I remember that all the time. Good. Hello, everyone. Welcome to our fireside chat with Neurogene. My name is Mitchell Kapoor. I'm a senior biotech analyst at H.C. Wainwright. Today, I have the pleasure of welcoming the CEO, Rachel McMinn. Rachel, thank you so much for joining us. Yeah, happy to be here. Thank you so much. Great. I like to start off every conversation with just a level setting on Neurogene, what the company does, what the key priorities for the company are, so that everyone who's not up to speed with the story can kind of get on the same page. Yeah. Thanks for the opportunity. Neurogene is a full-stage biotechnology genetic medicines company, focused on developing treatments for devastating neurological diseases. Our lead program is NGN-401 for the treatment of Rett syndrome. Rett syndrome is a neurodevelopmental disorder that starts in early childhood and is really lifelong. It's a chronic debilitating disorder, where multiple core functions that we think about and take for granted, like communication, our ability to use our hands, our ability to ambulate and walk around normally, all of these are drastically impaired in Rett syndrome. There's a massive unmet need. So 15,000-20,000 patients in the U.S. and major European markets with Rett syndrome. There are no treatments available that really treat the underlying cause of disease, and that's where NGN-401 comes in. It is a genetic medicine. It's an AAV gene therapy, and we can get more into the design and differentiation shortly. It is delivered as a one-time treatment to really get to the important areas of the brain that matter in Rett syndrome. I think important for this discussion and before we can just kind of give you a high level view, but we presented phase I/II data in June, so very recent cut of the data with 12-30 months of follow-up and saw just really substantial improvement and gain in function, which is again, something that we're privileged to be able to observe in these patients with Rett syndrome. We can talk more about that data, but 100% of patients responded based on both an improvement as judged by the clinician as well as gaining developmental milestones. We also announced earlier this year in the second quarter that we completed dosing of our registrational trial, Embolden. That is a 12-month primary endpoint with data available in the second half of 2027. So a lot going on for Neurogene. We are rapidly advancing towards commercialization in a market that desperately needs new therapies, and we're very excited about the profile that we've established in phase I/II, to be able to support that. Excellent. Great overview. I think another great place to start would be kind of the design of NGN-401 and what the technology EXACT is designed to solve. Also since a lot of the focus from investors comes from comparing, as we naturally do, the Taysha versus Neurogene construct, could you tell us a little bit about EXACT versus miRARE? Yeah. Happy to talk about some of the key design choices. Neurogene, we really take a very intensive biology first approach. We designed this construct from scratch. This was not a business development deal where we in-licensed it. We really had to think about first principles, what are the most important aspects of this drug product that we're going to build in. First and foremost, we wanted to include the full length, MECP2 gene. MECP2 deficiency is what drives Rett syndrome. This is a gene that is highly conserved throughout nature, so very important, and thankfully, it is a gene that readily fits into an AAV. We didn't have to do any tinkering to make the gene smaller in any way to have it fit. That was sort of point one. Point two was, and this is a little bit what you were alluding to, we know based on both preclinical as well as human data, that too much of this protein, MECP2, can be toxic. As a result of that, we need a little bit of a Goldilocks type situation where we need to be able to control the levels of transgene that is being produced by the vector. In order to be able to do that, we developed a new technology which you referenced. It's called EXACT, and it's a microRNA-based feedback loop that's literally built into the vector. We have a microRNA, along with the transgene, and complementary suite of microRNA binding sites that are on the transcript such that every time the transgene is produced, you also get the microRNA, which then is able to bind the transcript and then basically cause a shut off valve, if you will, to maintain a therapeutic level of MECP2 without overshooting and getting into that toxic range. That was a key feature. Then finally, the other critical feature in gene therapy is really about delivery, right? We had a very intentional, purposeful choice of ICV delivery. That stands for intracerebroventricular. It's a way to access the cerebral spinal fluid locally in the brain to really maximize the number of brain neurons that we're delivering NGN-401 to. That's critical because Rett syndrome is a brain disease primarily, and so being able to maximize that exposure was really critical. That's quite different. We could do the compare and contrast, but relative to the other program out there, but we're very pleased with the features. These were very intentional, and it seems to be coming through in a very competitive data profile that we presented in June. Excellent. Great. Thinking about how you measure the efficacy of NGN-401. Milestones are an important measure of that, and there is a lot of ways to look at that in terms of the number of milestones, which milestones. The disease is so heterogeneous. Could you help us understand how you benchmark how patients are doing, and what you are looking to see in longer-term follow-up from patients with respect to milestones? Yeah. Milestones, just to level set. In Rett syndrome, a typical child is gaining developmental milestones all of the time, right? Whether that is learning how to sit up unassisted for the first time, learning how to talk, for their first words, being able to go up the stairs, being able to use a fork. These are basic developmental milestones that anybody who has kids or grandkids, they are sort of front and center. Unfortunately, in the course of Rett syndrome, while girls do start to develop milestones, they do so in a delayed fashion, but more heartbreakingly, they actually go through a regression phase of the disease where they actually lose many of those previously acquired developmental milestones. Universally, these girls become non-verbal. Some of them might have had a 100-word vocabulary, or at least were saying a few words. They stop speaking. They typically had some level of hand function. They were feeding themselves or holding objects, and they lose that ability to control their hands. About half of them never even learn how to walk because they are so impaired from a gross motor perspective, and they never gain that balance. That is just the kind of level set of what is this disease. Then, what I can say based on the phase I/II data is as the data were being generated, we started realizing that these girls are gaining back some of the milestones that they had either previously acquired or were learning things that they could never do beforehand. As we compare that to the natural history that is available across a wide range of patients, it is a very large database. We were able to basically in this analysis show that spontaneously gaining back or regaining these developmental milestones after the age of three, after a time in which these patients have done regressing, it is extraordinarily rare. That is really the basis for the entire excitement around the phase I/II data, as well as the Embolden trial design, which is set up as a baseline controlled study, meaning we are literally taking what can a girl do at baseline and then looking 12 months out and saying, "What can she now do at this particular time point?" and comparing it. If she can gain at least one developmental milestone, plus be improved as assessed by the Clinician Global Impression of Improvement, she would be then considered a responder. All of that is rooted in a way, in her individualized kind of catching her where she is and figuring out, what has she gained from what she was able to do before. So a very innovative design that is able to lean on the natural history data and what we know, that this patient population does not spontaneously gain these developmental milestones at an appreciable rate. Then also being able to handle the heterogeneity of the population because every girl is a little bit different with Rett syndrome. Great. Is there a way in the future we will be able to tell who benefits the most based on variability of when they are treated, how early they get treated, the different symptoms they have? I guess who benefits the most when you think about the different presentation of Rett syndrome, if it is the ability to utter words or use your hands. Is there a way to think about where this therapy helps patients the most? So, as you know, for full disclosure, we have 10 patients, 10 participants in the phase I/II study. So I think any statements and extrapolations I am going to make is on the basis of the 10-patient dataset. But with that caveat, we enrolled participants as young as four years old all the way up through 18 years of age. We had mild, moderate, severe disease. We had a range of genetic mutations as well. We did not sort of define, like, well, only this kind of patient responds, or only this patient with these kind of baseline characteristics. So I think what we can say today is that what was established in animals years ago that really gave us the huge amount of enthusiasm, seems to be kind of coming to fruition to some degree in patients, in that what was shown in animals was that this disease is actually reversible. So unlike a neurodegenerative disease where the neurons are gone. If you were to take an SMA or Alzheimer's disease and ALS, where neurons are dying. They are not dying in Rett syndrome. They are not functioning like they should be, but they are there, they are available, and when you restore with the genetic rescue, you do rescue animals, and in humans, what we are seeing is, again, this kind of restart of a developmental trajectory. That you seem to be completely halted. Completely static is what you would expect based on the natural history, and now we're seeing this kind of sequence, coordinated gain of multi-domain, multiple milestones. It doesn't seem to be like, well, only in a young patient or only with this particular mutation. There's nothing in the data today to suggest that only a certain kind of patient can benefit from treatment, which is very exciting. Right. Absolutely. Can you help us understand the current regulatory environment, your perspective on the FDA considering natural history data and considering that whenever you're filing for approval and weighing the benefits of NGN-401 versus what we would see in natural history? Well, I was just at an American Society of Gene & Cell Therapy policy forum yesterday in Washington, D.C. I was invited and had the opportunity to talk about our experience in the START pilot program. It was a wide range of audience, including members of the FDA. Just to remind everybody, START, because most people don't really know what it is, but it was the pilot program really aimed at advancing, completely blowing up what we think about in terms of FDA communication with sponsors. Type A, Type B, Type C. The alphabet soup of meetings, and literally replacing all of that, reimagining that with regularly scheduled meetings. So every quarter, we're able to get in front of the FDA. The reason why I bring that up in response to your question is we had a multiple iterative opportunity to really align with FDA over a series of meetings on the pivotal trial design. Before we dosed our first patient in Embolden, we were able to go in with sort of like a final check on like, "Are you sure we have everything?" Just wanting to really nail down every single detail that we possibly could. We had oral, verbal, written, all of the feedback of, "Yes. Go forward. You can dose your first patient." We made sure that before we dosed anybody, there was very clear alignment on what we were measuring as part of all of that. You ask about where the FDA is headed. I think we're thrilled that Karim Mikhail has decided to take the position as head of CBER. I think we're very excited about where the FDA is headed. They're putting out tons of guidances to really support advancing rare disease treatments. I think you've seen that play out in kind of the recent events with some of these packages being revisited. I think we've certainly done everything we've been able to do. We're continuing to meet with FDA on a regular cadence to be able to ask as many questions as we can to help de-risk the filing. Wonderful. I think it's important for the audience to touch upon safety of the go-forward dose, because whenever we speak to some folks who haven't visited the story in a while, they just remember your experience at the high dose a long time ago now. Just help maybe folks understand what HLH is and that you haven't seen any and so how many months, and with the patient data that we have on the safety side, how confident can we be that that story is behind us? Yeah. Just to back up. When we were running the phase I, II study, we had started with our 1E15 dose. That is the dose that we have continued on with, as you know, and we've dosed successfully 35 total participants between the phase I, II and the Embolden study, safely with no evidence of hyperinflammatory reactions or other types of very severe, life-threatening AEs. What happened in the phase I, II study was that because we were seeing this great data and we had a good safety margin, we, as we should, took the opportunity to explore a three times higher dose. The first two participants were dosed successfully and safely, but tragically, the third participant developed a hyperimmune response, which is short for HLH, and ultimately, tragically, passed away. When that happened, obviously, we did a ton of work, and I remember having conversations with you at the time. When it was like a real fresh situation. What we've learned is that, a number of things, but dose is definitely a driving factor in AAV that there seems to be a tipping point that when you get to this kind of 1E14 vg/kg, we can translate that our dose is kind of in that range, that higher dose. That more of these significant AAV-related toxicities have been occurring. If they're going to occur, they seem to be happening at these higher doses and/or in patients that are getting weight-based dosing, where they're getting very, very high levels that even exceed the level that we were giving. We could spend like three hours on this topic. In any case, to cut a long story short, as a result of that, we discontinued that three times higher dose. We had always had a plan to stay with the 1E15 dose because it was doing very well. We were already seeing benefit. It was well-tolerated. Just to kind of close out, HLH specifically, it is a very immediate reaction. So within the first few days post-dosing, if you're going to see it, you would see this reaction. We made that announcement the first week of June that we had completed dosing, and there was already some buffer between when the last patient was dosed and then to be able to put out that press release with high confidence. So we are well past the window in which you would expect to see that or really any of the acute AAV-related toxicities. Great. Okay. Moving to delivery. ICV delivery, when you are comparing competitors, you have ICV and IT. We had a KOL call, which was really interesting, where Dr. Lieberman, who had treated with both Taysha's and Neurogene's therapy, said that patients preferred this direct to brain approach because they just think it is better. That may be the case, but the patient just has the idea that going directly to the brain is beneficial. I think that helped us a lot, but now we are wondering a little bit about scalability of ICV. Can you maybe help us understand what that looks like from a launch perspective? How familiar are physicians with this and people who do it? Yeah. Scaling for ICV is really not a problem. We are not pioneering a novel neurosurgical technique. This is something that junior neurosurgery residents learn how to do literally in their first few months of becoming a resident. It is very much bread and butter for the neurosurgeons, very straightforward. Anyone who is going to have the wherewithal and the capacity and the training to be able to treat with gene therapy, it is really in the monitoring and follow-ups. Whether you are delivering IV, ICV, IT lumbar, ICM, pick your favorite delivery method. It is really not the upfront piece in terms of training the site per se. It is really more about making sure that the monitoring and the following of patients, that is really, as you think about launch dynamics, is going to be very important. But yes, we agree with you, from a pure patient, family perspective, what we have been told is it is very intuitive. You don't have to take out fancy diagrams to explain why your daughter who has a brain disease should get an injection near the brain. To the brain, yeah. It's very straightforward and intuitive for families. We don't think that this is a barrier from a launch perspective. Okay. Wonderful. I wanted to talk about durability and how you think about the long-term data. Obviously, we're going to have 12-month data. But wondering about the follow-up of what makes this attractive to payers on a longer term basis. Yeah. First of all, durability matters for every stakeholder, right? If you're a family, you care about durability. Right. If you're a physician, you care about durability. If you're a regulator, you care about durability. If you're a payer, you care about durability. This is something that we've really spent a lot of time on, which is why this data update, I think, that we gave in June was so powerful because it was a minimum of 12 months, but out to 38 months of follow-up, and it's really the longer term patients that we chose to focus on because we know that's where the market is really focused. From a payer perspective, this is, I think, not difficult. The market is actually well set up for a gene therapy price point. If you look at the marketed product DAYBUE, which is not treating the underlying root cause of disease, but is approved for the treatment of Rett syndrome. That price point, anywhere from a $500,000 million- $1 million a patient, relatively, if you just own that drug for a few years, you're basically at a gene therapy price. Right. It's not like we're coming in and there's these super cheap, $5,000 treatments that we're somehow competing with. There's a massive unmet need in this population, and we believe that, and certainly the early two, that that would really not make a gene therapy price point particularly challenging. So we've gotten this question a couple of times recently. What's the outlook for EXACT technology beyond Rett? EXACT is definitely a platform technology that we've spent a lot of time on. We have other indications in our discovery stage pipeline, and I would say, I think at this point, just stay tuned on that. Sure. Yeah. Great. Okay. Finally, I'd like to wrap everything up with an outlook at the next 12 months and what we can expect as value inflection points for Neurogene. Yeah. So, it's a very exciting time. As I mentioned, we completed dosing in the second quarter of this year, and our guidance, the major inflection point for the company is clearly going to be that pivotal data in the back half of 2027. But in the meantime, obviously, we'll have a lot of milestones along the way. We've talked about manufacturing milestones. We've talked about pre-commercial milestones and presenting data at medical meetings. So we'll have a presence and be educating people along the way. But I know eye on the prize. Everyone's very focused on that data readout for EMBOLDEN. Excellent. All right. Thank you so much, Rachel. Thank you to the Neurogene team, and thanks to all the audience members that joined us for this fireside chat.