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

All right. Thanks. We'll get started here. Good afternoon. I'm Eric Joseph, senior biotech analyst with JPMorgan. Our next presenting company is Prime Medicine, and to present on behalf of the company is CEO, Keith Gottesdiener. There's a Q&A after the presentation. If you have one, just raise your hand. We'll bring a mic over to you. And folks tuning in via the webcast can also submit questions in the portal. With that, Keith, thanks for joining us.

Thank you very much for having us, and it's a pleasure to be here today. And I'm here also with our CFO, Allan Reine, as well. So since our founding in Prime Medicine, we've had really a single goal. It's transforming the life of patients with debilitating diseases through the application of Prime Editing, really our next-generation gene editing platform and technology. With Prime Editing, we have a really unique opportunity to provide safe, effective treatments that provide long-lasting cares to patients with a wide spectrum of diseases. Thus, while our initial efforts are focused on CGD, Wilson's disease, cystic fibrosis, all of which we'll discuss today, our vision and our ambition are much greater. Over time, we intend to maximize Prime Editing's broad therapeutic potential to treat genetic diseases, immunological diseases, cancers, infectious diseases and other common diseases as well, which collectively impact millions of people. We're entering 2025 in the midst of an important transformation. We were founded in 2020 or soon after Prime Editing was discovered in the laboratory of David Liu. And in the 4 to 5 years since, we made incredible and very rapid progress. We've achieved preclinical proof of concept in multiple diseases across multiple tissues. We've established our own proprietary delivery capabilities. And in April of last year, we secured FDA clearance of our IND application for PM359 less than 1 month after the IND was filed. Now we're nearing our first ever clinical data with the initial data for PM359 in CGD, chronic granulomatous disease, anticipated this year. We expect this to be a major milestone for Prime, validating our belief that Prime Editing is safe and that it's uniquely suited to really ameliorate CGD. But it's also a really important step for the field because this will be the first ever clinical data in Prime Editing. In parallel, we continue to invest internally in our programs for Wilson's disease and cystic fibrosis, both of which we believe are very high-value opportunities. Importantly, we believe that each of our current programs could also serve as a beachhead indication. In other words, allowing us to advance from those indications and advance our technological capabilities into R&D, research, regulatory, CMC and delivery aspects that we could potentially use to move our other programs forward. And coupled with our plans to secure additional strategic collaborations to expand and accelerate our pipeline growth, we believe strongly that this positions Prime Medicine for sustained long-term growth and commercial success. With the next couple of years, we expect to deliver on our foundational mission, which is delivering Prime Editing therapeutics to patients and launching our first therapeutics. Now before turning to 2025, allow me a moment to reflect on 2024. At JPMorgan last year, I showed a version of this slide, an earlier version, where we laid out our views and our key priorities for the year ahead. They were to mature into a clinical-stage company to advance our next waves of therapeutics across target tissues, to strengthen our platform and to leverage business development to really advance our reach. And I'm delighted to say we accomplished each and every one of those goals during the past year. As I mentioned a moment before, PM359 is now being evaluated in a Phase I/II trial. In September, we unveiled the strategic decision to focus our programs and to prioritize and to really focus on high-value programs. Importantly, we believe this prioritization would allow us to move more quickly, both for our current programs and for our follow-on programs as well. And in fact, I'm delighted to say that it's already paying off. Each of our high-value programs, Wilson's disease and cystic fibrosis, had advanced remarkably more quickly since our prioritization. And I'm going to share some exciting new preclinical data on each during the course of the talk. We continue to advance our Prime Editing modular platform, generating additional data supporting the potential of our universal LNP system, really demonstrating what we think is a highly differentiated safety profile and progressing regulatory paradigms to support streamlined development. And on the BD, business development front, we announced a strategic collaboration with BMS to develop ex vivo T-cell therapies, including using our PASSIGE technology, which I'll explain in a moment. And we secured funding from the CF Foundation to advance hotspot and PASSIGE Prime Editors for CF. This progress positions us exceptionally well for 2025 and beyond. Looking forward, we really are entering a new era for Prime Medicine. Over the next couple of years, we plan to quickly and sequentially advance our prioritized programs into the clinic and towards launch. With time, we hope to expand our pipeline within and potentially beyond our current area of focus. So beginning with CGD, as I mentioned before, we expect to report initial clinical data from our ongoing Phase I/II trials this year. If successful, these data will allow us to move rapidly into a pivotal trial in '26 and to begin preparing for our first commercial launch. In November last year, we initiated IND-enabling studies for our Wilson's disease program. And now we're turning our focus to preparing for clinical entry. We expect to file an IND or a CTA for the program in the first half of 2026 and to report clinical data in 2027. And in parallel, we'll continue to advance other Prime Editors against other mutations in Wilson's disease preclinically, leveraging the modularity of our platform to move these efforts forward rapidly. Finally, we will continue to generate new in vivo data across our other high-value programs, enabling us to advance these programs into the clinic in '27. Of course, we expect business development to accelerate our existing pipeline and to expand our reach, both within our priority focus areas and beyond. So let me take a few minutes to first orient you to Prime Medicine or Prime Editing before I really talk more about our clinical programs. So briefly, we believe Prime Editing is the only gene editing technology that can edit, correct, insert and delete DNA sequences in any target tissue. And if you look below, you can see many of the different types of edits that we can do, many of the different types of corrections, and beneath them, some of the diseases where we've already achieved preclinical proof of concept. I'm going to take 1 minute to just point to the bottom of that particular slide, our PASSIGE technology. So PASSIGE technology is now entering all of our development programs. It's being used in our X-linked CGD program, our CAR-T program and cystic fibrosis. And this is a place where we could do targeted insertion of gene size pieces of DNA, really adding a major new component to what Prime Editing can do. Prime Editing has a highly differentiated safety profile, as I mentioned. We're unable to detect off-target activity, unwanted editing in any of our lead program. In our programs, we see no detectable double-strand breakage, no detectable off-target edits, no detectable bystander edits, no detectable off-target deletions, chromosomal translocations or rearrangements. These are all being assessed with really robust assays, the type that we validated with the FDA as they accepted our IND submission. And it's important to realize that in these programs, we actually use CRISPR/Cas9-type editing as the positive control. In other words, the example of what we don't want to see to really differentiate that as we go forward. I also mentioned briefly the modularity of our programs, and this is an important idea. Prime Editing itself is a modular technique. Basically, we can take the Prime Editing machinery, make a small change to what we call the guide RNAs, and we can direct that machinery to a different locus, a different tissue, a different type of edit. What most people don't realize is the whole set of programs that we're doing are, in fact, modular. Each piece is designed to be done well once and then to carry it from program to program to program. And so it really means that the newest programs will benefit from all of the learnings and many of the opportunities to accelerate those programs, do them more efficiently. So with that, this is what our pipeline looks like today. It's aligned to our core modular programs. And on there, you can see we work in 3 areas. But most importantly, we think there are 3 very high-value programs or areas that we're working on that belong to Prime Editing -- to Prime Medicine itself. Now as part of this prioritization process that I mentioned briefly before, we had a good number of programs that we were very sad to put and deprioritize. Some of them were doing remarkably well. Two of them that we had to deprioritize, in fact, would have filed INDs by the end of this year. But in the end, we wanted to focus on these very, very high-value programs to show we can progress them towards the clinic. And we think many of those programs will be great BD out-licensing opportunity, and there seems to be tremendous interest. So let's talk about CGD, chronic granulomatous disease, a disease with huge unmet medical need. People with this disease have serious life-threatening infections because they're unable to clear bacterial and fungal infections. They also have autoimmunity and inflammation overall. And today, the only curative treatment is an allogeneic bone marrow transplant. We're working in 2 forms of CGD, one p47phox CGD is what's currently in the clinic with PM -- with our PM359 program. You can see on the right, we're also working in X-linked CGD, where we're pulling our PASSIGE technology into that development program. Our first program represents about 25% of CGD patients, while approximately 2/3 of CGD patients are represented by X-linked. In total in the U.S. alone, and we believe similarly in Europe, there are over 1,000 and potentially up to 2,000 patients who could be treated. Now this shows some of the data, which is pretty remarkable, of what we can actually do with Prime Editing. This is preclinical data to support our entry into man. And there are 3 important points to make about this data. And in many ways, as you look at this data, this will be exactly the data we believe we will show this year in 2025 to really show that Prime Editing works. The first is, if one does editing ex vivo, one has to show that you can put those cells back into, in this case, an animal, but in the future, a human, and you get high levels of engraftment. And you can see our levels of engraftment are exactly the same as mock edited cells. The second thing one wants is high levels of editing efficiency. You want to be able to show that you can actually change and correct the mutation that's a problem. And the third is a phenotypic correction. We know exactly what's wrong in these patients. They have an enzymatic defect to produce certain -- to basically have an activity that kills bacteria and fungal. And so what we can do is, measure that enzymatic activity directly with a test called DHR. And you can see here, too, we have over 80% correction of the DHR overall. So this is a very, very profound effect overall. And it's important to realize this greatly exceeds sort of what we would call the threshold effect. There's great human clinical data that helps to support that if you could even do corrections in DHR at 10% to 20%, well below what we're achieving in our preclinical models, it will have very important therapeutic impact. So our trial actually has 3 cohorts, very sequential, one in adults, one in adolescents, one in children. Each of them is quite small for this rare disease. And this trial is ongoing. You could see again that when we report initial clinical data, it will greatly mimic and mirror what I just showed you on the previous slide. But one of the important things to point out is how quickly this trial can be converted into a pivotal trial. It was designed potentially to be pivotal from the beginning. And as soon as we have robust data, we intend to go to the FDA and to work with them towards that type of conversion. Now I mentioned that we're also treating X-linked CGD using PASSIGE. And PASSIGE reagents are designed to precisely insert a healthy CYBB gene, that's the gene that causes or is missing in X-linked CGD, at the prespecified site in the patient's own locus overall. So an all-in-one delivery of PASSIGE reagent for this gene replacement in CD34 cells has the potential to treat over 90% of X-linked CGD patients. So we'll have data during the 2025 year. We're very excited about it. The second program is moving forward. We have not yet announced when INDs will be available, but there's great synergies between the program, which we hope will really accelerate. Now also falling into this category is our collaboration with BMS. So our collaboration with BMS, Bristol Myers Squibb, was the first broad, multi-target collaboration advancing Prime Editing for the treatment of complex oncology and autoimmune indications. And they've been a great partner. This deal was very substantive. There was $110 million upfront, $185 million in early preclinical milestones, $1.2 billion of potential milestones in the development space and overall $3.5 billion of total value to us. So this is a place where we could extend our reach of Prime Editing by doing some pretty amazing editing overall. And you may ask, why did BMS come to us to develop CARs? People are developing CARs today. And the answer is because of the quality of the work and the types of edits that we can do. We can get an extraordinarily high integration efficiency of the CAR, much greater than are seen with current methods, and we can aim them to a specific locus. In this case, this is all work done before the collaboration, not necessarily in the collaboration. We can aim at the T-cell receptor locus, the TRAC locus. And we can knock out the T-cell receptor, an important part of forming a CAR while putting in the new CAR. We can multiplex edit. Currently, [ we can do ] up to 7 multiplex simultaneous edits. So you can make all kinds of changes in that CAR that you think are important. It's entirely nonviral, so much cheaper and more efficient to do it and can be done with single step editing. And you can just see here very, very briefly the multiplex editing over the right, where with 5 multiplex edits on this slide, we can show each one of them can be done simultaneously. Now we do think our first really high-value program that we want to highlight is Wilson's disease. And we're advancing Prime Editors for multiple mutations in Wilson's disease overall. This is a much more prevalent disease. At least 20,000 people in the U.S. and Europe have this disease. The first mutation we're attacking is 30% to 50% of those individual patients. So what happens is these patients go on and have liver failure, many neurocognitive defects and all because they're unable to excrete the copper in their diet into the bile and out of the body overall, and it causes liver fibrosis and as I mentioned, brain defects as well. Many patients die without a liver transplant. And today, there are symptomatic treatments in -- such as standard of care, but that standard of care is very difficult for patients to take, very, very poorly tolerated. It's lifelong overall. We've tested the idea with many KOLs. Does this work well enough for your patients? Or would you gladly put them on to a once-and-done curative procedure if it were available? And the overwhelming answer is yes, we would. Now here, too, it takes a very small degree of corrections of hepatocytes, we believe, to be curative overall, likely only 20% to 30%. So this slide shows some of the data that we're developing as we move forward. And it's important to realize that this data is done in humanized H1069Q mice, mice that have that mutation. Our editors are so specific. They can't work in nonhuman primates or in mouse. We need to really humanize that so we can go after the human sequence. And this allows us to test the actual editors we're going to use in humans under those circumstances. We also do these experiments with our universal LNP, the delivery system which we'll be using as well. And on the left-hand side, you can see we can get just about 80% precise correction, well above the threshold of this particular mutation overall. So it's a very highly relevant degree of editing in vivo. But I think it's the right side that's really some remarkable data. These mice load copper into the liver because it can't be excreted during their whole lifetime. And when we actually do the Prime Editing, you can see in just 7, 14, 28 days, we're markedly decreasing liver that's -- the copper that's accumulated in the liver by approximately 75%. If we can duplicate this in humans, it's going to be an extraordinarily successful therapeutic event overall. Now we can't duplicate this exact experiment, can't do sequential liver biopsies to look for liver copper. But we expect that many of the patients of that volunteer for at least a pre- and post-liver copper approach, and there are other markers we can use to follow copper. Now of course, in order to develop a liver gene editing product, you do need a good delivery system. So we've developed a Prime proprietary universal LNP. And we're using that in all of our liver programs overall. Now we test that actually in nonhuman primates, where we also look for the safety of that particular LNP formulation. In practice here, we have to use a surrogate guide. In other words, one that's aimed at the monkey genome sequence. We don't have to optimize that guide to the same level as we do with therapeutics. So in this experiment, we optimized that guide to about 50% editing in vitro. And then we looked at in vitro, in vivo translations of editing with our LNP delivery. And you can see here, we have up to 51%, a very close in vitro-in vivo correlation. Probably just as important as the safety profile, this was very well tolerated, no clinical observations. Like all LNPs, there are transient LNP elevations. But the rest of the pathology, including histopathology, all seem negative. The mice lived a normal life out to 44 weeks and seemed totally healthy. And we're able to benchmark it against other lipids that were in the clinic and show really markedly less pathology in our animal experiments. And when we talk about a universal LNP, this slide very briefly shows you why. Our LNPs are complex mixtures. It takes 8 different components to put them together. The 2 at the bottom are the private guide RNAs. They're the one that direct the therapeutic activity. But you could see at the top, 6 of the 8 components in the LNP are the same for every single liver program as we go forward. And that allows us for any backup mutations, any backup programs to move forward quite rapidly. Now the third high-value program that we could talk about is cystic fibrosis. We're advancing Prime Editors there as well. I don't need to spend a lot of time explaining cystic fibrosis to a group of people like those in this room, but it's a very, very big opportunity. And obviously, we've made over the last decade or 2 amazing advances in cystic fibrosis. But it's important to realize there's absolutely no curative treatment. And more importantly, existing treatments are ineffective or not tolerated by approximately 15% of patients. So there's a real opportunity here to deal with those patients, and I'll explain to you how we're going about it. So about a year ago, we joined with the Cystic Fibrosis Foundation to enter into an agreement to develop Prime Editors for cystic fibrosis. And in the process, we're taking 2 parallel approaches, one with hotspots and one with the PASSIGE technology. So how does hotspot work? Hotspots work because with Prime Editing, you can lay down a long stretch of DNA that's totally corrected, 50 to 100 base pairs or maybe more. And what that means is that anybody who has a mutation within that stretch will be cured. This person may have a mutation in site #1, that person in site #17, that one in site #34, counting across that stretch. It doesn't really matter. The same editor will give everybody a perfect copy of the DNA and do what we hope will be a genetic cure. So we did the bioinformatics and we looked and we said, of these 15% or so of these unmet need mutations, how many hotspot editors essentially identical to each other would it take to cover every single one of them? And the answer is we believe we could do with 8 hotspot editors as well. But interestingly enough, if you develop those 8 hotspot editors, within those same ranges is well over 90% of the total mutations in CF. So with a hotspot approach, you could potentially offer, even to patients who are currently treated with TRIKAFTA, the chance for a cure for their lung disease under the circumstances. And many patients may choose to take that cure instead of taking TRIKAFTA for life. On the right is the PASSIGE approach, which also can potentially address, not just the unmet need mutations, but any mutation in CF. It basically uses a single super exon insertion sequence, which we can put into the genome of the CFTR and replace essentially what's missing there. Now this sounds in some ways like gene therapy, but the key thing is it's integrated into the genome and it's integrated in a precise spot, which is a major differentiation. And I think that integration into the correct spot in CFTR is probably a critical point. Restoring CFTR function in Prime Editing cells leaves them under normal endogenous physiological control. And the CF expression is regulated in many ways, depending on what the state of the patient is. It might be different, for example, in your lungs environment, in air environment and humidity, whether you're running a marathon or you're sitting at home, or might be different requirements when you're in the Nevada desert versus being in the Amazon. So under the circumstances that endogenous control could be a very important part of the therapeutic journey. Now some of the data we've generated is all preclinical. It is very important. Both of those programs are moving forward in parallel, but I'm today going to show you just some data from the hotspot approach. And in the hotspot approach, we've taken 5 of those 8, just chosen there to start to work on, and all 5 of them are going in parallel along with PASSIGE. But I'm going to show you data from just one of them today. And that's from a mutation called G542X HOM. This is a mutation that represents about 5% of CF patients. They have absolutely no gene expression at all. We've developed the editor, and you could see on the left that we can get 60% to 70% precise editing, and we're getting it in the primary human lung progenitor cells. These are essentially the stem cells of the lung that you want to reach, so it's a once-and-done therapy. And on the right, using something called an ALI culture, which has been developed to really assess CF therapies. You can see, in fact, that we can take the 542 null patient who has absolutely no expression of the CFTR in this western blot. With Prime Editing, we can restore that. In addition, we're making efforts towards in vivo delivery to humanized mice and large animals, and we hope we'll have more data to share later this year, more likely in 2026. So just a few last words before we finish. We do think business development will continue to play a critical role in building Prime Medicine. We've shown this slide before. Our business strategy hasn't changed. It's a major focus. But it's also important to point out that Prime is also developing the tools to really protect what we need as well. And we do believe we hold the extensive foundational intellectual property for Prime Editing, not just the original work, but all of the improvements that have helped to make it a therapeutic. And currently, we hold 5 U.S. and 4 ex vivo issued patents. So in summary, Prime Medicine is an amazing technology. And frankly, we think Prime Editing has really executed on the vision over the last 4 to 5 years and worked very, very rapidly to move things towards the clinic. We think we're the leader in Prime Editing, that the platform modularity that I briefly explained today is oriented towards rapid growth, that the pipeline is positioned for value creation. And it's really strategically focused on the high-value programs with a clear path to value inflection that represent multibillion-dollar commercial opportunities. And we do think that partnerships and BD potential are there with great interest overall. And we think this builds the stage for long-term sustainable value for Prime Medicine. With that, I'll stop. So thank you very much. So questions.

Yes, we have time for some questions. If you have one, we'll bring a mic over to you. But I can get started here while the mics are being brought around. Just first question on chronic granulomatous disease just with an initial readout anticipated in a little later this year. Can you just orient us around sort of what's clinically meaningful about a 20% normal DHR neutrophil function? And in trying to get to that goal in patients, what kind of role perhaps supportive GSF (sic) [ G-CSF ] use might play?

I'm sorry, what?

Does GSF use play a role at all in getting patients to goal?

Generally not.

Okay.

In this particular case, the data is very well supported by studies in patients who have had an allogeneic bone marrow transplant. So allogeneic bone marrow transplants have very profound immunosuppression that lasts for a very, very long time. They have graft-versus-host disease, lifelong immunosuppression after they recover. Many of the patients have chimerism, which means they have a mix of their cells and the new cells that they're being transplanted with. People have looked at that chimerism so they can see in any individual patient what percentage are the new, hopefully improved cells and what part are the old cells. And with that data, they've been able to show that if you have even 10% to 20% of those new cells, essentially, the risk of infections drops down to 0 going forward. So it's a great, very well-validated, human-validated threshold overall. Certainly, we hope that we'll beat that based on the editing we've done, but it's very important to keep in mind what will be important from a therapeutic point of view. And it's really the 10% to 20% range.

Okay. Question here.

Great presentation. Just a simple question to me, hopefully, a simple answer. As you're going through scaling up from proof of concepts, going through the IND and thinking about I'm going to be successful, then you get through to the scale up beyond IND, Phase I and hopefully beyond. On the CMC side, what prep are you doing so that the people at the FDA and you are aligned as to what you're doing and how you're doing it so that the clinical doesn't get way out in front of your CMC or somebody says, "Oh, by the way, I think that's great, but I don't think we're going to accept that"? And maybe you're going to have to do some things over again because you made some changes.