Welcome to the Neurogene webcast to review the interim data from the NGN-401 gene therapy clinical trial for Rett syndrome. At this time, all participants are in listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I'll now turn the call over to Cara Mayfield, Vice President of Corporate Affairs at Neurogene. Please go ahead. Thank you, and welcome to the Neurogene conference call to review the interim clinical data from our phase I/II clinical trial evaluating NGN-401 gene therapy for Rett syndrome. This afternoon, we issued a press release detailing the data, which can be found on the investors' page of our website. Today's event is being webcast with slides. To ask a question, please join the conference call by registering at the conference call link on our investors' page. Before we begin, we would like to advise that certain remarks we make during this call about Neurogene's future expectations, plans, and prospects, including without limitations, statements regarding the therapeutic potential and utility, efficacy, and clinical benefits of our product candidate NGN-401 for the treatment of Rett syndrome, the safety and tolerability profile of NGN-401, anticipated future improvements for participants in the NGN-401 phase I/II trial for the treatment of Rett syndrome, trial designs, clinical development and timing for NGN-401, including anticipated timing of enrollment in and clinical trial results from NGN-401, and the expansion of that clinical trial to a third cohort for adults and adolescents, expected benefits of RMAT designation and participation in the FDA START pilot program, and any future interactions with the FDA, and the company's plans for scale-up of commercial production of NGN-401 constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the risk factors section of our annual report on Form 10-K for the year ended December 31, 2023, filed with the SEC on March 18, 2024, as well as our most recent quarterly report on Form 10-Q for the quarter ended June 30, 2024, and other filings the company has made and may make with the SEC in the future, which can be accessed on our website. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so, even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. On our call today are Dr. Rachel McMinn, Neurogene's founder and Chief Executive Officer, Christine Mikail, our President and Chief Financial Officer, and Dr. Julie Jordan, our Chief Medical Officer. We plan to begin our presentation with an NGN-401 program overview, and then we will briefly review Rett syndrome and the natural history of the disease before providing details around the NGN-401 clinical trial design, interim safety data from the low and high-dose cohorts, and interim efficacy data from the low-dose cohort. We will then review next steps in the program before opening up the line for your questions. I will now turn the call over to Dr. Rachel McMinn. Thank you, Cara. I would like to set the stage for the data that we are about to present. As you look at these images, imagine you have a daughter at the age of between six and 18 months. Now imagine that she starts to lose skills that she has already developed, such as being able to point for something she wants or use her hands to feed herself or pick up her favorite toy or her favorite blanket. Imagine that she cannot communicate what she needs, wants, or feels. If you offer her two things, she cannot tell you which she would choose. Imagine knowing she's uncomfortable or in pain, but you have no idea why. Now imagine that she is able to walk, but she cannot do utterly mundane acts such as getting on or off a bed or a chair or the couch by herself, and she never learns more complex skills like going up or down the stairs on her own. Or imagine she never learns to walk. She cannot stand on her own without you supporting her. This is a narrow snapshot of Rett syndrome, a rare genetic neurological disorder that affects approximately 1 in 10,000 females globally and is caused by a mutation in the MECP2 gene on the X chromosome. We developed NGN-401 gene therapy with the goal of treating Rett syndrome, which uses our EXACT platform technology, and we are pleased to be sharing today the interim efficacy data from the first four patients dosed in the low-dose cohort of our ongoing open-label phase I/II trial. We believe the data for NGN-401 are compelling, driven by gains of functional skills in the core clinical domains of Rett syndrome, which include hand function, communication, and gross motor function. Before I review these highlights, I want to thank the girls with Rett syndrome, their families and caregivers, and the investigators participating in the trial. We appreciate your trust in Neurogene and your integral participation that enables us to evaluate NGN-401. Across multiple Rett syndrome scales, we have observed consistent improvements in all four low-dose participants, with follow-up data ranging from 15 months to three months post-dosing. Notably, all four participants experienced a two-point improvement in the Clinical Global Impression of Improvement, or CGI-I, scale, which has never been observed in a Rett syndrome clinical trial before. Moreover, these data are concordant across additional clinical assessments. All four of the girls included in the interim results we are sharing today achieved clinically meaningful gains of skills and developmental milestones, and importantly, we are going to share with you a detailed natural history analysis to put these gains into context. The analysis will show that it is quite rare to learn or relearn the skills these four girls were observed to gain in our trial. We also have objective data demonstrating improvements in autonomic function for these participants. On a global basis, across these four participants, we observed a rapid treatment effect, but more importantly, the improvements and gains in skills appear to deepen over time. This finding is consistent with the biology of replacing MECP2. Low-dose NGN-401 continues to demonstrate a favorable safety profile. I'm also pleased to provide an update on the progress we have made towards advancing NGN-401 to a registrational trial. As we announced earlier this year, NGN-401 was chosen for the FDA's START pilot program, which has a stated goal to accelerate program development in rare diseases. This program specifically provides enhanced communication opportunities with the FDA that we expect to leverage to accelerate registrational planning. Additionally, NGN-401 received RMAT designation, which is synergistic with the START program and provides eligibility for an accelerated approval pathway as well as rolling BLA review and potential for priority review. The two new updates today are shown in bold. We have aligned with the FDA on our potency assay strategy required to support starting our registrational study. We also aligned with the FDA on our CMC manufacturing plan at our Houston facility, which we expect will allow us to prepare material at a larger scale in support of a future anticipated commercial launch. In addition, we initiated an adolescent adult pilot cohort to generate initial data with the goal of supporting the potential for a broad label to allow more patients with Rett syndrome to have access to treatment. I will now turn things over to Christine, who will review the natural history of Rett syndrome. Thank you, Rachel. Classic Rett syndrome is characterized by what starts off with apparently neurotypical development until approximately six months of age, where girls enter the early onset phase of the disease and acquire simple skills in fine motor, gross motor, and communication, but in a manner that is developmentally delayed. For example, neurotypical children learn to sit at around six months of age, while girls with classic Rett syndrome acquire this milestone later at a median age of approximately 12 months. This is what generally drives parents to the pediatrician as they notice that their children are developmentally delayed. Then girls will enter a period of regression, as you see in the orange box. This is the stage in which those who have gained developmental skills and milestones generally begin to lose them. This period of regression is a hallmark feature of Rett syndrome and is part of the diagnosis criteria. Thereafter, there is a period of relative stability where children are generally not gaining or losing skills, which we will show you in our review of the natural history study data on the next slide. This is also important for our clinical study in which our entry criteria required children be aged four to 10 years old. This allows us to see improvements from baseline in an open-label setting that you would not expect to see occur spontaneously in the context of the natural history during the relative stability stage. I will now provide some insights into the natural history of Rett syndrome, which are critical to the data that we are about to share. As background, the NIH sponsored a 1,000-patient natural history study of Rett syndrome, which included a developmental log of skills for caregivers to fill out. This log included key skills in the areas of hand function, communication, and gross motor, which are the three clinical domains. Key clinical domains. We looked specifically at girls aged 4 to 10 years old who had a CGI-S of 4 to 6 to align with the pediatric cohort entry criteria. As you can see, girls with Rett syndrome generally acquire simple skills. These are things that a neurotypical child would likely gain in the first year or so of life. In fine motor, approximately 85% acquire a raking grasp. Approximately 80% acquire the ability to hold a bottle. 70% acquire a pincer grasp like that needed to grab Cheerios, for example. In gross motor, greater than approximately 90% learn to sit and approximately 60% learn to walk. In communication, approximately 90% learn to babble. 66% use single words like mama and dada. However, during developmental regression, children who gain simple skills generally lose them. In hand function, for example, approximately 50% lose the raking grasp and the pincer grasp. Approximately 60% lose the ability to hold a bottle. In communication, approximately 45% lose the ability to babble and approximately 60% lose single words. In gross motor, children who learn to sit and walk generally retain those skills but don't improve from the base level of function that they had acquired. This is in stark contrast to complex skills, which Rett children do not generally acquire. In hand function, learning to use utensils like forks and spoons without assistance is a complex skill. Approximately 80% do not learn this skill. In gross motor, 82% and 86% do not learn to climb up and down the stairs without assistance. In communication, approximately 80% never learn to point, to express their wants, or speak in phrases. Approximately 50% never learn to wave bye. What is important to take away here is that in regards to complex skills, children in our study, in some cases, are either on their way to acquiring these complex skills or have actually gained them. Rachel will take you through patient vignettes later in the presentation that will show you this. I will now turn the call over to Julie to share our exciting clinical data. Thank you, Christine. Our phase I/II clinical trial is enrolling two parallel cohorts in pediatric females aged four to 10 years old, one cohort with low-dose and one with high dose. As Rachel mentioned, we just initiated a three-participant adolescent adult cohort in females aged 16 and older. The trial is enrolling females with classic Rett syndrome who are in the post-regression phase of the disease. Clinical Global Impression Severity score required for entry in the trial is between four and six. We have dosed a total of eight participants, five with low-dose and three with high dose, with that third high-dose participant just recently dosed. Today, I will be presenting safety data as of the data cut-off date of October 17, 2024, from the first five participants in the low-dose cohort and the first two participants in the high-dose cohort. At baseline, participants ranged in age from 4 to 7 years old. We've enrolled participants with moderate to severe disease, as reflected in the CGI-S scores of 4 and 5. Safety follow-up ranges from approximately 15 months to one month. The interim efficacy data being presented today is from the first four participants in the low-dose cohort of the trial, with follow-up ranging from approximately 15 months to three months. Of note, despite the similarity in baseline CGI-S scores, the heterogeneous nature of Rett syndrome is reflected in the fact that these girls actually present quite differently as it relates to their baseline function in the individual clinical domains of disease. To provide context for what that disease heterogeneity looks like, here is an overview of the first four participants in the low-dose cohort as it relates to the core domains of hand function and fine motor, ambulation and gross motor, and language and communication. What you will see throughout the presentation are artist representations of the participants in the trial. As you can see, the first two participants are ambulatory or can walk independently, while the third and fourth participants cannot walk independently. Starting on the left at baseline, low- dose one had an impaired gait and walked on her tiptoes, often freezing. low-dose two had the worst hand function of all girls at baseline. She also had an impaired gait. low-dose three could not sit, stand, or walk independently, and she required all her meals to be pureed and spoon-fed because of dysphagia and risk of aspiration. low-dose four had the best hand function of all participants but cannot stand on her own and is very unsteady and requires both hands held to stand or advance her feet forward. These characteristics give you a sense of the heterogeneity of the participants at baseline and are important to remember as we share details of the efficacy data shortly. I'm pleased to share that updated safety data continues to show that NGN-401 has a favorable safety and tolerability profile for the low-dose. As of the data cut-off date of October 17, there were no treatment-related SAEs and no signs or symptoms indicative of overexpression toxicity. Most adverse events or known potential risks of AAV have been responsive to corticosteroids and have resolved or are resolving. There have been no ICV procedure-related adverse events. As a reminder, ICV is a commonly performed neurosurgical procedure. And importantly, we have not seen any seizures reported in any participant after treatment with NGN-401. On the right-hand side of the slide is a table of treatment-related adverse events. The low-dose cohort has only experienced Grade 1 or mild AEs related to NGN-401. In the high-dose cohort, two Grade 3 AEs of ALT/AST elevation have been reported, which is as expected with a higher exposure to AAV. These transient elevations in liver enzymes, as well as decreased platelet count, occurred in the first few weeks after dosing, which is consistent with the timing observed from other AAV therapies. All labs have resolved following treatment with corticosteroids. In addition, there were two Grade 1 or mild AEs of abnormal nerve conduction studies reported, one in the low-dose cohort and one in the high-dose cohort. Both participants are asymptomatic. We learned today of an emerging serious adverse event in the third high-dose participant that was recently dosed. The case is evolving, but timing and labs are consistent with an inflammatory response in line with a known side effect profile of AAV. The case was discussed with a DSMB, and enrollment of the low-dose cohort is continuing as planned and is unaffected by this event. And now on to the efficacy data. This slide gives you an overall summary of the clinical picture, as Rachel mentioned earlier. I'm excited to report that all participants have a two-point improvement in their CGI-I score from baseline. This outcome of every participant achieving this level of improvement has not been seen in any clinical study of Rett syndrome with any treatment in development or approved treatment to date. One participant has had a one-point improvement in her CGI-S total score. All participants have had concordant improvement in their Rett Syndrome Behavior Questionnaire, or RSBQ, in a range from 28% to 52%. Importantly, on the right-hand side of the slide are gains of skills and developmental milestones in the clinical domains of Rett syndrome. You can see that all participants have demonstrated improvements in hand function, even with very limited follow-up duration in the last participant dosed. Consistent gains of function have also been observed in gross motor function. In the communication domains, not surprisingly, gains of skills are observed in participants with the longest follow-up. Meaningful improvements in autonomic function have been observed in all participants. Attentiveness has been an early sign of activity after treatment, with reports of participants being more engaged and alert. Although we are not assessing attention in a quantitative way, we have heard consistent reports of participants having increased awareness of their environment. As an example, several of the participants are now more attentive in the classroom at school and are interacting more with their classmates, suggesting an emerging awareness of external stimuli that was not present before treatment. For those not familiar with the clinical global impression improvement scale, this is a clinician-assessed scale. It's a Likert scale that goes from one to seven, with a score of four indicating no change. Importantly, a one-point change or improvement to a score of three is considered clinically meaningful, supported by approvals in the field of psychiatry, as well as the approval of the only treatment available for Rett syndrome. The CGI-I is the most sensitive measure we have to detect improvement. The reason for this is that the clinician is able to assess the child globally, looking at her entire clinical picture and asking the question, "Is she minimally better, much better?" All inputs are able to be considered, and the rater is not constrained by requirements for certain levels of function in pre-specified clinical domains. This is the CGI-I data longitudinally. As you can see, as of the first three-month assessment, all participants demonstrated a clinically meaningful improvement, and those patients who are minimally improved saw their response deepen over time, and the response is durable over the period evaluated. Moving on to the clinical global impression severity scale. This is also a clinician-rated 7-point Likert scale, but should not be confused with a CGI-I. The CGI-S is looking at severity of illness and measures disease severity across seven clinical domains, including communication, ambulation, and hand function, which have the greatest weighting on the total score. As a reminder, we are including participants with a screening severity score of 4 to 6 for entry in the trial. This is essentially the definition of classic Rett syndrome. A CGI-S score of 3 means the child has skills beyond what is typically seen in classic Rett. Unlike the CGI-I, it is very difficult to improve one point on the CGI-S, as the scale is not designed to be sensitive to change. For further detail, it is important to note that the clinical domains of the CGI-S provide insights into core functional areas. However, measurement of these domains was not designed as a clinical outcome measure, and the scoring system of the CGI-S is not sensitive to reflect functional gains. If you look at hand function, a CGI-S score of four indicates a raking grasp at baseline. The patient can have substantial gain in hand function skills from that baseline. However, if she does not develop a bilateral pincer grasp or write with a pen, by definition, her score cannot move to a three, and thus there is effectively a floor effect with the subdomain scale. As another example, in the ambulation domain, if you have a patient who cannot sit independently, she is scored a CGI-S of six. To move to a score of five, she must go from not being able to sit to being able to walk. So improvements in function, which could include sitting or standing independently, are not captured on this particular scale. On autonomic function, there are a number of different items included in here, including temperature and color extremities, but the only clinically meaningful symptom, according to Rett experts, are breathing dysrhythmias. However, there are other autonomic domains relevant to Rett that are of importance to families, not captured in the CGI-S. And with attentiveness, not surprisingly, many thought leaders in the Rett community feel that following commands is what is clinically important. The next several slides have aggregate data from all participants looking at each of the core domains so that you can compare how these girls are performing domain by domain. Starting with hand function, we have data from the first four low-dose participants here, and I would like to make several points. One, we are seeing universal improvement in hand function, and these skills have shown to be deepening over time. The second point is that we are seeing gains in hand function as early as at three months. The third point is the floor effect I mentioned earlier associated with the CGI-S scale itself. Most participants entered the trial with a CGI-S hand use subdomain score of four at baseline. Because no participant has achieved a bilateral pincer grasp or can write with a pen, their subdomain score is unchanged at four. Now on to gross motor function, which is also a core clinical domain. The key point is that we are seeing meaningful gains in gross motor function in multiple participants that have led to greater physical independence from their caregivers, even though these improvements are not reflected in the CGI-S subdomain scores. We have broken the communication domain into two slides. On this slide, we have the ability to convey choices and follow commands. All participants have demonstrated improvements in choice-making. Being able to follow commands is a clinically meaningful skill in this domain, and importantly, the most significant gains in this area are shown to deepen over time during the period evaluated, which is exactly what you would expect for a complex skill, such that the participants with the longest follow-up, low-dose one and low-dose two, are now consistently following commands. As we turn to expressive communication, we are seeing exciting improvements in the participant with the longest follow-up, including the ability to wave hello and starting to express emotion. As you consider typical childhood development, expressive communication happens at a later age than the other skills, so these findings are also consistent with a pattern of learning. Lastly is the autonomic function domain. Breathing is difficult to monitor in the clinic, and it's something that can fluctuate minute to minute. For example, some girls hyperventilate when excited or performing taps for some of the in-clinic assessments. We have observed improvement in other autonomic function areas, such as sleep and constipation, using objective measures, and I will review that data in subsequent slides. As we move to the RSBQ, there are a few things I want to highlight before we review the data. This is a caregiver-completed questionnaire that was developed to differentiate females with Rett syndrome from those with intellectual disability. Details of how the scale is rated are here, but it is important to note that the RSBQ is driven more by Rett behaviors versus function. While there are limitations of the RSBQ, the data are supportive. All participants improved on the RSBQ, and we are seeing a 28%-52% reduction in the RSBQ score, regardless of baseline score, which is a consistent trend of improvement. As I mentioned earlier, we measured autonomic function using objective assessments. There's a lot more detail in the appendix, but we are excited to share that for girls with sleep deficits at baseline, we were able to quantify improvement in sleep efficiency, which was measured with a wearable device. For girls with constipation at baseline, all experienced improvements in constipation as measured by the modified Bristol Stool Form Scale. Finally, the girl with dysphagia. She was unable to drink clear liquids due to aspiration. It was a choking hazard and safety issue. Nor was she able to chew foods, and her diet was restricted to pureed foods only that had to be spoon-fed to her by her caregiver. Following treatment, she is now able to drink clear liquids from a cup without choking. She's able to chew and swallow solid foods like meatballs and cooked carrots, foods that any child would want to eat at this age. The improvements in swallowing ability are clinically meaningful changes. I'll now turn it over to Rachel to take you through the patient vignette. Thanks, Julie. I'm going to bring this data presentation down to a more human level to help you understand how these little girls are doing on an individual basis. In addition, I'll help contextualize the gains and skills and developmental milestones we are seeing in the context of the natural history that you've seen walk through earlier in the call. low-dose one, who was seven years old at dosing, had a raking grasp and could only briefly hold objects. She dropped items quickly and was limited in her ability to self-feed. You can imagine, if you were dropping things all the time, it will impair your ability to feed yourself. She could walk independently, but she stayed on her tiptoes, as illustrated in the artist's rendition. She would stop often and required a caregiver to help her go up and down the stairs and get on and off of furniture like a bed or a couch. She had no ability to communicate in any functional way. So what does she look like 15 months after treatment? She has developed a pincer grasp, which allows her to feed herself, and she is now beginning to use a fork to eat. She can hold onto a smoothie cup with both hands for the full duration required for her to drink the smoothie. In terms of her gross motor function, her gait is much more fluid, and she has a more normal heel-to-toe walk. On her own, she is able to climb up and down stairs using alternating steps. Imagine a high-rimmed bathtub in the middle of the bathroom. She is able to climb out of the tub, placing her arm on the rim, flipping one leg, then the other, all by herself. She is able to get on and off furniture by herself, and she can get down out of her car seat and get out of the car. Perhaps most heartwarmingly, without being told, she is now able to follow a daily routine of getting to school. Once she has her backpack on, she is able to navigate steps out of her house, down a complex pathway to her dad's car, and stands by the car door waiting to go to school. She also has daily video calls with her grandfather, and she knows to wave hello to him. When she is in the kitchen, she taps on food items that she wants to eat. For better or for worse, she is now able to express emotions, frowning or shouting in displeasure when her mom brushes her hair. Impressively, she is able to understand and follow more than 10 commands, such as, "Give me a kiss," "Sit down," "Give it to me," "Put it in the trash," "Open or close the door," and "Flush the toilet." When we take all these skills and organize them by their core domains, fine motor, gross motor, and communication, you can see three key observations. First, she is gaining skills across multiple domains. Second, these are durable gains of skills for the period evaluated. Third, she has continued to gain new skills over time. On the right-hand side of the slide, we are comparing some of these skills against the natural history data that Christine described. As you can see, the complex skills of going up and down the stairs, more than 80% of girls with Rett syndrome never learn these skills. In addition, when we look at waving hello, this girl was able to wave hello when she was a baby and lost that skill during regression. When we looked at the percentage of girls in the natural history data who relearned this skill, it was 4%. This is the data that gives us the conviction that the improvements we are seeing are not by chance and not anticipated based on what is documented in the natural history data. Now, let's go through low-dose two, who is four years old at baseline. This is the girl who had the worst hand function at baseline in our cohort. As you can see from the artist's rendition, her hands were generally in a rigid fixed position. She could not grab, reach, or hold any objects. If you tried to put something in her hand, it would fall out. While she did walk independently, she was unsteady and uncoordinated, leading her to fall frequently and requiring the support from her caregiver to stand up from a seated position. Like the other girls, she had no functional communication skills. What did she look like 12 months after treatment? She is now able to hold a juice box and drink from it. When you put food in her hand, she can feed herself, something that all parents can relate to. Her favorite thing in the world is her pink security blanket. She is now able to grab it and hold it to her face. In addition, she has a pacifier clipped to her shirt. She is now able to take the pacifier and put it in her mouth to soothe herself. She now has the ability to tap on a tablet to watch her favorite videos. On gross motor, she can walk faster and steadier, and she now falls less frequently. She is able to stand up from a seated position on her own. When she sees her blanket on the floor, she can now bend over and grab the blanket with both hands when she wants to. And more recently, she is able to step off a curb with just one hand held by her caregiver. She now says the words any child learning to speak would say: "Mama, Dada, and Nana," her caregivers, purposefully and in context. For example, she will only say "Nana" when she's with her grandmother or sees her on a video call. She is just starting to follow simple commands, such as "Come here" and "Give a kiss," and she is more reliably choosing foods she wants to eat. When we take her skills and line them up by functional domain, you can see the pattern is very similar to what we observed with low-dose one. She also has multi-domain improvements. The skills are durable for the time period evaluated, and she has continued to develop new skills over time. To put her gains of function and developmental milestones in context of the natural history data, you can see on the right-hand side of the slide that 64% of the girls with Rett syndrome never learned to follow a command without a gesture. When you look at the skills she has relearned, as one example, she had a raking grasp as a baby and lost it during regression. Only 3% of girls in the natural history relearned this skill. You can see the other skills listed here are also rarely relearned. Moving on to low-dose three. At baseline, she was six years old. She had a raking grasp, but because of her severe dysphagia or difficulty swallowing, she wasn't able to do much with her hands. As Julie mentioned, this girl was on a pureed diet and required spoon-feeding for all meals by her caregiver due to the safety risk. She had the worst gross motor function of all girls in our cohort. She couldn't even sit independently. To give you a sense of what this looked like, as you can see in the artist's rendition, the full weight of her body is resting on her caregiver if she is pulled into a standing position. Like the other girls, she essentially had no functional communication skills. What does she look like nine months after treatment? As Julie mentioned, she is now able to drink clear liquids like water and apple juice from a cup without choking. She is now able to chew and swallow, which itself is remarkable. When an apple slice was placed in front of her, she was able to pick it up on her own and eat it. The ability to feed herself was something no one thought she would be motivated to do or able to do. In terms of her gross motor function, she developed the skill to sit independently. More impressively, as illustrated in the artist's rendition on the lower right, her core strength, posture, and leg strength have improved such that she requires much less support to stand up, with just the support of a hand on her side and at her shoulder. Related to expressive communication, she is now laughing at jokes made by her caregiver. When we put her skills together, you can see she also has multiple domain improvements. As you can see in the natural history data, she hasn't yet gained any complex skills as of the period evaluated, not surprising given how severe her gross motor function impairment was at baseline. However, when we look at the skills she has relearned in fine motor, you can see that the percent of girls in the natural history data set that relearn these skills is single-digit across the board. Lastly, I will review low-dose four, who is seven years old at baseline. As a reminder, she had the best hand function at baseline in our cohort. She was actually able to self-feed with special adaptive utensils that were basically strapped to her hands, and she had the dexterity and coordination to feed herself. She couldn't use a regular utensil because it would fall out of her hands. On gross motor function, she could not stand or walk independently and required her caregiver to hold onto both hands in front of her to stand or walk. Similar to the others, she had limited communication skills. Keeping in mind she has the least amount of follow-up at just three months post-treatment, she's now able to use a regular utensil to feed herself. She is also reaching out and using her hands to grab toys and objects with more precision. Given the limited time period of follow-up on this participant, it is too early at three months to say anything about her gross motor function. On communication, she is now laughing at appropriate moments when watching her favorite movie or listening to an audio program. When her physician played a children's audio program in the clinic, he was really surprised by how she was laughing at the right time of the joke, something she never did before. When we look at her skills, you can see the gains in hand function. Despite this early time point, you can see that 80% of girls in the natural history never learn the complex skill of eating with a utensil unassisted. In summary, we believe the data generated thus far support that this treatment has the potential to be best in class. The interim data we have reviewed from the first four participants of the low-dose cohort of our ongoing phase I/II open-label clinical trial have shown durable and concordant improvements across multiple scales and consistent gains in the core clinical domains that are among the top concerns to caregivers, including hand function, gross motor, communication, and autonomic function, and the data also demonstrate that NGN- 401 continues to maintain a favorable safety profile to date in low-dose. We are enthusiastically engaged with the FDA on registrational trial planning and intend to maximize our opportunities to expedite development through START and RMAT. We are also making significant progress on our goal of advancing NGN- 401 towards registration and planning for launch from a manufacturing perspective. In terms of next steps, we are on track to finish enrollment of eight patients in the low-dose pediatric cohort this quarter. In the first half of 2025, we expect to provide a regulatory update on our pivotal trial design. We are maintaining our guidance to share additional pediatric data in the second half of 2025. I would also like to close by mentioning that our EXACT technology is applicable to other neurological disorders that require transient regulation. We are maintaining our guidance of advancing an additional product candidate into the clinic in 2025. Thank you all for your time, and I would now like to open it up, the call to all your questions. Thank you. Thank you. If you'd like to ask a question, please press star one one. If your question has been answered and you'd like to remove yourself from the queue, please press star one one again. We ask that you please limit yourself to one question and one follow-up. Our first question comes from Paul Matteis with Stifel. Your line is open. Hey, thanks so much. Congrats on the initial efficacy data. I wanted to ask one question on safety and then one on the potential pivotal. On the safety side, I was just curious if there's anything more you can say. Specifically, I was wondering if there's things you can do around a prophylaxis regimen like other companies like Prevail have done and just what your general thinking is on the viability of the high dose. And then on the pivotal trial, Rachel, I was just wondering, I know it's early, but maybe you can walk us through what the range of outcomes are there as it relates to sort of most flexible, easiest to maybe most cumbersome or higher risk. Thank you. Yeah, so let me just start by saying the good news here is that the low-dose is not impacted, and we have what we think is a very compelling efficacy profile with a low-dose, and we are continuing to enroll that cohort, so in terms of some of the details, I will turn it over to Julie to provide additional information on this event. Sure. Thank you, Rachel, and thanks for the question, so just bear in mind, this is very much an evolving clinical picture. We literally just learned of this SAE within the last several hours, so the data is very much emerging, and also keep in mind that this dose is three times higher than the low-dose. What we know so far, as I mentioned, is that the timing and labs are consistent with a heightened inflammatory response to AAV. We are monitoring the situation closely, and the site is monitoring and treating the patient as appropriate. In terms of high dose, as I mentioned, we are still collecting information. It's very early on, and what we do know is that this does not impact the low-dose. And recall that the low-dose efficacy and safety is favorable, and we don't imagine that this will impact or change anything related to low-dose. Yeah, so for regulatory, Christine's going to take that question. Sure. Thanks for the question, Paul. So from a regulatory perspective, I mean, we're very excited about the data that we're seeing in the low-dose right now. If you look at the different assessments, we're actually seeing consistent gains that are concordant across all patients in the four patients that have been dosed. So I think that leaves a significant optionality on what the design could be for the pivotal study, including on what we could talk about with the regulators. So I think at this point, things are very favorable for us. From the best to the worst, I think was the question that you asked. What I would say is, from a best-case scenario, thinking about how the agency and CBER have continued in relation to gene therapy, from a best case, at least from a control perspective, we see no need for a randomized placebo-controlled study. So that's really good news from our perspective. So we think that this study could be an open-label study. And then from a control perspective, you'd have to fill in from there, right? Could you possibly have an open-label study that has a baseline control? That's definitely something that is a significant possibility for us. As far as endpoints go, again, as we've said, we're seeing really good data across all scales, and so if you go off and you take a look at this, the primary endpoint could be constructed looking at any of the things that you're seeing here. It's just something that we have to sit down and talk to the agency about, and then lastly, Paul, think about the duration. The data is being presented to you in the slides to give you a sense of when we're seeing gains of skill occur, as well as at what time points, so those are the things that we're going to talk about with the agency in the first half of 2025. We think we're set up pretty well to do so, and we look forward to providing that information to you in that period of time. Next question, please. Thank you. Our next question comes from Sami Corwin with William Blair. Your line is open. Hi there. Congrats on the data, and thank you for taking my question. I was wondering if you could provide any detail as to when that third patient treated at the high dose was treated. And I appreciate that this is a situation evolving in real time, but do you anticipate providing an update on that patient in the near term? And then I just want to follow up. Yeah, so Sami, she was dosed very recently, and so the effects that you're seeing here are very consistent with the timing of known AAV adverse events. So obviously, if there's anything further to discuss, we will certainly discuss that. When we have more information, we will be discussing this case with the DSMB to make any appropriate decision. Great. And then do you anticipate any differences regarding long-term benefit depending on the mutation severity of each patient? So as you can see, we've provided data on patients that have varying mutations. So low-dose one, if you go back and look at that slide, she has a mild mutation, and the other patients have more severe mutations. But really what's important here is there isn't a perfect correlation between mutation and phenotype. It's really important to understand the clinical presentation at baseline. And you can see that all patients, regardless of their mutation and regardless of their severity, right? They're so different when you look at all four. We're seeing these consistent gains in skills from their baseline. So that's why having that baseline information is so important to really understanding the meaningfulness of the data that you see following treatment. Great. Thank you. Thank you. Next question, please. Thank you. Our next question comes from Ritu Baral with TD Cowen. Your line is open. Hi guys. I, too, have a safety question and then an efficacy question. On safety, Rachel, do you have room to ramp the prophylactic regimen that you're using on immunomodulators and steroids in the high-dose cohort protocol? And is this a side effect that we should be thinking about potential Soliris treatment, pretreatment, etc., that we've seen with other AAV9 therapies? And then I have a follow-up on efficacy. Yeah, so just as a reminder on safety, with the high-dose cohort, we already have prophylaxis. In addition to corticosteroid treatment, we have rituximab as well as sirolimus. So that was put in place because we know that as you dose escalate with AAV, there are certain side effects that are expected. So we put that in place already. And in terms of your question of is Soliris warranted, this is literally something, as Julie mentioned, we just found out hours ago, and the information is rolling in on a very regular basis. And certainly, if it makes sense for her to receive Soliris treatment as a result of the clinical picture, that will happen. But that information is not yet available. Yeah, your follow-up question? How mature do you want the efficacy data in hand before you sit with the FDA? You've given yourself sort of a broad range to sit with them. Do you hope to go to them with some mature high-dose data as well? I'm going to ask Christine to take this question. Thanks for the question, Ritu. As far as it relates to the data that we have on hand, again, we're pretty excited about what we're seeing in the low-dose, both from an efficacy and safety perspective. I've collected a significant amount of information to help inform what the pivotal design could look like. From a good news perspective, we feel pretty confident that we have enough data, at least in the low-dose, to help inform that picture. We will be going to the FDA. We're in active discussions with the FDA, and we need the time to be able to come back to you in the first half of 2025. That's how at least we're thinking about it. From a high-dose perspective, the high dose is 3x the low-dose. We're seeing these adverse effects that are not somewhat surprising as a result of the 3x difference in the dose. And our current low-dose data, from our perspective, is strong enough. We weren't really waiting on the high dose at all as it relates to the efficacy picture. It was really dose exploration to see if that we could, based on the biodistribution data that we saw non-clinically, be able to push the efficacy. But as far as we're concerned, the low-dose data is strong enough to go to the agency with. And that's really where we've collected the most data to date. Got it. Thank you. Thank you. Next question, please. Thank you. Our next question comes from Mitchell Kapoor with H.C. Wainwright. Your line is open. Hey, everyone. Thanks for taking the questions. I wanted to ask specifically, what was the AAV-related SAE, and did it come on gradually? And were there any other signs of this across, I guess, a less threatening level across any other patients? And then on efficacy, could you talk about the fifth low-dose patient? Are they before the three-month mark, or how are they doing? Thanks. I mean, just to take it in reverse order, you can see the follow-up. So we don't have enough information as of the cutoff date to make any assessments on the fifth patient. There's insufficient follow-up. In terms of the safety event, obviously, no, this has not been reported in any other patients. Otherwise, that would be disclosed. And again, as Julie mentioned, I'm just going to underscore this has literally happened today over the last number of hours. So this is consistent in terms of timeline. As I mentioned, she was dosed very recently. And we know with AAV that in the first few weeks of treatment, as Julie mentioned, this is when these adverse events tend to present themselves. So there's nothing obviously, it's not something that we would want to see, but it's nothing unexpected as it relates to AAV itself. Okay. Thanks. Next question, please. Thank you. Our next question comes from Keith Tapper with BMO Capital Markets. Your line is open. Hey, guys. Congrats on the data, and thanks for taking my questions. Investors are clearly focused on the safety issue. Could you talk a little bit more about this? Maybe could you talk about how you arrived at the low-dose to begin with? Remind us of how this pairs with your base case for the program. And when you say the low-dose was not effective, maybe could you walk us through exactly what that tells us about the safety driven by the AAV9 dose burden versus the safety of the underlying mechanism and ICV administration route? Thanks. So I'll take a stab, and if it makes sense, we'll have additional comments. So the low-dose, just as a reminder, we have preclinical data that pointed both from an efficacy and safety perspective that this was a safe dose and also had the prospect for clinical benefit based on the overall profile from multiple sets of data. So we moved forward with that low-dose. And in fact, the 1E15 total vector genomes, it is a dose that we expected to be effective. Indeed, that's what we found translationally. And so given the efficacy profile that we have, just to re-underscore what Christine said, we've designed this entire program to really be supported by the low-dose. The whole program is leveraged to the low-dose. But that being said, given the severity of Rett syndrome, which itself is the symptoms of Rett are very, very challenging, we also, based on our preclinical data, knew that the high dose offered the potential for perhaps better efficacy. And so we wanted to interrogate whether that would translate in the clinic and whether the safety profile would also translate. So I think we have an emerging adverse event that we will provide additional information as appropriate. But we're very happy with the low-dose profile. And as Christine mentioned, has a very compelling profile that we are already in discussions with the FDA. I mean, Keith, one other thing to add is just looking at the low-dose, just to be very clear, because I don't want it to be mistaken for what you see in this one high-dose patient where it occurred today. All events in the low-dose are grade 1, right? So AAV9 has its known risks. All the events in the low-dose that we presented are grade 1 and are resolving for the most part and consistent with any of the known risks. And the efficacy profile has been quite strong. So I don't think there's any question. The way you asked the question, it almost suggested there was an issue with the low-dose. There is no safety concern as it relates to the low-dose, and the efficacy picture is showing quite well. It's really as it relates to the 3x dose at the high dose. So it's three times the dose of the low-dose where we're seeing this emerging clinical picture that is an SAE. But there are no other SAEs in the study across the board, and there are certainly no SAEs in the low-dose. I just want to make sure that's clear. Okay. Great. Thanks, guys. Great. Next question. Our next question comes from Mani Foroohar with Leerink Partners. Your line is open. Thanks for taking the questions. Always tough to see an SAE from the patient, but not surprising when you're breaking new ground and a pretty severe indication. We've seen this happen in a couple of other gene therapy indications in cases where Rocket, for example, have moved forward with the lower dose. How do you think about strategically moving forward with the lower dose versus exploring a mid-dose? And should adolescent versus younger patients have different doses based upon what you've seen preclinically and in the early data? And I have a quick follow-up. Christine, do you want to take this question? Sure. Hi, Mani. Thanks for the question. As it relates to the low-dose, I think we feel pretty good about what we're seeing in the low-dose, such that we don't have concerns from a safety perspective currently, and we certainly are seeing a very good efficacy picture. So today, the low-dose continues unaffected by any of the events that we're seeing in the high dose. As it relates to the adolescent and the adult cohort that we announced today, I think the reality is we were starting in the high dose. And the reason for it is this is a weight-based concern, right? So adolescents and adults are generally heavier than these juvenile, pediatric patients. And so from a biodistribution perspective, if we could start in the high dose, that might be presenting for a better efficacy profile. Today, we need to go back and have these discussions internally to see. But to your point, I think is what you're getting at, if we could go in the high dose in that adolescent and adult cohort, certainly that puts us in a very good position with respect to the efficacy picture just based on their weight. That being said, we're doing dose exploration for a reason. We're seeing a very good picture in the low-dose today. And it's clear that at least in these pediatric patients, we feel comfortable being able to move forward and going to the agency with what we have. That's really helpful. And I guess as a follow-up to that, would it make sense to move forward with the low-dose initially and pursue higher doses separately as part of a life cycle extension, later supplemental filing? Or do you think it's important to get all the patients across all ages in a single study? How should we think about the degree of regulatory flexibility here? Thanks for that question, Mani. So from a pediatric standpoint in the low-dose, given what we're seeing in the safety database we've built and the efficacy database that we're starting to build, we certainly would not want to delay moving forward in the pediatric cohort given where we are today. As far as the adolescent and the adults, we're just starting this n = 3 sort of pilot study so that we can better understand what the efficacy picture could be in these subjects. So we would not want to delay the pediatric aspects of it, but we wanted to start moving forward to broaden the label over time. So once we see what these three patients look like in the adolescent and adult cohort, we'll have a better sense as to how we might proceed with the agency, but certainly not in a way to risk timelines associated with the pediatric cohort. Great. Thanks. And I know I've already gotten a few in, so I'll hop back off. Thanks, Mani. All right. Thanks, everybody. This concludes our call, and we really appreciate you joining the call. We look forward to keeping you updated on our progress. Thank you for your participation. You may now disconnect. Good day.