us at Jefferies, and it's with great pleasure that I'd like to welcome our guest today, Keith Gottesdiener, the CEO of Prime Medicine, and, we're gonna do a fireside chat format. So Keith, maybe for those who are new to the story, if you can give a one-minute intro to the company.
Yeah, so Prime Medicine is a next generation gene editing company, came out of the laboratory of David Liu at the Broad Institute of MIT and Harvard. It's really a new approach to gene editing that really allows you to correct genes, not just inactivate genes overall, and it's really marked very much by the versatility of this approach. You can use it almost anywhere. The breadth, which is really the number of places you could use it across different kinds of diseases or different kinds of genetic edits.
The efficacy that we're achieving is also quite good, well above the 90% range, for example, in our lead program, and maybe the most important when you think about a new technology like gene editing, the safety profile, yeah, really just outclasses anything else that we currently are seeing, at least from our point of view. So we have a very expanded pipeline. I think Maury is gonna take us through some of the elements of that, so I won't spend too much time on it, but, you know, in the course of four years, we've gone from a laboratory phenomena to our first IND, which was just approved last month.
Got it, and maybe digging a little bit more into the technology, the prime editing, how does that compare to other editing modalities in respect to versatility, safety, and efficiency? And how do you envision the editing landscape will shape up given the continued iterations in the technologies?
Yeah. So first of all, I think of editing technologies, gene editing technologies in a number of generations. I mean, there's no question we've been trying to manipulate the genome for decades now as well, but I think gene editing, particularly the advent of CRISPR, really changed the landscape in many ways, 'cause CRISPR gave the ability to find an individual particular spot in the genome, so you started to get a different kind of specificity for what you wanted to do. Unfortunately, I think CRISPR has turned out to be a little bit more limited in what it can do. So it's a great technique, amazing things are happening.
But when you look at where you can work, CRISPR has been most successful, maybe even only successful in inactivating genes, knockdowns overall, and it carries some additional risks with it because of the double-strand breaks, literally rips your chromosome apart and puts it back together again in order to inactivate genes or areas of, you know, genetic areas. Base editing was a second generation. It was the first attempt to really begin to make corrections to DNA, to fix things. And in practice, that's also a great technique, but it turned out to be fairly limited. It can only work on four single-base-pair mismatches, so that's great if you want to repair one of them, but if you want to think more broadly, it's really quite different. Prime editing can work on all single-base-pair mismatches, can fix small deletional mutations.
Good example is Delta F508 in cystic fibrosis, small insertional deletions, like the two base pairs in Tay-Sachs. It can work in bigger chunks of DNA, 50, 100, 150 base pairs. We call that hotspot editing, where we focus on a region of space where mutations may cluster. And more recently, we've spent time educating investors about our PASSIGE technology, which is something we've been working in the company since 2019, since 2020. But really, we've been talking about a way to very, very precisely put a very large piece of DNA into one single pre-identified spot in the genome.
The second thing I think that's been important is, beyond the fact that we don't cause double-strand breaks, we also have the ability to really cut down on the off-target editing, and we think the safety is a really critical component, because frankly, if you're gonna ask somebody to have their genes edited, you need to really be able to say to people, "We're gonna go in, we're gonna make that individual edit. When we're done, we're gonna get out, and we're not gonna do anything else while we're in there." So I, like I think the FDA, really feel that really demonstrating that safety profile, and primarily, lack of off-target editing is really a critical area as well. Now, where do I think the field is going? I don't know.
I'm not a fortune teller, but what I do think is I don't actually think that there are continued iterations of the editing technology. What people have been doing is around those three generations that I mentioned, they've really been doing a little bit of tweaking. They do a lot of PR, they use a lot of new terms, but when you really come down to it, at least it's our impression at Prime Medicine, is those are really the three stages where we've gotten to today, really. We can knock down things with CRISPR, we can begin to fix them with base editing, and with prime editing, we can look much more broadly with the technique to move forward.
Got it. Yeah, it made sense, and that's kind of a great overview of the space and a way to think about it.
Yeah.
Let's dig into your lead program, PM359. Congrats on the IND acceptance, for this first prime editor, for chronic granulomatous disease or, or CGD. And, maybe talk about, some of the gating factors, for activating your initial clinical study and, sites in the US and enrolling your first patient into this study.
... So I'll be happy to do that, but let me take one minute to just celebrate the fact that we have an IND for a new technology like this. Four years ago, this was being done in one laboratory anywhere in the world, and today we actually have progressed into an IND and are beginning our clinical trials. And I would also point out, it probably marks, it's probably just a marker of the improved relationship that gene editing companies have with the FDA. Our IND, unlike some of the other INDs that came before us, and I think we've learned from those other INDs, so I don't want to suggest people did a bad job before, and they're doing a good job now.
But what we've been able to do is get better clarity from the FDA about what they want and what we need to do in order to open IND. And in our particular case, we submitted the IND. It took 27 days for the IND to be, to be approved. The FDA essentially asked no real questions, and the few they asked, we gave them an answer. They said, "Fine." They did ask for one small tweak to one of our stopping rules in our protocol, but it says something very, very different. That's the kind of process people have been going through for years with small molecules, and I think no one's been expecting with gene editing companies, and I'm just pleased to say that that's happened, and we expect other countries' worth of, you know, approvals to come very much in the near future.
So when you ask what are the gating factors to actually start the study, because I'd like to be able to tell everybody the IND came out at the end of April, and, you know, the first week in May, we dosed our first patient. That actually is not what will happen. We will need to take approximately six months to dose our first patient. The FDA was very clear they didn't want us to do any patient activities until we actually had gotten the IND approved, and many of the academic sites for this rare disease also wanted to see the IND before they were ready to accept applications to the institutional review boards, et cetera. So we have to activate the sites. We have to enroll the patients.
We've done a lot of pre-work on enrolling patients, but when patients are faced with an informed consent, and they have to say yes or no, they have to remake that decision. Once that's done, we need to mobilize from these patients the stem cells. Typically, we expect that take one round of mobilization, but it's not uncommon that it takes two weeks apart, and then we have to process them, as we do in all cell therapies, do all of the release testing, and then put them back into a patient at a time where the patient is ready to spend weeks in a hospital, you know, getting the immunosuppression that's needed beforehand. So we've guided people for the first patient. We expect it'll be six months or more before we actually dose that first patient.
Now, I don't expect it to take that long for the second and third and the fourth, but the FDA has required for gene editing companies pretty routinely, and so have other regulatory agencies, that we do one patient at a time until we see engraftment and safety before we go to the next one.
Got it. That's, that's a great answer, and maybe just one clarification for the one tweak to the study on the stopping rule. What exactly is that?
Oh, so in practice, we had a particular rule that said if we had a type, you know, a level 5 SAE, that we were gonna do the following things, and they said, "Well, what we'd like you to do is to consider an additional step in that, not involving the FDA. We'd feel better if this, this, and this happened." And we went back to them with a proposal on that, which was perfectly acceptable to us, and they said, "Okay.
Got it. Okay. And, so for the study, you plan to enroll 2-3 stable, CGD patients in your first cohort, followed by sequential expansion into adolescents and pediatric cohorts. What do you expect the screen failure rate to look like for this study, and will your first 2-3 stable patients come from the same site in the United States, or do you plan to get, multi-site experience early on?
Yeah. So frankly, we expect the screen failure rate to be pretty close to zero. You know, most of these patients are being lined up for the alternate treatment, which is an allogeneic bone marrow transplant, in many cases without a particularly good donor, in that particular case. So in practice, under those circumstances, many of the sites, the patients that have at least had discussions with their investigators about that, seem very, you know, very, very positive about coming into this because most of them are already thinking about a much more toxic procedure overall. Probably the two most important gating factors at the beginning are the age, because we have to start in adults, test at least two before we move to adolescents, and then we get to move to children.
The second is, these patients do have quite severe infections or very severe inflammatory processes, and when we start with the first patient or two, we want patients who are not in that situation where they have a severe infection. Because the first thing we're going to do is immunosuppress them to remove their old cells from the bone marrow. It's a very risky thing to do until we're certain that we could go in, and we can engraft these patients and really restore their function. So those are probably the two critical questions. Now, of course, those kind of patients who do have severe infections are a wonderful opportunity for us.
After we've gained just the smallest bit of, shall we say, experience, we hope to actually do one of those patients because these allogeneic bone marrow transplants have shown that many of those patients with severe infections respond very dramatically from the transplantation. As a matter of fact, for some patients, it's the last resort that they're offered because the infections can't be cured, and they're gonna die in the near future, shall we say, you know, close future? And so they've been offered these allogeneic approaches, and most of them have been fraught with a lot of danger, but it has cured people both of the disease, but also the infection as well.
So we hope we'll get into some of those more severe patients, and frankly, it'll be a wonderful story to be able to tell when those patients came in with the help of the return of their functional white cells. They'll be able to go forward and really look cured in more than one way, infection and disease.
Got it. Interesting. And will you have more than one site in the U.S., and do you plan on opening up sites outside the United States?
Yeah, so this is an international study. We definitely will be opening sites. We will be opening sites outside of the US. Currently, we only have one place where we're manufacturing the materials, the cell therapies, and they have a limited shelf life. For example, people will often ask me: "Why are you starting in Australia or New Zealand?" We don't have the ability to process them and to send them to Australia and have them come in reasonable shape. But Europe, for example, other parts in the Americas, are all places that we've considered, and we plan to go to many of those. We don't plan to focus on just one site.
In practice, I think if we just took patients from one site, and again, I'm interpreting what my clinical team has said, I think the other investigators would basically shoot us because they all have patients lined up that they want to get into the site. I hope our problem's gonna be sorting between these patients to give many of the sites an opportunity to get patients in. Now, keep in mind, this trial's designed to rapidly progress to what we hope will be a pivotal trial or to convert. So if that were available, once we've gotten, for example, two adults in, we hope to have a discussion with the FDA about, can we start the pivotal trial for adults, even while we're working our way down to adolescents and to children?
It could be quite rapidly if the, if the agencies agree, but I should point out, we haven't really discussed that with the FDA. So those are really our plans, our intentions.
Got it. For that transition to registrational study, would you also want to treat the severe infection patients as well?
We would. It isn't required, because the way these patients—most of these patients are is they have bouts of severe infection, and they recover, but they're debilitated. They can go on to the next one and the next one. Very different frequency of these infections among individuals. Almost all of them, particularly at an early age, when we'd really like to focus, have very good periods for short periods of time where a bone marrow transplant would make sense. So when we go, I don't think we're gonna be pushing specifically that the infected patients need to be in the study, but we do think that data is gonna be really helpful in helping to build out that this is something that has great efficacy. Frankly, it'll give sites and doctors and patients much more flexibility about when they do the transplant.
Got it. And you've estimated it could take approximately six months to recruit, mobilize, manufacture, and condition CGD patients with prime-edited hematopoietic stem cells. Can you talk about... And you also mentioned that the first patient would be in the hospital for a couple of weeks as well. Talk about ways or areas where you could potentially optimize these processes and how that's going to look when you scale up.
Okay, if I could be just a little bit jocular for a moment, I'd like to start processing the second patient one day after I did the first. I can't dose that patient until I see the first patient is mated and engrafted, but there's really very little harm to anybody to begin to process those patients. Now, of course, we're not gonna start doing that in the second patient, the day after the first. Anytime you do something for the first time, you want your whole team focused on that first patient to get it going. But we plan to do many of these things in parallel as we go forward. Second of all, the first time you do the manipulations and the release, you work out all the kinks in the procedure.
We've clearly done multiple practice runs to do that, but when you do it first for the real time, you find out that there's something you may not have done, and we expect that it'll get better and better. And of course, important things, you know, are no longer on the critical path, activation of sites, you know, enrolling of patients. It really comes down to, you know, mobilizing the stem cells from patients, processing them as quickly as possible, and then getting them back into patients.
Got it. And, we've talked about your DHR assay, and, it's the first, key outcome measure that's listed in your design, and it's the gold standard diagnostic test for CGD. Is this going to be part of your 2025 readout?
So I certainly hope so. You know, it's a test that comes back approximately at the same time as white cells come back. So basically, there are three things I'd like to see, Prime would like to see as we go through this. The first one is safety, okay, of course, which is the goal of every Phase I trial. In this particular case, there's an element of the safety that's obviously foremost, which is a return of the, you know, the bone marrow. So engraftment and producing white cells, red cells, and platelets is critical, obviously, to going forward. And of course, many folks in this room know that was a problem that one other company had, where they started this, and on their second, third patient, you know, they really weren't able to show robust engraftment.
The second thing is, you wanna show that what people come back with are the edited cells. And certainly, in all of our animal models, when we do that, the amount of edited cells that comes back is extraordinarily high. 80, 90, 95% of the cells actually have the correction. And then the third thing is that that show that that correction translates in an improvement in the enzymatic defect, which causes this particular disease, and DHR is a direct measurement of that enzymatic approach. So as the white cells come back, we expect we'll be able to look at DHR along with it.
We know from chimeric bone marrows, bone marrows where people haven't fully taken, but only a small portion of the new, bone marrow cells from the donor have come in, that even 15% or 20% of the cells that are normal in this particular area is enough to appear to correct things. I don't think we want 15%-20%, but it's great to have a very well-determined number, so we know exactly what we're aiming for when it happens, and I certainly hope that we're sharing DHR data when the time comes. We're a cautious company, and frankly, we're not an N=1, let's put out a press release type of company in general.
So I'm expecting that we're not gonna have a champagne party the day that the first data comes back, but we wanna be able to show people prime editing works in humans, and this is the first case, and we'd like people at the end of it, when we bring the data out, to give them a complete data set and for everybody to say, "You know, these guys really delivered on what we want." So let's hope that we can do that.
Got it. And just to clarify, so for the DHR measure, what percent positive neutrophils do you want to achieve or what do you need to achieve?
We're aiming for above 15%-20%. Now, I do want to state that we've discussed that with the FDA, but we haven't had discussions of pivotal trials, so they haven't said to us, "Yep, that's exactly what we want on an endpoint for registration." But they did understand that particular data, so has other regulatory agencies, and the data supporting it is pretty strong. So those discussions, at least at the conceptual level, have been very positive from our point of view.
Got it. And is there a way to quantify infection burden in CGD patients, given the potential variability in infections across patients, and yeah, what are your thoughts on that?
Yeah, so that's very hard to do. I'm actually by training an infectious disease doc, though God knows you wouldn't want me to treat any of your infections these days after being away from it for 20 years, maybe 30 years, now that I'm thinking about it. Our CMO is also an infectious disease trained doc. There are measures one could look at, but probably more than anything, it's the frequency of the infections that happen, and that's has different paces in different people. It's a very stochastic process. So we've certainly argued with regulatory agencies that supportive data, but it wouldn't necessarily be something that was required for registration because, you know, there are people who go a whole year without an infection, and they have 3 severe infections in a year, and this is a very rare disease.
I think we've made a lot of progress in that overall. On the other hand, we also hope to show, as I said, some of the cures of those patients who have those infectious diseases, like they've seen with the allogeneic bone marrow transplants. And I should point out, these folks have very severe, inflammatory and autoimmune, problems as well, and so under those circumstances, that's something else that we can show improvement on, also following what happened with the successful allogeneic approaches. Of course, our biggest advantage is we're much simpler than an allogeneic, we're much safer than an allogeneic. Based on everything we know, we're gonna have a much higher success rate at that as well. And we have an endpoint that measures exactly the problem, so it is the problem in these particular patients.
It's a pretty important, you know, part of trying to convince the FDA this is an important surrogate.
Got it. Is discontinuation of antibiotics, could that be an endpoint or-
Yeah, we've been thinking about it. I don't know that we have an answer today.
Okay. And lastly, on the endpoints, I guess, what's your base case view on what would be needed for an accelerated approval path, and-
You think about number of patients and time type of thing or?
Yeah, if-
Well, it's certainly our hope that less than 20 patients would be required. I mean, when you look at the CRISPR/Vertex for sickle cell, a much bigger disease, the FDA in the end required, I think, about 40 patients overall to approve. If we get very dramatic data, I'm certainly hoping it'll be well less than 20 patients that we could show it. It's probably more a matter of the safety that we have to demonstrate than it would be the efficacy if people, in fact, look like the animal models that we've been studying.
Got it, and yeah, let's shift gears and talk about the liver LNP platform. Maybe give us an update on how you're optimizing your universal lipid nanoparticle platform for liver delivery and translating the technology to larger market opportunity indications.
Yeah, so people worried, in fact, about whether LNPs, lipid nanoparticles, would work with prime editing. In fact, we didn't have a lot of doubts, and last year, we showed quite a bit of animal data that demonstrates up to 80% specific editing in hepatocytes in non-human primates. Our goal is to make this a platform, and in fact, much of prime editing is platform. We call it modular. All the pieces are the same. If one makes an LNP, six or seven of the eight components of that LNP we hope are gonna be exactly the same from every liver program to every liver program.
So we've been making a lot of progress and spending a lot of time and effort to make them modular, we call it a universal LNP, with the hopes that each time we'll do it, we'll be convincing the FDA, "No, you don't need to go back and have us test every single thing along the way." And frankly, I think we've been making a lot of progress. We love the fact that Peter Marks tends to use prime editing as an example of such a modular platform approach going forward. So we think it's gonna be a, a great boon as we move into other liver indications.
Got it. And, for your Wilson's disease program, probably can't go into the details too much, but could you potentially have a non-human primate data this year?
So I really don't wanna comment beyond what we've actually told people. The liver programs are going well, but there's a lot of data coming in this year, and we need to do... We're juggling three programs, and we have to decide where we're gonna put our resources. Frankly, it's been a brutal, brutal environment for us, and, you know, it requires us to sometimes say, "Three great programs, but we may have to push one or the other a little bit ahead of the other as a result.
Got it.
With that, I see a lot of motions in the back to wrap up as well. If you had a last question or something?
Yeah, I guess for a last question, if you could just highlight other key aspects of your pipeline briefly and talk about what investors should be focused on in the next 12, 12 months?
Yeah, our eye data that we just presented at ASGCT is remarkable. We work with retinitis pigmentosa and certain forms of that. We were able to stop a disease dead in its track in an animal model of retinitis pigmentosa and show that we preserved all of the critical rods that were really necessary, so that was great. Some of the best things in our programs are things that still are not, are still a little early, like some of our beautiful data in CNS and muscle diseases, so I won't have much to say about it here today. But if you look at the long-term value of the company, not the short-term milestones, I think those are the places where the company is really gonna excel and do special things.
Great. Keith, thanks so much for joining us today.
My pleasure, everybody. Thank you.