Hello. Good afternoon. Thank you for those in the room who are joining us, as well as those who are joining us via webcast. It is our pleasure to welcome Rachel McMinn, Founder and Chief Executive Officer of Neurogene to the 45th Annual Global Healthcare Conference, to walk us through a corporate overview. Rachel, thank you for being here.
Thank you for inviting me, although I wish, for those of you who are here, you can feel the pain of how miserable it actually is in Miami. So, I'm not looking forward to traveling away, but it is my absolute pleasure to make the most of the time here, and introduce you to Neurogene and provide an update for those of you who don't know. It's really just an incredible time to be at Neurogene following some really great news about the FDA that I'll get into in a little bit in the presentation. Just know that these there are forward-looking statements, and we refer you to these disclosures.
So Neurogene, we are a differentiated neurological gene therapy company, and really what makes us differentiated is the EXACT technology platform that we have that underpins our ability to really go beyond what conventional gene therapy is able to deliver and go after commercially attractive indications. Rett syndrome is the lead indication that I'll be talking to you about today and the EXACT platform. We do have internal manufacturing, which is a very important strategic asset. Very few companies have that these days. We have a cash runway into the second half of 2026 that really allows us to comfortably fund the company through important inflection points and does not put us in a situation where we're sort of forced to be, you know, kind of prematurely disclosing data, because of the cash situation. In terms of the pipeline, two programs to mention. They're both clinical stage.
We're gonna spend most of the presentation on the Rett syndrome program. This is a program with a key interim data coming out in the fourth quarter of this year, with some additional more mature data coming out in the back half of 2025. For the CLN5 Batten disease program, this is a program that is much rarer. And while we have mentioned that there's a data update in the back half of this year, probably the more important inflection point is really the regulatory update that we'll be providing on this program, going to the agency and really making a go, no-go decision on the Batten disease program. In terms of what, you know, what is out there, what are we trying to tackle, you know, right now in gene therapy, there's a number of real limitations.
There's variable gene expression, which ultimately leads to potential safety issues, especially in complex neurological diseases. And then there's very inefficient gene delivery. When you're trying to get to the brain, think about, you know, gene therapy, like, like real estate, it's location, location, location. And in gene therapy, it's delivery, delivery, delivery. If you can't get the gene to where it needs to go, it's obviously not going to be effective. So really what I'm going to tell you about is both of these, or all three of these, challenges that we've really begun to overcome. One is with the EXACT technology platform that's super exciting, that really overcomes the limitation of this variable gene expression and really is able to kind of cap the amount of protein being expressed in any given cell, which leads to a widening of the therapeutic window.
And then, in terms of inefficient gene delivery, you'll see that we've made a very purposeful data-driven decision on how we're delivering our product in order to maximize the amount of neurons in the brain that are getting our therapy. This is just a plug for our facility in Houston, our manufacturing facility that is currently supplying gene therapy for our Rett syndrome program. It's located in Houston. It's, you know, got a lot of capabilities, so not only GMP manufacturing capabilities, but all the way from, you know, toxicology, process development, you know, quality assurance, et cetera. And the goal here is, you know, we were able to manufacture this facility at a low cost. It allows us on a batch-to-batch basis to control our own destiny. We control the quality.
Because we've been, you know, using our own process from start to finish, we're hopefully gonna be able to avoid some of the comparability challenges that have really plagued the gene therapy field. Just briefly, I won't go into the entire management team, but I am the founder and CEO. My partner who helps co-run the company with me, Christine Mikail, is the President and CFO. Then Julie Jordan, recently hired Chief Medical Officer, has taken leadership there. And Stuart Cobb is really kind of the scientific founder of the EXACT technology. He's our Chief Scientific Officer. And of course, all these other folks below just have a fantastic team to be able to move our programs forward. So let me tell you a little bit about Rett syndrome. This is an absolutely devastating, devastating disorder.
It is a disease caused by a single gene, the MECP2 gene that falls on the X chromosome. So it makes it a disease that's a very interesting disease scientifically because, as many of you know, and with X genes, you know, half of your X genes are turned off, and half of them are allowed to be expressed. That's how we achieve the right doses of these genes. So, and I'll get into this in a moment, but that actually makes Rett pretty complicated because it means that about half the cells in a girl's brain are functioning normally and the other half are not. When this happens in boys, there's a really wide spectrum of disease. In the most severe case, the boy has no MECP2 at all, and so it dies at a very young age.
In a case where it's more mosaic, it can end up looking a little bit more like the female version. Most important takeaway is that there's a huge market opportunity here, 6,000-9,000 potential patients in the U.S. alone. So when you start applying global numbers to that, and a gene therapy price point, you can get to a very significant market opportunity very quickly. In terms of the unmet need, there are no treatments that address the root cause of the disease. There is one approved product, and, you know, that product has actually demonstrated that there is significant need and that the market is really rallying to come and try that treatment modality. So, there's significant room for a gene therapy program here, and we're very excited about this opportunity.
So a little bit more about Rett syndrome and really just the idea of requiring tight transgene regulation. So as I hinted at before, Rett syndrome, about half of these cells are deficient in MECP2. That's shown here in the purple cells with the green cells depicting normal. Unfortunately, there's a sort of similar disease in which you can actually have two copies of the MECP2 gene, and that's basically just as bad as Rett. So when you think about that biologically, then you really need a balanced treatment goal. And this is, you know, the idea then, of course, is you wanna be able to give just enough MECP2, but not too much to cause that overexpression toxicity. So how do we do this? This is a technology stemming from our collaboration with the University of Edinburgh.
Our Chief Scientific Officer has a dual appointment there and with Neurogene. This is really, you know, comes out of his lab, this idea of how do we control for when you get too many viral copies in a cell. If you look here on the screen, it's supposed to be orange, but it looks a little, I don't know what color that is right now, like maybe a little bit of a mustard yellow, but that box there is showing you a non-mammalian microRNA. That microRNA is very much like any other microRNA in the body, except it doesn't bind to anything in the human transcriptome. It's, we specifically purposefully designed this so that it would have no ability to bind to any of the human transcripts.
In the green box, so that's the other part of the secret sauce of the EXACT technology, are fully complementary recognition sites. That means that they're literally the antisense of the microRNA. So as you think about this in conventional gene therapy, you've got a promoter, you've got a transgene, you get transcription. So no different here, except on top of that transcription, you also get the microRNA co-transcribed with the transcript. And then every transcript has a recognition site, a series of recognition sites hanging off of it. So as you can see here, as depicted on the left, when that microRNA binds the transcript, because it's fully complementary, it then causes that transcript to undergo very rapid and efficient degradation. Anything that escapes the system would then go on to become transgene-derived protein. So how does this work in practice then?
Well, as you think about gene therapy, when you give gene therapy, no matter how you give it, some cells get a little bit and some cells get a lot, right? And how do you control for that? So if you have a cell that's getting 10 copies or 20 copies of virus in a conventional setting, you get 10 or 20 times the amount of protein. Like you don't want that 'cause that's gonna be highly, highly toxic. So what happens with EXACT when you get all of those excess transcripts, the probability of the microRNA and the transcripts finding each other goes higher and higher and higher until you reach a steady state. So as you get higher and higher doses, you basically get the same amount on a cell-by-cell basis, the same amount of transcripts because all the excess transcripts are being destroyed.
So that is the concept of how it works. And this is just kind of depicting it a little bit further. So if you look in the purple and the green cells, you know, we've talked about the variable AAV transduction. So some cells get a little bit, some cells get a lot. EXACT dampens that overexpression such that you get this kind of capping of the level of protein on a cell-by-cell basis. And as long as you're in the green zone in this sort of therapeutic window, you're able to then give cells that already have MECP2 a level of expression that is not toxic 'cause you're still in the green zone. But for cells that are totally deficient, the goal then is to make sure that those deficient cells are getting a level that's actually gonna cause a rescue. So that's the problem statement.
That's what we're trying to do is being within that therapeutic and tolerable treatment window in the green zone. So this is really, you know, it's not the only data, but it's my favorite data slide because it just sort of summarizes the key experiments that highlight how incredible this technology is. So if you look on the left, these are male mice that are literally the deficient cell. So these mice have no MECP2 at all. You can see in the black line, this is a survival curve. Like they start dying at about four or five weeks in terms of NGN-401. And you treat these mice, you can see a very nice dose-dependent improvement in survival all the way out to 37 weeks.
And just to give you a little bit of context, in a genetic rescue model where you're literally turning on a transgene throughout the mice, they live till about 40 weeks or so. So the 37 weeks, we were jumping up and down for joy, excited by it because it's saying, hey, we're pretty close to like what's even possible in this mouse model. So that's what happens on the efficacy side, right? You have a deficient cell, you put in NGN-401, and you see this nice dose-dependent improvement in survival. What about the safety question? Well, it turns out there are female mice with Rett syndrome. Unfortunately, they don't have much of a phenotype. They're not very good for evaluating efficacy, but they're a great safety model.
So we took these female mice and we did a really cool experiment where we gave a bunch of mice NGN-401, right, our drug, and we gave them the same doses at the same time point that we're demonstrating this efficacy. And that's modeled in the green line. And you can see there's no impact to survival in our appendix slides and our corporate presentation. You'll see there's also no toxicity at all. So very well tolerated. So that whole problem statement of, are you in the green zone or not? You're like, yes, you're in the green zone. You're effective and you're safe. Interestingly though, if you look in the purple box, if you take out the microRNA, which is that safety valve, right? That is the thing that's actually dampening the expression. If you take that out, the mice are dead at two to three weeks.
Same doses, same time point, same everything. So this, there's lots of other data. You can take any unregulated construct with the full-length gene and a strong promoter, and you'll get the same result. It's a highly toxic gene. So this really, you know, for us was, you know, some of the critical, you know, work showing how well the EXACT technology is really able to dampen that overexpression while still delivering efficacy. So delivery, you know, I mentioned this earlier in the presentation, we are a very data-driven company. I'm a PhD scientist by training and, you know, was a Wall Street analyst for over 13 years and everything's about data. Show me the data. So ICV or intracerebroventricular administration. And it's really, we ran a non-human primate biodistribution study where we compared a whole series of different ways of delivery.
We're just showing you two here to give you a simple, kind of a very simple way to look at this. ICV is accessing the cerebrospinal fluid from the brain and IT lumbar is accessing the cerebrospinal fluid all the way at the base of the lumbar. So all the way down here. And what you can see is, you know, ICV gives you very good coverage in cortical regions and the hippocampus. It's not in the, in the deeper areas of the brain like the cerebellum. That's, that's well known and the limitation of AAV9 does a good job of getting them. And then of course it washes all the way down the spinal cord and does a good job of transducing the spinal motor neurons as well. When you look at intrathecal lumbar in red, you can see, you know, not so much.
It gets into the spinal cord, but it really doesn't get into the brain very efficiently. And Rett, by definition, is the brain disease. And so if you wanna treat a brain disease well, you need to get into those brain neurons. So, you know, what we're showing here on the right are really some of the key deficiencies in Rett pathology. So communication, motor, and autonomic function. So, you know, this was really the decision. It was really a very straightforward decision to employ ICV administration in human subjects as well. So all of our studies from mice to non-human primates to humans are using this delivery method.
So it was on the basis of this and much more other data that we really don't have time to get into, that, you know, really, you know, these are the key kind of differentiating aspects of NGN-401. We've got this incredible, you know, preclinical package. You're delivering the full-length gene, which is really important, as has been demonstrated across many, many indications that the full-length gene is always going to give you a better outcome than lesser than that. So we chose that intentionally. We really chose our ICV administration very intentionally. And, you know, not shown here, but of course we really were off-target testing to really make sure, it was very robust. So on the basis of all of this, we're really one of the only companies that I'm aware of where we were able to go directly into a pediatric population.
So very unique regulatory narrative. So the FDA's default is to, you know, always evaluate safety in an adult population before you're allowed to go directly into children. We, you know, made the case to FDA, it's a much higher bar to go directly into children, without going into adults. And so it was this data where, the bar that you have to meet is not only having a safety, a good safety package, but actually demonstrating a prospect for efficacy. So we met that bar, and we were allowed to initiate directly in children. Following that FDA clearance of our IND, that was in January 2023, we then subsequently had regulatory approvals in the U.K., as well as Australia. So, very exciting to see a global concurrence about the, you know, overall robustness of our package.
So just briefly in terms of Rett syndrome and what are we looking at here, this is an absolutely devastating disease. You know, cardinal features are an inability to communicate, that is both, you know, through hand function, right? We're so used to people being able to, at least if they're non-verbal, they can sign language or they can, you know, grab your hand and take you or point at something. These girls don't have the ability to do that. They're non-verbal. On top of that, they have impaired, gross motor as well as fine motor skills. So not only can they not point, but they're not able to really pick up objects, in a purposeful way. They can't feed themselves in an intentional way. Some of them can't hold anything at all, and they have complete loss of their hand function.
About half of this population is ambulatory, half is not ambulatory. But even the ones that are ambulating have significant ataxia. They can't climb the stairs, they can't run, they can't ride a tricycle. So they're very impaired. And then there's this whole other bucket of autonomic dysfunction. So what does that mean? It's like they don't sleep well, they have significant breathing abnormalities and they're also constipated. A good majority of them are highly constipated. So, and then you sort of list a whole bunch of other disease manifestations. So this is the cardinal features, but I'm, you know, only really talking of symptoms that are really most common across girls, but there's certainly more.
The other cardinal thing to mention just in terms of the natural history course of the disease is the girls are born typically normal. They go through a regressive phase. They tend to be diagnosed between the ages of two and three. They land in the neurologist's office because they've lost skills. So it's not just that they're delayed, but like they were talking and then they stopped talking or they were using their hands and then they stopped being it. They started like doing weird things and like mouthing or, you know, using these weird hand stereotypies. And, you know, some of them never learn to walk. Some of them have a little bit of standing and then they wobble and they fall off. Once they go through that regressive period, there's this period of relative stability.
So the reason why we're studying for the 10-year-old girls is because we wanted to look at these girls who are relatively stable and say, okay, can we actually get these girls to gain skills that they had lost, right? That, that they don't have anymore. So these girls don't gain skills. They don't typically lose a lot of skills either. There is some progression of the disease during this time, but it's, it's relatively minor. And then eventually as they go on to become adolescents and adults, their muscle tone gets a lot worse. Their risk of scoliosis gets more severe. They get things called contractures, and they have, they can have seizures that are very profound that can impact cognition. So this is a snapshot of our clinical trial design. We're in a Phase 1/2 study.
So we went directly into children four to 10 years old with a diagnosis of and a genetic confirmation of Rett syndrome. We're enrolling cohort 1, which is our low dose. This was expanded from initially five patients to eight patients. We made that announcement in March. And then at the same time, we introduced a second cohort that is enrolling concurrently. So the guidance there is to initiate enrollment in that high dose. And the way to think about it is, you know, I just showed you a few slides ago that we had two different doses in mice that had two different survival endpoints. The low dose is 1E15 total vector genomes. This dose is kind of between those two mouse doses, right? Kind of bracketed between, so expected to be efficacious.
That higher dose cohort is actually above, just slightly above the highest dose tested in a mouse, but falls very much within our safety margins for non-human primates. So the goal here and the reason why we're enrolling concurrently is, as you know, with gene therapy, it's you know, very challenging when you, from a timeline perspective, when you first start enrolling, you enroll a patient, you wait for safety, you gather the safety data, you get a DSMB clearance, and by the time you're ready to dose your next patient, a whole quarter has transpired. So while that high dose cohort is enrolling, we're continuing to collect additional data on the low dose. So there's no slowdown of the trial. It's actually an ability to collect all this data concurrently, and the thought here is that this will help you know, further inform endpoint selection.
We do not need to necessarily complete enrollment of all these patients, but we wanted the ability to go to the FDA and, you know, have a you know recommendation on endpoint selection. We are very focused on objective measures of assessments, whether that's autonomic hand function, communication, gross motor function. There are behavioral assessments that are done here, but as we think about an eye towards approval, we're very focused on objective, clinically meaningful, assessments, for these patients. The earliest assessments we have are at three months. But as you think about the program, obviously, because there's a stagger, there's some patients that have a lot more data, some patients that have less data. And so we have assessments at three, six, nine and 12 months and thereafter.
And there are, you know, both these more objective assessments as well as the caregiver-driven assessments. Just to briefly introduce the CGIS, this is a Clinician Global Impression of Severity scale. I will not bore you. This is a very long table, but that's probably the top three domains that you need to focus on are communication, ambulation, and hand use. This scale was developed, published in 2015 by a number of the top Rett researchers in the world, which, you know, really sat down and said, okay, how do we classify these girls? Are they sort of more mild, moderate, or severe? They came up with a scoring system and all these subdomains. And really the communication, hand function, and ambulation are really the drivers of that severity.
These are the things that we can measure, measure very objectively from a functional perspective. It's not to say the other, the other pieces of this instrument are not important. They are, but as we think about objective, you know, potentially approvable endpoints, the, the, the top three are, are really where we're focused. We did recently present clinical safety data at the ASGCT meeting and we'll be presenting an updated version of that, next week at the International Rett Syndrome Foundation meeting, the ASCEND meeting, on the first three patients. So you can see here a range of ages from four to seven years old, with a range of, of race. And interestingly, we, we did have one patient with a mild mutation predicted to have some residual MECP2 function. We have the most follow-up on her at, at not nine months as of this data cut.
You know, I'm pleased to be able to tell you that there really was nothing to see here on safety, very well tolerated, very favorable profile. So the only thing that we saw of significance that was expected were transient increases in liver enzyme elevations. This is typical of any AAV gene therapy, so nothing unexpected there. The ICV procedure was very well tolerated, no serious adverse events. And in terms of, you know, is there overexpression related to the transgene itself, we looked very hard across all domains and there was really no evidence of anything. So very excited to see the safety profile. And again, that was sufficient to enable us to go to an even higher dose. And it's really the EXACT technology that's able to, you know, control as we talked about the overexpression concern. So here's the big new news.
The FDA selected us for the START Pilot Program. This is Peter Marks' brainchild and we're just super excited to be selected as one of four companies from CBER. If you look across the programs, you'll see three of them were gene therapy and they're all ICV administered programs. And really the benefit of START and the intention, this is Operation Warp Speed for rare diseases. So Dr. Marks was very clear, you know, in many of his remarks, he's been out on the road really trying to publicize this campaign, where he said, look, during COVID we were able to, you know, really amass the resources necessary at FDA and that resulted in, you know, getting an approval in a year for vaccines, like never been heard of, never been done before.
If we can do that for a vaccine for 300 million people, can we do that for rare diseases? And we're so thrilled that, you know, he's, you know, got this incredible mindset and really looking to take the START program and then operationalize it. And so what he's said publicly is, you know, he'd love to be able to take these wins from START and we hope to be one of those wins, where he's showing an acceleration of getting us into a pivotal trial, and then actually staff the agency over time. So in PDUFA 8, he is, you know, if all goes well, would then be asking for additional resources. So we get the question 'cause a lot of investors have not heard about START, like what, how is this different from Breakthrough and how is it different from RMAT?
This is really different. This is a commitment of FDA resources in order to accelerate you to pivotal, right? And so we've heard, you know, I think RMAT has good intentions and Breakthrough, you know, all of that. It's, it's a good program. You know, we, we will be taking advantage of every regulatory designation that we can get. So I don't view this as an either or, but the idea of being able to have the agency's ear and, and really work through some very complex discussions and getting us to the right place as quickly as possible. We just, we couldn't be more thrilled. It's, it's great for the program and really great for rare disease in general. We also get the question of, you know, what did the FDA see? I wanna make sure that's really clear. We did provide efficacy data along with our safety data.
The applications were open from January through March 1st of this year. So, you know, when we dose our patients, we've been very public about dosing our first patient in the third quarter of 2023 and our second patient in the fourth quarter of 2023. So, you know, you can get a sense of how much data we have. So it's very early. But on the basis of that, you know, FDA was certainly looking for companies with a promising clinical profile as well as, you know, a company that had made significant advances in CMC.
If you're very behind and, you know, again, Dr. Marks has said this very publicly, you know, a lot of programs are behind on the CMC front and, you know, if he does all this work to help you accelerate, but then you don't have the infrastructure or the means to advance something from a manufacturing perspective, that that's not something he's looking for the pilot. So that was another important piece is not just the clinical profile, but also our ability to execute on manufacturing. So basically we're gonna be doing everything we can to maximize the selection into this program. And you, you know, stay tuned obviously, as we progress on this, but certainly hopeful that this will help accelerate our program. And with that, you know, I know we're closing in on time.
So just to say, you know, in terms of key milestones, really the next big milestone is, you know, we mentioned we'll be dosing in cohort two, this quarter. So stay tuned on that. Completing our dosing cohort one in the second half of 2024. I know everyone's very eager to see data. We gave guidance in July of last year that it would be the fourth quarter and we've stuck to that. We're very much looking forward to being able to share what we hope is a set of data that provides the context both in terms of interpretability, durability, reproducibility, that is often lost if you only have one or two patients followed for a very short period of time. So again, very purposeful on our part in terms of data disclosure.
Very briefly on Batten disease, just to mention it's, I mean, again, another horrible disease. This is a fatal disease. No treatment options at all. We're treating one subtype. There's 13 different genetic causes of Batten disease. This is just one small slice, but a devastating disease outlined on this slide. We had really incredible sheep data. The green line on the right-hand side shows just a complete halting of neurologic progression compared with the sheep that were untreated. This is conventional gene therapy, so there's no EXACT technology in here. But what's exciting about it is that we're treating both the eye and the gene with the same product. So these kids go blind in addition to having cerebral atrophy and ultimately death. So the hope is to try to rescue as much as possible.
We are currently enrolling the high dose cohort and, you know, visual as well as motor scales are really kind of the focus of the program. And, you know, on the FDA side of the world, as I mentioned, this is a very rare disease. So, we did go to the FDA, we got concurrence on our potency assay and manufacturing plan. So that was a really great achievement for the fourth quarter of last year. And really in the back half of this year, we're gonna be taking the data that we're collecting and, you know, taking it to the FDA to see, you know, really make a go, no go decision for this program. You know, if we can find a streamlined way to advance the program to pivotal and ultimately get approval, we will do that.
But this is, you know, it's a taller order, as we think about, you know, heterogeneity and smaller patient population, smaller return, you know, is really around the ultra, you know, ultra rare nature of this program. And that, that's really it. So I, I've kind of already hit all the milestones. Maybe last thing to say is we did end the quarter of March 31st with approximately $170 million in cash. As I mentioned, that runway goes into the second half of 2026. So if you think about those key inflection points that, you know, probably the biggest value driver for the company right now is the fourth quarter Rett syndrome data. And then there will be additional data re-readouts in 2025 and in particular in the back half of 2025. So with that, any questions? Thank you. Yeah.
Hi, just a quick one.
You mentioned that under START, the FDA is committing real resources to support the companies that selected as part of the program. Can you say a little bit about what FDA's commitments are to you as one of the selected companies under START?
Yeah, I think the way to think, the way we understand it and the way to think about it is that, you know, currently right now there's a very rigid set of kind of meetings you can have with the FDA, whether it's a Type A, a Type B, a Type C, a Type D, like there's these rigid structures and there's certain structures around the structures where you, you know, submit a request and then there's a couple of weeks and then you get a meeting date and you submit a briefing package.
And then it's like, you know, these timelines can be 60 days, 90 days, and sometimes it's not even that. So what START allows us to do is sort of push that to the side and say, hey, let's talk about the potency assay tomorrow. Let's talk about, you know, obviously we have to align on all these things, but basically having an open line and not having to follow that sort of rigid structure where like, yeah, three months from now we might be able to talk about this. We have new data. We wanna be able to show you our updated clinical data. So just being able to provide that enhanced ad hoc communication with the FDA to really kind of eliminate some of these, you know, protracted timelines that can really delay a program.