Good afternoon. This is Eun Yang, a biotech analyst with Jefferies based in New York. Our next presenting company is Prime Medicine. This is gonna 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, and we can bring microphone to you. And presenting from Prime Medicine is Jeremy Duffield, Chief Scientific Officer. Jeremy?
Thank you. 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 a really fabulous 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 a 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. 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, those mutations need to be fixed back to the normal sequence that you and I have. That would be the ideal genetic cure for those patients. So they designed and invented and developed this heavily engineered technology, which is a combination, and it's shown in the top right, but a lot of this information is on our website.
So, 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 one strand in the DNA, and it's fused to a reverse transcriptase. And then embedded in the enzyme is a piece of RNA, which is a little bit similar to a guide that CRISPR uses, and it has a search domain. You can see up there, but it also has this extension, which brings in a blueprint for the sequence that 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 one strand, creating a flap, and that flap then becomes a template for the opposite strand, that's the 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 with 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, you know, we could make all types of single base substitutions. A lot of mutations in that cause disease are single substitutions. We can fix all of those substitutions back to normal. You know, 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, you know, partly in the Broad Institute, but partly through our innovative 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, you know, insert and replace up to kilobases 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 occur 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 retinal degeneration 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 t he second section here, you know, 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, you know, a 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 translocations. And this can 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 four programs, I'm gonna 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 gonna 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 gonna find off targets in the future, but so far, it's really, really encouraging. Of course, you know, we have high efficiency, and we've shown many examples now. We're getting 80-90% efficiency. We're gonna 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, you know, 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 pegRNA here.
We simply swap that out of the components, and we have a whole new product. And that's really, really important when you're thinking about regulatory interactions, developing a package, a 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 gonna 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, and even smaller companies about partnering programs. We wanna 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 for partners to help us bring many of these programs forward. When we started these programs, we wanted to go broad. I think one question that was asked of me was, you know, "Why do you have so many programs, and how do you prioritize them?" The first group we called an 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. You know, we know that for all of these next-gen technologies, getting the editor, which is essentially an enzyme with a piece of RNA stick in it, getting into the nuclei of 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 prime editor.
Our lead program that we're hoping will be in the clinic early next year. By the way, that's four years since the technology was invented. We're gonna 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 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 will, you know, 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 one panel here, but we have, you know, high efficiency editing in adult murine brain that we're showing here. This is in 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 two 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've developed in-house, it's custom for our cargo. It has a targeting ligand, so it goes to a hepatocyte. It has tropism and is 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's really real until you see large animal data, so you know, we've obviously been developing capabilities to scale up our materials, and we're making a lot of these materials in-house. We've developed actually unique capabilities, I believe, for developing these 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 hypoglycemias. So those patients, the vast majority of them have a single mutation at position leucine 348 in this gene shown here. And we're showing you here in primates, we've developed an editor for the primates that's very, very similar to the editor for 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 are edited. So remember, the liver is about half, it's about 60% hepatocytes and 40% other cells. So you know, our studies indicate that we're actually hitting very high levels of editing in the liver. And then you know, on the right here, just talking about that 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, you know, in cells a few years ago are now coming true in primates. These were well tolerated without any significant side effects. So very similar to the story you heard from Verve, we're maybe a year and a half 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 a IND-ready off-target pipeline looking for those unintended edits elsewhere in the genome. You know, this, 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 those at-risk sites.
They're spread along the X-axis here, and then off-target edits are shown on the Y-axis. And you can see that, you know, there are, you know, between 500 and 1,000 off-target sites at risk we identify, and then when we do deep sequencing for them for our programs, you can see the on-target edits are 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 guide, you will see a very different outcome. So we think this is gonna be important going forward from a safety element and from convincing regulators to, you know, to move advance things into clinical trials.
I think the last thing I was asked about, just to comment on, you know, our program that's gonna hit the clinic first is chronic granulomatous disease. This is a rare disease of children. Their neutrophils in their blood don't work. They can't kill pathogens 'cause 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, you know, gonna get early clinical data. But just to show you, we, you know, we have high efficiency editing in the patient's stem cells.
When we edit them with about... In this experiment, so 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 back to 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 gonna have a wave of products coming forward into clinical trials soon.
You can go sit down.
I'll sit down there. Great, thank you.
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 a 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. You know, what I would say is that, you know, the patient population is very well identified. Their genotype is well known, so the patients will be readily identified. That, you know, 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, to the patients after they've had the therapy. Now, one of the really promising things for this disease is that there, 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 been 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, you know, it has the potential. I can only say potential at the moment. It has the potential to be a surrogate biomarker. So the patients have, you know, recurrent severe infections.
They also develop an inflammatory bowel disease, and so these are other markers of clinical outcome that we will be, you know, looking at very carefully. Of course, the other area to look at very carefully is the fidelity and the durability of those edited stem cells.
Mm-hmm.
And so those are 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 program is liver, targeting the liver, and then you show non-human primate data about liver editing.
Yes.
-which is, 50% in the liver, close to like 80% in the hepatocyte-
Yes.
liver cells. So with that, the delivery set up, it's so widely applicable for a lot of liver indications.
Yes.
The two liver indications that Prime Medicine has disclosed, at least as far as I know of, are this glycogen storage disease that you just mentioned-
Yes.
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 health of the liver itself. So there are a lot of opportunities for Prime Medicine to take on additional diseases that are either liver diseases or systemic diseases where the liver is a major target. You know, one of the other areas we haven't really touched on, I talked about all the things that Prime Medicine can do to fix genes, but we can also-
Mm-hmm
... manipulate genes to turn them off very precisely by putting stop codons in, you know, similar to, to, what Verve has done, you know, for PC, PCSK9. So there is also that breadth that we, you know, is untapped right now, but it's something that Prime Medicine could, Prime Medicine can jump into. I'll also add that, you know, we, 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, I, is something I'm very excited about, and I think the company could, could really evolve, liver editing for a whole range of indications.
So, when you look at, like, other companies doing gene editing, 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 editing? So now you are showing like up 80%-
Mm-hmm
... gene editing efficiency. Do you think that's 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 than to edit human liver. So I think we're, you know, we're very buoyed by these data, and we hope other people will see that we're really, you know, been 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 potentially safe way.
Okay. And there's 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-
Yes
... as you pointed out. But the next category of diseases that you have is a differentiated target.
Yes.
There are repeat expansion diseases, like particularly neuromuscular areas.
Yes, absolutely.
There are, I mean, there are many different neuromuscular diseases that, you know, industry is targeting.
Mm-hmm.
You have a different delivery modality that you are testing for those indications. What would 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 weigh up here. I mentioned to you, you know, although, Friedreich'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, you know, bring them, further forward. So I think, I think this is a complex set of criteria. So one is the age of the individuals, you know, another is the unmet need and the severity of the disease and the way we'd measure clinical outcomes. These are all factors that we're really actively looking at right now. Patient population size, patient identification. So I, I think there's a lot of factors that we're thinking about.
I'll go back to that point again, that, you know, we're trying to build that 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 Friedreich's ataxia, where you may want to deliver to a different part of the brain. So we're very actively looking at routes of administration. You know, are we going to do this via a CSF infusion? Are we going to deliver this more locally in the brain? Are we going to try and deliver this systemically, crossing the blood-brain barrier?
So we're very actively looking at all these different routes of administration and how they can apply best to those patients. So I, 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 a different delivery method, like LNP, AAV, things like this. So are you actually working on your own delivery systems, or are you actually looking into kind of like a partner in the delivery?
Yeah
... system to expedite the program?
So the answer is both. You know, we've really invested heavily in RNA and nanoparticle technology, so we've got a lot of capabilities internally. You know, we've built you know really extensive end-to-end capabilities there. For AAVs, we decided to invest heavily on engineering the genome to be the safest, most efficient, fastest, smoothest, 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, safest system with the lowest dose possible for those patients.
And so that those things will come together. I will say, even in the nanoparticle space, we can't cover it all ourselves. You know, 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 of that work ourselves.
Okay. I think the
I'll see where the time-
Linking bit is over. So thank you very much.
Oh, there's a question at the back. Oh.
Oh, you have a question?
Yeah.
I was going to say it's,
It's done. Okay.
Out of time. Okay. All right.
Thank you.
There we go. Well, it's great to meet you all. Thank you. Thank you.