Hello everyone, my name is Mitchell Kapoor, I'm a Senior Biotech Analyst at H.C. Wainwright. It's my pleasure to welcome you to the Genetic Medicines Conference. Today we have the pleasure of having Neurogene Inc. and from the company I have Rachel McMinn, the CEO. Rachel, thank you so much for joining us today. Yeah, thanks Mitchell for the opportunity. Looking forward to it. Absolutely. A lot of recent news in the space, a lot of news that you put out recently. I think it would be a good place to start there. Maybe you could give us an overview of all of the things that we need to pay attention to. A lot of reaction in the market, a lot of questions. Maybe we could start there. Yeah. Just recently we were excited to share two new and important updates. First, that we completed our discussions with the FDA and we'll be dosing participants in our embolden registrational study this quarter. Second, we shared results from a head-to-head non-human primate study. These results were presented at the ESGCT conference comparing directly that ICV administration to IT lumbar administration and showing once again that when you want to get drug directly to the brain for a CNS mediated disorder, ICV is superior to IT lumbar with approximately 10 to 100-fold higher margin in key areas of the brain impacted by Rett syndrome. The other point, to meet enrollment demand, we also announced that we more than doubled our U.S. presence and we now have 13 clinical trial sites in total. This is important because it further allows us to convert those U.S. clinical trial sites from a footprint rapidly into future commercial sites. Another point to note, in terms of the data that we presented, there's been some noise and notion out there that there's a difference between ICV and IT lumbar, that somehow IT lumbar is more liver sparing. This is just incorrect. We've showed this in a head-to-head study where there is comparable expression in the liver, showing that there's no liver-sparing benefit for IT lumbar. Here's the simple bottom line. If a disease is CNS mediated, getting drug into the brain is key. It's very clear that ICV at 10, 100-fold gets more drug into the brain than IT lumbar. It's not just Neurogene who thinks this and proven this, but it's really every other lab that's been running this experiment is showing the same thing. Lastly, just an important point on all of this because at the end of the day we're looking at caregivers, they're asking and they know about the route of administration. They're very sophisticated and they like drug that gets into the brain. ICV is also the answer for them as well. Yeah, a lot of positive things there. I thought it was interesting in our tail work that we also heard that patients are not deterred by ICV. They're actually encouraged by ICV because they have this perception the drug gets to the brain, and that perception is validated by clinicians and other studies as well. Very, very helpful. One of the biggest takeaways that we had also was the speed that now there's really no question, and it may have been that way all along, that you were planning to dose patients in this quarter. With that in mind, what's the real push and pull between who gets to market first, between you and Taysha, who builds the stronger approval package, and what actually defines a first move advantage in Rett gene therapy? Yeah, to us it's very simple. This population is looking for meaningful gains of function in this absolutely terrible neurological disease, not what gets the drug approved as fast as possible. Although we're thankful that the FDA is allowing a very reachable bar, this is especially the case because caregivers are being asked to consider taking a gene therapy. This is a one time treatment and in its current state is an irreversible decision. It really may result in foregoing other genetic medicines. As a result, we think that first to market is not as important as best in class. Caregivers really want to see results in data that is multiple domain and durable over time. Given that this is a permanent change, it's not the speed to market that counts for them. It's really the best option to deliver meaningful gains. With all that in mind, we understand that getting the drug to market expediently is still very important. That's why we spent a lot of time and effort getting our infrastructure in the U.S. up and running to support the demand that we are seeing for enrollment. Finally, I'd make the point that we do have an RMAT designation or are a member of the SAR pilot program. We do have all of the avenues available to us from a regulatory standpoint to expedite the future BLA. Lastly, Mitchell, you and I have talked about this. The point here is that families are considering this one time treatment decision. We know that the entire Rett population of estimated 6,000 to 9,000 prevalent population is not going to jump onto a gene therapy within a few months of a product being approved. We just don't see that current situation as very likely, even if there is one product approved a few months ahead of another. Makes a lot of sense. Okay. With the pivotal differences in terms of the centers you're enrolling at, there's a limited number of key centers, centers of excellence, that you may have overlap with. Taysha, can you just talk about what that overlap looks like and what that means to ensure site experience and Investigator Familiarity with NGN-401 that could translate into consistent data and patient flow? Yeah, look, it's a great question. I mean, demand for gene therapy from the Rett syndrome community is strong and we do not believe that there's going to be a barrier here for enrollment in terms of the numbers of sites. We think the fastest way to expedite registration and commercialization is to rely primarily on U.S. sites. These are going to be the fastest to convert to commercial sites. We've concentrated our efforts in the U.S. There are some sites that overlap with both studies. There are sites that are specific to Neurogene and some sites that are specific to Taysha. How much of the overlap is not yet clear. We are working with top Rett investigators and we're working with them to make sure that they enroll families that are committed to being part of a clinical trial. Ultimately, making sure we have families that understand the structure and the rigor and the follow-up requirements is really essential for not just collecting data for the endpoint, but also that longer term data which is going to be important for following patients post approval into commercialization. Great. Okay. As you prepare to share the final durability data from the phase 1/2 portion, what should investigators look for to understand how those findings translate into the 12-month efficacy bar that you're looking at for your pivotal program? Combined with the five participants that we dosed last year and the five we dosed primarily in the second quarter of this year, we have a total of 10 subjects that were dosed. Since the last five patients were dosed more recently, we plan to share an update later this year with participants that have the longest amount of follow up. What's really key for families is durability and deepening of effect over time. It's not enough that they just improve and gain a skill. What matters more is that they retain those skills and that they continue to improve over time. Great. Okay. Taysha's last analysis highlighted the ongoing functional improvements within their 10 patients, and using validated Rett scales. Do you view these incremental gains as true markers of durability of the therapy, or do you think it's kind of noise around the same early benefit they're seeing? I don't believe that Taysha showed or has ever shown any patient-level data like we have, nor did they show any durability data for their patients. What I believe they intended to show is multiple domain improvements. You'll see those words on the poster, and that's kind of matching our messaging. They're relying on these neurological scales, likely because they may not have been able to demonstrate this when using just the developmental skills list. In our case, participants are showing multiple skills acquired from the developmental skills list across multiple domains important in Rett syndrome, which, as you know, include hand function, gross motor function, communication. These skills obviously were durable and deepened over time. Got it. Beyond the 28 predefined milestones that they had, they're reporting 165 additional skills gained. How do you view that? I guess the composite endpoint that you have, does that better capture the functional quality and reproducibility of the patients? Yeah, look, it's really quite difficult to contextualize these absolute numbers when there's no patient-level data. Much of what has been captured in these additional scales appears to duplicate what's already been reported. Not all the scales they reported were evaluated in all their patients either. What's important here? Has the child's global clinical picture improved? Can we use scales across multiple domains that are important to Rett to validate that in our data set? If we just take, for example, our first subject, who acquired multiple domain improvements that included the ability to self-feed, understand, and interpret commands from their parents in a way to assist her family in helping her get ready for school, this is something that gives you a real sense of how this patient is doing. We're just not seeing that in the way Taysha is describing their data. Got it. Okay. In the key milestones that are being measured, they reported 22 milestones across 10 patients. You all have had 23 scaled across four patients. Should the focus be on the% of responders or the average number of milestones per patient that is achieved? Getting the drug approved based on a single skill is very different than showing caregivers how their daughters are improving globally over time. The latter is a combination of the skills gained, but per patient in a way to show improvement in activities of daily living, especially when they choose only one option. You're trying to pick between two gene therapies. Consistently, families want a product that has the potential to deliver the greatest benefit for their daughter, and they're going to want to understand how the skills translate to activities of daily living and improvement for the patient and, of course, the overall family. The specific 28 milestones that you all have versus what Taysha is measuring, how much overlap is there and the differences that there may be between those, what are the implications for the interpretation from a clinical and regulatory standpoint? Yeah, look, almost all of the milestones are identical between the two studies. We completed caregiver market research as part of our trial design, and we validated that gains in any one of these milestones would be considered clinically meaningful for families. We don't believe there's enough of a difference between these two milestone lists unto themselves to really differentiate the products. It's really going to be more important to understand the depth of response in treated patients across the studies and how the patients perform over time. That's really going to be the setup for product differentiation. Okay, and your endpoint, combining CGII with the milestone gain versus Taysha's, just the milestone gain, how does that strengthen the interpretability of how patients are doing in a heterogeneous disease like Rett syndrome? Yeah, look, Rett syndrome, as you know, presents very heterogeneously, and that's why it's really important that we're comparing each patient to her own baseline. The milestone list is selected here to really have a broad list of skills that, if you gain or regain, would be unlikely to be gained or regained spontaneously in the absence of gene therapy, while also supported by the natural history of the disease. To allow for a baseline control, when you add the CGII on top of that, that allows the clinician to really take into account the overall global impression of improvement. How is this girl doing? It really helps define, is this clinically meaningful or not? We think that it really helps strengthen the overall evaluation of the product profile. Okay, awesome. The FDA previously indicated that a six month endpoint may not be considered clinically meaningful. Now that the FDA is agreeing to let Taysha file on six month data, how do you interpret that decision and what precedent does that set for Neurogene? Is there anything that you know you're going to go back to regulators with about that? Yeah, look, there's a lot of confusion out there as it relates to six months. This is an interim analysis, not a defined endpoint. There's nothing that we see from Taysha Gene Therapies' communications that the FDA is somehow accepting six months as an endpoint, serving as the basis of FDA approval. If you note the language used here, it's very carefully worded. They have discussion about a BLA submission, not BLA approval. Anyone can include an interim analysis. This is part of a statistical analysis plan. It's really the sponsor's decision and the sponsor's risk based on the level of alpha spend that the company wants to assign right out of a P value to establish statistical significance. We asked the FDA a different question, which is, is six months unto itself an acceptable endpoint? In other words, is data at that six month cutoff sufficient to gain approval? FDA questioned the clinical meaningfulness of the endpoint at six months and really encouraged us to proceed with a 12 month endpoint. Frankly, both companies have 12 month primary endpoints. There really is no difference in how FDA is setting the precedent for gene therapy in Rett syndrome. When you really walk through the timelines of a six month interim analysis, by the time you'd be able to file a BLA, you're going to be really close to having your 12 month assessment data, which means when you kind of walk through the math, you're going to need to submit that data in the middle of your BLA review. You know what happens when companies submit clinical data in the middle of an FDA review. We certainly have a recent example of that with Regenexx Bio. They got the okay to file, but then FDA required a 90 day PDUFA date extension. At best, this approach is a 1/4 gain. Of course, that's assuming that the FDA accepts the filing based on the data generated from the interim analysis. That's a great point. Really, the lead, if any, would be up to a quarter. Yeah. Okay. Moving again into the trial design, you can enroll patients as young as three years old, while Taysha can enroll patients as young as six. How meaningful is that for long term market share to be able to enroll patients that are age 3 and older? KOLs have indicated that it's rare for patients to regain a milestone after the age of six. Does that change how investors should interpret the efficacy signals in the patients who are ages 3 to 6 at all? Given the early onset and progressive nature of Rett syndrome, initiating therapeutic dosing as early as possible may offer the best opportunity to restore MECP2 function before irreversible neurological deficits occur. This is not controversial, and it's especially the case with an ICV route of administration that gets drug into the brain and is using the full-length version of MECP2. The ability to dose as early as 3 years of age is important because it will allow us to capture a subset of the Rett population that Taysha Gene Therapies will not be able to address based on its trial design. If you recall, they have a completely separate study. It's confusing because there's not a lot of details out there. There will be some cohort of patients that need to be studied there. We do think having efficacy data in this younger population is very important from an FDA perspective. We've been able to design this trial in such a way that they have endorsed enrolling patients as young as 3. We believe having that in the marketplace is going to be very valuable. Great. Okay. In Taysha's recent update, they emphasized a few structured efficacy scales like R-MBA and ORCA. Will Neurogene conduct similar structured analyses in embolden for a comparison? Is that important? Are those scales particularly important? How do you view that? In the early genesis of our program, we certainly evaluated both of those scales and we determined that they were not particularly useful instruments in our clinical study. We're not using those instruments. We have our own assessments that we've included to generate an expansive body of evidence focused on functions that are well outside of our primary endpoint, and we think are going to be important for caregivers and families and from a regulatory standpoint as well. We haven't gone into details on that publicly, but we certainly have other things that we're looking on to contribute to the overall body of evidence that are clinically meaningful in Rett syndrome. Even after the recent run up in your stock after the positive news, patient valuation remains much higher than Neurogene's. What do you think the street is missing still about NGN-401? They're starting to realize a lot of this as you're seeing the stock run up, but what are they still missing that could help narrow that gap once we get data? Yeah, look, you rightly point out that despite the recent significant positive momentum in Neurogene shares, there's still a significant gap. Last time I looked, it was over 2.5x valuation gap. It's not a little gap. First thing is moving past the catastrophic HLH safety overhang. Neurogene stock took a significant hit to valuation when we experienced this hyperinflammatory event at the now discontinued 3e15 vector genome dose. Since then, it has really been either off investor radar screens or just on the short screens. We continue to believe that as we gain distance from that absolutely tragic and devastating event, logic will ultimately prevail. What I mean by that is both companies are using the same 1e15 dose. We've shown that regardless of delivery, the same amount of virus gets into circulation. The only difference here is that we actually have a monitoring protocol in place and we are positioned to intervene very early and potentially reverse the inflammatory cycle if it were to occur. Actually, the monitoring for us is now an advantage for us. I don't think that's appreciated. Next piece is route of delivery has been perceived as a weakness, but it's really a strength. The story has been that ICV is more invasive, lumbar is easier, so Taysha commercial adoption will be more substantial. Our data on ICV superiority has replicated what's already been demonstrated by multiple other labs. At this point, it's well established that IT lumbar is really suboptimal as an approach to target neurons in the brain. Caregivers, KOLs, you know, intuitively appreciate that targeting more neurons in the brain is likely to lead to better outcomes. Of course, we need to demonstrate that in the clinical data. Faced with a one-time treatment irreversible decision, we believe that families are going to opt for a product that demonstrates greater efficacy. On timing, we've touched on this in this podcast or, you know, this Fireside chat, but time to FDA approval for both products is more similar than different. Investors have been hyper focused on this interim analysis that we discussed with Taysha at six months. When you really walk through the timelines, by the time Taysha is able to file a BLA, they'll be very close to having their 12-month assessment, which means they're going to need to resubmit that data in the middle of the BLA. We've kind of talked about this and at best we think this is a quarter gain. Finally, we've built in product differentiation into our trial design both in our composite primary endpoint and the ability to enroll patients three years and older. This is intended to support a broad label with efficacy data in patients where caregivers and clinicians are most interested in intervening, which is early in the disease course. Great. This has been a wonderful discussion, Rachel. Thank you so much for offering your time for this Fireside Chat, and really want to send a special thank you to all the investors that dialed in as well. Yeah, thank you so much, Rachel. Take care.