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

All right. Welcome back to day 2 of the Citizens Life Science Conference. My name is Silvan Tuerkcan, and I cover precision medicines at Citizens. Now it's my pleasure to host Allan Reine, CEO of Prime Medicine. Thanks so much for joining us.

Yes. Thank you for having us here.

Maybe to start at a high level, it seems like it's a very pivotal time for Prime. As you move into the clinic, you've got to execute a bit, but then 2027, we could have the first-in-human data with Prime Editing, very exciting. Could you just walk us through kind of like the highlights and the key inflection points that you see going forward?

Yes. I mean I think I say every year, it's a pivotal year. And I'm sure I'll keep saying every year is a pivotal year. But it really is a big year for the company. We are right on the precipice of getting our first two in vivo programs into the clinic for both Wilson disease and Alpha-1 Antitrypsin Deficiency. In terms of clinical data, you're right, like we're on track for both of those programs to get clinical data in 2027. But I would say we do actually have clinical data in patients, but that's -- and for our ex vivo program in chronic granulomas disease, which I know we'll also get to talking about. So it is a very big year for the company in terms of getting those programs into patients. I think what these -- both these drugs can do can be pretty revolutionary for those patient populations, and they are both high unmet needs. And as we do that, it continues to really derisk the -- our liver platform, as you think about it. And that's from a delivery standpoint. And as we think about how we can leverage that going forward, it's really going to put us in a position to take additional programs to the clinic to patients a lot faster and a lot cheaper.

Great. And yes, maybe talking about that one program. So recently, it was a very positive surprise for me in CGD that you're bringing it back, and you're going to try to bring it in front of the FDA and see what they say. Kind of what prompted that decision? Was it a lot of the patients or the patient community that demanded it, or was it just the attention it was getting with the first two patients?

Yes. So I think it's -- there are a number of factors that changed. So we made this decision to deprioritize this program in May of last year. At the same time, we announced that one patient worth of data, we ultimately came out with a second patient that we had treated. And at the time, as we thought about going forward towards licensure, we estimated that cost if you include all of the CMC requirements for licensure, obviously, the FTEs, the employees that you need to get there and the clinical study that would be needed to get there, even if it's a small clinical study, could cost us between $50 million and $100 million and take a few years. So as we thought about that from a shareholder investor standpoint, there's no way that we could justify that investment. I think a lot of things have changed, and they started to change actually really soon after that May 19 announcement last year, where the FDA has really shown that they can be more flexible, would like to be more flexible when it comes to programs like this, especially in indications where there is high unmet need, where there's, I'll call it, plausible mechanism, but we understand the biology well. We understand the endpoints well. And I think this is a program that fits perfectly within that. It's a disease that affects people at a young age. And so the only real treatment for these patients today is allogeneic transplant with many of them undergo. This could be a much better option for these patients in allogeneic transplant. But importantly, a lot of patients have aged out of allogeneic transplant, and so they really have no option. And this is a treatment that for the first time, these patients will now have an option to really change the course of their lives. So we're really excited about getting this to a BLA. There's still kind of a couple of steps that we're thinking about going through. For one, we'll probably enroll one more patient. We do have rare pediatric designation here. We'll enroll probably one more pediatric patient. And the timing of enrollment will depend on do we need data for that patient or not. So whether we kind of decide to submit a BLA this year, or if it's sometime next year and just finalizing some of the final CMC requirements. So really excited about getting this program to patients, and we think it's a really important program for Prime.

Yes. No, it really seems like the FDA has developed a sweet spot for gene editing because of, I guess, the promise of the technology. Maybe thinking about the concrete steps, you said maybe not one more patient and see how much follow-up we need there. But like what -- so you'll have a meeting with the FDA to discuss the BLA filing or the scope. Or -- is that a first step, or will you just be...

What I would say at this point, we're not commenting on sort of our FDA interactions. I commented more broadly on what our plans are. What I would say is I think we've got the data in hand today to get approval for this drug. I don't think we need additional data to get approval. I think it all comes down to the ultimate label, and do we want to get a label? Can we get a label with the current data set? We've treated an 18-year-old, we've treated 57-year-old, can we get a label for -- that includes pediatrics with the current data set? Or do we want to enroll one more patient under 18 to get that label. And that's still a conversation that we're going to have. And on the CMC front, when I talked before about it being $50 million to $100 million, now it's a small fraction of that to get this drug to approval. So it makes it a good opportunity for us to now to make that much smaller investment. From the CMC side, the FDA is also being a lot more flexible, I'd say, in sort of what the CMC requirements are. So we want some sort of final alignment there, but even what we understand could be a worst case is not a bad case for the steps that we'd have to go through and not too costly either.

Great. So the financing needs from your balance sheet are the manageable while you execute.

Yes. Cash runway guidance unaffected.

Okay. Great. Thank you. Maybe moving on to in vivo, which I think most people are focused on here on the story. Maybe with Wilson's disease, often it's viewed as treatable. Yet you're emphasizing how significant the unmet need here is. Can you just highlight what is underappreciated, and what Prime Editing will bring to the table here?

Yes. It's a great question. And I think it's a really important one because I think there are some out there that -- and we've heard this from investors at times, this is a disease that has standard of care. You can take copper chelators, you can take zinc salt. What I would encourage these people to do is kind of the work that we did, which is talk to the key opinion leaders, talk to the patients. And you'll quickly learn this is a very high unmet need. These patients are not happy on standards of care. Many of these patients can still progress. So up to 20%, 30% of patients, even if they're compliant with standard of care, actually can still have progressive of liver or neurological disease. So yes, some patients, if they're adherent, may live a relatively normal life. They'll be in a low copper diet. These medications aren't easy to take. You have to take them multiple times a day, sometimes fast, sometimes with food, depending on what medications you're on. So it's not -- they argue about lifestyle, but you also don't know if you're that patient that is going to progress, is going to be more impacted even on standard of care. And again, almost half of patients or close to it are not able to be compliant on standard of care. You can quickly get copper buildup, you can quickly get additional end organ disease. So this is something where we have seen a broad desire amongst both physicians and patients where I think it would be pretty universal that if they're candidates to get our Prime Editing drug, I think the majority of patients and the majority of physicians will opt for this ultimately.

Great. So it seems like there's a fair amount of patients that don't tolerate standard of care. And would those be predominantly the population for Prime Editing, or would it be all of the patients? And also, there is a gene therapy in development there. What would be the limitations of that versus Prime Editing?

Yes. So I think -- and we've asked those questions, too. I mean, I think the easy low-hanging fruit are going to be those patients that are not compliant, whether it's because of tolerability or something else. That's obviously the low-hanging fruit. But when we ask the same question around patients that actually are managing to be compliant with standard of care, many of those patients, if not, the majority of those patients are also -- would opt for this treatment and the physicians would opt for this treatment for them. So I think it's actually going to be applicable to both. Like how that ramp looks in the different populations, don't know yet. We're doing some of that work now. But I really believe there'll be broad acceptance of this therapy across those patients. Again, just given the fact that this chelators and zinc salt, they're not curing the disease, right? They're helping their -- zinc salts are helping to prevent absorption, copper chelators because the copper is going to your blood is helping to excrete it into the urine. So it's kind of doing something a little different. That's not the normal excretion of copper, right? What we're offering is we can really fix the mutation. We can take your gene, your mutated gene back to normal. If you treat a patient early enough, they could never get disease. Like that's a pretty exciting profile as you think about a drug. And what we'd ultimately like to do is say, obviously, we're going to treat that prevalence pool. But as we think about the incidence pool, how do we get in to treat patients that are 5, 6 years old really before they develop clinical disease. Sorry, you asked about Ultragenyx. I do you want to answer that question as well. Yes, gene therapy and gene editing therapies, there's a lot of differences. So I'll just tell you what the differences are from the competing gene therapies out there. So one, they're using a truncated version of the protein. So it's not the full-length protein. Yes, it does contain the active site, but as people know, in protein biology, the truncated protein might have slightly different activity than the full-length protein. Two, hepatocytes turn over. They don't turn over as quickly as epithelial cells or other cells in your body, but they turn over, whether it's over 6 months, a year, et cetera. So there'll be a dilution of effect because half the daughter cells will have the -- maintain that gene expression and half won't. We're, again, fixing that mutation in the DNA. So every daughter cell is going to have that correction. So this should be a -- and we've shown this in longer-term studies as some others, these gene editing therapies tend to be very -- well, they are very durable. So that -- those are two of the key differences. Obviously, they deliver through AAV. So there is required, I think, significantly more immunosuppression as you give that drug, which you don't have to do when you think about an LNP to the same degree. So I think there's a lot of important differences. And I think ultimately, that will play out in the clinical data.

Great. And what are the remaining steps to get to IND or CTA? And what's kind of the time frame that -- if you remind me of that?

Yes. So we haven't given sort of the play by play, but I can remind you what our guidance is. So our guidance for Wilson disease is a regulatory filing in the first half of this year. It's, what, March 11. So the first half of this year has a -- 3 and some months left, so you can imagine kind of where we are there. And the Alpha-1 program, we have guided to a mid-2026 regulatory filing. And I'd say we're only a couple of months behind Wilson disease as you think about Alpha-1.

Right. And Wilson's disease, looking at your Phase I trial design, what would they look like? What are some of the endpoints you would measure? And maybe I'll ask about the efficacy bar later, but...

Yes. So it will be a dose escalation study. We haven't said how many patients, but usually companies will typically do 2 to 3 patients per cohort. You hope to start at a biologically active dose. We think we've got a pretty potent molecule here. So we don't expect there to be a significant number of dose cohorts to get to the optimal biologic dose, but we'll have to see what happens when you get into humans. The things that we're going to measure that I think are going to be really important in the study. So one is a radiolabeled copper PET study. So what we'll do and we have -- if people want to pull up our presentation, you can see the radiolabel copper PET study that we did in mice. And what you can show at least preclinically is what it looks like in a wild-type mouse, mutated mouse and then a mutated mouse that has our treatment. And what you could see is a complete normalization of copper metabolism in a Prime Edited mouse that has the mutation for Wilson disease. So we're going to do that same study in humans. We are going to do a baseline study before they get treated, and then we're going to do a 6- to 8-week study as well. We're not going to mandate this in every patient, but we're going to be doing this at sites that can do it in the majority of patients. So we should be able to see a pretty early read of proof of concept if we can translate what we see preclinically to clinical of normalization of copper metabolism or very improved, I'd say, copper metabolism. We'll look at other measures. We'll look at urinary copper that is significantly elevated in mutated in Wilson disease patients. Once we -- if we treat them effectively, that should be reduced down, hopefully closer to normal levels. In some of these patients, you can get liver biopsy, you can look at liver copper in addition to a percent of hepatocytes that have been edited. Again, we're not going to mandate that in every patient, but we should get that in some patients. And then we'll look at seroplasmin, which is another enzyme that you can measure that is very low in patients that have Wilson disease, which you can see go back up to normal levels on treatment. And I think ultimately, you also want to look at how do these patients do if you remove standard of care. So if we can show that these patients do not require standard of care, you can remove that standard of care, and they still have normal copper metabolism or normal copper levels, then you can show you've effectively, at least genetically, hopefully cured or greatly improved these patients.

Great. And without obviously going too much into the details here, but like what is your read at this point from your animal work of where we can get to? Will it be a cure? The metabolism is someone rectified in all patients, a portion of the patients? Like can you lay out like where do we get to? Is this like where the [indiscernible] is getting to an [ HAV ] or is it...

Look, it's a great question. I'll -- this is how I'll answer it. I'll say, again, preclinically, we -- at pre and, I'll say, reasonable levels of editing, we can get to normalization of copper metabolism. How that translate clinically, if that translates clinically, then you'd expect to at least, I would call it, genetically cure these patients. Why do I call it a genetic cure? And I'm hesitant to sometimes use the word cure. If a patient has neurologic or psychiatric disease, so patients with Wilson disease will get both liver disease, they can also get neurologic psychiatric disease as well. Some of those symptoms, like if you have neuronal cell death, you're not necessarily going to reverse that. Some of those symptoms can reverse, but some might not reverse. So I would hesitate to call that a cure. I could -- we could definitely halt that disease getting worse, but you won't necessarily cure a patient that has really deteriorated. I think the same goes for liver disease. We -- I think we've seen significant improvements even in patients that have grade 3, even grade 4 liver disease. But once there's enough fibrosis, once there's enough cirrhosis, we'll have to see how much you can reverse that. I think what we've seen, and what's been a positive, if you transplant these patients, and they get 1/3 of the liver, that's going to regenerate, and you're going to have almost normal liver function, and you can help with the neurologic and psychiatric too, which leads us to believe that we believe we can have a pretty significant impact. And it gets back to what I said earlier. If we can treat early, then I believe this can be a cure.

Great. What about the regulatory pathway and the endpoints? Is that pretty much figured out by the gene therapies that are ahead of you, or is there some uncertainty?

I think this is something where I hope we're trailblazers. I think it's all going to always be data dependent. The better the data is, the more flexibility there may be, and the more I think both sides are going to try and figure out how to expedite a therapy to patients. So we have some ideas in mind on how to get to, I would say, faster endpoints in a sort of registrational setting. If the data plays out how we believe it will, we don't think these will have to be large studies. We think this can be relatively small studies. But I think it's a little too early to comment on specific endpoints for registrational study.

All right. Great. And then maybe last question on this topic. Obviously, you cover some mutations. There are some outside of the range of what you can target. What's kind of your long-term path on getting to all the patients in Wilsons?

Yes. So to break down the mutational background here, if you think about U.S. and Europe and predominantly the Caucasian population, the first mutation we're going after is called H1069Q mutation. That affects about -- we say somewhere between 30% to 50% of that population. So it's the most prevalent mutation in the Caucasian population. So call it, 40%. And then with a handful of other editors, we think we can get to somewhere around 60%. So we're probably not going to be treating -- we're not going to be treating 100% of these patients. We think we can treat 60%. Hopefully, it might make sense to even develop a few editors and do even more. And the importance there is all we really need to do is swap out the guides, right? Everything else stays the same, same LNP, same mRNA. We can do these all under one IND. And so it should be pretty rapid as you get additional mutations into the clinic and just getting to proof of concept there. And ultimately, we hope to licensure. Now as we go outside of the U.S. and Europe, and you go into the Asian population, there the most predominant mutation is called R778L. That mutation affects maybe even up to 50% of that population or more. And then a handful of editors might even get you to 70% of the population there. So this is a global disease. We'll have plans to pursue this globally. And it's an unmet need on a global basis. So we'll continue to pursue multiple mutations.

Yes, moving on to AATD,, Alpha-1 Antitrypsin Deficiency. It comes up a lot. Like there's a lot of excitement around it, a lot of people jumping in. Maybe if you can tell us where Prime Editing fits in there with all the other modalities that are out there, and what you hope to bring to the table?

Yes, I mean, look, it's a competitive field. We know there's a lot of people working in the space. I think the reason for that is if you think about genetic diseases, this is a genetic disease where 98%, 99% of patients have the same mutation. So if you think about an editor and whether it's an RNA editor or a gene editor, it's sort of the perfect disease for that reason. It's also -- there's an unmet need, right? There's replacement therapy. It's questionable on how effective the replacement therapy is. So this also is a disease where I think patients and physicians also are looking for better options. As we think about Prime Editing, and I'm not going to go through all the different modalities. What I would say is the -- what -- Prime Editing is the only modality that offers taking a patient back to wild-type protein. We are fixing the mutation at the DNA level, right? We are fixing it at its source. So what does that mean? That means the patient is under -- that gene is under endogenous control. Your body is dictating how much alpha-1 protein you need, and when you need that protein. That's -- in my opinion, that's a huge benefit to Prime Editing over other technologies. No other technology can do that. The RNA editors work obviously, at the RNA level, and there's going to be limitations there versus, again, fixing this as a one-done therapy at the source. Base editing, there's bystander edits and other things that can happen. So again, I think this is sort of the perfect application for a Prime Editing approach.

Maybe in terms of clinical development, would you just follow the footsteps of base editing in terms of patient population, endpoints, duration, everything, et cetera, or is there anything that you would change?

Yes. I think the clinical path there is -- has been somewhat simplified. I don't know that there's anything more that we need to do. There's a lot of patients out there. There's a great biomarker that we can look at, just looking at AAT levels. You can see that impact very early, right? You probably see in a couple of weeks and have optimal effect at 4 weeks, 6 weeks. So you've -- there's kind of no reason to reinvent the wheel there. I think we've got a really good framework to how to think about studying that disease with a gene editing approach.

Great. And then maybe zooming out a little bit across your in vivo programs, safety and delivery are obviously central themes here, right? And we -- when we talk to investors, we sometimes get pushback across all CRISPR therapies or gene editing about the irreversibility of it and maybe off targets and what -- why that will be holding back the field. Just can you talk about what gives you confidence to your LNP approach and the therapeutic index you've achieved to date?

Yes. So I'll talk about the LNP, but I also want to address sort of the off-target and other things that are not LNP related. So as we think about LNP specifically, we have an LNP. This will be the first time that's going into the clinic. We have benchmarked this LNP against multiple other LNPs that have gone into the clinic and others that we know others are bringing into the clinic. And I'd say when you look at liver function tests, when you look at cytokines, when you look at coagulation markers, at least from what we've seen preclinically, we seem to have a much wider therapeutic index. So that gives us hope as we go into the clinic that, again, we're not devising drugs that we need to necessarily dose higher. We're looking for drugs that you can dose under 1 mg per kg, but it's nice to know that you might have the ability to go well above that, if needed in the clinic. So -- and that will play out as we get to that data set. And I think when you think about the technology, that's the beauty of Prime Editing. We really don't see a lot of off-target impacts with this technology. And so -- or on-target impact as we think about indel and other things. So it really creates, I think, a technology and a platform that can really overcome some of the limitations of other approaches.

Great. Well, thank you, Allan. Thanks for joining us today. And yes, I look forward to seeing your programs in the clinic.

Great. Thanks.