Hi, everyone. My name is Maury Ray Crofton, one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome the CEO of Prime Medicine, Allan Reine. Thanks so much for joining us today, Allan.
Yeah, thank you for having us. I think this conference keeps getting better and better every year, so great to be here.
Yeah, good to hear. We're going to do fireside chat format. Maybe for those who are new to the story, if you can give a brief intro to Prime.
Yeah, it's hard to do the brief intro, but I'll go as fast as I can. I mean, I think of Prime Editing as really the most versatile gene editing technology in existence. I think it's both the most versatile way to edit the genome, but it's also the safest way to edit the genome, which I think is becoming even more important as we think about other things that are going on today. I always use the line, if you're doing any type of gene editing, it really should be done with Prime Editing. I think there's a lot of kind of reasons to kind of back that up. We're seeing more of that become a reality.
We're really excited about the sort of future of this technology and where we can take it, both with our internal programs, but hopefully broadening out with business partners and other ways to get what I think is a very important technology to more patients over time.
Got it. Yeah, it's a good intro, and we'll dive into individual programs. Maybe to help set the stage more, if we could just talk about how your technology differentiates versus the other modalities.
Yeah, so the way the technology differentiates, so I think about it as CRISPR-based editing and as Prime Editing, sort of the main gene editing technologies out there today. As we think about CRISPR Cas9 editing, there you're making it, you've got a guide, which is very effective at finding the right place in the DNA to cut. You're doing a double-stranded break. You're going to get indels and the possibility to form proteins that ultimately the body can react to, potentially, because some of the indels can form frame shifts and other things. There's also the potential for off-target effects as well, so off-target editing with CRISPR-based therapies. Also, you can get chromosomal translocations and rearrangements. There's a lot of stuff that can happen with that type of technology. We potentially are seeing some of that occur in patients today.
Base editing was, I think, a huge leap forward in that now you're adding an enzyme to the mix. This was invented in David Liu's lab. You're using that same sort of search RNA guide. Now you're adding onto it a nickase. Instead of a double-stranded break, you're making a single-stranded break. They're using an enzyme where now you can modify a purine to a purine or a pyrimidine to a pyrimidine. You can make four of the base changes, but it's only that single base pair that you're changing. With that technology, you can also get something called bystander edits. Let's say you're going from A to a C. Every A within that editing window could be converted to a C. You're not always getting sort of wild-type protein when you're trying to make a correction.
With Prime Editing, also at David Liu's lab, you're adding reverse transcriptase to the mix. Now you're getting that single-stranded break. We can write in any amount of DNA. We can go right back to wild-type protein in every case. We don't get any of the unwanted off-target editing, on-target editing that's unwanted. This is a really powerful technology. We can also do very specific, large multi-kilobase insertions. There are a lot of different places to take this technology.
OK, that makes sense. A lot of people ask about your LNPs, too, and how those are differentiated. Maybe talk about your universal LNP technology. What are some of the specifics that make them unique?
Yeah, I think everyone's got sort of a different LNP. Even if they're using the same ionizable lipid, they'll have different ways of formulating them. There's a lot of know-how and expertise that goes into this. We're using an LNP, at least an ionizable lipid, that we don't believe has been in the clinic yet. We've done some benchmarking preclinically because we know kind of what the acute toss lipid that many are using is and how that's formulated. As we look at LFT elevations and coagulation effects and effects on cytokines, we see a very sort of favorable profile, at least preclinically. We're encouraged that, one, we think we'll have a nice therapeutic index. We've got to see if that plays out in humans.
Also, the potential that we can even dose higher, where we've seen others dose in the clinic, not necessarily like we have to dose higher. We're looking for potency levels where we can be under that sort of 1 mg per kg. There is the potential, based off what we're seeing preclinically, that maybe we could go higher if needed.
Got it. OK, that's helpful. Let's dive into Wilson's disease, where you've shown some great preclinical data from that program. I had an event, I think it was last week, on that as well. You're going to file IND, CTA, or CTA in the first half of next year and show clinical data 2027. Maybe talk about the program there, different biomarker endpoints that you plan to focus on in the phase I and II study to demonstrate functional restoration of copper transport.
Yeah, so it's a really interesting disease because I still think there's high unmet need here. The mutations that we're going after, called sort of most of them are transversion mutations. There's no other gene editing technology that can really do these corrections. It can't be done with base editing. Can't do it with CRISPR. That's why you don't see a lot of competing programs for Wilson's disease. It's also a sizable market opportunity. In terms of biomarkers as we go into the clinic, if patients are on standards of care, which are chelators or zinc salts, what that does, it could cause one thing. One, you're trying to prevent copper absorption. Two, it's trying to sort of chelate. It's trying to bind to the copper and allow for excretion through the urine. Typically, you'd want to see copper.
If you don't have the mutation, your enzyme is binding to copper, and you're getting excretion through the bile and ultimately through the feces. That's kind of what you want to see. There are a number of ways to try and visualize this. One thing we're doing in some patients is going to be a copper PET scan. We actually just released some data at AASLD last week, which is in our corporate deck, which I encourage people to look up, which shows you a really—we're basically taking these animals, and we're taking a diseased animal with Wilson's disease and essentially normalizing them. You can see even a picture of the copper PET in our presentation. You can see what wild-type looks like, what the diseased liver looks like, which is just lighting up with copper.
You can look at what a treated animal looks like. It's almost right back to wild-type. When you look at the data, we're showing almost complete, we're showing complete resolution of liver copper in those animals. You're seeing all that copper excreted in the feces, which is where you want to see it excreted. It's a really nice data set. We're getting very high levels of editing efficiency. That's one thing that we can look at to try and ascertain essentially what dose levels you're at and if you're kind of getting to the point where you're getting sort of full copper homeostasis in these patients. There are other things that you can look at. You can look at seroplasmin, which is, and what the amount that's bound to copper, unbound to copper. That shouldn't be affected necessarily by standard of care.
That's something you can see even a patient on standard of care. There's a couple of other biomarkers we're looking at. Ultimately, you want to take these patients off standard of care and show that they're maintaining that normal copper balance.
Right. To take them off standard of care, I guess, how would you do that? What are some of the key biomarker thresholds you're going to be looking at to do that?
Yeah, so we're going through some of those protocols now. I'm not going to disclose exactly how we're doing that. We're still talking through some of that. You want some signals that you think these patients are stable. You want to give the we should have a pretty quick impact. If the drug, if the editor is working, you should be able to see that effect in a couple of weeks. At least in mice, that's maximizing even at four weeks. It could be pretty early that we could potentially take patients off those standards of care. We'll look at all these different biomarkers to ascertain if we think that patient is, so one example is looking at fecal copper.
These patients that are on standard of care, they're going to be excreting the majority of their copper through their urine and not the feces. If we can show we're getting normal copper excretion through fecal copper and urinary copper showing that's decreasing, that's one example of, OK, this would lead you to take away standard of care. If we can show through copper PET that we're really de-coppering the liver effectively, then that can be another reason, hey, this patient is a patient that can come off standard of care. We are still working through those protocols and finalizing those protocols. We actually did an event last week, which a number of the thought leaders across the world to try and figure out what the right approach is going to be as we think about the clinical plan.
Got it. OK, that's helpful. Given that this is a rare disease, can you talk about strategies to expedite screening, sequencing, and enrolling patients with the H1069Q mutation and target the fibrosis score?
Yeah, so we've actually already started a pre-study. We're actually doing a screening study now. It's not obviously a study where we're treating patients yet. What we're doing is we're going out there and enrolling patients to genotype them so that we can really figure out kind of where the patients are today. We think that'll really allow us to expedite, one, getting those sites up and running once we clear our regulatory filing to start the studies. Also, we'll have identified a lot of these patients and have them genotyped or regenotyped if they've been genotyped in the past to confirm their mutations to be able to move very quickly. It's rare. I think about really rare and rare but not as rare because you can have some where there's ends of ones or 10 or 20 or 100.
Wilson's disease affects about, call it, 10,000-11,000 patients in the U.S. The first mutation that we're targeting goes after, call it, 30%-50% of that patient population. We think ultimately, with a handful of editors, we can probably get to 60%-ish of the U.S. and European population. If you think about Asia, that number is even higher because the prevalence rate is higher. The mutational backdrop is we might be able to get to an even higher percentage. It's rare. Those patients are there. Just talking to a number of KOLs at AASLD last weekend, there's a lot of patients that they'd like to get in the study when this opens. There's a lot of excitement around what we're doing here.
Can you say how many patients you've genotyped so far?
We just started that study. That is just getting going.
Got it. OK. For type of liver disease at baseline, I guess any perspective on that? You've mentioned moderate liver disease. Can you clarify whether that means that you're going to go into F2 or F3 patients? Will you enroll patients with compensated cirrhosis?
Yeah, at the outset, we're going to exclude patients at the outset that have decompensated liver disease, which is a minority. I think it's important to not start with those patients. I don't think we're going to restrict beyond that. I think the ability to treat compensated liver disease will be there even at the outset. We may, for the first number of patients, treat kind of a little bit earlier on. Ultimately, we'd like to get to we will definitely enroll those compensated liver disease patients. Ultimately, once we prove safety, look into enrolling even decompensated liver disease patients.
Got it. For those patients that you're genotyping, those will go into natural history data set. Is that?
I mean, I think those are patients we'd like to enroll. I don't know that a natural history data set is going to be particularly helpful as it comes to Wilson's disease. If these patients, and again, noncompliance is a huge issue with a lot of the current standards of care, but if they're compliant with their low copper diets, they're compliant on zinc salts or the chelators, the disease can progress. It will progress slowly, and many patients can be stable. I don't know that natural history is necessarily what we'd think about here. I think it's going to be more about, hey, can we cure this disease? Can we really change the lives of these patients? If we can do that, I think that's going to be pretty obvious with the therapy that we're, with these therapies.
Got it. From a comparison standpoint, it'd probably be versus baseline? That's how you're thinking about it?
Again, this is an FDA conversation once we're in the clinic. Yeah, I think ultimately, this is against baseline. Can I take a patient off their standard of care and show that we've essentially normalized their copper metabolism?
Got it. OK. Any other perspective on competitors in the space? There's been chatter around Monopar with the next-gen chelator. Any thoughts on physicians?
Yeah, look, I think Monopar is an interesting drug. It's basically a different way to chelate in a sense. It's not something that I see it could be competitive to the chelators. I don't see it competitive to what we're doing, which is really a cure. It's not a it's potentially something you could take less frequently. There's still some debate. Is it chelating? Or is it causing an effect on actual copper absorption? There's some debate over mechanism there as well. I hope it gets approved. I hope there's more options for patients. I don't see that as sort of a competitor to what we're doing to really cure this disease.
Got it. What are your thoughts on the FDA's plausible mechanism pathway that was published last week in the New England Journal of Medicine? Does this de-risk the umbrella IND framework for different mutations and platform approach for Wilson?
What I hope it does is ultimately to help de-risk in the future, maybe getting to commercial faster for some of these as you think about multiple mutations. I think there's already been a pathway, at least we believe in our conversations, where you can do multiple mutations under one IND. I think what they commented on last week further emphasizes that. Also, is there a way to get to approvals without studying every mutation, as an example, once you have the drug? To me, that's the FDA really trying to go after these unmet needs, figuring out a way to make it not as burdensome to the companies in terms of costs or academics in terms of costs, et cetera. I think they're really putting their words, and I think there's actions behind those words.
I think it's really promising as we think about Prime Editing technology, what we can deliver to patients and how to get these more Prime Editors to patients faster.
Got it. OK. Let's shift gears and talk about your AATD prime editor program that's on track to enter the clinic in the middle of next year and read out data in 2027. How do you think that your prime editor is differentiated versus the base editing approach from Beam? What are variables that could lead to as good or better results?
Yeah, so the base editing approach and they've shown some decent data, I think, today. As you think about what base editing is doing, that edit also, the majority of edited protein, it'll have the correction. It'll also have a bystander edit. The bystander edited protein, it is functional against neutrophil elastase. It's not as functional as wild-type protein. I think there'll always be some questions sort of lingering as you think about activity. Obviously, alpha-1, I mean, it's active against not just neutrophil elastase, but multiple serine proteases throughout the body. It's also how functional is it against other serine proteases as well. I think you'll also want to see some data on how does it traffic out of the liver. There's always going to be some other questions.
To me, I think if you have the option to edit something back to wild-type under endogenous control versus edit something that's not quite wild-type, I think most physicians and patients will probably pick something that takes you back to wild-type where there aren't some of these maybe theoretical questions, but real questions that we won't necessarily have answers to.
Got it. OK. Do you think your universal LNP delivery system could lead to better delivery and higher levels of editing?
It's possible. I think it's definitely possible as we dose patients. I can't say I've looked at data preclinically that necessarily says what we're going to see in terms of editing efficiency or anything versus Beam. I'm hopeful we'll see we've shown at least preclinically in our models, we get very high levels of editing. We're normalizing alpha-1 levels in the serum. I'm hoping that that will translate into humans.
How are you thinking about the clinical study in terms of types of patients and other design elements relative to Beam's study?
Yeah, look, I think they've done a good job in how they designed that study. I don't think we need to kind of reinvent the wheel here. I can't say it's going to be identical. I think it's a reasonable way to think about how to design an early study in alpha-1. They're not the first. There are many alpha-1 therapies that are out there. There's obviously the RNA editors, both of which have just had data recently. You've seen what they've done in early studies, how Beam's run their early study. I think there's a pretty clear pathway on how to, one, what type of patients you want to enroll and what type of, we can look at a pretty clear biomarker pretty early in this indication.
Right. How are you setting expectations for AAT levels and percentage correction to MAAT? What do you want to see there?
Yeah, look, again, what we see preclinically is we're getting serum levels into that normal level. So what is that? That's above 20. What we're seeing in terms of M is we're seeing high 90%+ M protein. The hope is you'll see good translation from animal to human.
Got it. Yeah, so you think the data from preclinical should be pretty translatable to humans then?
I hope so. I mean, I think we've seen with a lot of gene editing therapies that have gone into the clinic that that translation has been really, really strong. I think that's the one, not the one, but it's a nice advantage to this type of technology that we've seen that happen. As I think about translating our data, I think it's very promising. Again, we've got to do our studies and look at our data. I'm very hopeful we'll see that.
For moving into the clinic, anything more you can say about just how much data you'd want to get to in 2027? I guess how do you think about the different doses you're going to assess?
Yeah, I mean, for alpha-1, you're asking about alpha-1, not Wilson. For alpha-1, you can go pretty quickly. We've seen other companies do this in even nine months. Going pretty quickly from dosing your first patient to getting a number of cohorts in, I can't promise you we're going to do nine months. I'm saying you've seen that happen before. You're really looking at AAT levels, and you can look at that pretty early. You can know pretty early in your study. In terms of doses and patients, we haven't commented yet. Obviously, once you finish all your tox studies and you submit, you'll try and dose at the highest biologically active dose you can. We'll see kind of where we end up starting. Yeah, I would say it's somewhere probably a dozen or so patients would be my guess, give or take.
Is it kind of the same principles for Wilson's disease as well?
I think so.
OK. OK. Let's talk briefly about cystic fibrosis. For this program, you're going to have preclinical data 2026. Maybe talk about how you're tailoring your LNP platform to deliver Prime Editors to the lung. What are the challenges here?
Yeah, so it's not just LNP. For the lung for cystic fibrosis, we're working with and the Cystic Fibrosis Foundation is essentially funding this program right now, which is great. They've been incredible partners to us. We have two approaches. We're doing both AAV and LNP. We're also doing hotspot editing, I guess, more than, and we're doing sort of passage as well behind that. In terms of sort of from a platform basis, a lot of the AAV stuff we've done internally. We're looking externally for technologies as well. We're working with a couple of companies just in sort of different models to assess different LNPs and different AAVs. There are some technologies we think look really promising to carry forward. We haven't sort of presented, but we've had some nice breakthroughs, I think, on both the AAV side and the LNP side.
We hope that momentum continues. We can ultimately work towards getting a DC that we can take in IND enabling studies at some point. I think this is a really important program. I mean, what Vertex has done for these patients has been incredible. There are patients that still either can't tolerate that therapy or there are certain nonsense, certain mutations where the therapies are ineffective. Somewhere between 10%-15% of patients, this disease is not what it's become for the other 85%, which has been a dramatic change. I think that's why the CF Foundation and us are really focused on how do we get these therapies to really change the lives of these patients that have not been affected by the current standard of care. We're really excited about this program.
We're really pushing hard here because we know how important this is to get this to patients in need.
Got it. You have talked about additional BD deals in the past. Obviously, cystic fibrosis has a lot of pharma interest. Is this a program that you could try to partner out? Is it important for you to keep this one in-house?
Look, I think nothing's sacred. I think as we look across both our pipeline and some of the other programs that we're talking to partners about, there's just so much potential for this technology. I mean, we're focused on the liver today and the lung and obviously ex vivo CAR-T with BMS. As I think about the potential, whether it's developing best-in-class iPSC-derived, cells derived from iPSCs, as I think about the many different diseases we can go after in the brain, the eye, the ear, et cetera, other liver diseases we can go after, I mean, there's just so many different indications we can ultimately pursue. Some of these are going to be done via collaboration. We're definitely active there.
In terms of CF, I mean, when I say nothing's sacred, for the right business terms, at any point, we would partner anything because there's just so much for us to do. It's not a one-product company. It's going to be a many-product company over time. I do think this is an area where we could take this forward on our own. I don't see any reason to partner that program today. That's something we might reevaluate in the future.
Got it. For the Bristol partnership, do you think is there a potential to get some preclinical milestones?
Yes, yes. They're pretty sizable milestones. There definitely is that potential, yes.
For next year?
Potentially next year.
OK. OK. Maybe back to the clinical program. For initial doses they are going to pick, are they going to be therapeutically relevant for the first?
That's the goal. We don't make the final decision, the FDA does. The goal is to be at a biologically active dose.
Would you consider a multidosing approach?
Eventually. We might not start with that. Eventually, we'd like to get there, yes, where we hope we have a therapy that we don't need to redose. In the future, we'd like the ability to redose, especially for patients that are starting at subtherapeutic doses to be able to get your therapy later on.
Got it. OK. So maybe in closing out, maybe just talk about the key catalysts ahead that investors should focus on over the next 6-12 months.
Yeah, I mean, it's going to be getting the regulatory filings done for both Wilson's and alpha-1, ultimately enrolling patients next year, getting to really strong preclinical data for CF showing we're getting high editing and the right types of cell types in the lung, and ultimately gearing towards clinical data. Also important, I think, is getting some BD deals done as well to help to continue to fund the company and move more programs forward. We're also continuing to have conversations with the FDA on CGD as well. There's still some potential there, which I know we don't have time for today. Still actively pursuing that.
Got it. OK. Thanks so much for joining us today, Allan.
Thanks.