Prime Medicine, Inc. (PRME) Earnings Call Transcript & Summary

Good afternoon. This is Eun Yang, a biotech analyst with Jefferies based in New York. Our next presenting company is a Prime Medicine. This is going to be a hybrid format. So Prime is going to give us a short presentation, and then we are going to go into Q&A. And during Q&A, if you would like to ask questions, please raise your hand so we can bring microphone to you. And presenting from Prime Medicine is Jeremy Duffield, Chief Scientific Officer. Jeremy?

Well, thank you very much. It's great to be here this afternoon, and it's delightful to be in London, and I'm impressed at how thriving London is, it's raining probably these couple of days. So I want to talk to you a little bit just a brief introduction about Prime Medicine. This company was founded actually in 2020, right in the middle of COVID. It was founded through an incredible invention out of David Liu's lab. David Liu is a serial entrepreneur at the Broad Institute in Cambridge, Massachusetts. He and Andrew Anzalone looked at the CRISPR technologies that was evolving. CRISPR, as we know, is very good at going to specific places in the genome and breaking the DNA there and damaging the DNA, and that's essentially how it works. But the problem that I think we were all facing was that while CRISPR is very good at destroying genes, we really want to be fixing genes. There are 7,000 rare diseases where we know the mutations that cause the disease. Ideally, the vast majority of those mutations need to be fixed back to the normal sequence that you and I have. That will be the ideal genetic cure for those patients. So they designed and invented and developed this heavily engineered technology, which is a combination, shown in the top right, but a lot of this information is on our website. But you can see at the top right, it's a fusion enzyme, which has a Cas domain, which has been heavily engineered, so that it just nicks 1 strand in the DNA, and it's fused to a reverse transcriptase, and then embedded in the enzymes is a piece of RNA, which is a little bit similar to a guide that our CRISPR uses, and it has a search domain, you can see it there, but it also has this extension, which brings in a blueprint for the sequence you want to put into the DNA. And so the enzyme, if you just go down the bottom left there opens up the DNA by nicking 1 strand, creating a flap, and that flap then becomes a template for the opposite strand that's replace sequence that activates the reverse transcriptase and writes directly into your DNA, the correct sequence that you want to be there. There's a series of steps that are highlighted in a movie on our website. You can look at all of this, what are the final steps that enable the final outcome, and that is a precise correction of the DNA back to the sequence that you and I have. So without breaking the DNA in half, this technology can fix mutations. Now when we first started, we could make all types of single base substitutions, a lot of mutations in that core disease are single substitutions. We can fix all of those substitutions back to normal. It's the only technology that can do that. But in addition, we could fix small deletions and small insertions and there are quite a good number of diseases caused by deletions or insertion mutations. But what we have gone on to develop partly in the Broad Institute, but partly through our innovation group within Prime Medicine. We're able to do bigger and bigger edits now in the genome using expansions and extensions of this basic technology. And so now we're able to insert and replace up to killer bases of DNA very, very precisely without breaking the DNA. This has become very important because a lot of diseases have hotspots in the gene where mutations are occurring in clusters. And so a single editor now can fix many mutations that patients have. So one of our programs, again, available on our website, but I'm not going to show you today, one of our [indiscernible] on the generation programs, we have a single editor that can fix 18 different pathogenic mutations that cause that disease. So these are the expansions and extensions of this technology. One of the other areas that we've developed is we can now loop out very large pieces of DNA very precisely without making breaks in the DNA. And that's been very useful for a class of diseases called repeat expansion diseases, where the mutation is actually not a small mutation, but it's actually an expanding repeat. And we can precisely remove those repeats and put back a normal number of repeats to precisely fix the gene back to normal. So these are some of the things that the technology can do. In the second section here, we don't create double-stranded breaks. And double-stranded breaks are an alarm signal for cells. And lots of outcomes can happen. So one is you get damage repair response at that site, but the other is that you can get pieces of broken DNA joining together across your DNA, creating large deletions and even translocation. And this is going to have important consequences. So what we're finding is that our technology does not create off-target edits anywhere in the genome. So far, our lead for programs, I'm going to show you a slide in a moment. We haven't actually found a single off-target site. This is very, very different from CRISPR technology. And we think it's going to be a really important differentiator going forward as we're bringing more products forward to regulators and really needing to prove safety to regulators. So we're very excited about those data. Obviously, we're not saying we're not going to find our targets in the future, but so far, it's really, really encouraging. Of course, we have high efficiency, and we've shown many examples now. We're getting 80%, 90% efficiency. We're going to show you that in vivo as well as in vitro. That, of course, the edits are permanent, and we're developing platforms so that we can deliver the therapy once and essentially, that's it once and done. So that's a very different paradigm from the current daily dosing or weekly dosing of medications. I think another element is that we think we can address over 90% of all disease-causing mutations. There are 7,000 diseases that are well curated. That's an incredible breadth. It's not something a company of this size can take on by any means, but it does indicate to you the magnitude of the possibilities that this technology could bring to healthcare. And then I think the final piece just to highlight here, we've developed multiple delivery platforms for delivering in different contexts to different sites in the body. We're trying to build these as modular platforms, so that you simply swap out a small guide RNA, you see the featured PEG RNA here. We simply swap that out of the components, and we have a whole new product. And that's really very important when you're thinking about regulatory interactions, developing package, CMC package developing a safety database and coming forward with new products for patients in the same disease area. So we think these modular platforms are going to be very important for our future. So, we do have a large list of programs. For a company of our size, there are more programs here than we can possibly develop on our own. We're very actively talking with large pharma, medium-sized pharma or even smaller companies about partnering programs. We want to get this technology to patients. So this is a very active place for us right now. We've brought a lot of these programs forward. We're trying to work out which of those to advance to the clinic. I'll tell you a little bit more about that, but we're certainly actively searching good partners to help us bring many of these programs forward. When we started these programs, we wanted to go Broad. I think 1 question that was asked to me was, why do you have so many programs? And how do you prioritize them? The first group, we call them immediate section, where we knew there were proven delivery technologies. So ex vivo, editing of cells and then put the cells back in the body in the first blood category, lipid nanoparticle delivery to the liver, AAVs to the eye and the inner ear in a very small compartment, where we could deliver the editor with an AAV. And then the bolder targets at the bottom editing the brain and editing muscle and editing the lung. All of these programs actually are making great progress. So this is a single slide just talking about delivery capabilities. We know that all of these next-gen technologies getting the editor, which is essentially an enzyme or the piece of RNA sticking in it, getting into the nuclear, the right cells in the body is a big, big challenge. We also know that many challenges have been overcome recently. We just heard today about the sickle cell program with Vertex and CRISPR. That is an electroporated cell product, electroporating a CRISPR enzyme into those cells to do the editing. So we've developed a similar system for a Prime Editor, our lead program that we're hoping will be in the clinic early next year. By the way, that's 4 years since the technology was invented. We're going to be hopefully starting first patient treatment. But you can see we have very high efficiency editing of hematopoietic stem cells for our first program, chronic granulomatous disease. Importantly, when we edit these cells because we don't make double-strand breaks, we're using an all RNA components to edit these cells, they are very happy. Those are very delicate stem cells that permanently make all your blood cells. When we put them in vivo, they fully engraft. You can see in the second point there, more than 90% of the long-term stem cells that permanently make all your blood cells that reside permanently in your bone marrow. They're edited and they're healthy without any signs of abnormalities. And as I mentioned, that first program we're anticipating an IND next year. In the middle section, we've developed these AAV delivery systems for the eye and for the CNS. You can see that we -- just 1 panel here, but we have high efficiency editing in adults, murine brain that we're showing here. This is public. We have ongoing large animal studies. And we'll hopefully be able to talk more about that in the brain shortly, but we also released recently very high-efficiency editing in the retina for retinal degeneration in humanized mice. So retinal degeneration is a terrible problem for many young people. Rhodopsin is a protein that's mutated most commonly. We have 2 editors that address the vast majority of patients with Rhodopsin-caused retinitis pigmentosa, and we have high efficiency correction, again, precise correction of those mutations back to the normal sequence you and I have. And then on the right, we've developed this lipid nanoparticle delivery system, encapsulating our editor in an all RNA format. So very similar to Intellia or Verve or Beam. Our LNP we developed in-house that's custom for our cargo. It has a targeting ligand. So it goes to hepatocytes, it has tropism and it's taken up specifically by hepatocytes. You can see we have dose responsive high-efficiency editing in the liver, but we're also now evolving that capability for other places such as T cells, stem cells, in the lung and so on. And I know I was asked to talk about primate data. Obviously, nothing is really real until you see large animal data. So we've obviously been developing capabilities to scale up our materials. We're making a lot of these materials in-house to develop such a unique capabilities, I believe, for developing the synthetic RNA and so on. But you can see some of our first data for one of our liver programs, glycogen storage disease. This is a disease of children where glycogen can't be broken down. So when they don't eat, they become hypoglycemic, so severe at night that they can have seizures and develop neurological abnormalities as a result of severe hypoglycemia. So those patients, the vast majority of them have a single mutation position leucine 348 in this gene shown here. We're showing you here in primates. We developed an editor for the primates that's very, very similar to the editor of patients. And you can see we're able to very precisely in this case, swap that G for the C, but do nothing else. And when we deliver with our lipid nanoparticle to primates that go to the liver, you can see we have high-efficiency editing with levels hitting 50% total alleles edited in the liver. And actually, because we're targeting only hepatocytes, we actually think that's about 80% of hepatocytes edited. So remember, the liver is about -- has about 60% hepatocytes and 40% other cells. So our studies indicate that we're actually hitting very high levels of editing in the liver. And then on the right here, just talking about a precision issue, if you really look for any other unintended outcomes within 300 bases outside of this, we don't find any. So we only make that edit. We don't do anything else in the genome. So all the things we talked about that were in theory or in cells a few years ago are now coming true in primates. This were well tolerated without any significant side effects. So very similar to the story you've heard from Verve, we're maybe 1.5 years behind, but I think we're making great progress towards delivery in vivo from an IV infusion. I just put this panel together. This is some of our off-target work. We have an IND-ready off-target pipeline, looking for those unintended edits elsewhere in the genome. We're calling it IND ready. It's ready for our first program, but it's very similar for our follow-on programs. We map at risk sites in the genome, then we do deep sequencing for all of these at-risk sites that is spread along the X-axis here and then off-target edits are shown, I want the Y-axis. And you can see that there are between 500 and 1,000 off-target sites risk we identify. And then when we do deep sequencing for them for our programs, you can see the on-target edits identified, but we don't find any evidence of off-target editing. Very, very different. If I put a panel up with a CRISPR -- even highly curated CRISPR guides, you will see a very different outcome. So we think this is going to be important going forward from a safety element and from convincing regulators to move advance things into clinical trials. I think the last thing I was asked about just to comment on our program is going to hit the clinic first is chronic granulomatous disease. This is a rare disease of children, the neutrophils in their blood don't work. They can't kill pathogens because there's an enzyme missing that normally squirts oxygen radicals to kill fungi and bacteria. We're fixing the mutation to turn that gene back to the normal gene you and I have. It's a genetic cure for these patients. We're editing their stem cells and putting them back into their body. The patients are sort of almost lined up for us, we think. And so we're hopefully going to get early clinical data. But just to show you, we have high-efficiency editing in the patient stem cells, when we edit them with about hitting this experiment from over a year ago, we're now hitting over 95%. But in this experiment, we're hitting about 80% editing, and you can see that 80% of these cells when they're differentiated into neutrophils, restore the protein that's missing. And then that protein, 80% of those cells have normal protein function. So as you would expect from a genetic cure when you do the genetic cure, you fix the protein, that's the normal and you essentially are restoring the function back to normal. There aren't many technologies that can offer that as a potential for patients. I think that was my last slide. Obviously, I could talk all day, but I wanted to give you a flavor of some of the exciting things that are happening. And I think you can see that pipeline that's sitting behind the lead program, where we're going to have a waiver products coming forward into clinical trials soon.

All right. Thank you for the presentation. So CGD is obviously your first clinical program, the program to enter clinical development. And today, there is a CRISPR based sickle cell disease got approval. So it's kind of the same way of doing it ex vivo. And CGD is a very, very rare disease. So can you talk about -- you said that you're going into clinic next year. So can you talk about how the clinical program would look like for the pivotal study?

So I'm not sure I'm at liberty to talk about our clinical trial designs at the moment. But what I would say is that the patient population is very well identified. The genotype is well known. So the patients will be readily identified that as with other rare diseases and particularly with a once-and-done therapy, you can't really have a control group in the way you would have done in the past that you really need a sort of run-in period, so you either have a historical control from the same patients or from a cohort of patients. And then you look at outcomes related to the patients after they've had the therapy. Now one of the really promising things for this disease is that there's a very robust biomarker. I actually just showed you some data from that biomarker. It's called a dihydrorhodamine test. It actually is a blood test where you take live neutrophils out of the blood and you essentially measure the activity of that enzyme, and it gives you a robust fluorescent readout. It's an approved diagnostic test for the patients and it's also being used in clinical studies elsewhere to measure efficacy. So we are very hopeful that, that will give us a really early and very robust readout in these patients. And potentially, it has the -- I could only take potential at the moment -- has the potential to be a surrogate biomarker. So the patients have recurrent severe infections. They also develop an inflammatory bowel disease. And so these are other markers of clinical outcome that we will be looking at very carefully. And of course, the other area to look at very carefully is the fidelity and the durability of those edited stem cells, and so those are the things that we'll be looking at very closely in those studies.

Okay. And the second program, I mean, I don't know if it's a second program, but next the program is liver -- targeting the liver. And then you showed non-human primate data about liver editing, which is 50% in the liver, close to like 80% in the hepatocyte, the liver cells. So with that, the delivery set up, it's a widely applicable for a lot of liver indications. And then 2 liver indications that Prime Medicine has disclosed at least as far as I know of are this glycogen storage disease that you just mentioned and then Wilson's disease. But are there other liver indications that you are thinking about?

So there are a lot of opportunities in the liver. So the liver is a factory for many things in terms of metabolism, in terms of the immune response, in terms of the health of the liver itself. So there are a lot of opportunities for Prime Medicine to take on additional diseases either liver diseases or systemic diseases where the liver is a major target. One of the other areas we haven't really touched on, I talked about all the things that Prime Medicine can do to fixed genes, but we can also manipulate genes to turn them off quite precisely by putting stop codons in, similar to Verve has done for PCSK9. So there's also that breadth that is untapped right now, but it's something that Prime Medicine can jump into. I'll also add that, again, we've built this delivery platform where we just have to swap out a single guide that has some Watson, Crick sequence changes. Everything else is the same. And so the ability for us to double down on these delivery systems and bring forward new programs is something I'm very excited about. And I think the company could really evolve liver editing for a whole range of indications.

So when you look at like other companies who are doing gene engineering, whether it's CRISPR or base editing, there is a real translatability from monkey studies to humans. So do you expect that with the Prime Medicine. So now you are showing like 80% gene editing efficiency. Do you think that is something that we should be also expecting in humans?

So until we're there, we don't know for sure, but you're absolutely right. I mean the Alnylam data, followed by the Intellia data followed by the Verve data, I think data from Beam also consistent with what you're seeing in NHPs translates very, very closely to what you see in humans. And in fact, it may be a little bit harder to edit NHP liver through an IV infusion, [ that's edit human liver ]. So I think we're very buoyed by these data, and we hope other people will see that we're really being able to bring the technology forward very quickly to the state that we can give an IV infusion now to edit the genome in a potential safe way.

Okay. And there is a liver. There is an eye, there is an ear. And then that's more of the immediate indications because it's a proven delivery as you pointed out. But the next category of diseases that you have is a differentiated project, there's a repeat expansion disease, particularly in neuromuscular areas and you have -- there are -- I mean, there are many different neuromuscular diseases that industry is targeting. And you have a different delivery modalities that you're testing for those indications. So what would they be the kind of gating factors which neuromuscular indication that you would go after? Would that be delivery or something else?

So there's lots of factors to way up here. I mentioned to you, although Friedrich's ataxia has sort of led out the gate, actually, all the other programs are continuing to advance, and we're trying to work out right now, whether to accelerate one or other and to bring them up or even bring them further forward. So I think this is a complex set of criteria. So one is the age of the individuals, another is the unmet need and the severity of the disease and the way we measure clinical outcomes. These are all factors that we're really actively looking at right now, patient population size, patient identification. So I think there's a lot of factors that we're thinking about. I'll go back to that point again, that we're trying to build our modular platform. In this case, it's an AAV delivery system. And so one of the other elements that's gating for us right now is how are we going to deliver this best to those patients. And it's a little bit different if you have a motor neuron disease compared if you have a sensory neuron disease like Friedrich's ataxia where you may want to deliver to a different part of the brain. So we're very actively looking at it. We're out of administration. Are we going to do this via a CSF infusion, are we going to deliver this more locally in the brain, and we probably going to try and deliver this systemically crossing blood-brain barrier. So we're very actively looking at all these different routes of administration and how they're going to apply best of those patients. So I would anticipate that over the next few months, we'll be able to talk more about that and what we think is the best route of administration for these different indications.

So obviously, you're looking at different delivery methods like LNP, AAV, things like that. So are you actually working on your own delivery systems? Or are you actually looking into kind of like a partner in the delivery system to expedite the program?

So the answer is both. We've really invested heavily in RNA and nanoparticle technology. So we've got a lot of capabilities internally. We've built really extensive end-to-end capabilities there. For AAV, we decided to invest heavily on engineering the genome to be the safest, most efficient, faster, smoother sleekest genome you could make. And indeed, that can give you log orders of potency, but we decided not to invest in the capsids ourselves. And so we're very actively in discussions with a number of organizations that have next-generation capsid capabilities, targeted ligands on capsids, these kinds of things. So that's a big effort for us right now. And obviously, we want the very, very best safer system with the lowest dose possible for those patients. And so those things will come together. I will say, even in the nanoparticle space, we can't cover it all ourselves. Targeted ligands on nanoparticles, we think is a really important way forward. We're very actively speaking to collaborators there as well because we can't do all that work ourselves.

Okay. I think the linking that is over. So thank you very much.

There's a question about.

We have questions. Okay.

Here we go. It's great to meet you all. Thank you.