All right, everyone. I think for time we're going to go ahead and get started. Thank you all for joining us here in the room and online at TD Cowen's 45th Annual Healthcare Conference. I'm Jeff Little, one of the senior biotech analysts here on the team at TD Cowen. It is my pleasure to have with me today two members of the Prime Medicine team. We have President and CEO Keith Gottesdiener and CFO Allan Reine. Thank you very much for joining us.
My pleasure.
Maybe just to kick things off, if you could just give us a little bit of a brief overview about kind of the recent progress at Prime and maybe what is to be expected over the next kind of 12 months here.
Yeah. First of all, I think Prime is in great shape, really, to bring forward a whole series of high-value programs over the next 12 to 18 months. We're very, very excited about that. In practice, we talk quite a bit about our clinical data coming this year, but probably just as important to us are some of the high-value programs that we're doing in both Wilson's disease and cystic fibrosis. Before we do that, it's probably important to just point out we really think prime editing is the best way to do gene editing. Clearly, we believe the safest one overall. There's a tremendous amount of significant interest, both from the academic community as well as from strategics in what's going on in Prime Medicine.
As we look forward with all of that sort of as background, this is the year where we're going to have proof of concept. We're going to have our first clinical data in a disease called chronic granulomatous disease, or CGD. We'll be moving very rapidly in 2026 towards progress in our Wilson's disease program and also in cystic fibrosis. We can talk a little bit more about those as well.
Perfect. Maybe to kick things off, you did mention that the first clinical trial is enrolling for PM359 in CGD. Maybe can you touch a little bit about the specific gene mutation that this therapy corrects and maybe how specifically the therapy was developed as this is going to be the first or is the first prime-edited therapy in play?
Correct. We actually work in two forms of CGD. CGD is a disease where one needs a particular enzymatic activity to basically kill bacteria and fungi. When people have mutations in the different forms of CGD, they literally are prey to lifelong infections and many other inflammatory issues and autoimmunity issues as well. We're working in a type called P47 as our first approach, but we also have programs in X-linked CGD. P47 is approximately one-third of the patients, and X-CGD is mostly most of the other two-thirds. What we can do is we can go and find the exact defect which is seen in the genes that are needed to produce this enzymatic activity, and we can correct them. We've been able to do that in our preclinical models to a very precise degree and at a very, very high level.
Can you maybe talk a little bit about how you interrogate both on and off-target editing with prime editing? And sort of what was the FDA looking for in order to get this into the clinic?
On-target editing, which means can we make the therapeutic correction, is very, very easy. We know exactly where we want to make the correction. We can certainly sequence across that area, and we can see what the level of sequencing is across a great number of cells and get a percentage of cells edited. We actually do our preclinical models by taking human stem cells that we're editing and putting them into a mouse model to reconstitute the bone marrow. Everything we're doing, we're using the human editors, and we're using human cells, both patients and healthy volunteers, even though we're using the animal model to sort of recapitulate what's going to happen this year in humans, which is to infuse them back into the bone marrow. We can get a very, very good look at what's happening on-target.
We're seeing 85%-90% precise correction with what we're doing today with great ability to engraft those cells back into the body. Off-target editing is different because essentially you have to look hypothetically every place but the place where the therapeutic edit is occurring. We now use approximately 12 different assays that we've developed, brought to the FDA, had them really critique, and we validated it to really meet the requirements. We apply them to every single one of our programs. We have a number of programs where we're using these FDA-qualified assays to really look for off-target editing. Some of them are deterministic. We do bioinformatics, and we say, these are places that look like the CGD place we're trying to correct. Others of them are totally empiric. Some of them look for rearrangements and translocations. There's a variety of different edits.
We can't detect a single episode of off-target editing in our CGD program. As a matter of fact, as of today, we really can't detect a single example of any off-target editing in any of our clinical programs. It's pretty remarkable, the specificity of what we do. Even at the target site, we either make the edit or we don't make the edit in a small number of cases, and we get out and we leave the cell behind. We think there's an important differentiation with prime editing because we don't muck around in the genome. What you aim to do, you either do it and get out or you get out. In the end, we can say to people, this is exactly what's going to happen to your genome, and you shouldn't worry about anything else except what we're telling you we're going to do.
Perfect. For the 359 study, can you just remind us how enrollment progresses?
Sure. 359 is the PM359 is the prime editor for the first form of CGD. The way the study enrolls, it's a fairly rare disease. There are two adults, two adolescents, and two children, six years and above, who are actually part of the initial studies. The FDA is very, very cautious with these ex vivo programs. They have asked us to do what we believe is what everybody is doing, which is the first patient is treated. They look to be sure that it's safe. In other words, that we can engraft these patients back and then let us do the next one. Because we want to move down in age very, very rapidly, our first cohort is only two patients. After the adults are clear, we're going to move to the adolescents, again, very carefully, and then to the children.
In some ways, this is a little bit different because most people who are doing ex vivo editing then go on to a third adult, a fourth adult, a fifth adult. Most things can happen in parallel. In our case, these are very, very small cohorts that will be following sequentially. Of course, our goal is as soon as we have what we think is damn good data, we're going to go to the FDA and say, let's start the pivotal trial for this because we expect it's only going to be handfuls of patients that are required in order to get this approved. To be fair, we haven't had that discussion with the FDA, but we're expecting it to be potentially 10, maybe a few more patients overall, including those that are in the first half. Certainly, that'll be our proposal to the FDA to get moving into a pivotal trial quite rapidly.
You mentioned a little bit at the beginning in the overall remarks, but maybe can you touch a little bit on sort of just the unmet need in this population and where does allogeneic HSCT kind of fall short?
First of all, the unmet need is really quite dramatic. These patients fight off infections their whole life. They tend to die in their 30s and 40s. It isn't just infection. Some of these autoimmunity and inflammatory problems can be as debilitating as anything that happens with the infections overall. These are not just garden-variety infections. For those who remember what it used to be like in cystic fibrosis, where people got deeper and deeper and more persistent infections, and you could beat them off for a little while with antibiotics. That's what happens to some degree with these folks is they get worse and worse and worse over time. Not everybody. Some have a little more insulin, but in general, it's quite huge. Today, it requires an allogeneic bone marrow transplant with all the issues of matching and the donors and such.
Those treatments require very profound immunosuppression to go forward. People have to stay on immunosuppression in many cases, in most cases, for the rest of their life. They're subject to graft versus host disease. What we offer really is a once-and-done procedure. We go in. It's a more gentle bone marrow transplant with more gentle immunosuppression. When we're done, if we do what we've done in animals, these people are literally cured. They will never need another bit of treatment the rest of their lives.
The company has guided to initial data from this study this year.
Correct.
Can you kind of outline as best as you can and the company is willing to do right now, how many patients will be included in that? What are the main signals of activity that you're going to be looking for?
We haven't given any more guidance on the number of patients, but keep in mind the first cohort is only two patients. That puts some kind of maybe two to three. It puts some limit on the number of patients just to give people a general idea. There are three things we'd really like to deliver with the first data set. One is safety, and that's really engraftment. We need to show that we put the cells back into patients. They went to the bone marrow. They engrafted, and they reconstituted their bone marrow. They have platelets and red cells and white cells. Second thing is we want the white cells to be edited. I'll talk about our target for that in just one minute. The third thing is we want that the important surrogate biomarker for this disease, a test called DHR, is positive.
Let's take those one by one, starting with the % editing. In animal models, as I've said, we've gotten 80%-90% editing overall. We would love to see that, but there's very good clinical human data that suggests 15%-20% editing will be curative. It's one of the reasons why I picked this disease early on is the amount of editing we need to do. When we chose this indication, we thought it was low. Of course, then things went swimmingly well in our animal models. We certainly hope it'll be higher, but anything above 20% is going to cure patients. As far as we're concerned, that's the most important thing that we need to do. The DHR test actually measures the direct enzymatic activity that's missing.
Calling this a biomarker in a sense is not correct in my mind because what it's really measuring is the lack or the problem that actually causes the disease. What you want is a biomarker that's not indirect at all, but totally direct. It actually shows that you've reconstituted the enzymatic activity, and now you can fight off white cells. We're expecting that to also hit about 20% because the same data suggests that's more than enough to actually cure folks.
Perfect. Maybe jumping over to, you alluded to in the beginning, the X-linked program, maybe how many more patients or larger could this subset of patients be? This therapy was developed a little bit different than your first program. Can you kind of walk us through that a little bit?
Yeah. The X-linked is about two to three times bigger than the p47 type X-CGD. The way we're actually doing the correcting is using a technique called passage, where we can put in very large pieces of DNA in a very programmed or determined spot. It is a little bit different about how we do the editing. Everything else is exactly the same in this program. The clinical trials, the off-target activity, all the manufacturing is essentially the same for almost all components. We think there's a huge amount of synergy between these two. Discussions we had with the FDA for other similar programs suggest that we will put them under the same IND.
When you put it together, there clearly is a different style of editing, but under the circumstances, we think there should be tremendous amounts of ability to do it faster, cheaper, and frankly, with very high probability of success to get those patients through.
When you think about passage, and I think you just touched on this, but there's no additional screening or any sort of changes in terms of on or off-target editing versus prime?
On-target, pretty much no. Off-target, there probably is going to be a tweak or two that we have to do, but essentially it's the same thing.
Maybe we'll dive into some of the other pipeline programs in a little bit. Last year, the company did kind of refocus the pipeline and also struck a deal with Bristol. Maybe can you just walk us through both of those processes, kind of streamlining the pipeline, and then how important is sort of clinical partnerships and things like that for the future of the business?
Yeah. I'm going to ask Allan Reine. We don't want him to be up here and not earn his pay while he's sitting up here. So Allan?
Yeah. I joined the company back in January of last year. At the time, I'm sure you remember well, there were about 18 programs in the pipeline. There were probably actually a few more than that. We always knew that was not a number we were going to take forward to the clinic, and there would be a lot of sort of what I would call natural attrition. On the positive side, everything was actually working. All these programs were advancing, some at different paces, but I think importantly, we were showing good editing in a number of different tissue types. The bad thing was all these things were working, and you have to figure out also how you are going to pay for them and what makes sense to take forward. We underwent an exercise that honestly took months to do.
We were really dug into every single program in the pipeline to really understand, obviously, what's the unmet need in the indication that we wanted to go after? What's the commercial opportunity? Is there synergy between that program and other programs that we were working on? What did the regulatory environment look like? What's the clinical tractability? Another example of a parameter that we looked at. We kind of put that all into the blender, so to speak, and came up with what I think is a pipeline of programs that we really believe can drive significant value for this company. That's what's important. These editors are working in all these different places, but for us to treat the most number of patients over time, we really need to build value for the company and for our shareholders.
It was really thought of like, let's talk about Wilson's disease as an example. If you take Wilson's disease, you have 10,000 patients in the U.S. Our initial editor can go after 30%-50% of that population. For a gene editing therapy, that's a good-sized population, a multi-billion dollar opportunity to go after. These patients are on chelators and basically therapies that they're not compliant with, that are very difficult to take, and obviously that don't cure this disease. We see this as a very high unmet medical need. We talked at tons of KOLs to understand if this would be a therapy they would use in their patients. Almost universally, they would use this in almost all of their Wilson's patients, except for the most maybe advanced neurologically diseased patients that were irreversible.
To us, that sort of hit, almost checked every single box. Obviously, delivery is important, right? We've got what I think is a universal LNP to deliver. A delivery system that works well, that we believe is safe. Again, that sort of checked every box and time to clinic. We can get to the clinic. We have an IND date now in the first half of next year, but also clinical data. When can you de-risk, right? What can investors look to? We believe in that indication, you can get some pretty early data to tell you that this drug or this gene editor is doing what it's supposed to do. Unfortunately, there are some other assets, a couple of which could have IND'd this year. These were not easy decisions to make. One was one of our ocular programs.
Another was a smaller liver disease program that could have IND'd this year. For various reasons, whether it was commercial opportunity or looking at what I call clinical tractability or the time to that value-creating event, if that was maybe three, four, five years in the future, it was not the right investment for Prime to make today. This kind of segues into the other part of your question. Some of these assets that we are not taking forward on our own today, there is significant interest. Across neurological disease, hearing loss, and others, there is actually a lot of interest in those assets for good reason. We have created drugs that essentially can cure some of these diseases, we believe. I expect us at some point to do some deals around some of these assets.
Even beyond that, I would say the interest in the technology today is very high. There is, as always, a lot of conversations ongoing and a lot of interest in what we're doing. This is an incredible technology, to what Keith said. We own this technology, and it's very powerful in terms of the edits that we can make and the safe way in which we could do that. I think companies really are understanding that. There are other BMS-type deals where people are interested in those types of things as well. BD's never done until it's done, but we are hopeful that more BD will occur.
I was just going to say the tone of our discussions with Strategix has really changed over the last year. If you look back a year, there were clearly some far-thinking, this is in our opinion, of course, far-thinking Strategix were saying, "How can we use prime?" It is also true that many companies were not sure whether it was time to dip their toes into the water. They were still thinking about immediate-type BD, et cetera. That interest has really picked up. Just about a good proportion of the big pharma, even the mid-sized pharma, have wanted to have interactions about these things. They have had discussions with us. Some have decided this is not the time to put it in their program. Some have come and looked over our program, like Allan said, some of the pieces we paused.
Actually, some of the most interesting things are a little more BMS-like, where people have come to us and said, "We've seen something. We see something there that has great value to us. Let's craft a deal around that in order to use prime editing in the way we can." Listen, I think I have to give BMS credit. When you think about how you make a CAR-T, and our partnership was about ex-vivo CAR-T cells, there's just such incredible advantages to the way prime can do it. It can do it at higher levels of editing efficiency without off-target, without being sequential, with an extraordinary amount of multiplexing, with a non-viral approach.
Squibb looked at it and said, "We could do it the old way, or we could do it the new way." Frankly, I can't speak for them, but I believe they've come away and been real converts to the fact that prime editing just is or will revolutionize the way that they make CAR-Ts.
Perfect. I want to jump into some of the intricacies of the Bristol deal, but some of the things that you're saying maybe want to go slightly elsewhere first. We have seen over the past year, gene editing companies have kind of taken steps to refine the pipeline, or we've seen private companies interested in the gene editing space maybe kind of not be able to make that next jump. I guess, is there an inherent kind of pay-to-play to be in the gene editing space and maybe have some of the developments that you've done on the front end kind of potentially lessen the expense further on? How do you think about expense management?
First of all, we have been building this company. When I say, let me start, we have been building this company with the idea that this is an extraordinary technology. Now, you could take that many ways. One way you can take it is that means they've been reaching into their pocket and throwing money at everything under the circumstances because they have no judgment and they don't know how to discipline themselves, et cetera. That's completely wrong. It is true that Allan's correct. It was this year we took things off our pipeline, but for many years before then, we were making very selective investments in particular areas, prototype diseases to go forward. We have been thinking very carefully about how to do this for a long period of time. The underlying thought was, is the first time you do something, it's very expensive.
You shouldn't do it unless the next time you do it, you're going to get some synergy, some benefits from that. Everything we've done has been based on the idea, if we get that right first, it's going to be good for us forever. Let me give you a good example. You asked about it for off-target edits. We do an extensive degree of off-target editing. In each program, there will be a cost to do that. For CGD, though, we had to develop each and every one of the assays, have interactions with the FDA, redo some of the assays to meet the requirements, validate them, et cetera. We never, ever have to do that again. That's just an extraordinary savings. It's like having money in the bank that you can draw on at any point.
Our modular LNP, which we call a universal LNP, is exactly the same thing. For every liver disease that we use LNPs and potentially even in other areas, that LNP will just keep on giving. The agency and other agencies have been very aware of that. They have pointed out to us, and when we have talked to them, that there are those synergies. We do not have to do everything over and over and over again because we have really proven this component is safe, or this way of doing things is safe, or this manufacturing method meets their requirements. I think there is no question that each and every program we do will get progressively cheaper each time that we do it.
Probably the next liver within liver where we have an undisclosed program, we can't talk about, we aren't talking about it today, but it's a place where those synergies have just come roaring through.
Perfect. Maybe back to the Bristol deal, if you could give us just an outline of the overall structure of that and maybe what made Bristol the ideal partner to work with you.
Yeah. I mean, I'll answer the last part first. I mean, I think the ideal partner really is they've got a, they have a CAR-T franchise that they're really focused on. There's a lot of competition within that space, as you know. To me, I think this really is the premier technology if you want to continue to be a leader within that space. I think BMS saw that. I think from a scientific collaborative standpoint, I think they're really impressed with what they saw internally at Prime, but us as well. We're really impressed with their scientists and their approach. I think it's a really nice collaboration from that standpoint. The deal was $110 million upfront, $55 million cash, $55 million equity. There's significant, what I would call preclinical milestones as part of that deal, $185 million in total.
$185 billion.
$185 million. Sorry, the early stage milestones.
You said million, but it's billion. $185 million.
Yeah, yeah, for the first one. The total buy a box, yes, going to the billions. I will take that in preclinical.
Sorry, I was talking about something different.
No worries.
A little mixed up there.
We haven't said the number of targets that are total part of the deal, but obviously that would get split up amongst that amount. To Keith's point, billions of dollars as you start to get to both development milestones, which are substantial, and the sales milestones.
Perfect. Maybe jumping over to Wilson's disease, can you just remind us kind of where that stands in the pipeline? What are the next things that investors should be looking out for there?
Yeah. First of all, we've put out really already data which we've shown that shows that the development candidate that we're working with can already meet all of our requirements. There are sort of two elements that you wanted to show. One is high degrees of editing, which we've shown. The other is that the pharmacodynamics, the biomarkers are very impressive. The editing we've got is somewhere well north of 70% of hepatocytes are now edited with that. Just as important, you can see what actually happens if you do that kind of editing in the mouse models. In the mouse models of Wilson's disease, these are basically humanized mouse models who are testing the actual clinical candidates.
You can see over the course of 28 days, literally 75% of the iron that's in the liver that's been there in the lives of that animal that's accumulated is completely taken out in those individual animals, returning things in just a short period of time to near normal or into normal levels. It's really, really impressive. I mean, to tell you the truth, if we could do that in humans where we make the corrections and one month later, in fact, most of the, sorry, the copper that's in these folks, I don't know why I'm mixing up my words today, but most of the copper that's in the liver comes out, that would be just an extraordinary event overall. It really just would. The thought leaders who have seen this kind of data and not have just been overwhelmed with just how impressive this data would be.
It's what you really want to show. It's the kind of thing that'll give people once again a lifelong cure once you've done that. Keep in mind in the liver where the cells turn over again, other technologies have to think about what happens after five or seven years potentially. In our case, this is carried into each of the daughter cells. In fact, it is a lifelong cure. Many of these patients are picked up in their teens or early adulthood or maybe sooner. That's an awful long life that you have to deal with. Using a different approach that people have to worry about for the next 50 plus years, this just seems to be the kind of approach that's going to make an extraordinary difference in these people.
Maybe what proportion of the Wilson's market will 577 address? Maybe how are you thinking about the initial candidates for clinical trial?
Yeah. First of all, we believe anybody with this mutation, which is 30%-50% of Wilson's disease, would be eligible. Most people, again, do not get diagnosed until they already have some kind of symptoms, almost invariably liver disease at that particular point. These are all patients who, if they are identified, in practice would be eligible for the trials. There is no question the thought leaders would like us to start with the most severe patients. Maybe not the most severe because the most severe are completely decompensated cirrhotics. Those patients may be too fragile to do a trial, but they would really like us to start with the cirrhotics or the what is called F4 patients, really those who have significant fibrosis.
Those are patients for whom there is quite a bit of data from other diseases as well as these diseases that if you are on top of treatment, you can actually begin to reverse things. One will never know till we do the trials, but our hope is, in fact, to catch these people at a stage when the liver can regenerate itself and actually improve over time. That is certainly the way the thought leaders that we have talked to have really thought about it as well.
Maybe in the last question here, in genetic medicine, we've seen some launches go particularly well. Others have had a little bit more of a challenge in terms of reimbursement and patient enthusiasm. I guess, what have you been able to learn from those experiences? What can you do even at this stage to make sure that once you're launching in CGD, it's going to be successful?
I'll share my thoughts, and then I'll turn it over to Allan to amplify on that a little bit. Listen, the most important thing you can do is to present to patients an extraordinarily compelling value proposition. You do this and your disease is over. Genetic medicines in general have the ability to do it, but in practice, some of the prime editing with that incredible amount of specificity and the lack of a safety issue with off-target so far, that's just a very, very compelling picture overall. The second thing is you want to work in diseases for which there are really no alternatives and there's great unmet need. We've generally tried to pick our indications to be exactly that, places where people can look at this and say, "Wow, I need this.
Not I want this, but I need this when you go forward." I think the diseases we're talking about really fall into that category. There's no question that's true in CGD. It's small. There's no question that's true in Wilson's disease. If one looks at cystic fibrosis, particularly those patients not treated by Trikafta, I think there's an extraordinary opportunity to give those patients something that really is special.
Yeah. I mean, I would just emphasize one of the points you made, Keith, which is there really needs to be an unmet need. If that unmet need is there, then I think you'll get much faster penetration into these markets. When there's alternatives, when you have a very expensive therapy and there are alternatives, it's a little bit, or it's a difficult procedure to get with risks associated with it, I think that makes it a lot more complicated. Back to the sort of prioritization of our pipeline last year, that was a very important component, right? Looking at different diseases and really understanding, are there other alternative therapies that might be a barrier to uptake?
In many ways, this is going to be a really important year for us into next year. We're going to have proof of concept in the clinical program this year. Our really high-value, commercially interesting programs will really be moving towards the clinic next year. We really feel like it's our time to really move into that realm of potentially a very valuable company overall.
Perfect. We look forward to an exciting year, but thank you very much for joining us and thank you to those in the room and online.
All right. Thank you all. Bye-bye.