cover, you know, the majority of mutations essentially with one large insertion. That's something we are also working on with the CF Foundation. You know, that is, you know, 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 passage, that's going to be a great pan solution as well.

Moria Raycroft, Analyst — Jefferies

And you've highlighted potential to expand into larger liver-based syndications, and noted development plans are still being finalized. When should we expect more clarity on that?

Alan Ryan, CEO

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, you know, frankly, a lot larger even than Wilson disease and alpha-1, antitripsin deficiency. And so hopefully we have more to say on that as we move along there.

Moria Raycroft, Analyst — Jefferies

Any update on the collaboration with Bristol?

Alan Ryan, CEO

No, continues to progress well. A lot of big preclinical milestones there. So, you know, continue to make good progress there. They don't let us say anything, so not more I could say there, but good progress.

Moria Raycroft, Analyst — Jefferies

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.

Alan Ryan, CEO

So obviously, you mentioned the arbitration. We'll have that coming very soon. Getting these two programs ultimately into the clinic, getting to data and what I think is going to be proof of concept data from our first two 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.

Moria Raycroft, Analyst — Jefferies

Alan, thanks so much for joining us today.