Good afternoon, everyone. My name is Arthur He, Senior Biotech Analyst at H.C. Wainwright. Thanks for sticking around and joining us for Fireside Chat with Dr. Allan Reine, the Chief Financial Officer of Prime Medicine. Prime Medicine is a clinical stage biotech company focused on developing gene and cell therapies based on its transformative gene editing platform called Prime Editing. The company is currently advancing a diversified portfolio across multiple drug modalities, as well as a broad spectrum of disease. To better understand Prime's story and its growth strategy in 2024 and beyond, I'd like to welcome Allan to our conversation.
Thanks. Thanks for having me.
So Allan, just to set up the stage for our audience, could you give us an overview for Prime, the pipeline right now?
Yeah, and maybe I'll just take a bit of a step back for people that aren't as familiar, and just tell a little bit about the company as well. So Prime Medicine, and I like the way you called us a clinical stage company, because I think it's the first time we've been on a podium where that's been the case. The company was founded back in 2020 out of David Liu's lab. The company Prime Medicine is named after the technology that came out of that lab, which is Prime Editing, and we'll talk a little bit more about that as we get into the conversation.
But I think that what I would take away from this is it really is, I think, the most versatile, powerful, and safest way to do gene editing, I think, that, that exists today. In terms of the pipeline, you know, we bin things into different areas, depending on the tissue or cell type that we're going after, and I'll give you a few examples of those. So our first program, which again, I mentioned, we started in 2020, and we just had our first IND accepted at the end of April. So now we, you know, are getting that trial up and going, and that's in a disease called chronic granulomatous disease. So there, via an ex vivo approach, we're targeting hematopoietic stem cells. We have some other hematologic diseases that we're also going after.
I think next, I would talk about our programs that are targeting the liver through our proprietary lipid nanoparticle, or LNP, delivery technology. The two that we talk about publicly there is one disease called Wilson's disease and another called GSD1b, or a type of glycogen storage disease. Maybe two more or a few more examples within our pipeline. One is our ocular franchise where we've talked about going after retinitis pigmentosa or a form of that called RHO. There, we're using our AAV delivery technology to give our prime editors directly into the retina of the eye. Now, we presented some really nice data there at ASGCT recently that shows preservation of photoreceptors.
In addition, earlier this year, we got some funding from the Cystic Fibrosis Foundation, so we're developing novel prime editors that will directly target the lung. We can think about targeting, you know, greater than 90% of cystic fibrosis with just a handful of editors, or even with our PASSIGE approach, which I know we'll talk about.
Sure. Thanks, Allan, and for those in the audience not that familiar with the technology, could you walk us through how the prime editing works and how these technology differentiate from the early generation of gene editing?
Yeah. So maybe we can start from the earlier technologies, and I'm sure people here have a lot of familiarity with the initial companies like Intellia and CRISPR and Editas. And there, what you really have is a, you know, a Cas9 enzyme, and a RNA guide. So it's very good at finding or searching for a place in the DNA and telling that enzyme kinda where to cut, right? So it's very good, we think about the search part of that, and then really deleting something or blocking something or knocking something out. But there are limitations there, and I would say a couple of the limitations that I think about are, one, you can't really add things in, and two, because you're doing these double-stranded breaks in DNA, you get a lot of off-target editing.
And you can also get chromosomal translocations and rearrangements. And, you know, when we actually do some of our off-target assays, we often use, you know, the CRISPR-Cas9 system as an active control. So what David figured out in his lab is, one, instead of using that enzyme that does a double-stranded break, we use a nickase that just does a single-stranded break. In addition to that, the other components of prime editing include that guide RNA that I talked about, that CRISPR uses, that can locate a specific sequence or loci within the DNA. However, the difference here is what's also included in that guide RNA is a template that can then be transcribed or written into the DNA, and that's really what is, you know, to me, groundbreaking in this technology.
And the way that template is transcribed into the RNA into the DNA, sorry, is using a reverse transcriptase enzyme. So you can think of the components as the prime editing guide RNA, which again includes both the guide sequence, but also one needs to be transcribed, and then an mRNA, which is gonna code for both a reverse transcriptase as well as the Cas9 or nickase enzyme. The other things that though we can do with this technology is using our PASSIGE system.
So there, we're using all the same elements or components that go into prime editing, but in addition, we're adding a DNA donor template and recombinase technology that lets you put very, very large pieces of DNA, you know, kilobase pieces of DNA, into a very specific locus again. So it's very precise, it's very safe, and we think it has a lot of applications across many disease areas.
Sounds interesting 'cause it sounds like these are a very versatile tool in terms of manipulating the genes. Speak of the pipeline about the CGD. Congrats on get your first IND down. So could you talk us about, in general, about the disease background, and what's the unmet needs right now for the CGD area?
Sure. So, chronic granulomatous disease, it's a patients with this disease have a mutation in the NADPH complex. And essentially, they have a defect in certain cells within the body that you know phagocytose. So, one important component of that is neutrophils. So these patients have, you know, essentially defective neutrophils. As a consequence of that, they get recurrent infections that start at a very young age, and these infections become very difficult to eradicate. Beyond the infectious sequelae of the disease, they also get inflammatory-like syndromes as well.
Mm.
They often only live into the third or maybe early fourth decade of life, so this is something that's life-threatening. The only real treatment today is, you know, be on recurrent antibiotics and interferons to try and help with that. But again, when infections break through there, they can be even more severe. The only curative treatment today is an allogeneic transplant. The downside to that is, one, it's a pretty severe preconditioning regimen that these patients need. You need to ensure that you can, one, find a match. It's an allogeneic approach, so they're also gonna likely need post-transplant immunosuppression. There's also the risk of failure. So we think a minority of patients ultimately are getting allo transplants.
The other thing is there's a treatment window. As patients get beyond adolescence, transplant tends to be less effective as well.
Sure. Thanks for that. And we know that CGD could be very heterogeneous, and my question is: Why are you guys picking these particular patient population?
Yeah. So the first is going after the NCF1 gene. So there are different mutations that can cause CGD, and depending on the mutation, you can have, you know, some level of activity within your neutrophils and other cell types within the body. The type that we're going after represents about 25% of patients out there with CGD. So with this one mutation, we can go after a pretty significant percent of the population. You know, if successful, we think there are other editors that can potentially go after even a greater percent of the CGD population, like X-linked CGD, as an example. And I think it's a, you know, a place where we can really demonstrate the power of this technology, really curing patients of this disease.
So patients that do have this mutation will have fairly severe disease, so it is something that is, again, a high unmet need, and we believe can be addressed with our drug.
So for that sake, could you highlight the... so far, what you guys get on the preclinical data for this program to support IND?
Yeah. So we, we've presented a lot of preclinical data historically. We also presented some additional data at the ASGCT meeting, was it last week or two weeks ago? Which also further supports pushing this program into the clinic. And what we see is very, very high levels of editing within our cells. So we're getting very high efficiency, well over 80% editing of these cells. What we've shown in vivo is we get engraftment as well, and normalization really of enzymatic levels that show that you're getting functioning neutrophils or restored NADPH activity. The other thing I would say is we measure the functionality of your hematopoietic stem cells that you're editing, and you wanna ensure that once you've done these edits, that these cells are functioning normally.
And, you know, the hope is that once you give those back, that these cells will successfully engraft, and we show normal function with these cells as well. So the way I look at it, it's a very compelling preclinical package, as we go into the clinic and, you know, the success ultimately of this program.
Sure. When we are looking forward, I know you guys go soon to getting the patient in the program. Could you elaborate the phase I, II study design and you guided data in 2025. So what should we expected from the data update?
Yeah. So in terms of the study, let me walk you through that first. So we're and you can see in this on the slides on our website as well, but we're looking to enroll in three different cohorts. So cohort one will look at patients, adult patients over 18. We'll likely start with patients that don't have an ongoing infection right away. Ultimately, we would plan to go into patients that do have an infection. But and then as we dose that, so call it each cohort will have somewhere in the range of, you know, two to three patients. So they'll be, you know, pretty small cohorts that you can go into. And then the second cohort, we think about, you know, just kinda going younger as we go.
So the second cohort, thinking about 12- to 17-year-olds, then the third cohort going into younger, a younger pediatric population. In terms of data, and we've talked about, we've guided to get to having data for this program, sometime in 2025. What's great about this indication is assuming you get these cells successfully engrafted, the ability to test if you have normal neutrophil function, you can do with a really nice enzymatic assay looking at something called DHR levels. And so in a fairly short period of time, calling it, you know, a couple of months or a few months after these patients have received these cells, you should be able to then see that enzymatic recovery, and you know, validation that you're seeing.
You know, what we would expect is the disease ultimately being cured. We'll also look at patients, any new onset of infections and look at any new onset of inflammatory-like complications of disease. And ultimately, once we are treating patients in the future, we can look at resolution of ongoing infections and resolution of these inflammatory like syndromes.
Cool. We're very much looking forward to the data.
Yes, so are we.
Yeah. So yeah, beyond the CGD, let's look beyond the CGD. So which programs... I know you guys are moving a lot of different pieces together at the same time. Which program should we focus on? And how are you guys think about the, the construction of the, and priority of the portfolio?
Yeah. So in thinking about what to focus on, I think would be the next wave of INDs. So we, we've talked about, if you look at our liver programs, which there are three, so I mentioned Wilson's and GSD1b. There's also an undisclosed program in our pipeline, so it's just called undisclosed program. And we've talked about moving at least one of those programs into IND-enabling studies by year-end. That could be more than one, so we have a lot of investment, and I think we've made some great progress with our proprietary LNP delivery technology as well.
You know, I like to say every gene-editing company is a gene-editing company as well as a delivery company, 'cause that's a very important component of getting where you need to go to make sure you're doing the right edits in the right tissues. So very excited about what we're able to do in the liver. And I alluded to before, but looking at our ocular program and, you know, the data that we recently presented showing preservation of the photoreceptors in treating a form of retinitis pigmentosa, I think that's really exciting data as we think about using our AAV technology delivery technology to deliver that to the retina. Sure.
Um-
I think one story that I failed to mention also, earlier, is looking at our neuromuscular pipeline as well. I think a couple of the programs that we've talked about, one was Friedreich's ataxia, which is a repeat expansion disease. There, we showed the ability of prime editing to excise very long stretches of DNA. So here you can have repeat expansion that can go into the hundreds, sometimes thousands, of repeats. And that's another area where, again, we're still working, I think, on delivery there, as you're thinking about getting AAV effectively to the brain, but another area where we're investing.
As you mentioned, the delivery, I know you guys developed your own liver-targeted LNP formulation. Could you tell us more about that? What's different, compared to the conventional LNP?
Yeah. So I appreciate the question, and I'm not gonna directly answer it. I think a lot of what we're doing is proprietary, and I think there's a lot of trade secret when you think about the LNP approach. What I will say is, you know, we have a library now of, I think last count was 800, maybe over 1,000 different lipids.
Wow.
That we look at. So we do a lot of screening, and, you know, analyze a lot of different formulations for our LNPs. As you know, it's usually a mix of four to five to six lipids, depending on what formulation you're using. And you know, what I can say is we've kinda seen what's out there, and we know there's been a lot of noise recently looking at LNPs with some of our competitors' data. But I would say we have our, you know, own proprietary formulation. Everything that we've looked at preclinically so far tells us that we can effectively and safely dose the liver. But you know, and hopefully we'll be able to talk more about that as we show more data.
Sure, yeah. So let's switch back a little bit on the technology-wise. You mentioned the PASSIGE system. I know it's kind of delivery for the large payloads. So in your opinion, what's the most useful application for this platform compared to a traditional prime editing?
Yeah. So when you wanna put in large pieces of DNA, I'll give you one example to start, maybe, where I think this technology, in my opinion, you know, can really do things that other editing technologies can't. So one example would be in CAR- T, in editing, CAR- Ts. It would—I'm sure people are very familiar with because there's a lot of companies doing CAR- T therapies right now, but none doing anything quite like the way we are. So the way we do our PASSIGE approach is we don't have to use lentivirus. So you don't have the risk of, you know, random, you know, integration into the genome.
So with lenti, you can get the DNA transcribed into, you know, once every cell can get it transcribed into somewhere slightly different. Here, we actually put in a landing pad right into the locus where we wanna deliver our DNA. So let's take an example in CAR- T, where we can get greater than 80% editing at the TRAC locus with our landing pad and DNA donor. So you can think about sort of how powerful that is. And when we're doing CAR- T, it's not just the PASSIGE edits, but we can also then do multiplexing and really in one step instead of having to do multiple steps, you know, which again shows that we don't get any off-target or any unwanted editing effects that you do see with other technologies out there.
So we do think it's the best way to actually edit CAR- Ts, and we think it's a pretty powerful technology for that application. I think some of the, you know, other areas that we're looking to utilize our PASSIGE approach, one would be, you know, PASSIGE to the liver. So being able to make large changes in the liver, where you might have genes that have a large number of mutations. Another area that we've talked about is with the Cystic Fibrosis Foundation. We're taking a couple of different approaches there.
One is something that we call hotspot editing, which is, you know, if we have a number, a large—you're editing a large piece of DNA, so, you know, five different people might have five different mutations within this large, call it 50-100+ base pair editing window, and we can get all of those patients just with one editor. But the PASSIGE approach, too, is another where we're looking to do those edits, where we're just putting in a large replacing the defective gene with again a large piece of DNA.
Interesting. Definitely, the multiplexing part is really interesting.
Yeah, and I should say, it's not just multiplexing with knockouts and you could actually do bicistronic as well, and we've shown the cells, you know, maintain great health with a bicistronic and multiplexing as well. So it's pretty incredible technology when you look at what we can do with CAR- Ts.
So as a platform company, I'm sure partnership is in getting into your mind, your mind. So how should we think about the business development opportunity for you guys in the near to medium term?
Yeah. You asked the question earlier about prioritization, and I think that's where also business development comes in. Because if you look at our pipeline today, I mean, we're not gonna push everything forward that's on there on our own. So I think that's where business development is likely to come in. There is a lot of interest in what we're doing. I think given the foundations of this technology and what we've been able to achieve and where we've been able to push a lot of our programs, I think there's a lot of excitement out there. There's a lot of ongoing conversations. I would never, you know, BD's never done until it's done, but I think there's a lot of promising conversations that are ongoing.
And I think we're gonna have to, you know, decide what we wanna take forward on our own, and what's best to be partnered. I think as we look at, you know, the pipeline today, and I've talked about CAR T as an example, you know, that's an area where I think we've made a lot of strides, but we, you know, don't have the internal expertise around, immunology and oncology. So we could choose to build that, but that's also something we could look to partner as well. I think when you look across our, our pipeline, I think there's other areas where, there's a lot of interest, some that are on our pipeline, and frankly, some programs that are not even represented in our pipeline today, where companies have come to us and, and are interested in working in.
Sure. Thanks, Arthur. So to wrap up our conversation, could you remind us the upcoming catalyst and your cash position right now?
Yeah. So the cash position, last updated was the end of March, was $224 million. That takes us from a runway perspective into the second half of next year. Upcoming catalysts for the year, I talked about, a number of programs have the potential to go into IND-enabling studies by the end of this year, which would really kick off what could be the next wave of INDs, call it late 2025, first half of 2026. In addition to that, obviously, we've got our first prime editor, which is now about to go into patients, and getting data for our first program, clinical data, on patients, which, you know, should be hopefully curing these patients of this awful disease sometime in 2025.
Thanks, Arthur, for such an insightful conversation. For the audience, we just launched Prime Medicine this morning. If you are interested in have a copy of our notes or have a chat on the name, feel free to reach out. Also, I want to thank all the investors and the company attending our conference today, and I hope you guys had a productive day. Thank you again from the H.C. Wainwright team. See you guys at the AI panel.