Good afternoon, and thank you for joining the Guggenheim Securities Healthcare team at our sixth annual conference. Joining us from Prime Medicine is President and CEO Dr. Keith Gottesdiener. Thank you so much for your time, Keith. Maybe we can just do a very quick overview of Prime Medicine and then take it from there.
Sure. Prime Medicine is a gene editing company that spun out of the laboratory of David Liu in 2020, so the company's about 3 years old. The company and the technology, which is Prime Editing, we think is incredibly versatile in terms of the types of edits it can do. And during the course of the last 3 and a half years, we've moved from a laboratory, brought the technology to the point where we'll be filing our first IND this year, first half of this year. So really a rapid progression from, you know, from the laboratory to the clinic, which I think we're very proud of overall. Prime Medicine itself resides in Boston.
We have somewhere around 230-240 employees, marvelous employees, and, you know, we're really determined to bring some of the therapeutic benefits of gene editing to patients as quickly as possible.
Got it. It's been a tough environment last, let's call it, two years or so, for gene editing companies, especially.
Mm-hmm.
One of the, you know, biggest concerns or questions that we get is, how does Prime prioritize 18 programs within the balance sheet constraints the company currently has?
No, it's, it's a great question, and as you can imagine, we also get that question quite often, from folks. So Prime started out originally with a very, very wide pipeline because the purpose of the pipeline that we set up, among other reasons, but one of the important reasons, was to really determine where Prime Editing could work. And so we picked many different types of programs, different organs, different types of edits, different ways of delivering, really a chance to look across the therapeutic arena. Our expectation when we started was we'd learn a lot about those places where Prime Editing works well, and we would really double down and focus on them.
We have a really good problem, and the good problem is, over the course of the last three years, just about every place where we've tried Prime Medicine—Prime Editing, excuse me, has worked extremely well. So sort of trying to find the best place for Prime Editing really hasn't been a particularly spectacular approach 'cause the answer is, and I'm being a little bit, you know, facetious when I say that, it seems to really work just about everywhere we try it. So back to the question then, is really where to decide where we want to go. And in each case, what we've done is, in the past, is we've clearly had lead and secondary programs in many of the areas we're talking about.
So when you think about 18 programs, which were on our pipeline, it really wasn't just a list of 18, but it was a prioritized list within these different areas. Since people clearly were confused by that, this year at J.P. Morgan, we really helped people to get a better look at that. And what we talked about was, there are four main areas we're really working. One's hematology, immunology, one of them's liver, one of them is eye, and one of them is neuromuscular diseases. And then we had some additional programs on the side that we primarily were aiming towards partnerships with as well. So in our...
I won't go into all the details, but in each case, we've identified essentially one targeted program or a couple of programs that we're going to narrow down to one targeted program this year, and that's the way we really are approaching things. I would just also point out that Prime realized a good year, year and a half ago, that, you know, that the environment was changing. Remember, it was a year ago that a little over a year ago, that we did our IPO in October of 2022.
At that point, you know, bringing an IPO forward, it was totally clear that the environment was a little bit different than it was in 2021, and we took steps very early on to make sure that our growth, our spend, were things that are appropriate to developing, frankly, in my opinion, an incredible new technology, but also the environment around it. And so instead of really reacting to that sort of at a later stage, we really tried very much to build our spend and our growth across the last year, year and a half, to really be appropriate to what I think we recognized fairly early was going to be a very, very difficult time.
Of course, I can always hope that, you know, we're in the process of starting to move out of that time, but I think we're still very, very much in the defensive mode in terms of cash and cash spend.
So with 18 programs, how do you prioritize which ones Prime wants to take to fruition and which ones you would prefer to partner out to bring in some non-dilutive capital?
Yeah, it's a great question, and in practice, there's no simple answer to that one either. We've identified certain programs and areas where we clearly would like to partner. Probably the best example of that is we think we can do some really remarkable and differentiated work in making CAR-Ts, both for oncology as well as for immunology. That's an area where we know we don't have the expertise in oncology, and we're frankly, we're not really that anxious to build that expertise in Prime Medicine. In immunology, we have more of the expertise, but some of the folks on the outside clearly are looking at products that could be used either in oncology or immunology, and sometimes if you have the same product, it's very difficult to separate them out one way or the other.
So it's an area where we've clearly been thinking we should bring that out of the company, because really it just isn't in our sweet spot. And in fact, there's been an extraordinary amount of interest from a number of pharma companies, and I do hope that sometime in the future, I certainly don't want to make any predictions, so we'll be able to talk to you about a deal to really get a robust partnership in that area. There are other areas like ear, where once again, we probably in the end will want to outside partner as well. There are other places where companies have come to us and said, "We're really quite interested," and we have to really decide how to portion the programs in that area.
A good example of that is our neuromuscular programs, and many of them focus on repeat expansion diseases, where we could do some remarkable things. We can literally cut out the extra or pathological repeats and just save the normal physiological repeats. We have seven of those diseases in our pipeline. You know, I've often said in these meetings that if I had to partner one or two of them, even though they're great opportunities, so I could really fund well the other group, I'd be delighted to do so. And there clearly have been companies over the last year that have really been looking closely at, are there some of those targets they wanna look at really, you know, in depth and to partner with us? And those would be places.
Do I really wanna give up a repeat expansion disease where I think we can do things that absolutely no one else can do? Probably not, but that's the kind of trade-off that we're really thinking of. There are a few other places where it may very well be that today they're in, but in the future, they may out. A good example might be, for example, eye, where we certainly have some programs moving forward, and again, we think we can do things that no one else can do. It's, again, a very specialized area. We'd like to bring those programs forward. We're very ready to do them ourselves, but there clearly could be some advantages, for example, to work with a company that has special expertise there, as well. So what we really do is we keep a little bit of an open mind.
Last thing I would just say is some of our most interesting discussions, again, no way to predict whether they'll come to fruition, are companies coming to us and saying: We wanna talk about something that's not on your pipeline, but it's something where we believe we wanna work, and we believe Prime Editing could be a very important way or technique to use that. So, some of those discussions are things that are really under the radar in that sense as well.
So Keith, you laid out a litany of different targets, tissue, tissue types, et cetera. Within the company, how are you thinking of the delivery challenges? And when you think about partnering some of those, does it become handed over to the partner, or the partner is looking for a delivery solution as well?
It depends a little bit on where we're going. So we now have proof of concept in three different delivery modalities. Once again, we started out with a variety of different delivery modalities, ex vivo approaches, you know, LNP approaches, as well as AAV approaches, partially 'cause we didn't know which one would complement best with Prime Editing. Again, we have a problem because we've been able to find out that all of them work well with Prime Editing. So this last year, we showed that with LNPs, we can do high-level efficient editing in non-human primates with a proprietary LNP formulation. We've certainly showed very high-level editing in animal models with ex vivo approaches, and just last November, we showed some really important results with dual AAV vectors in humanized mouse models. So we can work with each and every one of those approaches.
Those three approaches don't settle every issue. Even with those approaches in places, there are places like neuromuscular diseases, where those approaches are partially effective, not entirely. When we go out and we look at partnership, one of the things we look at is what do the partners bring to that particular deal? Obviously, one thing big partners can bring is non-dilutive cash, and in this environment, that's extremely important to us. But some of them also bring other things along as well. Some of them bring actual delivery methods that may help us get to a particular target more efficiently than we're currently working. Some of them have access to those delivery methods as well.
Some of them have come to us and said, "We really need to leave it in your hands." So I really hate to beg the question that you asked, but it really depends on the individual partners and how they wanna go forward with that, you know, go forward. We are a delivery company now. We didn't start out that way. We didn't expect to be a delivery company, but we have 40-45 people, if I remember correctly, who are working in delivery. We've built an LNP technology group that really is soup to nuts from, you know, discovery all the way till GLP and really on the edge of GMP manufacturing. And part of the reason we had to do that is when... Over the last couple of years, it's clear that other companies and other approaches weren't gonna solve our problem.
So we can deliver many things for those partners as well. But on the other hand, I don't think we want to become a manufacturing company as opposed to a delivery company. We'd like to develop the technology, show how they work with Prime Editing, make sure we understand them in depth, and in each case, provide them to someone who will carry the heavy lifting, in some cases, particularly for our partnerships.
The recent partnership with the CF Foundation-
Mm-hmm.
How quickly can you move with, you know, targeting the hotspot mutations there?
Yeah. So we're very proud of the fact that just, I think it was two weeks ago, we announced that we're doing a, you know, collaboration with the cystic fibrosis Foundation. I wasn't part of all the early discussions, but apparently, not apparently, it has been going on for, for a fairly long time leading towards this. I'm really pleased the CF Foundation has been very excited to work with us and understands sort of the robustness of our technology. We're actually taking two approaches with them because the CF has very ambitious goals, and so they've joined with us in a way that we're very pleased about, which is to say, we need to get to patients, but the purpose isn't in the first day to figure out the one spot where we can be therapeutic today.
Let's start to take a little bit of time and look a little bit more broadly. So they asked us, or they're supporting two approaches to, to genetic potential cures of cystic fibrosis. One of them, as you said, is a hotspot approach. If you look at cystic fibrosis, and you look where all the known pathogenic mutations are in the gene, they cluster into seven or eight hotspots, places where a 100 base pair or interval area can be edited all at once with one editor, potentially. And in that process, all the mutations that fall in that 100 base pair range can all be cured by one editor.
So that means 7 or 8 individual Prime Editors that are absolutely identical except for the guide RNA, the rest of the Prime Editor, all of the delivery, et cetera, so it's a very modular type of thing, could be cured with a very small number of them. We love that approach 'cause it works. We've certainly developed 2 very good hotspot editors, seriously, okay? And we showed some of that data at J.P. Morgan, and we'll be working to develop additional ones under that approach. The second one uses our PASSIGE technology, which is really combining Prime Editing with recombinase approaches to put in larger pieces of DNA. So even better than doing it hotspot by hotspot, might be really replacing the gene for cystic fibrosis or whole sections or exons for that gene. It's a more efficient way to do it.
And the PASSIGE approach is a little bit early in development, so the cystic fibrosis Foundation is helping us to build out PASSIGE technology aimed at cystic fibrosis. But of course, that's valuable to us at Prime Medicine because what we learn from that can be applied to other places where that PASSIGE technology can be used to put in gene-sized pieces. And remember, we can put gene-sized pieces of DNA into the genome today. That's what lentivirus does, but this is very precisely targeted, so we can put it into a single spot. We don't have to worry about semi-random, you know, integrations, for example. It's really a wonderful way to get pieces of DNA in, and if that technology continues to build, I think it's going to be very important therapeutically.
Again, depending on what the problem is, you might use different parts of Prime Editing in different ways to do so. So our hope is to really move that forward. Clearly, at this stage, it's a little bit more a research project than it is a therapeutic project. It's to make sure the technology works. I should point out a very good size chunk of that goes into delivery, particularly for LNP delivery, potential ideas for the lung as well, where we're making, we think, some very good scientific progress there, but there's still a lot of work to be done to really think about using LNPs for delivery to the lung.
Got it. So something which is tangible near term, the ex vivo CGD program.
Mm-hmm.
- You plan to file the CTA in the first half of 2024?
Yeah, we said IND/CTA. This is a global study. I hope we'll be able to tell you that we filed both because we're certainly looking at many different regulatory agencies, but all we've promised is that one or the other would be filed. But we're pretty confident that an IND will be part of that. We've had a lot of interactions with the FDA, as I know you know. We describe both informal and formal interactions with the FDA about that program, also about the platform as well. And we've had a number, you know, of informal discussions with senior members of the FDA, just in general about the program. And the FDA is very, very interested. They've invited our founder down on numerous occasions to talk to them about Prime Editing.
Peter Marks often uses examples from Prime Editing without identifying the company or the technique when he talks about the fact that it's very important from a platform approach. If you're going to move from mutation to mutation and correct them, you need to have very, very robust way not to make every mutation a separate IND, and he, he personally has stated that he's committed to it. At least that's what I've heard from his public statements. There really is no one else using any technique, except Prime Editing, that really falls into that particular category. So we hope that we'll make some progress more formally with them on that particular approach as well, 'cause the whole project, the whole approach is incredibly modular. We use the same techniques, the same assays, the same delivery methods. Everything's the same except the guide RNA.
And there are some parts, because the guide RNAs are sequence-specific, right? They aim you to a particular part of the genome that are going to be unique to every program. But when you really think of even just a guide as a chemical entity, 100 base pairs or 130 base pair guide, every one of the guides from a manufacturing point of view, looks exactly the same, as does the rest of the Prime Editor. So there's just wonderful synergies here that we'd like to capitalize on. Too early to say how it's going to turn out, but frankly, there's no question it makes extraordinary sense. That doesn't always mean that the FDA will agree with us, but in this particular case, at least it seems like they are leaning towards thinking the same way about it as we are.
I would just say, a year ago, when I was at conferences like that, the first question was: Is the FDA ever going to allow gene editing to move forward, right? You know, there were a whole bunch of INDs on hold. No one knew whether any product would be approved. We're a year later, and I think it's entirely clear, not just from Prime Editing, that the FDA and other regulatory agencies are very supportive or very interested in gene editing because of the actions that they've really taken.
... Yeah, that's a point well taken in terms of, you know, the speed at which the agency has moved, and, there's maybe one company to really thank for that. When you think about CGD, which is ex vivo, versus when you go to in vivo, how different do you think the ask is going to be from the agency versus, say, what they've asked from Verve or Intellia?
So let me step back just one second. When you, when you put an IND in, you know, when you really think about the areas where the FDA really focuses, you know, things like CMC are the commonest reason in general, and I'm not talking in gene editing, in general, that an IND isn't granted, okay? It's by far the commonest reason. There are many other aspects of an IND that you have to get through. So when we look at this, the difference between an ex vivo and an in vivo approach to gene editing, this is an estimate, but 80% or 90% of it is stuff that you're going to have to put in, whether you're ex vivo or you're in vivo.
Really, to a great degree, you're focusing on the 10% that'll be different in vivo as opposed to ex vivo, and I think what's happened to Verve and to Beam certainly gives strong hints or guidance as to where the FDA is concerned. Clearly, it's, you know, related to off-target activity, and in particular, where that off-target activity or editing could occur. It's really a biodistribution question and what happens when you actually can edit much larger groups. So it's a major difference between ex vivo and in vivo. You expose many more tissues to your gene-editing approach. But let's also be clear, the biggest problem that the FDA has, at least in Prime's view, is the off-target activity. I don't really think the FDA is concerned that tissues have perfect therapeutic edits in more places than they might expect.
It's more a matter of could they be really finding off-target, unanticipated edits in places that might be tissues where things could actually happen? Ties into the fact that Prime has an extraordinarily clean, at least so far, off-target profile, and in some ways, I think in the long run, that will help us. Now, I don't want to suggest that for the first in vivo submission we do, the FDA is just going to lean over and give us a hug and say, "You know, based on all those theoretical arguments, we're just going to give you a pass." It's not going to be like that. But that particular clean approach, I think that will build up over programs. In the long run, we think it's going to be a very, very important part.
Now, the last thing I'd just say, because I'm giving a long-winded answer to this, I can see you getting a little antsy over there, is that 10% that we know is different, we're clearly going to be focusing very, very directly on. And I think frankly, they're going to ask us to provide exactly the same kind of data that a Beam, a Verve, and Intellia, other companies have to do. I think the difference is, is we know they're going to focus on, and we're doing our best to make sure that we're ahead of the game, and that's one of the few advantages of being just a little bit later than some of the other programs.
Within Prime, you have access to various editors, right?
Mm-hmm.
PE 2-PE 6. Should we think about these as horses for courses kind of strategy, depending upon what you're going after, or is there one perfect, you know, PE?
There's definitely not one perfect PE. These are all tools, but they're all extraordinarily similar, each with a different hook or piece of information that may apply them to certain places. Think of them as optimization-type approaches. The way I think about it when I used to work in small molecules, they're like, you know, looking at a molecule and saying, "Hmm, the biodistribution isn't exactly right, the half-life isn't right. What should I do? Hmm, maybe I'll put a fluorine on that corner, and it'll be a slightly different compound, there's no question about it." But now, its half-life may extend from one hour to 10 hours, and suddenly it's a therapeutic candidate. There are all sorts of things that you find out when you're working with our Prime Editors that help you to fine-tune them.
Some of it is the actual editor, some of these optimizations that occur. And when you think of all these different PE versions, they're all really mostly optimizations for using them. So in some cases, very clear from the beginning, this is the type of approach we want to use. We want to use PE6g. I'm making this up, of course, because the last time we faced this tissue or this particular edit, that really worked well, and it took us a lot of time to figure that out. Why don't we just start with, PE6g right from the beginning and see how far we get? And so that learning that you do helps you to get there. In the end, these are not very different. There's mostly modifications or related to the pegRNA, which is obviously different from every Prime Editor to everyone as well.
So under the circumstances, you could almost think of it as, you know, deciding on a Prime Editor, but the Prime Editor is just a little more complex than just the sequence alone.
Got it. And in the last minute, with the C, if assuming the CGD, the CTA IND is cleared-
Mm-hmm.
How quickly should we anticipate IND validation, platform validation, and INDs for all the ex vivo from Prime Editors?
Ah, so if you're asking when are we going to have Prime Editing data in humans, the answer is all of the guidance we've given is it'll happen in 2025. What we have told people in our JPM slides is the FDA won't really allow us, other agencies either, to start all the patient activities, like mobilization, et cetera, till the IND is open. So the process of enrolling, mobilizing, you know, editing, clearing, and such, we gave an estimate at JPM that from that moment, it's probably six months till we can dose our first patient. We'll obviously try to cut that shorter. The FDA has also made it clear that at the beginning, we can do one patient at a time, because if they didn't feel this way before Graphite, they certainly do now.
By the way, that's our interpretation, not something the FDA has said to us, that they want to see that you can engraft before they'll let us go to the next patient. So for the first couple, they're clearly going to be staggered, and that's why we've really said 2025 is when we expect to give data. We generally are not the kind of company that reports n=1 approaches. Maybe if the data is so overwhelmingly incredible, I won't promise it could never happen, but generally, we'd like to be pretty sure that it works the way we're hoping before we share it with folks.
So I think we're just going to keep it 25 for now and get that data out to people as quickly as we feel, you know, makes sense, where we can look people in the eye and say, "Here's the result. You can stand by it. We can stand by it.
Awesome. Keith, unfortunately, we are out of time.
No, thank you.
Appreciate you coming over, and good luck.
No, thank you very much. Thank you, everyone, for listening. Bye-bye.
Thank you.