Great. Good afternoon, and thank you for joining us today. We have with us Keith Gottesdiener, the CEO of Prime Medicine a nd today we're going to be talking about your portfolio and some recent progress that you've made with your Prime Editing platform. To start, Keith, could you provide us a snapshot of where Prime Medicine stands today?
Yeah, no, it's been a very interesting time for us in Prime Medicine. The company is just approaching its four-year birthday. W hen you think about the fact that the technology that we're talking about, Prime Editing, was in one laboratory four years ago, and now we actually have opened up an IND, it's been a really quick and very interesting journey forward.
So when I think of the company today, what I would say is the technology continues to advance and really show its robustness, its versatility, its breadth a nd I think to some degree its safety as well in terms of a really pristine off-target activity for gene editing. We've also begun to make the transition to becoming a clinical company.
I'm sure we're going to talk about it, but we're at the point now where we have opened an IND, and next year we'll have clinical data that we hope will really show that Prime Editing works in humans. We continue to really build out the pipeline.
It's now a little bit more focused. We've really been helping to guide people as to what's going to come forward over the next couple of years as they look forward and really built an extraordinary company. So that's really what the state of the company looks like from our point of view today.
Got it. To level set for those that are not as familiar, if you could just provide an overview of the differentiation of Prime Editing versus some other kind of next generation or third generation gene editors?
Well, the way I typically think of it is, in fact, three generations of gene editors. That's our approach to describing, and I think there are many different ways people do so. Really thinking of CRISPR technology as the first generation, a great way to find a very specific spot in the genome and do things there.
But over time, it's become clear what CRISPR technology alone can do in the gene is a little bit more limited. So it does great things within that limited sort of space, but if it gets beyond it, it really hasn't manifested all the hopes that people have had over the last 10 years. Base editing, I think of as a second generation gene editing technology. It's one where people began to start correcting genes as opposed to what CRISPR does, is mostly inactivate genes.
There's some great work that's going on, but it's also very limited to what it can do. Prime Editing really can look really quite broadly. It can fix probably well over 90% of known pathological mutations. It can work in very, very small edits, single base pair mismatches. It can work at larger edits, 100 or 200 base pairs at a time.
We call that hotspot editing because often mutations cluster in hotspots in a particular gene. O f course, there's also more recently we've described, though we've been working on this since the original founding of the company, what we call PASSIGE technology, which is using the combination, the specificity of Prime Editing to put large pieces of DNA in very specific spots.
When I look across sort of the companies that are doing sort of third generation prime gene editing, frankly, most of them look like they're doing prime editing, at least from the outside. It's a little hard to know. Many of the companies haven't really shared the technology in the way Prime Medicine has and the way Prime Editing is now in literally hundreds, possibly thousands of papers and abstracts.
So people know exactly what we're doing. Many of the other technologies use names like gene writing or gene rewriting, which scientifically don't mean anything. I think we and I, we're looking forward to seeing what the technology is b ut from the outside, much of it looks very duplicative of what we're doing.
To that point, could you speak about Prime's IP position and how investors can get comfortable with that in the context of what you just mentioned?
Yes, I certainly can. I mean, I think the story on our IP position is very, very, very straightforward. Everybody knows who invented Prime Medicine, Prime Editing. It came out of the laboratory of David R. Liu and Andrew Anzalone helped to do it.
They really created Prime Editing, and all the patents that they put forward, which have the earliest priority date and incredible breadth, really broadly protect Prime Editing from whatever you actually call it.
Prime Editing involves a targeting area, and it includes reverse transcriptases that actually make copies back into the gene. We have patent technology or patents that actually cover both of those quite broadly.
But it's important to keep in mind that that original filing of the original data, which has the early priority date, really included eight major patent families, and the patents are still coming out of that data as well as all the improvements that have occurred since that time. So it's an incredibly robust patent portfolio. I think we own Prime Editing is probably the easiest way to say where I think our patent portfolio looks today.
Got it. That's super helpful context. So you had a pretty meaningful milestone this year with your open IND and CGD. You could discuss that indication, the current standard of care, kind of what the commercial opportunity could be like, and then what this means for Prime to have this go into patients over the next few months.
Yeah. So the disease, chronic granulomatous disease, is a disease that starts in childhood and can continue through early adulthood as well in some patients. It's a disease where your white cells are unable to fight off infection.
So at the beginning, patients often will have small infections that could be treated with antibiotics. Sometimes they can become very severe at a very, very early age as well. A s time goes on, the antibiotics stop working, the infections get more deep-seated, they become more resistant, and people die usually in their 30s or 40s at the latest.
Along with that are a whole number of inflammatory as well as autoimmune phenomena that come along with that as well. So these patients live a totally miserable life. Today, most of those patients receive, if they want to have a curative therapy, they receive an allogeneic bone marrow transplant.
So it's really a quite horrific process, particularly since it's often given to younger folks as well to sort of prevent the buildup of all the serious pathologies of these diseases. A s a result of that, they undergo the transplant with very, very profound immunosuppressive periods, often quite difficult because often they're infected at the time that that might occur.
In addition, they carry the risk of lifelong immunosuppression, graft-versus-host disease, et cetera. It is curative. Quite a number of these are done every year, but in practice, many of the patients don't have very good donors in order to really allow them to have the chance to lead something close to a normal life. So what we can do is we can do an autologous transplant with a corrective edit. So we know exactly what the defect is in these particular folks.
We can make that correction. We can put it back in with a milder immunosuppressive regimen. In the process, give them a once-and-done cure. When we're done, they basically reconstitute their bone marrow with fully corrected cells, and then the disease really disappears.
Why was this the first indication that Prime decided to focus on and bring forward?
So it is the first indication, but it isn't the first indication that we chose a nd the reason I say that is because we picked a whole handful of indications that we hope to bring forward to really test where Prime Editing could work.
So back in 2020, 2021, it wasn't clear whether Prime Editing would work in every organ, every type of cell, with every type of delivery method, with every type of mutation a nd so in the process, what we did is we picked a small handful, some in liver where LNP delivery exists, some in the eye, some in the ear, and some very similar to CGD, ex vivo hematopoietic types of approaches.
W e really started them all off together. All those programs are continuing towards the clinic. What happened in practice was chronic granulomatous disease was one where everything we did worked from the beginning.
I don't want to suggest it was easy. The team that did it used an extraordinary amount of effort to get forward to make it work. There were a lot of technical challenges to solve. But in general, everything we tried to move forward moved forward very, very rapidly a nd so it moved ahead of its fellow indications to really come into play.
Now, having said that, there are many reasons why I'm glad that this was the one that came in first. Number one is it's in fact ex vivo. So actually, the delivery methodology is slightly easier than some of the others, so it's a great place to start. It's a little bit simpler from a regulatory point of view because some aspects of this are ones that others have taken going forward. It's really a huge unmet medical need.
Probably most important is the patients are getting a horrible alternative to this, and what we can offer them is something substantially better. So we don't have to worry about these patients thinking about, "Would I go through a bone marrow transplant for a cure?"
These are all patients who are lined up to get a very bad bone marrow for a cure, and we're offering them something different. Now, in the end, there are probably hundreds of these patients in the U.S. overall and probably an equal number in Europe. So it isn't a big indication, but it certainly isn't a proof of concept, which sometimes investors come in and tease me about.
Are these patients well identified?
They are. First of all, it's a disease that manifests itself pretty rapidly. These patients have infection after infection after infection. I think every mother and father starts to realize that you bring your son in for two, three, four, five, six major infections a year, pneumonias, other kinds of things. That isn't normal, and every pediatrician understands it.
It can be diagnosed very simply with a test called DHR, which people have been doing for at least one or two decades, which really rapidly makes the diagnosis for what's going on a nd so these patients do get identified. Almost all of them get sent to tertiary centers.
So there's probably a dozen such centers in the U.S., mostly, not all, exclusively, but mostly at major children's hospitals. S o these patients rapidly go there, and they're really handled there. As a result, getting to these patients is relatively easy for us, particularly the ones who are probably the most severe overall.
Got it. What can we expect in terms of enrollment updates and site initiation over the next second half of this year and then ahead of first data next year?
So we're probably going to be very sparse in information on the progress of the trial. Frankly, the idea of investors looking over my shoulder and asking when the next site's going to be activated and such isn't something that really thrills me a nd in practice, I think the teams need a little bit of room. I don't even do that to my own teams, let alone provide that information to others.
So it will probably be pretty sparse. What we do hope to do is get our first patient dosed by the end of the year. It's been a little bit slow to, not slow, but it's definitely been that the FDA has made it hard for us to do advanced work because they insisted that we not do any work before we actually have the IND open.
Many of the academic centers also require an IND in place in order to really do all the bureaucratic work that one needs to do to open a study. We've estimated it'll be about six months from the day the IND was cleared until we could potentially dose a first patient. The FDA has also asked us, as have other regulatory agencies, to do one patient at a time at first.
We have to see the first patient engrafts before we do the second. We have to do adults before we do adolescents and children. The study will clearly get off to a slow start. We'll be working so that every additional transition that we go through will go faster and faster. We plan to announce clinical data in 2025.
So could you help us kind of frame expectations for that clinical data and what you intend to show in terms of clinically which kind of assay components? I think you mentioned the DHR assay. T hen what the bar is that you're going to be looking for from that data?
Sure. So what we're hoping to show in humans almost directly parallels what we've done in animals. So in animals, what we've been able to do is to show that we can edit something north of 90% of the cells with a corrective edit. We can put them into the animals. We can get rapid engraftment of those animals.
In this case, they're immunodeficient mice. W hen the cells, we wait 16 weeks to clear out all of the non-stem cells and to wait and see what actually the stem cells are left in the bone marrow. We're finding, again, 90%+ of the cells have the corrective edit.
So the first two things we want to see in humans to parallel that is, first of all, that engraftment occurs. T he second is when the engraftment occurs that we see high levels of editing in the cells themselves.
The third thing, of course, is editing alone almost invariably should result in enzymatic reconstitution, b ut we think it's very important to literally test or demonstrate each step. So the next step after editing would be to show that you in fact have recovered the enzymatic activity that is missing in these white cells, which is directly measured by the DHR test.
So we would expect that to be a very, very important part of the story overall. A s far as the level that we would like to hit, that part actually there's great clinical data on because many of the patients who get these allogeneic bone marrows end up in many cases with chimeric marrow. In other words, their bone marrow has some of the old cells and some of the new cells.
So if you take those patients and you look at the percentage of their cells that are the new theoretically corrective cells from the allogeneic donor, you find that as many as little as 15% of the cells will actually give protection from the infection and the inflammatory effects that go on.
So we've set our threshold somewhere between 15%-20% of editing as being the most important point a nd the same thing is true for DHR because the DHR test measures the number of cells who actually express the correct enzymatic activity: 20% of the cells added, 20% of the DHR. So we would expect to show data. Now, of course, in our animal models, the numbers were markedly much greater.
Will the follow-up for, I guess, the patient or patients included in this first data be long enough to see a potential reduction in the infection event?
So the answer is potentially, but keep in mind two things. One is just if you look in these patients and you look at the course of these infections, it's very stochastic. People will get five infections in a year, and then they may go a year without one.
So when you start to work with diseases like that or endpoints like that, you need a good number of people in order to average all those things out. So I think the ability in a very relatively rare population and what we hope will be a very small study, at least our planning is that 20 patients or less may allow us to get registered.
The chance that we're going to have statistical or definitive evidence on, for example, a decrease in infection seems small. Now, having said that, it could become very clear because of these patients, and there will be some who've had multiple infections in the course of a year, for example, have none.
At least by contrast, it'll be important. But I think there's a second way that we can show the effect on infections a nd that's that the allogeneic transplants have shown improvements or have shown that you can take patients who actually have an infection at the time of transplant, and you can actually cure them.
So there are a number of patients who get transplanted because they're really in a very serious position, and they have very resistant infections a nd under those circumstances, the allogeneic transplants have actually caused those patients to decrease and eventually get rid of their infections. The same is true for all the inflammatory diseases they have.
So they have a very bad sort of, not all of them, but they have sort of something that's very similar to some of the inflammatory bowel diseases that are called by different names and other folks a nd there's a very clear pattern that if you actually treat these patients, those disappear.
So we think that kind of data will almost certainly come out if this is working and delivering the same sort of effects as what's happening with the allogeneic transplants a nd if that's true, that will be very strong corroborative data.
Got it. Fo r those patients that are in an active state of infection, how do we think about kind of applying immunosuppressants to those patients for them to get the Prime Medicine?
So it's a great question. So we won't be starting out with patients who have active infection. But we've discussed this with regulatory agencies a nd the general feeling is that with an autologous bone marrow transplant where an engraftment can occur fairly rapidly, once we've shown that in non-infected patients, we can go into infected patients and see.
In fact, if we can give them cures under those circumstances. So we don't know exactly what patient number it would be, but certainly in the first handful of adults, we would expect that there would be a patient with an active infection in there.
Got it. T hen in your view, would this first-in-human data, could it potentially be kind of true proof-of-concept for Prime Editing in humans?
Well, proof of concept means different things, different people. My answer to that is unequivocally yes. What you really want to know is when the cells get, can you edit them? W hen you get them back, do they continue to produce what you hope would happen? There's every reason to believe that's true. You're editing the genome itself.
Our data has already shown 6-12 months of persistent in all of our animal models. So we're not really worried too much about that, b ut in the end, the question is, does gene editing cure the disease? Fr om my point of view, that is definitely proof of concept. It doesn't mean there are other diseases where we're not going to have to show other steps.
If we deliver to the liver, I wouldn't say that we have to prove concept again, but we have to show that delivery works and we can get high-level editing. The same for many of our other places where we want to go. But I think it's going to be an extraordinary positive thing to be able to show that for the first time this new technology works in human beings.
T hen before moving to your portfolio from CGD, any thoughts of how Prime is going to approach the data release? Would a press release or presentation at scientific conference make sense?
I think I really can't speculate. I think I'd only make two comments that I've made before in investor meetings. One is that we always like to present things at scientific conferences, but I'm certainly not going to tell you that's how we'll do this. The second thing, though, is we'd like to be sure of our data. We're a very conservative company in that way.
I don't think the minute we get our first piece of data we're going to put out a press release and blast it to the world. I guess it's possible. It could be so extraordinary we would check off every box and exceed it greatly that that could happen. But in practice, we generally have taken the approach of let's make sure that what we're bringing out is something we can stand by overall.
So now that doesn't necessarily mean that there's going to be 20 patients' worth of data. The whole study, the phase I/II study, is only six patients. So I suspect it'll be somewhere between one and six. Sorry, that isn't very helpful.
I thought it was helpful. It's good context there as we think about that data. So moving towards your SCIP technology, you are working on preclinical development there this year, I believe. I guess, could you frame how Prime is using that technology and kind of what the milestones would be?
Sure. So if I step away from the jargon, what this technology is is probably better described by cell shielding, a nd it's an approach that we are not alone in doing. But the idea really is that if it were ever possible to edit cells in a way that did a genomic correction like we're doing in CGD, as well as making an edit that could protect those cells in some ways from the immunosuppression or other chemotherapy or other treatments that you have to give to clean out the bone marrow, that would be great.
So we're working with another company to really develop cell shielding approaches a nd the idea is to use an antibody that attacks or destroys HSC cells, the stem cells in the bone marrow, but then no longer can work against the edited cells.
So what we would do is we would take cells out in the first iteration. We would make two edits because we can multiplex edit with very high efficiency, one to correct the genetic defects, one to protect the cells and put them back in. O f course, what that means is you don't have to wait for that long period of time for the chemotherapy to disappear.
You can do things that may overlap eventually or simultaneous at the same time to move it forward. Of course, that's just a step on the path to what I hope will become in vivo editing of stem cells. Maybe that will be possible directly. There are companies that are working on it. We're a little skeptical that it's going to be easy to get to very therapeutic levels of the stem cells themselves.
So the idea really would be is even if you got small editing in vivo of those stem cells, so you really, for example, put something in intravenously, it caused, for example, 2% editing of stem cells, you could use this antibody, which will attack only the old cells, but not the new cells that you put in with the genetic correction and the cell shielding, and you continue to select for those new cells.
So under the circumstances, we think it's going to be a very, very powerful technology. Now, of course, people are much very interested in this. In the general sense, it's the same problem that may have faced CRISPR and Vertex and Sickle Cell Disease, b ut it is really something that could really revolutionize the diseases you could do with HSC.
We're working to get proof of concept on that in animals. If that were to work, we would like to think about nominating our first program with cell shielding by the end of the year. It's a little bit of a stretch to be able to do that, but we're certainly thinking about whether that's possible.
What are some disease areas where this could fit?
Well, this is focused entirely on hematopoietic stem cells. I mean, there are diseases like sickle cell, for example, would be a perfect example. We've licensed that to a sister company, Beam. But Beam could, for example, use the cell shielding technology as well. But they could also be used in many different forms of thalassemia as well. So there's a number of different places we could use it.
Got it. T hen wanted to touch on your PASSIGE technology and what are some potential clinical applications. I know repeat mediated diseases has come up as an addressable.
So for that, we don't use PASSIGE. So for the repeat expansion diseases, I think you're talking about, or triplet diseases, we generally use a technique called Dual Flap Editing, which literally can cycle out just the pathological repeat of triplet diseases like Huntington's or ALS or other diseases like that.
That progress is going forward quite nicely, though it's a much more difficult place to edit the brain and certainly much more difficult to deliver to the brain. PASSIGE technology is the ability to use Prime Editing to put a very specific, to target a specific spot and then use recombinase technology in combination to put in a much larger piece of DNA. So let's call it 10 kilobases. Those are certainly gene-sized pieces of DNA a nd you could put it with incredibly precise approaches.
Now, that requires, first of all, that you use Prime Editing to get the specificity. So every PASSIGE approach, and there's another company or two that are using almost identical approaches, but everything starts with the Prime Editing because that's what gives you the specificity of where you want to put things.
Once you've done that, you can use any of many recombinase technologies to put into that spot very large pieces. It does it without double-strand breaks. It does it very, very cleanly with very, very high specificity overall. We've been using that or the data we've shown. We're using it in many places. The data we've shown is really to do some remarkable editing of CAR T cells because you can put in polycistronic or monocistronic approaches, and then you can also do multiplex editing.
F or a variety of reasons, Prime Editing as multiplex editing is one that the cells seem to tolerate quite well and do at very, very high editing efficiencies. So we can, in CAR Ts, put in a CAR. As a matter of fact, we use the preciseness of the PASSIGE technology to destroy the actual T cell receptor.
So that's usually a two-step process. T hen we can also do at the same time, all in one go, the multiplex editing as well. If we get very, very complex, we may want to do it in two stages as well, b ut the idea really is you can do some extraordinary editing, and frankly, it's just amazing. Now, of course, the other place you can use PASSIGE is basically the equivalent of replacing a gene that has multiple mutations that you want to cover a very, very large area.
A number of genes have one predominant mutation. Many genes have limited areas where the genes are clustered. Every once in a while, there's what I call a peanut butter gene where the mutations are just spread out across the whole gene itself.
Those are hard to do with Prime Editors because you need a number of them to handle different segments of the gene. But PASSIGE technology would allow you to essentially put a new copy of the gene in just upstream of the old gene, but still under the same regulation o r potentially, some of the more advanced forms of PASSIGE may be able to replace that gene or at least swap out whole exons if needed.
Understood. I know you have the personalized effort, which is the walk-up the chromosome effort. If you could touch on that.
Well, basically, based on the idea that it might be a predominant mutation, and then there might, for example, 50% of the patients, there might be two more mutations that are each 15% or 24% mutations of the genome a nd they may not all cluster. Some genes, they cluster.
For example, in Cystic Fibrosis, we know that eight clusters of genes, and we can treat a whole cluster at once, probably compromises well over 90% of the known pathogenic mutations, even though there's more than 1,000 of those mutations overall. There are other places where they're really spread more widely, as I mentioned.
So the idea would really be the idea of what you do with the first editor, let's say for the predominant mutation, second and a third, without having to really do all of the work you would with a separate IND, NDA, etc.
T his scenario with the FDA is extremely interested as well. As a matter of fact, Peter Marks typically describes Prime Editing as an example of a platform of a modular approach. Occasionally, he actually names us by name. More often, he just describes the technology.
But the idea really is, if you make the guides the same way, which are an important part of your targeting mechanism, and you just do it over and over and over again in a gene, do you need to treat each one with exactly the same data package?
W e've gotten some strong signals from the FDA. The answer is no, that they're expecting that some of the data we generate with the first one would apply to the second and the third, so each one becomes easier, cheaper, etc. Of course, you can all put them all into one clinical study, etc. There's tremendous advantages to really doing that. We think we're well on the way to having a great dialogue with the FDA on that issue.
Got it. In the last few minutes here, if you could touch on Prime's cash runway and cash position and kind of how you think about capital allocation across the portfolio.
Yeah. So currently, our cash position is about $225-$230 million. That takes us into the second half of 2025. Frankly, one of the things we hope that will improve our cash position is we're very actively talking to folks about business development and partnering opportunities.
We've certainly identified some areas where we're particularly interested in doing it. CAR T, for example, is one of them. Hearing is the second. Those are places where we hope that'll extend our cash runway in some way as well. Y ou never know what's going to happen with BD deal. It's over.
But generally speaking, we know we can do everything where Prime Editing, even in our limited pipeline, can work. I shelved additional mutations or different diseases that we've considered going into, just to put it into context.
W e're unable to do the 18 that are currently on our pipeline, of course. So to some degree, we expect that'll have an important impact on things. Cash allocation is a very difficult problem when you have lots of great places. What's wonderful about Prime Editing has been essentially nothing we've tried has failed. F rankly, nothing we've tried has actually come close to failing.
So I joke that the 18 things in our pipeline that we started with are still all moving to the clinic. Some very slowly because we don't have the bandwidth or the ability to do all of them to the way we'd like to. But in fact, what we've been doing, as we described back in January, is to put our focus on a couple of areas. One of them is the ex vivo approaches like CGD.
We have three liver programs that are moving to the clinic. We think eye is potentially an excellent place to spend time as well. Whether we'll do it ourselves or in the end partner some of our programs is a little unclear. Then we're also supporting the programs that we hope will be partnership opportunities like CAR T and hearing loss.
Great. Well, with that, thank you so much, Keith, for joining us today. We look forward to hearing more about the Prime story this year.
Well, thank you very much.
Thank you.