Good day, everyone. Thanks for joining us today. My name is Arthur He, Senior Biotech Analyst at H.C. Wainwright & Co. Thanks for joining us to have a conversation with Dr. Allan Reine, the CEO of Prime Medicine. A little bit about Prime. Prime is a leading biotech company focused on developing novel gene and cell therapies based on its transformative Prime Editing platform. Allan, welcome.
Thank you. Thank you, Arthur.
So, Allan, for those who may not be so familiar with Prime, could you start by giving us a quick overview of this company and your pipeline today?
Yeah, so Prime Medicine is really named after the technology that we're advancing called Prime Editing. Prime Editing, you know, I like to think of as a next-generation sort of gene editing approach. It is really the most versatile way to edit a patient's genome, but it's also the safest way to edit a patient's genome. And we can get into a little bit of the science around this, but, you know, the way I think about it, what are the advantages, you know, versus other ways or other gene editing technologies? So if you think about sort of, you know, the original sort of CRISPR-Cas9 editing, we make only a single-stranded break in the DNA, so we're not making double-stranded breaks. When I talk about this being the safest way to edit the genome, we really don't see any off-target editing. We don't see chromosomal rearrangements, translocation.
So it's very, very gentle and very, very sort of safe as we think about the potential for these sort of off-target things to happen. In addition to that, it comes the versatility. So with CRISPR, you know, it does a very good job of sort of making a double-stranded cut and knocking things out. Technology called base editing does a very good job where it can change just, in four instances, one base pair to another base pair. But for the first time, this technology can really write in new genetic code directly into your genome and make a permanent change. And a permanent change back to what we call wild type or to normal protein. And we could do this across any different type of mutation. So it could be a transition mutation, transversion mutation, frame shift mutations.
We can do what's called Hotspot editing, where we can, through multiple base pairs, fix more than one mutation, so I might have a mutation, you might have a different mutation. One editor could treat both. With our PASSIGE technology , we can do very large insertions in very specific spots, so this is a very specific, highly efficient gene editing technology that just has incredible reach, as you think of the number of diseases we can go after. In terms of, to answer your question on our pipeline, we've really focused the company now on areas where we think we've got very high probability of success, or we also see we have high conviction in commercial success, so we've kind of merged those two together.
And for today, that really focuses us on our liver pipeline, which includes both a program in Wilson's disease and a program in alpha-1 antitrypsin deficiency. Both will go into the clinic next year. Wilson's in the first half of the year. Alpha-1, we've got it to an IND or CTA in the middle of the year. After that, we're working on our cystic fibrosis program. So we're looking, you know, to treat, you know, first, many of the mutations that are not amenable to current standards of care. So there's really a high unmet need as we think about CF. Ultimately, we think we can treat over 90% of patients. So we've got a couple of approaches there that we can talk to. We have a collaboration with BMS and ex vivo CAR-T that continues to progress well.
You know, and so that's sort of, I think, about our near-term focus. And as we think about the medium to long term, I think there'll be plenty of other opportunities as we think about liver disease, as we think about potential in neurological disease and other areas. So I think we're just sort of scratching the surface today of sort of what we could do with this technology. And I think as we think about kind of longer term, I really see sort of broad reach of what this company can do.
Oh, thanks, Allan. Speaking of the pipeline, so we know back in May, you guys made the decision to re-prioritize pipeline, even though I believe the CGD program had delivered a first clinical proof of concept. So could you walk us through a little bit on what drives the decision and how the discussion played out internally?
Yeah, so chronic granulomatous disease is something that affects maybe about, you know, let's call it 1,000 patients, give or take, in the U.S. So it's a very, what we call, ultra, ultra orphan disease. The first mutation we were going after there was called the sort of the p47phox mutation. This is something where, you know, maybe it's 25% of patients, about 250 patients in the U.S. We have an ex vivo approach where we're editing patients' hematopoietic stem cells. We did take that program into the clinic. And as you said, we saw two patients' worth of data, and it's really exceptional data. You know, in two patients, we believe we essentially have functionally cured their disease if we base it off of sort of allogeneic transplant and sort of what predicts, you know, long-term cures.
There's a sort of biomarker we could look at that sort of assesses if we're getting normal enzymatic activity. So, you know, this is a disease where you have a defective immune system. So your neutrophils essentially are not able to fight off infections like bacterial and viral and fungal infections. So, again, great data in two patients. But as we think about the commercial opportunity here, there really aren't enough patients to support, you know, a profitable venture for us to take this all the way and complete our clinical studies. So we made the very difficult decision to discontinue that program. You know, that being said, you know, we think this is really strong data. The only alternative is allogeneic transplant, which comes with, you know, increased risk of graft versus host disease, graft rejection.
You need to not just myelodeplete, but you need to lymphodeplete as well as part of the preconditioning regimen, so there's a lot of advantages to taking this Prime Editing drug, so we're going to have conversations with the FDA and see if there's, you know, something constructive we can do to try and get this to patients, and we'll, you know, see how that goes.
I see. So, as you mentioned, the CGD, the initial data look very strong. And how should we learn from that? And does that de-risk the broad platform-wise, both in terms of the in vivo and ex vivo potential from the Prime Editing?
Yeah, look, I think if you go back, you know, the company was founded when I would say the technology was discovered in 2019, you know, a company founded over the next couple of years. So it's not like we've been around that long, right? You know, and I think initially, it's like, wow, like this is just groundbreaking technology with what we can do with this. And I think the skeptics would say, okay, this is really cool. Like, this is an incredible science experiment. But are you going to be able to get to high-efficiency editing, right? Are you really going to be able to show that? Well, we've now demonstrated that. We've demonstrated that in multiple tissue types, right? We've shown it in the liver. We've shown it in the eye, in the ear, in the brain, in the lung.
So we've demonstrated the ability to do that. I always think about gene editing companies as both we're a gene editing company, right? Because that's what our base technology does. But we're also delivery companies in a sense, right? It's all about, can you deliver your cargo to the right cells, to the right tissue type to get the desired effect or the desired cure? So as we think about the HSC approach, we've demonstrated now that we can very effectively, in an ex vivo setting, get very high levels of editing efficiency, right? So we've sort of answered that question in human cells. We've now put those cells, you know, infused them back into the patient. They engrafted really, really well. The cells perform really well in the patient.
And so we've demonstrated if we can get the cargo to the right cell types, we can have the effect with our technology. So I think this helps sort of de-risk the, you know, do we have effective gene editors? Now the question is, you know, do you have the right delivery vehicle? And that's really why we prioritize the liver to begin with, because it's been demonstrated already, both with CRISPR-Cas9 editors, with base editors, that you can safely and effectively get this cargo to the liver using a lipid nanoparticle. So we feel like that creates a much higher probability of success. There are other areas where, you know, we've also been able to deliver very safely and effectively, like the eye and potentially the ear.
You know, for us, it's more a question of, is that the right allocation of capital today, you know, just given the risks in developing some of those programs? And the other area is the brain, where we think there is just a tremendous number of diseases to ultimately target. And we think the delivery, I'll say, problems there seem to be improving. We're seeing more, at least, gene therapy programs. We've seen improvements in delivery, and we think that will likely translate into improvements for gene editing delivery.
I see. So let's dive into your pipeline. So your leading program is for Wilson's disease, the PM577. I guess the first obvious question is, why did you choose this indication as your leading in vivo program? And maybe you can also help set the stage with a quick overview of the disease.
Yeah, so when I joined the company in January of 2024, one of the first things that I did, you know, the first kind of things that kicked off was a value framework exercise across all of our programs. We had, at the time, I think, listed 18 programs in our pipeline. And, you know, we kind of reviewed everything. It took us about three to four months to go through this. We looked at a number of different variables, parameters, you know, thinking about what's the commercial opportunity, what's the unmet need, what does the competition look like, you know, what's the clinical tractability, what's the technical feasibility. You know, so we really kind of evaluated everything to really feel like what's the right, what are the right programs to invest in today.
And as we think about kind of as we kind of went through that exercise, you know, what really came out at the top of that was Wilson's disease. As we think about Wilson's disease, it's caused predominantly by what are called transversion mutations. So there's no other type of gene editing approach that can correct that. You actually have to, if you want to do it with a gene editor, it has to be done with a Prime Editing approach. It is a disease where there haven't been really, you know, many changes, really, over the last, you know, decades. It's really just iron salts, zinc salts, and iron chelators, you know, medications that patients don't like taking, that docs would prefer to have alternatives to.
And so, you know, in patients where, you know, they can go on a low-carb diet, if they're adherent to their medicine, then they could live fairly normal lives. Many are non-compliant, given the difficulty in some taking these medicines. But also, even the ones that are compliant, they still do have a shortened lifespan, right? So this is not an answer for that disease. We could really, you know, if our preclinical data translates, you know, this could potentially, you know, cure these patients of their disease and normalize their protein and allow them to excrete copper in the normal way. So as we think about the market size here, you know, there are, you know, estimates around 10,000-11,000 patients in the U.S. alone.
And, you know, we think with a few different editors, because there would be a few different mutations that we go after, we can probably cover, you know, upwards of 60% of the patients in the U.S. There's probably a similar number in Europe. And then if you think about some of the Asian countries, the prevalence rate or the incidence rate is actually higher for Wilson's disease. So, you know, take Japan, for an example, where the population might be lower than the U.S., but they actually might have a similar number of patients with Wilson's. And actually, if you think about the mutational breakdown there, we might be able to get to 70+% of patients to treatment. So, you know, as we think about that, there could be, you know, well over 20,000 patients that we can treat globally.
That number could even be much higher, depending on which geographies we ultimately go to. And as we think about a gene editing therapy, that's actually, you know, a pretty big population. I know I put big in quotation marks because, you know, as we think about, you know, large pharma going after millions of patients. But when we're thinking about a one-and-done therapy, you know, when you think about where these therapies are generally priced, given what we think the pharmacoeconomic benefit could be, I mean, this could be, you know, potentially $20+ billion in revenues as we think about, you know, treating these patients over time.
I see. So for this program, you guys guided for the IND filing for first half next year.
That's correct.
So what has been done preclinically and what needs to be getting done before you guys submit the filing?
Yeah, I mean, so I'll just say we haven't kind of given an update on sort of where we are day-to-day other than the guidance and the IND. You know, you can envision all the things that have to be completed prior to an IND, which include, obviously, manufacturing your GLP lots, your GMP lots, your GLP tox studies, your sort of non-GLP tox studies that you have to do in addition to that. So, you know, we're making great progress towards that first half IND. You know, you could be assured we are working as hard as we can to get this filing in as early as we can, knowing how important this program is to the company, and the other thing, though, is we are guiding to data in 2027.
So, you know, given, you know, timing of when we think we're going to get into the clinic, and obviously, we haven't talked about this publicly, but what we think the number of dose cohorts, you know, will be, obviously, pending, you know, IND/CTA approval. You know, our expectation is data in 2027, and we think data will be pretty telling with what you have, right, so we think we should get a pretty early read of how well this drug is working.
Gotcha. So speak of the data in 2027. Could you give us a little bit of color on what we should think about the trial design? And most important, like, what sort of the biomarkers or even clinical endpoint we should be looking for?
Yeah, I mean, and we'll probably talk about A1AT, I'm guessing, or Alpha-1 interstitial disease after this, which is a little simpler, right? Because you've got a very easy biomarker, Alpha-1. You could just measure the AAT protein, right? So it's a sort of a simple measurement. Wilson's is not as simple because many patients, at least coming in, are going to be on standards of care. So although they'll still have copper in their liver, they will have, you know, kind of normalized copper to some extent, right? Although they'll see copper excreted in their urine versus copper being excreted in the feces. So it's a different way that copper is being mobilized. But many of the sort of biomarkers or things that you could test, you know, are a little bit more challenging.
So there are other things that we can go and measure that can be really telling early on. So first off, one thing we could look at is something called a copper PET scan, which is being, you know, utilized a little bit more in the field today. And you can get really nice images of what patients look like, and you can kind of take them off standard of care briefly to measure this. So you can kind of see what's going on. Are they excreting the copper through, you know, are you de-coppering the liver? And is that copper being excreted through the feces, meaning we've normalized the enzyme to facilitate copper excretion into the bile? Or, you know, are you still seeing copper in the liver and ultimately going into the bloodstream into the urine?
So that's a really, we think, could be a really effective tool to really tell us where we are on the dose-response curve, but also really tell us if we're, you know, mobilizing copper in the right way. Ceruloplasmin is another enzyme that really shouldn't be impacted by standard of care, something that we think we can look at as an important measurement as we think about this program. And then there's a number of other things that we can look at as well as we think about ultimately taking patients off of standard of care and assessing whether their copper maintains at normal levels.
Sure. So as you speak of the Alpha-1 program, which is your second liver program, and we see the space getting a little bit competitive as of today. So what makes you confident that the Prime Editing can stand out among the different treatment modality-wise?
Yeah, I mean, you know, we gave this question, obviously, a lot of thought before we became public with our program, right? We wanted to ensure that we had a best-in-class therapy because in this instance, we knew we were not going to be first, right? First in the clinic and potentially first to market, so as we think about the disease and what we can do with Prime Editing, so there are obviously replacement therapy, and we can, you know, have a debate over how effective replacement therapy is. I mean, this is sort of an interesting disease where, you know, the Alpha-1, it's an acute-phase protein that goes up considerably in response to inflammation or infection, right, so the question is, how much do you actually need of that protein in the lung for it to be protective?
And it's, you know, that's a level that, you know, your body is sort of responding to. So when you gene edit or you Prime Edit, we can keep the body under sort of its normal function, right? We call it endogenous control. It's using the same promoters, enhancers, everything. So when it wants you to turn on that gene to that level, it's doing that right at the source, right? So that's part one. So that's why we think, you know, replacement therapy, you know, is really not the answer because it really, you know, you're just giving a bolus that's coming down over time and then rebolusing the patient. In terms of, you know, there's RNA editors. We've seen some initial data. You know, and I think for the RNA editing therapies, one, it's chronic therapy, right?
So those are therapies that you're going to have to give, you know, continuously. I think still a debate over how frequently you need to give them. And still a question as well of maybe you can have the acute-phase response early, but are you going to be maintaining that acute-phase response sort of later in the dosing cycle? We don't know. There's questions to answer. And how high are you ultimately going to be able to edit? And so how high of a, you know, how high will it be able to get those AAT levels? I think right now we've seen levels that leave some room for improvement. We'll see where they get to on higher doses and more frequent dosing. And then in base editing, I think they've shown some really strong data that we've seen out of Beam.
But, you know, there you still do have what's called a bystander edit. So you're not getting the majority of protein you're producing is not the wild-type protein. And we think there's an advantage to going back to wild-type normal protein, which has, you know, 100% of the activity because it is normal protein.
I see. That's very helpful. And I just want to touch up on the delivery side. So you also mentioned Prime not only a gene editing company, but also a delivery company, right? And I believe both your Wilson's and Alpha-1 program are using your universal liver LNP, which has shown a very high hepatocyte editing efficiency already in the clinical models. So how scalable is that LNP delivery part across the broader liver indication or maybe even beyond liver? Could you give us more color on that?
Yeah, I mean, so, you know, this specific LNP that we're using, you know, we've seen, you know, at least so far, promising data where we think we've got a, you know, we look really good as we think about some of the studies we've done benchmarking against some of the other LNPs that we know have been in the clinic, and we see, you know, data that, you know, frankly, for Wilson's disease, if we're successful there, that's why Alpha-1 can go so quickly afterwards, because we can leverage both the manufacturing, but hopefully a lot of the learnings that we get from that program, so, you know, it's the potential to rely on some of the tox studies and other things as we go from one program to the next.
And each time we kind of use this LNP in the liver, you know, this is sort of what we call a modular approach, right? The path or the speed and the cost of getting programs two, which is Alpha-1, but then maybe three and four can also be protracted, cheaper, et cetera. So there's a lot of excitement for us as we think about, you know, what are other high-value programs that we can take to the liver in the future, you know, given the potential we have with the LNP that we've developed. You know, in terms of other organs, well, you know, this LNP, we use a GalNAc. So we do have a liver-targeting moiety as part of our LNP construct. For cystic fibrosis, as an example, we're doing both AAV and LNP approaches.
So we're trying to go delivery agnostic and just figure, you know, what's going to get us, you know, past the finish line. We've got some really interesting, you know, LNP approaches. They're different than the LNP that we're using in the liver. So this is a different LNP, you know. And yeah, I haven't seen anything yet to, you know, show an LNP to the brain, although I know there's companies working on it. You know, would love to see more development in non-AAV approaches if we think about the brain and other organ systems. But yeah, a lot of excitement and promise in the liver for where we can go next.
I see. So and speak of the strategy-wise, I know the business development has always been a key part for Prime story. From your perspective, how do you balance pursuing the external collaboration with advancing your own pipeline to deliver the most value for the shareholders?
Yeah, I mean, look, I think we know that we're not going to realize the, you know, the full benefit of this technology without collaborators, right? There are just too many areas to develop, and we're not going to be able to do it all on our own. So there's always different reasons to partner. Obviously, one is, you know, another source of funds, right? But I think about it as I want to get more Prime Editing programs into more hands and ultimately get this to more patients, right? That's our goal, and with that, we hope we can, you know, generate sources of funds along with it.
You know, we had a very, I think we have a very successful collaboration with BMS, as I mentioned before, ex vivo CAR-T therapies, where we got $110 million upfront and pretty significant preclinical milestones as part of that, potential milestones as part of that. You know, and as I think about, you know, whether it's, you know, other liver diseases, whether you think about geographic collaborations, whether you think about neurological disease or cell therapy, you know, this is a potential best-in-class gene editing approach for all of these use cases. And, you know, my hope is we're doing multiple partnerships across, you know, different disease areas and different organ systems in the future.
Gotcha. Let's get into our favorite questions. So can you remind us your key catalysts over the next 12-18 months and how's your cash runway right now?
Yeah, so cash runway, I'll start with, we had $260-ish million at the end of the second quarter. That takes us into 2027. You know, key catalysts for us, obviously getting our programs into the clinic next year, both Alpha-1 and Wilson's. And then ultimately, you know, it's all about clinical data at the end of the day, really getting to Wilson's and Alpha-1 data in 2027, you know, positive data, you know, for one or both, I think can be, you know, is a pretty significant inflection for the company.
Awesome. And thank you very much for taking time to talk to us. And I really appreciate your great insights today. And thanks again from H.C. Wainwright. Thank you.
Thanks, Arthur. Appreciate you having us at the conference.