Prime Medicine, Inc. (PRME) Earnings Call Transcript & Summary

Good afternoon. I'm Eric Joseph, senior biotech analyst with JPMorgan. Our next presenting company this afternoon is Prime Medicines. And presenting on behalf of the company is CEO, Keith Gottesdiener. There is a Q&A after the presentation. If you have a question, just raise your hand, we'll bring a mic over to you. And for those tuning in via webcast, you can also submit questions by clicking the Ask A Question icon. So with that, Keith.

So thank you very much, everybody. And I'm here today with other team members as well. Jeremy Duffield, our CSO; as well as -- sorry, the slides are not coming up yet. Jeremy Duffield, our CSO; and also Ann Lee, our CTO. They wondered how many things I get wrong in the first minute. Now we know the answer to that question. So let's start again and see if I could do this correctly. They're still not coming up on my screen here. If someone can come up and just help me to get this on the screen, that would be great. So in general, there's a quote on this slide that one of our Co-Founders, David Liu, used in -- recently to introduce a recent talk. And the quote is, "The age of human therapeutic gene editing isn't just coming, it's already here." All right. Let's start again and see if I can do this a little better. All right. Just one moment. I can't see the slides at all. And unfortunately, I'm near-sighted. I can't read off of this slide right here. But let me get started anyway, and hopefully, they'll fix it reasonably soon. So one of our Co-Founders, David Liu, used this quote to introduce a talk earlier this year, "The age of human therapeutic gene editing isn't just coming, it's already here." And I think today, when we look at what's happened over the last couple of months, I think we can all agree, in fact, that David was exactly correct when he said this many, many months ago. And I think we at Prime Medicine, who really are doing gene editing, believe this [indiscernible]. This now is our moment because Prime Medicine brings together the right people and the right technology at the right time. Now over the past year or 2, we spent most of our time talking to investors really introducing the groundbreaking technology of Prime Editing and the tremendous opportunities that Prime Editing has the potential to deliver. Instead, today, much of the presentation will focus on our pipeline and our path to entering the clinic. But before we do that, I want to highlight a couple of points about how we got there and what's important in our story. So first, excellent execution across our business, since we were founded in 2020, is something that's been very important to move Prime Editing forward quickly. Secondly, I have to highlight the tremendous power of our groundbreaking technology and the commitment we've made and others to the ongoing innovation that has driven Prime Editing forward. Also important, Prime Editing is uniquely positioned to address the widest spectrum of diseases. And I have to highlight the benefits from our highly differentiated safety profile. In addition, the modularity of our platform will enable us to rapidly accelerate follow-on programs and to expand our reach over time. And I'm going to expand on each of these points in just a few moments as we go through the presentation. So let's begin with operational execution. So Prime Medicine has a very strong, very experienced team, and we've performed and we've delivered. Now it's hard to realize that Prime Editing was a single laboratory phenomenon as recently as early 2020, just 3.5 years ago. And how much we've accomplished since then as we begin to enter the clinic. And we've built the foundation for our platform translation to enter the clinic. And you can see what happened over the last couple of years. In 2020, it was program gestation. And then we moved to program industrialization. And today, that transformation is beginning and will be a focus of what I'm talking about today. Now I mentioned the versatility of Prime Editing, which unlocks multiple opportunities across a wide spectrum of diseases. We can edit, correct, insert and delete DNA sequences in any target tissue. Now there are people who still think Prime Editing can only make small gene corrections, but the commitment to innovation has really led to extremely broad capabilities. For example, we can edit hotspots, in other words, places where gene mutations cluster, and repair 100 or more base pairs perfectly so that no matter what mutations fall in that area or that interval are all corrected with the same Prime Editor. We can precisely delete multi-kilo bases of DNA as we do in our repeat expansion or triplet diseases and their programs. And now what we can do is we can make large, precisely-targeted gene insertions into the DNA at a very specific spot. In particular, I'd like to highlight this last example. We call it PASSIGE. PASSIGE uses technology and Prime Editing to insert gene-sized sequences into a single spot into the genome. Our initial focus, for example, is to do -- is to make highly differentiated, nonviral, multiplex-edited CAR therapies. And I'll say more about that later, but we believe we can do things in terms of the engineering that absolutely no one else can do. But using this PASSIGE technology, it goes well beyond the things that people were expecting from Prime Editing when we first came out early in the 2020s. Second, we have this very highly differentiated safety profile. And what we've done is we' chronic granulomatous disease program, which is entering the clinic this year. The results are remarkably clean. As you could see on the left, where we studied greater than 500 potential off-target sites in this program, and we see no off-target edits. We also don't find large deletions or translocations, as shown in the middle, which is very different from CRISPR. CRISPR actually is our positive control for this assay to identify the presence of these deletions and rearrangements, and you could see it on the right-hand side of the panel. More broadly, we have yet to detect any off-target activity any deletion or translocation in our 4 leading programs to date. Now it's our hypothesis that showing that Prime Editing goes in and does a precise therapeutic edit, it doesn't muck around with the rest of your DNA, and then it gets out and leaves patients with a genetic cure. That's going to be the kind of message that is going to allow doctors and patients to decide that Prime Editing therapeutics truly are something special and allow their widespread use. And we also think that safety profile is going to become an important differentiation from other gene-editing approaches. Now many of you know that Prime Editors themselves, the machinery, are modular. And that you can swap out one component, the guide RNA, from a Prime Editor, and you can repurpose it to a different genetic location. But it's important to emphasize that every aspect of our program and every part of developing Prime Editing therapeutics has strong modularity. For example, we've developed these extensive assays for off-target activity. Those assays can be used from program to program to program, just as they are across all the different programs in our area. So all the hard work that we've done for the first program can be applied just as it is to other programs as well. The same thing is true in the CMC manufacturing area. So much of the work can be applied to the next program and the next program across our therapeutic pipeline. As a result, the core components can be readily leveraged to drive the pipeline acceleration, efficiency and execution. It allows us to develop more programs more cheaply and more quickly than we think people can do with almost other -- any other platform. Now later, we'll be providing an update on our first program to enter the clinic. But first, a few thoughts, especially on the evolving regulatory landscape, which we believe is growing more and more supportive for gene editing. On the left, you could see some of the things the FDA has done just in the last year that are very, very supportive of gene editing. And on Saturday, I had the opportunity to have Peter Marks speak at a symposium, where I had a chance to talk to him, and he reiterated that support for gene editing as an example of a platform technology which the agency is really excited about developing. And in fact, a bit closer to home, if one looks at the right side of the slide, Prime Medicine's own experience strongly supports this view of the regulatory environment. We've engaged in multiple formal and informal interactions with the FDA and other global regulatory agencies on the PM359 GSD program and on the Prime Editing platform. And we've aligned with the FDA recommendations in a whole area of very important for our clinical development programs. Now we've had a very large pipeline as we went forward. We originally started out with 18 programs in our pipeline, really to understand the breadth of where Prime Editing could work. And frankly, many investors have come to us and said, it's an awful lot of programs, can you help me to -- help us to understand what's most important in your pipeline. So in order to simplify a bit, we've presented -- pardon me, presented a new way of organizing our pipeline, focusing on 4 pillars: Hematology/Immunology, Liver, Ocular and Neuromuscular. And in each one of these, we've demonstrated high efficiency and precise in vivo editing, and each has its own modular platform. Now business development will also increase our reach and impact, and I'll say more about that later. And to reiterate our strong execution abilities, at the bottom, we highlight some key capabilities that provide a strong foundation to company efforts, which we think are important to unlocking future opportunities. Now we apply this same simplification to our pipeline chart here to help people to understand what we're going to be focusing on as we go into '24, '25. These include, by pillar, our CGD program in our hematology and immunology program. In our liver program, 3 programs there or 3 indications in Wilson's disease, GSD and 1 undisclosed program as well. In our Ocular program, retinitis pigmentosa row, and our neuromuscular programs, a little more complicated, but primarily Friedreich's ataxia. Now notice at the bottom, there are additional programs that are outside of this core, such as our CAR-T work and cystic fibrosis, and I'll say a few words about them later. But we think these are places where, at the proper time, business development and partnership may be the path to go. So let's take a minute and talk about what's happening within each pillar. So in the Hematology/Oncology pillar -- sorry, not Oncology, Immunology pillar, my pardon, let's first talk about CGD, where serious life-threatening disease presents in childhood, manifested by recurrent life-threatening infections. It's caused by a mutation in the p47phox gene. There are hundreds of these patients that exist in the U.S. alone. These patients also have severe ongoing autoimmunity and inflammation. We believe that prime editing is uniquely well suited to initially address this form of CGD. But it's important to point out as well, with our modular approach, we can also apply Prime Editing to other forms of CGD as well. Now this slide presents our first outline of our global clinical trial with PM359 that we intend to initiate this year, which we've discussed with regulatory agencies. In other settings, we can delve a little bit more so into the specifics, but let me make a few key points. One, we plan to file 1 or more IND CTAs in the first half of 2024. Second, our clinical program is in general alignment with the FDA and other regulatory bodies. As is the rule in ex vivo cell products, enrollment, mobilization of the CD34 cells, manufacture and release, they take time, and we've outlined that in the schema. As you also know, regulatory agencies insist upon sequential staggering in our dosing for the initial patients, which clearly will have implications. As a result, our first clinical data, we expect in 2025. But keep in mind that for each individual patient, our biomarker, DHR, gives a very early read on efficacy. Lastly, the study is designed to rapidly move into the pediatric population, the key target, and to progress directly to pivotal data, though the design of pivotal trials have still not been discussed with regulatory agencies. Now this particular area, Hematology/Immunology has huge potential. But to fully mobilize in this particular area and increase access to patients, a path to nontoxic bone marrow transplantation is required. I won't have time today to explain all of the work we're doing there, but our current efforts are providing the foundation for benign conditioning with CD117 cell shielding with our partner in this, Cimeio. And platform expansion could be the key to great opportunities in this clinical area. And you could see that the idea of moving from low-intensity autologous to low-intensity allogeneic to eventually, we believe, in the not-so-distant future, in vivo editing of HSC just unlocks literally dozens of diseases overall. Now I would also point out that in practice, while we're not going to show this kind of slide for each and every one of our pillars, this type of growth trajectory path exists for each of our clinical pillars as well. Now our Liver program is important because the key result to achieve this year was the safe and effective LNP delivery and precise editing of nonhuman primate liver, where we demonstrated approximately 83% precise editing of hepatocytes, and you can see that off to the left. Our approach is to use a universal targeted LNP. And building on this modular approach, we anticipate these results will accelerate the development of our 3 lead liver programs: GSD, Wilson and, as I mentioned, an undisclosed target. For our Ocular programs, early data with our proprietary dual-AAV system was a key step towards unlocking opportunities in retinal disease and larger indications. We achieved in vivo proof-of-concept in humanized mice and demonstrated high efficiency. In parallel studies, we showed no off-targets detected, and Prime Editors were shown to prevent degeneration of the retina in vivo. Now today, Ocular programs seem to be a little bit out of favor with investors. But I want to convey our excitement that Prime Editing has the potential to cure genetic forms of blindness. Keep in mind, we actually correct the cause of mutation with our approach, which we believe no one has been able to do to date, and that, that may result in additional therapeutic benefits. Now the Neuromuscular program is certainly one of those that I find most exciting overall. But these programs are a little bit earlier in development. Still we're very excited that the early in vitro and in vivo data suggest potential for Prime Editing to address many neuromuscular disorders, including a variety of significant repeat expansion disease, where Prime's leads include Friedreich's ataxia and also ALS. We have a lot of data on this slide, and I doubt many of the folks within this room can actually see the data from where they're sitting. But in the left-hand panel, we basically show that Prime Editing in Friedreich's ataxia really restores normal function in sensory neurons. And what you can see there, if you can see the slide, are the axons that grow from dorsal which are spinal cord afferents or spinal cord organs that help to bring sensory input into the spinal cord. And you can see the healthy axons in the first column. Their absence in the second column and the complete restoration of the phenotype once we've Prime edited the patient cells. While the second panel in ALS is probably even less legible without getting closer. It's a place where we've shown that Prime Medicine restores normal motor function in neurons. And again, you can see a panel where, in the first column, you see the results from healthy patients. In the second, you can see actual disease patients, how different it looks. And in the third column, you can see if we take the cells from those diseased patients and we Prime edit them, we return them to the phenotype that one would expect with healthy patients overall or healthy volunteers overall. Now our current focus is really on delivery for the CNS programs, where the solution is still not completely settled, but we're moving forward very rapidly in large animal studies. Now if there's one thing we have, it's lots and lots and lots and lots of targets that we can approach with prime editing. So business development remains a core focus for building up the company and also getting Prime Editing out into the community. So as a result, our BD strategy has a multipronged approach. On the sell side, within our core pillars, we intend to advance programs and create significant value. We may partner some of the programs at the right time to accelerate them or to globalize their market. Outside the core, we aim to collaborate or license potentially sooner in order to maximize the potential of Prime Editing beyond what we can do ourselves in the short term or to bolster our financial resources or to create future options for us. And we'll continue to be active on the buy side to access enabling innovation, particularly in the area of delivery and manufacturing capabilities. On the left-hand side, you can see that many of our recent accomplishments, and we believe that those accomplishments will provide a strong foundation on which to execute our BD strategy, and we are very, very actively engaged in doing it at this time. Now consistent with our BD strategy, okay. I want to describe a couple of examples of places where we think there are really great opportunities. And first, I want to talk about our highly differentiated CAR-T products. Current products have many, many existing limitations. They have quasi-random integrations, constrained to a small number of edits, they depend upon viral approaches, and there are many other things as well. And we certainly know that the FDA has highlighted some of the potential problems with some of the current approaches to CAR-T in some of their recent communications. Our solutions include directed integrations aimed at maintaining endogenous control, high efficiency, a nonviral approach and many other advantages as well. This is an area where we know we don't have full expertise, for example, in oncology to bring these things forward. And so it's a place where we're actively considering business development. Another area potentially is cystic fibrosis. Remember that about 15% of patients do not have a therapeutic option, and we could provide these patients with the potential for a full genetic correction. Now using our hotspot approach, where we can look at clusters of mutations, it turns out that if you map these unmet need mutations across the cystic fibrosis genome, just 8 Prime Editors, almost identical, but focused on a slightly different integral or different hotspot could potentially address approximately all of these unmet need indications. As an example, we can precisely correct the G542 mutation, as shown on the left, as well as demonstrate it in our phenotypic assays, which is intestinal organoids in the right. But our hotspots approach means that when a Prime Editor is designed to correct an important unmet need mutation, such as the I507del mutation, as shown in the sort of middle panel there below, okay, potentially, that same Prime Editor could also provide a genetic option to patients with the even more prevalent del508 mutation as well, probably the most prevalent form of cystic fibrosis today. So in the end, with 8 Prime Editors, we not only would cover all the unmet need mutations, but almost as a freebie, we would get the opportunity to also offer the genetic here to just about every potential patient with cystic fibrosis. Now just 1 or 2 more slides, and I'll finish. But it's important to note that Prime Medicine holds broad, enabling foundational IP for all Prime Editing technologies currently with 4 issued or allowed patents that have absolute clear priority in this space. Along with many additional patents working through the system from the foundational paper, we've also pursued an aggressive filing strategy for technicological advances because those advances have really allowed us to reach more and more places with Prime Editing. Now I just want to make a parenthetic question, a comment or 2. More recently, many variants of Prime Editing have been announced, which have been called by various names by various companies. Our position is for those that truly look like, act like, seem like Prime Editing, they probably are Prime Editing, and we're confident we have the foundation IP for these technologies. Of course, we're -- we continue to be slightly flattered by the limitation and rebranding of PE by others. But I think as one of our more outspoken director says, we invented it, we own it. And certainly, we and Prime Medicine certainly feel that way overall. But I should point out Prime Editing isn't all about IP. There's a tremendous amount of know-how in order to really do Prime Editing well, and that resides in the company at the moment, and it's a major plus as well. Last slide. We have a lot planned in '24, '25, and the milestones here are articulated pillar by pillar. But let me point out a few important ones. Number one, we plan to open our IND or CTA for our Phase I/II study in chronic granulomatous disease in the first half of '24, with the anticipated initial clinical data in '25. We plan to continue to advance preclinical studies for our 3 liver programs and to initiate IND-enabling studies for at least 1 in 2024, leading to an IND CTA in the second half of '25 or the first half of '25. We'll nominate a development candidate for our retinitis pigmentosa RHO program in 2024 and initiate IND-enabling studies to begin by the end of 2024. We intend to advance Prime Medicine's differentiated CAR-T program using PASSIGE technology into lead optimization. And last but not least, we plan to advance discussions with regulatory agencies on platform strategy for streamlined development. So in conclusion, we really believe this is our moment. We're on the verge of showing Prime Editing works in humans. And we have an exciting broad set of programs to follow. So with that, I'll say thank you, and I guess we'll open it up to questions, Eric.

Great. Absolutely. Thanks, Keith. And just a reminder, if you guys have questions, just we'll bring a mic around if you have any. Picking up on the CGD lead program, I guess, we could call it that, anticipating a clinical start in the first half of this year. Maybe you can just sort of set the stage a little bit for, I guess, operationally, how that study will proceed in terms of, I guess, enrolling patients, kind of prepping them for manufacturing sort of product? I guess, should we think of perhaps some of the sickle cell disease programs as a useful analog for what to expect with your Phase I with -- in CGD?

Well, first, I want to just make a couple of slight nudges on some of the things you said. We don't think of CGD as a lead program because we're bringing a wave of programs towards the clinic. CGD happened to come out a little bit in front. It wasn't a choice on our behalf. It's just that's a place where the technology steps with a brand-new technology just worked out best. Second of all, we really plan to file the regulatory documents in the first half of this year, not necessarily to start the clinical trial, however, that's defined immediately. Though, hopefully, that trial will be open very soon after the regulatory documents are accepted. In practice, the first patient for enrollment, mobilization of the cells, manufacturing and release is probably going to be the longest patient. We put an estimate of about 6 months into the schema that we showed there. It's hard to know exactly what that will be. Remember, once we've got the first patient in, the FDA and other regulatory agencies wants staggered dosing. So they want us to dose people to show that, in fact, that they engraft and then the fact we're on the path to a potential cure of their disease before we can really go forward. So the first couple of patients, there's no question it will be slow. But on the other hand, the data within each individual patient will come very fast because engraftment comes within weeks and the DHR biomarker could potentially be available within weeks as well. I don't want to make any promises. The minute we get our first stat on our first patient, we're going to put out a press release. Where we tend to be underdeliver in -- sorry, underpromise and hope to deliver, almost got that wrong. It's been a long day. No reflection on any of the sickle cell programs, but I certainly hope, and we're doing everything we can to try to keep it much more expeditious than some of the problems our competitors have held. We've really paid a lot of attention, and we hope we can learn from their trials and tribulations.

Makes sense. Not to drag, again, too much of a contrast with the sickle cell programs. But certainly, in that setting being able to dispense with busulfan as a conditioning regimen is thought of as a big unlock for that class of therapy. Because I would think similarly here, right, with...

Absolutely.

So I guess, in developing an approach that does just that, maybe you can sort of make the contrast with how your SCIP program with Cimeio perhaps compares and contrast with other folks also [indiscernible]