All right, thanks very much. Sorry for a couple minute late start here. That is my fault, not Rachel's. Super happy here to be moderating a fireside chat with Rachel McMinn, Founder and CEO of Neurogene. I'm sure most folks who are listening in, like, know the story at least decently well, but maybe Rachel, you can just sort of set the stage, give us the updates, and then we can do Q&A. Thanks so much. Yeah, absolutely. Thanks for having me. To take a step back, Neurogene is a genetic medicines company focused on developing treatments for patients with devastating neurological diseases. We do take a biology-first design approach to our pipeline, meaning that we're really looking to understand the biology in a deep way so that we can develop a treatment that's really life-altering for patients and families. Our lead program is NGN-401 for the treatment of Rett syndrome. This is an absolutely devastating disorder that affects primarily girls, but also increasingly we're hearing from families that have boys with Rett syndrome as well. What's in common here is that these children really lose their complete independence and they become completely dependent on their caregivers for the most basic daily functions for the rest of their lives. This is obviously a, you know, very devastating disorder with high unmet need. The market opportunity itself is multiple billions of dollars with 15-20,000 patients estimated in the U.S. and major European markets. We are rapidly advancing towards a potential commercialization with NGN-401. Our phase III registrational trial is called Embolden, and this is in females with classic Rett syndrome who are three years and older and have completed the regression phase of disease. We're actively enrolling and dosing patients, and we remain on track to complete dosing in the second quarter of this year. It's our view that NGN-401 is really de-risked based on the strong and compelling phase I and II data that we presented as recently as November and that supported a breakthrough therapy designation recently granted by the FDA. As we look ahead, we believe that Neurogene is really positioned for a significant value inflection with multiple catalysts this year. Two very near-term milestone catalysts include one, the completion of dosing for Embolden in the second quarter of this year. We believe, and I know Paul will get into this, but we believe this is a particularly important event for investors as it relates to a read-through on some of the safety concerns that folks have had. Beyond that, we'll have a presentation of additional phase I, II data from our phase in mid this year, and that's gonna include a minimum of 12 months of follow-up on all participants. Awesome. Great. Well, I hope you don't mind if we spend some time on the FDA because it probably deserves some minutes but I want to talk about what you're doing. Just in the context of that, right, like you've probably read our notes and a million public press articles about concern and agitation around the FDA, and maybe the FDA is becoming less flexible in rare disease. Obviously you had a number of dialogues. You're running a pivotal trial, right, that doesn't have a placebo arm, which would be evidence of flexibility. Do you want to talk about one, your sort of perspective on this narrative that's going on right now around the FDA? Two, maybe just walk us through the timeline of your regulatory alignment around the NGN-401 design. Yeah, absolutely. Of course, you know, we've been following the news very, very closely. We continue to believe that the industry and FDA really are aligned with this big picture vision of accelerating rare disease treatments to patients. I think high level, that's the positive. From a Neurogene perspective, you know, we are in a very fortunate position to interact with the FDA on a very regular cadence. We're part of the START Pilot program, as you know, and that gives us really an unprecedented level of access to FDA, you know, relative to really any other drug development programs. I think we're continuing to leverage those discussions. We've been using those discussions both you know, in the prior administrations and the current administration as you know, as leadership changes go on. As we think about Embolden specifically, our registrational trial, this has really been designed in close collaboration with the FDA, and it's been not just, you know, a single meeting or one piece of written feedback. It's really been over the course of multiple meetings and multiple, and as it turns out, multiple administrations as well. Before we dosed a patient in the Embolden study, we did go back to the agency as recently as this fall and received written confirmation to ensure that the key elements of our trial design were acceptable before we began enrollment and dosing. you know, we saw all the things that you guys saw and just really wanted to make sure that even that we had alignment earlier in the year that, you know, that if there was anything else that we should include in the protocol that we did that. In fact, we did have a discussion with the agency, and we did include some additional, you know, efficacy measures that we wouldn't necessarily have included had we not had that interaction. I think being able to have that really close interaction with the agency has certainly benefited Neurogene. The other thing that I would note, because there's been a lot of discussion around Accelerated Approval and as you mentioned, regulatory flexibility, the design that we're using is really. While it is an open-label baseline-controlled study, it is that the endpoint itself is really a traditional FDA approval based on gain in function. We're not looking to stabilize disease and sort of prove the absence of a negative. We're not looking for a biomarker. There's no surrogate. The endpoint itself of 12 months is consistent with FDA written feedback supporting this length of follow-up post-dosing is clinically meaningful. Frankly, the milestone gains supporting our endpoint are considered meaningful, clinically meaningful by both, you know, caregivers and thought leaders in addition to the FDA. I think from our perspective, you know, between the Breakthrough Therapy designation, which provides additional validation of the clinical profile of NGN-401, as well as, you know, the strong data that we've, you know, that we've shown to you all and the FDA has seen, I think we're feeling as confident as we can given, you know, the level of exchange out there in the marketplace on this topic. Makes sense. Rachel, can you hear me okay? I got some notice as my connection actually- I can hear you enough to answer the question. Sometimes you go in and out, but I'm gonna answer the questions. I think we're in good shape. All right. No one cares what I'm saying anyways. I'll repeat it. That'll all make sense. I guess maybe just one follow-up question about your FDA log. When you guys have interacted with CBER, you know, has the dialogue been with people who are senior enough that you can be confident that when you kinda go back with good data in hand, right? That you've had the sign-off with those that could be, you know, really making the final decisions around approval. Obviously, the side piece here is we don't have now a CBER head. Right. Any thoughts you have there as well would be interesting. You know, I think the reason why I ask this is because of some of the reporting around, you know, Vinay Prasad, you know, being this final decision maker that, you know, companies may have not interacted with throughout their process. Yeah. Well, we can move on from the FDA after that for you to touch upon. Yeah. Look, I mean, I think certainly, you know, there's a lot of people speculating. I don't have a crystal ball in terms of, you know, who's gonna be the next CBER head. I can say from that perspective that, you know, I'm a board member of ARM, which is the Alliance for Regenerative Medicine, and this is a leading advocacy organization for cell and gene therapies. We're certainly, from an ARM perspective, actively engaging with the FDA and other key stakeholders to really foster alignment. I think there is reason to be optimistic for the future. Dr. Makary has repeatedly stated he's in favor of expediting rare disease products to patients. We've certainly seen very recently, and, you know, I don't think it's a big secret, but there's a lot of key stakeholders in the government who are supporting this position, and really wanna see these important medicines for rare disease, you know, get to their constituents. You know, that's sort of the high level. I think the point that you made though is really important, which is like, you know, the data ultimately, you know, the data really matters. I think we can say our review team has not fundamentally changed across administrations. That's, you know, certainly a positive for us. You know, the data is really important. This is, you know, Rett syndrome is, it's a heterogeneous disease, and that means like, literally, no two of these girls are presenting exactly the same. We touched on this a little bit, but, you know, the developmental delay that is occurring in infancy and early toddlerhood, that is followed by a period of regression where these girls lose so many of these, you know, previously attained developmental milestones, whether that was the ability to speak or, you know, use their hands to feed themselves or even indicate what their wishes are. So after that period, which is roughly around, you know, three years of age, there's this period of stability, and it's extraordinarily rare for these children to gain any new developmental milestones. It's certainly even more rare, virtually impossible for them to like spontaneously gain the kinds of skills that we're seeing, the multiple skills that we're seeing. That's really based on the NIH-sponsored Rett Syndrome Natural History Study, and certainly been corroborated from you know the KOL experience with this population. As we think about our trial and how it's been set up and you know we can go into the details of that, I think the point here is that the likelihood of these girls gaining skills spontaneously these types of skills that we're seeing is really rare. It's clinically meaningful. We believe if our data in Embolden are able to replicate what we're seeing in phase I and II that would be a very strong support to approve this product. Great. Well, can you hear me better now, Rachel? Yeah, that's great. Okay. All right. Wonderful. All right. Trying the phone on the side. I think that's a good segue into talking about the phase I and II data. I guess, you know, if someone were to critique those data and say it's open label, you know, endpoints when you're talking about development can be somewhat subjective. Like maybe talk about the data and what would you hit as like the one to two or three key points on your level of confidence this is like super objective and not at all driven by sort of placebo effect or a behavioral change in the context of a trial? Yeah, absolutely. Just to level set, we presented efficacy data from eight pediatric participants in the phase I and II trial, and they had a really full spectrum of disease between, you know, mild, moderate, severe, whether that was genetic or clinical presentation. All of the patients had a functional improvement in one or more of the core domains of Rett syndrome. This would include hand function, gross motor function, and communication. Over that patient data set, we had 25 total developmental milestones gained, which is approximately four on average, four milestones per participant. These were durable, and they accumulated over time with no sign of plateau. 88% achieved an improvement on the CGI-I score, which is this clinician global impression of improvement. At the 1E15 dose, NGN-401 was generally well-tolerated. As we think about this context, is it to your point of, like, well, how do we know that this is real? Again, going back to the natural history dataset, we know that, you know, gaining one skill is pretty rare. Gaining two or more skills is even more rare, and we had, you know, some patients gaining well more than that, as I've just kind of articulated. When you think about, you know, the biological plausibility and the disease pathway, we know that MECP2 is critical for neuronal health throughout the lifespan. In other words, if you take away MECP2, it's detrimental and you develop Rett syndrome. When you restore MECP2, you are restoring synaptic function and that just takes time. It takes time for those synapses to fire and wire correctly together. When you kind of layer on the biology and then what we're seeing, which is this accumulation of developmental milestones and a deepening of that, you know, even in a particular skill where a girl's getting better and better at that over time, we think that that really, you know, fits together very well with the biology. I guess, you know, maybe just taking you through one patient to give you a lens of, you know, what I'm seeing as CEO of, like, why I'm so excited, and what we think is really remarkable. If we take the, you know, the patient who had the most follow-up, so two years of follow-up at the time of the assessment. Prior to treatment, she had, you know, a raking grasp, which kind of is like a big, full hand, but she couldn't hold on to an object for more than a second or two. She would just literally drop it. So that was kind of the extent of her hand function. She walked, but very ataxically and could not go up and down the stairs by herself. She wasn't able to communicate meaningfully with others. She couldn't follow basic instruction from her parents, and she certainly wasn't indicating what she wanted, right? Her wishes. 24 months after treatment, she just, she kept continuing to gain developmental milestones, but, like, what does that look like? Her hands became actually more purposeful. To the point of not only was she feeding herself, but she was, like, feeding herself with a fork, which is a complex skill to be able to use a utensil. Anyone with a child knows that they, you know, they kind of start off with their hands, and then they eventually graduate to a fork. In terms of moving about, she's, you know, walking up and down the stairs unassisted, and that skill itself was improving over time. She's also able to hold on to, you know, a handbasket, a shopping basket going shopping with her mom. In terms of daily routines, you know, she's able to participate in calls with her, with her extended family, like her grandfather. In terms of instructions, she's literally, like, able to follow the instructions of her mom. It's like, "Put this here." Now she's putting objects where they belong. She's playing games, like being able to pick out chalk, like pick out that blue color of chalk or pick out the pink one, and she's able to hear that, act on that, move with her hands, pick up that chalk, and even follow daily routines like getting into the car unassisted. You know, I think what we're excited about here is that this is clearly not the same girl that she was at baseline, and that is just really remarkable. You know, we hope to obviously continue to follow these patients over time, but it's really that durability and long-term follow-up that goes beyond just that sort of endpoint that we just talked about that's really important in this disease. Yeah. Okay. Well, congratulations on that. That's obviously exciting. Yeah, maybe we'll skip ahead to one question on safety and then just one question on the phase III protocol and powering. On safety, right? You know, we know the event that happened at the high dose, you moved forward with the low dose. You know, what can you say that gives you confidence, right? That your margin is there, and that the safety profile is gonna remain clean in the pivotal. Anything you can say about, like, the safety profile in the study so far? I mean, I would say on a blinded basis, but obviously it's an open label study. I don't know how much extra sort of color you can give, but, you know, just lay it out there and we'll hear from you, Rachel. Yeah. I mean, the short version is no news is good news. That's the very short version. Just to take a quick step back, we, you know, we did have a hyper-inflammatory reaction at a threefold higher dose than what we're giving now. That higher dose was discontinued, and that was really as a result of too much an uncontrolled immune response to this large amount of AAV present in systemic circulation. As part of our trial in the abundance of caution, we did implement a robust monitoring procedure, and we do have a treatment plan clearly spelled out in our protocol in the completely unanticipated event that a case would occur. We certainly know, based on all of the work that's been done that if HLH were to be detected early, it's been shown to be fully reversible in the setting of AAV with a simple treatment of high-dose steroids or Anakinra. What I can say to you right now is, you know, we do think that, you know, obviously again, no news is good news. You know, what you can take from our update, whether it's today or, you know, in the second quarter when we complete enrollment, we do view this as a really, you know, catalytic event because a lot of folks I know have, you know, sort of had this concern that you know, maybe we would have an event. We certainly haven't seen any cases of HLH or any other severe inflammatory reactions. Okay. That's certainly encouraging. Maybe let's just talk about the statistical hurdle for success in the pivotal and how much margin you have based on the phase one, two data. Then, you know, I'll throw another sort of regulatory question at you, Rachel, which is really. We talked about this before. You know, there's the statistical hurdle and then what do you think is actually the hurdle for approval? Is that the same hurdle? And the hurdle for kind of the broad commercial adoption and market that you're hoping for. Yeah. From a statistical perspective, we've established a 35% threshold for success. Again, this is based on the rigorous analysis of the Rett syndrome natural history data. That really restricts the participants that are aligned and matched to our trial's eligibility criteria. We did focus on a pre-specified set of clinically, you know, clinically meaningful milestones that under themselves have low spontaneous acquisition. Also, you know, this entire framework, you know, really informed our endpoint empowering approach with the FDA. That means seven out of 20 participants would need to be considered a responder in order to achieve statistical success. To your point about, you know, what is required for commercial success, of course, you know, people want to. Families want to see more than one skill gain, as we've talked about, right? They want to see their girls continuing to do better over time. We think that I don't know that there's a magical response rate number, but I think there's a response rate and then there's also what does this look like over time? Are these girls continuing to, you know, gain skills? Are they meaningful, you know, across the population? I think again, based on the data set that we've had, which is, you know, an 80% response rate based on the first five patients at 12 months, is very compelling, and we'll continue to, you know, monitor these patients for durability and long-term gain of function. Okay. Makes sense. From a competitive perspective, do you wanna give your quick two cents on sort of how your data compare? Taysha, you're doing ICV, they're doing IT. You know, I think that, to me, as like a neuro biodistribution nerd, that like seems intuitive but, you know, what does that mean for, I guess, from a competitive perspective, you know, ICV is more. Is it more cumbersome? Yes, it is more cumbersome, right? Like, what does that mean for the efficacy advantage you think you sort of need to have to be the best-in-class treatment? Yeah. Look, I mean, we purposely designed NGN-401 to be ICV administered because Rett fundamentally is a CNS-mediated disease. We know from our preclinical biodistribution data as well as the work from many other labs that ICV is really the best way relative to IT lumbar to get into key regions of the brain underlying the disease. In addition, we you know, beyond the broad biodistribution, we are delivering the full length MECP2 gene under the control of the EXACT transgene regulation technology. You know, we believe that this overall profile is really important. You know, as it relates to the procedure itself, it's really common. It's an hour long. It's really You know, I think as you think about like the one-time nature of gene therapy, that's sort of a blip in the bucket. You then have this period of safety monitoring, which is really the same for any gene therapy regardless of route of administration. You're going to need to and want to follow patients for safety. That's gonna be consistent across the group. I think, you know, as we think about the overall opportunity here, this is a large market, you know, 15,000-20,000 patients who don't need very large penetration into that market or the incumbent market in order to have a very compelling opportunity for both companies. I think there's room in the market for multiple players. Based on the profile that we're seeing, you know, we feel like we have a best-in-class potential for our gene therapy product. Awesome. Okay. Maybe lastly, just touch upon cash runway through these catalysts. We'll get full enrollment to queue the FC data next year. Where does your balance sheet stand in the context of this? We have capital that provides runway through the first quarter of 2028. When you kind of walk through those timelines, you'll see that that should be sufficient to fund both the key clinical and regulatory milestones, including Embolden results, BLA submission, and numerous pre-launch activities. Okay. Great. All right. Well, thank you, Rachel. Always great to hear from you. We appreciate it. All right. Thanks. Take care.