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And welcome to Neurogene's Webcast and Conference Call. Please be advised that this event is being recorded. I will now turn the call over to Lina Li, Executive Director of Investor Relations at Neurogene. Please proceed.

Thank you. Good morning, everyone, and thank you for joining us today to review the Phase I/II data of NGN-401 for the treatment of Rett syndrome. Before we get started, I'd like to remind everyone that we will be making forward-looking statements today. These statements involve known and unknown risks and uncertainties, which may cause our actual results to differ materially from those presented today.

I encourage you to review our latest SEC filings, including our Form 10-K and most recent Form 10-Q for a complete discussion of these risk factors. All of the information we will be presenting is as of today's date, unless noted otherwise, and we undertake no obligation to update any forward-looking statements. Our speakers from Neurogene today are Dr. Rachel McMinn, Founder and Chief Executive Officer; and Dr. Julie Jordan, Chief Medical Officer.

We are pleased to be joined by Dr. Bernhard Suter, Medical Director of the Bluebird Circle Rett Center at the Texas Children's Hospital and Associate Professor of Pediatrics and Neurology at the Baylor College of Medicine and an NGN-401 principal investigator. We also have Christine Mikail, President and Chief Financial Officer, available for the Q&A session.

With that, I will now turn the call over to Rachel.

Thank you, Lina. Good morning, everyone, and thank you all for joining us. As many of you know, Rett syndrome is a devastating neurological disease with no approved disease-modifying therapies. NGN-401 is a gene therapy designed to deliver functional MECP2. The unmet need is substantial with an estimated prevalence of 15,000 to 20,000 patients in the U.S. and major European markets and a sizable incidence rate of approximately 175 to 180 new cases each year in the U.S.

The market is approximately 50% pediatric and 50% adult, and all patients have a profound unmet need. A single idea frames everything today. In Rett syndrome, development stops after regression and effectively freezes. The updated data we're sharing suggests that development restarts after treatment with NGN-401. Over the longer term, with follow-up of 2 years or more, participants are gaining milestones in a stepwise sequence across domains, similar to what occurs in typical development.

The order matters as much as the gains. Milestones are returning in developmental sequence, the signature of development resuming rather than isolated skills appearing. And these gains are durable with no milestones lost in any participant and continue to deepen over time. Everything that follows is evidence of what a gene therapy treatment for Rett syndrome should deliver, the restoration of developmentally ordered progress, not isolated skill gains.

I'd like to start by thanking the Rett syndrome community for their support of this program and all of those who have participated in our Phase I/II and registrational trials. You are the true trailblazers and without you, this would not be possible. Now I'm pleased to share the positive updated Phase I/II data that continue to support the potential for NGN-401 to be best-in-class treatment for this devastating disease.

In the 10 participants treated at the 1E15 vector genome dose, we have observed clinically meaningful durable improvements with real-world impact for the participants and their families. First, every participant, 100% has gained one or more developmental milestones and improved on the CGI-I. At 12 months, 80% had met this composite responder definition that is the primary endpoint for the Embolden registrational trial, which far exceeds the 33% minimum success threshold for the Embolden trial.

Second, the magnitude of gain continues to build. Total milestones gained in the trial were 47, averaging 4.7 per participant. Importantly, these are not random milestone gains. They are occurring in a developmentally ordered stepwise sequence consistent with a restart of development and the continued ability to learn. Third, these gains translate into real-world benefit, improvements in daily living, greater level of independence and reduced caregiver burden.

Fourth, the improvements are durable and deepening. We now see improvement has continued out to 30 months with no plateau and no milestones have been lost in any participant. Importantly, the 1E15 vector genome dose continues to be generally well tolerated in the Phase I/II and Embolden trials. There have been no treatment-related SAEs or DLTs in Embolden.

Earlier this month, we announced completion of dosing in Embolden, surpassing our enrollment target by 25% and dosing 25 participants within our original time line in a broad age range of pediatric and adolescent adult participants. Clinicians and families chose to participate in the Phase I/II trial due in part to ICV administration to maximize the potential of NGN-401 as a onetime gene therapy treatment. We remain on track for top line data in the second half of 2027.

Diving deeper into the 100% response rate, here are some of the more detailed data that we will be reviewing today. The clinical response was rapid and a median time to improvement was 2 months. The treatment effect was durable and increased over time. Milestone gains increased by 95% from 6 to 12 months and by 147% from 6 to 12 months or beyond. There were no milestones lost in any participant as far as 30 months post treatment. The treatment effect was multi-domain and was observed across participant age, disease severity and genotype.

7 of 10 participants gained 2 or more developmental milestones, and these milestones were in 2 or more key Rett syndrome domains, including hand function, communication and gross motor function. These data underscore the breadth of response and lead to independence in activities of daily living, reduced caregiver burden and enhanced social engagement. There have been no new treatment-related SAEs and no DLTs in any participant and all have reached at least 12 months of follow-up.

In totality, these data from the 6-month, 12-month and beyond time points support a clear path to a strong BLA submission, exceeding the Embolden minimum success threshold by 2.4x at 12 months. The average milestone gains increased from 1.9 at 6 months to 3.7 at 12 months and deepened to 4.7 at or beyond 12 months. The over enrollment provides a larger registrational cohort, strengthening statistical power and potential for a broad label.

Before I hand things over to Dr. Suter, I want to briefly review our Phase I/II trial design. As a reminder, the Phase I/II trial, which subsequently converted to the Embolden registrational study is an open-label multicenter trial evaluating the safety, tolerability and efficacy of NGN-401. Key eligibility criteria, the key clinical assessments of CGI-I, CGI-S and developmental milestones as well as the Rett Syndrome Gross Motor Scale and Rett Syndrome Hand Function Scale are consistent across both studies.

Dosing is complete in both trials with 10 participants in Phase I/II and 25 in Embolden, bringing our total safety database to 35 participants at the 1E15 vector genome dose. The primary endpoint for Embolden is a composite in which a responder is defined as a participant who shows an improvement on the CGI-I and gains at least 1 developmental milestone at 12 months. As it relates to developmental milestones in the Embolden trial, this list was derived from an analysis of the Rett syndrome natural history study and a caregiver survey of meaningfulness.

The 28 milestones included here have low cumulative incident rates of gaining or regaining at or after age 3 when regression is complete, and they were all deemed clinically meaningful by caregivers. We applied the embolden milestone criteria directly to the Phase I/II data. First, we established which milestones were absent at baseline using medical history, caregiver reports and videos. We evaluated post-treatment milestone gains utilizing independent central review of video documentation using the same prespecified criteria that is being used in the Embolden trial.

By following the same standardized assessment criteria, the Phase I/II data are comparable to Embolden. This chart summarizes the baseline characteristics of the 10 Phase I/II participants, reflecting a broad age range with a wide spectrum of disease severity. Participants enrolled range from 4 to 18 years old. Baseline CGI-S scores were 4 to 6 or moderately ill to severely ill and the participants represent the full spectrum of genetic severity and classic Rett syndrome.

As of the data cutoff of June 16, 2026, participants had a range of follow-up from 12 to 30 months. I am pleased to turn the call over to Dr. Suter, one of our principal investigators to review the long-term data from the trial and provide context for how the data are maturing in those participants. Dr. Suter?

Thank you, Rachel. I've spent my career evaluating and treating patients with Rett syndrome and can share what this disease looks like in the clinic. Rett syndrome is a rare and devastating neurodevelopmental disorder, most often caused by a spontaneous pathogenic variant in the MECP2 gene. This gene is responsible for making MECP2 protein, which is required for normal brain and nervous system function.

What defines the disease is a period of regression. Children lose previously acquired developmental milestones followed by a plateau. By around age 3, it becomes rare for children to gain or regain developmental milestones, resulting in lifelong pervasive disability that requires intensive medical support and often 24-hour care. That natural history is critical context because it means that gains in the development after this point are highly unexpected and clinically meaningful if they occur.

The hallmark features of Rett syndrome include loss of expressive and receptive communication, loss of purposeful hand function with repetitive movements called stereotypies, gait abnormalities and mobility challenges and autonomic dysfunction, including breathing irregularities, dysphagia and severe constipation as well as seizures. With that clinical background, I'd like to now play a brief video that brings to life the true burden of disease represented by a family living with and caring for someone with Rett syndrome.

[Presentation]

Thank you to the family for sharing the story. What you just saw reflects more than a collection of symptoms. It reflects the day-to-day reality of living with Rett syndrome and the profound impact it has on both the child and the family. This is not simply the loss of an isolated skill or milestone. It is the development that is fundamentally disrupted where progress halts and the independence never fully emerging.

At that context is critical because to understand whether we can change that trajectory, we first have to understand how development normally unfolds. To frame how development typically occurs outside of Rett syndrome, we often reference the Denver 2 framework, which is one of the most widely used developmental assessment tools in pediatrics and neurodevelopment. The Denver 2 maps how developmental skills emerge across multiple domains in a concerted fashion.

In typical development, milestones are acquired in an organized cumulative and sequential manner with each new skill building on the last across domains. That is the curve on the left. In Rett syndrome, that process is interrupted. Children develop in an apparently normal manner, then between 1 and 3 years of age, they regress. And the critical point is this, once that regression happens, it is exceedingly rare to regain those milestones or gain new ones. The child's development freezes, the curve flattens and that plateau is what drives lifelong dependence on caregivers.

The goal with NGN-401 is the panel on the right. This is not about slowing decline. It is about restoring and improving function. Said simply, the goal of any gene therapy is to restart the developmental progression to get the curve climbing again and across multiple domains. And if that happens, the impact will be what families care about the most, greater independence and reduced caregiver burden. That is the hypothesis we set out to test.

I'll now walk through the data from the first 4 patients with 2 or more years of follow-up, where you can begin to see what that looks like over time and what it translates to in the real world. Let's start with participant 1. She is 7 years old, and her regression had been complete for several years before treatment. At baseline, she had very limited functional hand use, limited self-feeding, walked on tiptoes, froze often, needed help on every stair and couldn't indicate her wishes or follow a simple command.

The dotted line is the day she received NGN-401 and everything to the right occurred after treatment. What we started was not random. In fine motor, she progresses from a raking grasp and dropping objects to drinking from a cup, a pincer grasp using the utensils to feed herself and transferring objects between hands, a particularly difficult skill in Rett syndrome as it requires 2-handed coordination. To provide additional context, transferring objects is among the more advanced skills on the validated Rett syndrome Hand Function Scale.

In gross motor, she progresses from needing help on every stair to climbing stairs up and down independently and heel-to-toe walking, a key milestone on the Denver 2. And in communication, she progresses from not following commands or indicating wishes to following a command waving to her family in context and pointing to things that she wants. Overall, this participant gained 11 developmental milestones, completely unexpected in Rett syndrome natural history.

But the more important point is the pattern. These milestones emerge sequentially across domains consistent with restarting development rather than an isolated change. And here is what that looks like in daily life, getting in and out of the bath tub on and off furniture without help, shopping with a parent, carrying the basket with both hands, getting out of a car on her own and closing the door after her mom asks her to do so, following instructions in 2 languages to carry a backpack up the stairs and shut the door behind her, choosing the right color on command, demonstrating receptive communication, waving to her grandpa on a video call, demonstrating expressive communication.

These are not isolated skills. They reflect fine motor, gross motor and communication working together in a coordinated way, which is what development is supposed to look like. For this family, the result is greater independence, less caregiver burden and more meaningful participation in daily life. Participant 2 shows the same overall pattern. At age 4, several years post regression prior to treatment at baseline, she had no functional hand use, limited mobility with frequent fall, could not bend over and had minimal communication, unable to follow commands or make choices.

Following NGN-401, what we observed is not just improvement, but another example of developmentally ordered stepwise reemergence of milestones across domain. In fine motor function, the participant progresses from reaching for a toy to grasping and manipulating objects to drinking more independently and beginning self-feeding, skills that directly translate into increased independence in daily activities over time.

In gross motor function, she progresses from assisted transition to standing up from a seated position independently, recovering balance after bending at the waist to touch the floor, a milestone included on the Denver 2 and navigating real-world challenges like curbs and stairs. She also achieves more controlled positional transitions such as sitting up from lying down. These gains reflect meaningful improvements in strength coordination and motor planning.

And importantly, communication improves alongside these motor gains. She progresses from being unable to follow commands to following verbal instructions begins using words with meaning, including mama and dada, and she demonstrates increasing receptive communication by responding to her name being called. Taken together, these changes suggest a restart of development over time rather than isolated functional improvement.

In daily life, these gains translate into greater independence. She is now participating more independently in family meals, beginning to feed herself and hold her own drink. She moves through her environment with more confidence, bending, navigating and picking up objects with less physical assistance and less constant supervision. And importantly, she's more connected with her family, responding when called, following instructions and communicating with simple but meaningful words.

Participant 3, 6 years old at the time of dosing in several years post regression, began from a more severely affected baseline and provides another compelling example of restarting development. Before treatment, she had minimal functional hand use and was fully dependent on caregivers for feeding because of severe swallowing difficulty. She could not sit independently and required maximum support to stand or walk. Communication was also very limited with no ability to follow commands or make choices. Following NGN-401, we again observed milestone gains across domains in the developmental progression.

In daily life, these changes are meaningful. In the first example, she is actively engaging with her grandmother, following her instructions to select the correct puzzle pieces by color and participate in play. She is also the second participant in the trial who can now follow instructions post treatment in 2 languages, which reflects a meaningful improvement in receptive communication.

In terms of mobility, even though she has achieved one formal gross motor developmental milestone, her functional abilities have improved significantly from baseline. She previously required maximal assistance to transition from sit to stand and the support of 2 caregivers to remain standing. After NGN-401, she now requires only moderate assistance from her caregiver to transition from sit to stand and to remain standing, reflecting a meaningful improvement in functional mobility and independence while reducing the level of caregiver support needed to safely perform this transitional movement.

She now initiates steps from her baseline of an inability to sit without assistance. These are very meaningful gains for families. As she grows, needing less physical assistance will be absolutely critical as the physical demands of supporting a growing individual can place a significant burden on caregivers and may become more difficult or impossible to manage. At mealtime, she shifts from full dependence to active participation, selecting food with her hands and self-feeding rather than requiring spoon feeding from a caregiver for every bite. For this participant, we are seeing a meaningful shift from near complete dependence towards the early stages of increasing independence for everyday activity.

Participant 4, 7 years old at baseline and years after completing regression further reinforces the pattern we are seeing across the group of longest duration follow-up. At baseline, she had limited hand use, was non-ambulatory and had severely impaired communication. After NGN-401, we again saw gains across multiple domains. In daily life, these gains translate into greater autonomy. She is now able to participate more independently at meal times, feeding herself using utensils independently and eating alongside her family.

At the same time, her gross motor improvements are enabling greater independence. She can now sit up from a lying position on her own, allowing her to reposition herself in bed and prepare to be transferred without full caregiver support. These gains extend beyond mobility into control of her environment. She can turn a light switch on and off, reflecting purposeful hand use and giving her direct control over her surroundings, something that was not previously possible.

In addition, she can now actively participate in family celebration, strengthening both communication and social engagement. Notably, she has also greatly improved her ability to communicate with her AAC device, providing more consistent indications of needs and wants to her caregiver, which is high on the caregiver priority list.

Taken together, these 4 participants with the longest duration of follow-up show a consistent pattern. After treatment, we see coordinated restart of development across domains. These changes are not isolated to a single skill or domain. And importantly, these gains translate into meaningful functional change, including self-feeding, following instructions, setting up greater mobility and more independent participation in family life.

While each participant begins from a different baseline and follows an individual course, the overall pattern is remarkably consistent, progressive acquisition of skills that increase independence and reduce caregiver reliance over time. For me, the biggest thing is that there is potential for more over time. In Rett syndrome, we are faced with a complex neurodevelopmental picture, and these data show progress on every developmental domain in an orderly fashion, which is what would be expected biologically with a gene therapy.

Thank you for the opportunity to present these data on behalf of my co-PIs in the trial. Most importantly, thank you to the participants and the family who have enrolled in the study. I will now turn the call over to Julie to continue the review of the Phase I/II data.

Thank you, Dr. Suter. We are very pleased with these results. That trajectory reinforces our confidence in what we expect to see as we follow participants over time. Now let's turn to individual participant level data. This slide shows the rapid response post dose that deepened over time. The green bars represent participants, who meet the Embolden composite responder definition, improvement on CGI-I and at least one developmental milestone gain, 100% met the composite endpoint at the latest follow-up.

At 12 months, 80% met the composite endpoint, far exceeding the 33% response rate needed for success in the Embolden trial. Importantly, CGI-I improvement is observed at or before milestone attainment, reinforcing that the composite endpoint is both clinically meaningful and achievable. 47 total developmental milestones have been gained, which represents an average of 4.7 milestones per participant.

First clinical response occurred rapidly with a median time to response of 2 months post treatment. If we now step back from the individual participant level and look across the data set, we see that these gains are not isolated to a single domain. Developmental milestones are accumulating over time across multiple domains in fine motor, communication and gross motor function, domains that matter most to patients and caregivers.

At each time point, you can see the total number of developmental milestones gained. By 6 months, the total milestones gained doubles from the 3-month mark and continues to increase over time with milestones increasing 95% from 6 to 12 months and by 147% at or beyond 12 months to a total of 47 milestones gained at the latest follow-up. 7 of 10 participants gained at least 2 developmental milestones, and these gains were across 2 or more clinical domains. These data underscore the differentiated multi-domain response NGN-401 is delivering.

In terms of the specific embolden milestones achieved in the Phase I/II trial, you can see we had a robust 21 of the 28 total possible milestones achieved across the 10 participants. Remarkably, participants achieved all 7 hand function milestones, more than half of the gross motor milestones and 7 of 8 communication milestones. These multi-domain milestone achievements allow these participants to be more connected to the people around them and participate in their self-care.

These improvements also increase their independence in moving and interacting with their environment, ultimately easing everyday care for their families. We are also very encouraged by the meaningful gains we're seeing in the Rett Syndrome Gross Motor Scale, or RSGMS. The RSGMS provides an independent centrally rated quantitative assessment of gross motor function that complements the developmental milestone data. As will be highlighted in a poster presentation at the IRSF scientific meeting by Dr. Jenny Downs, who developed the scale, the mean RSGMS total score increased by 5.2 points when normalized to a 1-year rate.

This represents a statistically significant improvement on a scale that typically declines over time in Rett syndrome, where natural history shows a 0.8 point decrease over 1 year. Notable are the gains in transition skills, which are commonly impaired in Rett syndrome. Specifically, 5 of 7 participants who are unable to move from sitting to standing independently and 5 of 6 who could not stand up from the floor independently improved post treatment.

Improvements in these abilities not only reflect better motor planning, coordination and strength, but also reduce the amount of physical assistance required from caregivers. We see similarly encouraging and meaningful gains in the Rett Syndrome Hand Function Scale, or RSHFS, which is a centrally rated quantitative assessment of hand function that complements the developmental milestone data.

As will also be highlighted in a separate poster presentation at IRSF by Dr. Downs, 100% or all 10 participants demonstrated a gain in hand function over 1 to 2.5 years, a statistically significant difference from natural history data in which only 15% of patients improved over the course of 3 to 6 years.

Impressively, 7 participants showed improvements in both hands. Functionally, these improvements enabled greater participation in everyday activities, including self-feeding, engaging in play and increased independence in daily routines. In totality, the developmental milestone gains, CGI-I scores and the RSGMS and RSHFS data provide a compelling body of evidence that NGN-401 is providing meaningful efficacy across the core domains of Rett syndrome. With that, I'll now turn to the safety profile.

The 1E15 vector genome dose of NGN-401 continues to be generally well tolerated. All treatment-related AEs have been mild to moderate and are consistent with known AAV-related adverse effects. The majority have resolved or are resolving. There have been no new treatment-related SAEs in the Phase I/II trial since our last update. While 1 participant previously had 2 reported SAEs associated with sensory neuropathy, a known AAV class effect, those SAEs have resolved and there are no clinical symptoms. This participant has since become a responder.

A separate participant experienced sensory neuropathy, and this participant has also become a responder. Overall, these events appear to be transient and both participants have improved in CGI-I and gained a developmental milestone. We are pleased that the safety profile demonstrates that NGN-401 continues to be generally well tolerated at the 1E15 vector genome dose with follow-up now extended beyond 30 months. The efficacy data and tolerability profile highlight why we believe we are well positioned for success in the Embolden registrational trial, which I will now describe.

As Rachel noted, we completed dosing in Embolden with a total of 25 participants across a broad age range, representative of the Rett syndrome population and supported by our natural history analysis. The primary endpoint is a responder-based composite endpoint defined as CGI-I of less than or equal to 3 and gained from baseline of any developmental milestone. The primary analysis to support the planned BLA submission is expected to occur after the first 24 participants, the primary efficacy population have completed 12 months of follow-up.

The list of developmental milestones is prespecified and will be captured through standardized video recording and rated by independent blinded central raters. This registrational trial enables us to have a single study designed to have efficacy and safety data to support a broad label. To put our results into context, it's important to understand the natural history of Rett syndrome. Natural history data from the NIH-sponsored Rett syndrome natural history study accessed through IRSF show a clear and important pattern.

The figures shown here are Kaplan-Meier cumulative incidence curves, for example, milestones from the prespecified Embolden list of 28. Based on longitudinal data from the Rett natural history study, the likelihood of gaining a developmental milestone is rare at or after age 3. As you can see across these examples by key Rett domain, milestone acquisition rises in early childhood but plateaus by approximately age 3 with minimal incremental gain through age 6 and beyond. Importantly, the lack of meaningful increase between ages 3 and 6 demonstrates that these milestones are not simply delayed or spontaneously acquired over time.

Rather, the natural history is characterized by a persistent absence of developmental progress. Beyond age 3, the likelihood of gaining any individual milestone remains low, typically in the low single digits across domains and becomes even more limited in older children and adolescents. This is why age 3 was selected for the Embolden registrational trial. By that age, the regression phase has passed and spontaneous developmental gains are not expected, providing a well-defined baseline against which treatment effects can be evaluated within each patient.

Dr. Jeff Neul, who led the Rett syndrome natural history study, will present our analysis in a poster at the IRSF scientific meeting. Dr. Neul featured data from 3 representative treated participants, 1 participant aged 4 years at baseline, 1 aged 7 years at baseline and 1 participant aged 14 years at baseline. The age-matched cumulative incidence rate for each of the milestones gained range from 0.3% to 7.9% in the 4-year-old, 0 to 2% in the 7-year-old and 0% in the 14-year-old.

These natural history data highlight the rarity of developmental milestone acquisition at or above age 3 years in Rett syndrome and underscore the significance of the robust clinical responses observed with NGN-401. On the left, you can see that there was an 80% response rate in the Phase I/II trial based on the Embolden primary endpoint definition at 12 months post treatment. This responder rate is 2.4x higher than the 33% success threshold required for Embolden. NGN-401 has been generally well tolerated in Embolden. There have been no treatment-related SAEs or DLTs in the Embolden trial as of the data cutoff date of June 16, 2026. Together, we believe these data derisk Embolden outcomes.

I will now turn the call back over to Rachel.

Thank you, Julie. In summary, we have a robust clinically meaningful set of data that we believe will support a potential market-leading therapy for Rett syndrome. We are seeing consistent, clinically meaningful and multi-domain improvements that go beyond the isolated milestone gain. Instead, the progressive acquisition of milestones point toward a restart of developmental progression. While the response to treatment was rapid and all participants have gained one or more developmental milestones, we believe the more important focus is the depth of response.

At the latest follow-up, we observed an average of 4.7 milestones per participant with 7 of 10 participants gaining 2 or more milestones across at least 2 core domains of Rett syndrome, which we believe is unprecedented. As you can see, the number of milestones at 6, 12 and beyond 12 months deepens over time. No developmental milestones are lost in any participant, which is critical to support the durability of effect for a onetime gene therapy treatment. 80% of participants met the rigorous Embolden responder definition at 12 months, reflecting 2.4x higher than the minimum threshold needed for success.

Additional quantitative assessments of the hand and gross motor function showed statistically significant improvements relative to natural history data. In summary, we believe these data will support strong differentiation in a multibillion-dollar opportunity in a disease with a clear and urgent unmet need. We're at an exciting juncture as a company. We've generated compelling long-term clinical data. We've completed dosing in our registrational trial, and we have strengthened our leadership team as we advance our commercial readiness.

Looking ahead, we remain focused on several key anticipated milestones, initiating our PPQ campaign imminently, reporting top line data from Embolden in the second half of 2027 and advancing towards a planned BLA submission. Notably, we have used the same process and scale throughout clinical development that we intend to use for commercial manufacturing, limiting comparability challenges. In parallel, we will continue to build the infrastructure needed to support a successful commercial launch. Importantly, we are rapidly advancing towards commercialization with a strong financial position, which we believe will support operations through key value inflection points.

Finally, all of this progress is only possible through the extraordinary trust, partnership and ongoing support from the Rett syndrome community. We would again like to extend our deepest gratitude to the participants, caregivers, investigators, clinical trial site coordinators and the broader Rett syndrome community. We are excited about the path forward and the opportunity to bring NGN-401 to patients and families.

Thank you for your attention. And with that, we are ready to begin our question-and-answer session. Operator, would you please open the line for questions.

[Operator Instructions] Your first question comes from Ritu Baral with TD Cowen.

And congratulations on the data. In respect to data, was there any [Technical Difficulty] special thinking about [indiscernible] for baseline impairment and what this means for...

Thanks, Ritu, for the question. This is Rachel. So no, I think what you're pointing out is that Rett syndrome is inherently a heterogeneous disease, right? There's different ages. There's different baseline severities. There's different genotypes. And what you're seeing here is that 100% of participants are responding. We can confirm that 100% of participants have gained at least one developmental milestone in the last 12 months. And we are seeing a broad response regardless of age, both in the younger as well as in the older cohort as well. So I think we're very pleased with the overall product profile, demonstrating a robust effect across the population.

Your next question comes from Patrick Dolezal with LifeSci Capital.

Congratulations on the data. Just given the robust depth of response with 3.7 milestones gained per patient at 12 months and another milestone gain per patient in looking out further up to 4.7 milestones per patient at last follow-up, how should we think about the importance of the 12-month endpoint versus the complete patient experience with extended follow-up?

And then the second question, assuming patients in Embolden have a similar experience with milestone gains continuing to stack over time, how can you ultimately market those claims post-commercially?

Thanks, Patrick. So in terms of the long-term data beyond 12 months, this is very, very important for clinicians and caregivers to really determine the choice of a gene therapy. 12 months, as you know, is important for regulators to make a determination of efficacy, but it's really the data beyond that, that's going to be important to demonstrate a number of things, including durability and continued improvements to support the overall meaningfulness of a onetime gene therapy product for all stakeholders, including the FDA, clinicians and caregivers. As it relates to your second question on how to market those claims, Christine, would you address that?

Thank you, Rachel. Happy to do so. So Patrick, what we're seeing here is an extremely robust response that is actually supported by the clinical trial design that we have in the trial, both from a primary efficacy analysis as well as from a key secondary perspective. But as Dr. Suter also described, what we're seeing is this multi-domain coordinated response that suggests the restart of development. And so we think that not only will the label be very supportive of collecting milestones, showing the multi-domain response, but also being able to publish on this on the long term to be able to truly show and establish clear differentiation of NGN-401 with long-term clinical evidence.

Your next question comes from Debjit Chattopadhyay with Guggenheim Securities.

How would you characterize the time course and the importance of the CGI-I score versus the developmental milestones? And given the data that was presented today, if you were to prioritize a therapy between the 2 gene therapies, which one would you choose and why?

Yes. So I'll take the first question, and then I'll ask Dr. Suter to give his overall perspective as a clinician and also any perspective he has from a family perspective. As it relates to the time course, if you look at the chart where we lay out the individual patient data, you'll see that the median time to a CGI-I response was 2 months, so very rapid. This is the first time that we're disclosing that information, but people can see that the response overall is rapid in the majority of patients.

But in all cases, what we see is CGI-I either comes before or at the same time as the occurrence and recording of a developmental milestone. So it really is very consistent, if anything, is a predictor of future developmental milestone gain. And then Dr. Suter, could you talk a little bit about your perspective on how to prioritize gene therapy and your own experience and your conversations with families?

Sure. So what I'm learning from my discussions with families is that ultimately, families care mostly about efficacy overall. And I think we're still in a phase where we will learn about -- ultimately about the efficacy, but NGN-401 definitely has demonstrated in individuals, a very, very promising course of developmental gains. So I have no fear that this would speak to families strongly in terms of choosing this gene therapy.

And if I may, one more follow-up here. As you prep for commercialization, how are you thinking about the ex-U.S. opportunity? And where are you with respect to CMC currently?

Sure. That's another 2-part question. So I'll just speak briefly in terms of ex-U.S. from a regulatory perspective, we are engaged with EU regulators. We have prioritized the U.S., but certainly see the ex-U.S. market opportunity as substantial and a priority. From a CMC perspective, we are very much on track. As I mentioned, we are imminently initiating our PPQ campaign, and we'll be completing that this year. So very -- everything is on track from a CMC perspective.

Your next question comes from Mani Foroohar with Leerink Partners.

Congrats again on continued durable data showing benefit for these drugs and their families. As we get closer and closer to an eventual regulatory filing, commercial availability, but presuming positive Embolden data, help us understand how the evolution of this data will confirm the restart development of progression and how that informs your commercial and competitive strategy and messaging on an MSL basis, perhaps more than on a sales basis?

Sure. So I think, look, we're very pleased with the overall profile of Embolden and I think -- excuse me, the Phase I/II data and this being a helpful view into the future of what we can expect from Embolden. In terms of the restart of development, I think maybe I'll ask Dr. Suter to make a comment on that. And then as it relates to the commercial strategy, Christine can answer that question.

Sure. Thanks, Rachel. So just to weigh in there, these developmental milestones are really not gained in a random fashion, but really, as you would expect them to occur biologically, right? So these individuals gain these milestones, reaching and tapping them subsequently whole hand grasp then sign finger-based manipulation of objects, along with gains on other domains that are also acquired in a developmentally ordered sequence, which really clues us in that this is a restart of biological development and not random acquisition of individual skills.

And then I'll take the commercial strategy question. So Mani, essentially, what we're trying to do here is we've been pretty busy on pre-commercial activities in a couple of ways that are going to impact the answer to your question. The first one is expanding awareness for NGN-401. We've already built a pretty strong network within the centers of excellence activating sites in that U.S. infrastructure.

But as Rachel mentioned, we're also actually engaging with ex-U.S. KOLs to start to actually educate them on NGN-401 and educate them on the actual development that we've seen with our data. That leads into the second important strategic imperative that we've employing, which is to establish clear differentiation of NGN-401 with long-term clinical evidence. And there's where the MSLs come into that perspective. So ultimately, it's -- the short-term data is, we believe, going to help get the drug approved. But it's that long-term data that's going to impact adoption.

And in regards to what Dr. Suter is talking about between having MSLs to truly educate on what we're seeing both with what's going to go on in the label, but also publish on the information that Dr. Suter was talking about while we expand the network, we believe that's going to work very well in concert to educate on this in the long term.

Great. That makes sense to me. That's really helpful. And one more quick follow-up, if I may. You talked a little bit about commercial positioning, et cetera. Can you give us a heads up on where you are in terms of managing manufacturing process capacity? Obviously, this is a large pool of patients that are diagnosed, treated, many of whom rolled off Daybue. How should we think about volume and capacity upon an eventual commercial launch and potential investments around infrastructure scale for manufacturing?

So I'll take the manufacturing of where we are and Christine can talk about the investment aspect. As it relates to capacity, as I mentioned, we are initiating those PPQ runs imminently, and that can help to begin to support inventory build. We also have plenty of capacity available next year and beyond. And owning our own manufacturing facility gives us the strategic flexibility to be able to support the adoption rates projected for commercial supply. So there's no change in scale or process required to meet what we expect is going to be a robust launch. Christine, do you want to take the other part?

Sure. On the investments required, in fact, our cash runway guidance already provides for the investments that are required in order to commercialize this product from a CMC perspective with no additional investment.

Your next question comes from Paul Matteis with Stifel.

Congrats on the data. So as it relates to the efficacy, I wanted to just clarify one thing. Did you say that every single of the 47 milestones gained has been individually durable and all have been gained and sustained? And then for Dr. Suter, just from your clinician experience, have you ever seen patients in the age range in this Neurogene trial gain a milestone or 2 at this point in time in development spontaneously?

So to confirm, yes, all of the milestones are durable and sustained. Dr. Suter, do you want to talk about your experience?

Yes. No, I mean, we followed our center a couple of hundred Rett individuals, and I can say with confidence that, yes, you might see an individual skill gain, but you will not see a multi-domain skill acquisition as we've seen on the study.

Your next question comes from Mitchell Kapoor with H.C. Wainwright.

This is Ananda on for Mitchell. Congrats on the fantastic data. I was just wondering from our perspective, we had brought up the ICV administration. And in your view, does Embolden enrollment and dosing support the ICV adoption hypothesis? Or do you still see families decline or hesitate because of the route of administration?

So I'll just make a comment and then ask Dr. Suter to opine on the conversations he's had with families as it relates to route of administration and what's important for families in a onetime gene therapy. But from our perspective, we've had -- we've seen very robust adoption. Route of administration has absolutely not been a barrier. As you know, we've overenrolled our trial of Embolden by 25% in a very short period of time.

And families anecdotally have come in actually asking for the route of administration that is really directly delivering gene therapy to the brain because what we've heard is that they feel like they want that gene therapy that can really maximize the distribution. So it's a onetime treatment that is lifelong, and this is a lifelong disease. But Dr. Suter, please elaborate.

Sure. Yes. No, I concur with you, Rachel. Really, what I encounter from families is that their top priority is efficacy. They're interested in the efficacy. We know that ICV injection really gets the product to the brain areas where it matters the most. It's a fairly routine procedure for skilled neurosurgeon -- it's performed on a daily basis across the U.S. and families do not -- are not deterred from this procedure at all when they -- when we speak about the gene therapy. And suffice it to say that we have a continuing influx in interest on the sides of families for this gene therapy.

So even after enrollment, you're seeing some demand come in.

Yes. It is.

Your next question comes from Whitney Ijem with Canaccord Genuity.

Congrats on the data. This is Angela on for Whitney. Given the strength of your data and what appears to be a more reasonable FDA over the last couple of weeks, is there any update to thinking about a potential 6-month interim?

Thanks, Angela, for the question. And you can see, obviously, from our data that we have very robust data at 6 months with an average of 1.9 milestones per patient, and that continues to deepen very significantly over time. We have asked the agency in the past several times, and we know that the agency, given that Rett syndrome, while chronic is not the urgency to follow patients and show durability is much more important than a short time of follow-up. So the agency has been very clear that they are looking for a 12-month primary analysis for gene therapy in Rett syndrome. And so that is -- our trial design remains a 12-month primary endpoint.

Our last question comes from Seema Sheoran with Rodman & Renshaw.

Congrats on the update. My question is for Dr. Suter. So Taysha is planning to meet with the FDA and then communicate the 6-month interim data to the -- in first half of 2027. Assuming that it does get approved based on 6-month interim data, how much do you think that roughly 6-month difference in data timing between Taysha and Neurogene therapy will realistically impact adoption of NGN-104? Are patients going to wait for the 12-month data from Taysha as well before deciding or patients are just going to go for which therapy is approved first?

Thanks, Seema, for the question. So I'll start and then hand it over to Dr. Suter for his perspective. Importantly, the Embolden trial results, as you know, are anticipated to be available in the second half of 2027, well before any gene therapy product would be approved on the market. So it's important to note, in addition to that, that we will be continuing to follow our Phase I/II cohort. And what you're seeing right now is a snapshot of a minimum of 12 months duration of follow-up in all participants with up to 30 months of follow-up. But of course, next year, you can tack on another year of follow-up to that and then the year after, you'll have even more data.

So you'll have some patients with more than 3 years of data coming out from the Phase I/II, and that will be available for the marketplace and likely published in a way that clinicians and families will be able to interrogate the overall profile. So there'll be Embolden data, there'll be Phase I/II data. And so in that context, then Dr. Suter, is the timing of a few months difference of one therapy being available for another therapy, is that the main driver? Or are there other factors that families will consider?

Yes, I don't think that will be the driver. Really, ultimately, I'll circle back to what I said all along. It will depend on the efficacy data itself.

That concludes our Q&A session. I will now turn the conference back over to Rachel McMinn for closing remarks.

Thank you, operator, and thanks, everyone, for tuning in. We look forward to keeping you informed of our progress in this program.

This concludes today's call. Thank you for attending. You may now disconnect, and have a wonderful rest of your day.

Thank you very much. Happy to be introducing Rachel McMinn, Founder and CEO of Neurogene, who has some new fresh data to talk us through for NGN-401 in Rett syndrome. And so I'm really looking forward to this presentation, and then we will have some time for questions. So please take it away. Thank you, Rachel.

Yes. Thank you, and thank you, Paul, for hosting me. Today, I am absolutely pleased to share new interim clinical data from our Phase I/II trial of NGN-401 for the treatment of Rett syndrome. As Neurogene is a publicly traded company, I want to note this presentation includes forward-looking statements subject to risks that could cause actual outcomes to differ materially. See our filings with the SEC and especially our risk factors in our annual report on Form 10-K and quarterly reports on Form 10-Q for more information.

So these results just released reinforce our belief that NGN-401 has the potential to be both best-in-class and first-in-class. We believe that NGN-401 is setting the standard for Rett syndrome gene therapy. Caregivers and clinicians consistently tell us that a gene therapy for Rett syndrome must deliver multiple developmental milestone and skill gains that increase over time. One skill is not enough. Multiple domain improvements across key domains, hand function, gross motor function and communication, durability, once skills are gained, they are not lost and they're maintained over time and a favorable tolerability profile.

Our updated data shows that NGN-401 continues to meet all these criteria. Patients are gaining multiple skills with 35 skills gained in total across multiple domains and all gains have been durable with no skills lost and NGN-401 continues to be generally well tolerated. We believe NGN-401's potentially best-in-class profile is being driven by a number of key differentiators. First, the decision to use ICV administration. This approach is a strength. Other gene therapy programs have demonstrated that administering virus locally into the brain is essential for efficacy. ICV is a common procedure, not a barrier to adoption, taking approximately 1 hour of operating room time.

NGN-401 delivers a full-length gene, which we believe is essential to ensuring maximal functional benefits. And finally, our EXACT technology controls the level of transgene to avoid MECP2 overexpression toxicity. Today's efficacy data covers all 8 pediatric patients enrolled in the Phase I/II trial at the 1E15 vector genome dose. Patients in this trial are ages 4 to 8 with follow-up ranging from 6 to 24 months. This cohort represents the full spectrum of genetic severity in classic Rett syndrome. Safety data includes 10 patients at the 1E15 dose and additional data is planned for release in 2026. I'm going to start with the first 5 patients who had at least 12 months of follow-up post treatment with NGN-401 as it is aligned with our primary endpoint in the Embolden registrational trial.

All 5 patients have shown functional gains in the core clinical domains of Rett syndrome. 4 of 5 patients have met the CGI-I responder definition and CGI-I scores have remained durable over time. 4 of 5 patients not only meet the responder definition for Embolden at 12 months, they far exceeded the minimum threshold for success required for the Embolden trial. Skill gains are increasing over time. If you look at the right-hand side of the slide, you will see this illustrated here. All responders have gained additional milestones up to 24 months post treatment with 14 skills gained at 6 months post treatment in aggregate, with skill gains more than doubling beyond 12 months in these patients.

Moving on to the more recently dosed patients. We are also seeing skill gains here. 3 of 3 patients have functional gains. 3 of 3 patients have met the CGI-I responder definition and 2 of 3 patients have gained skills that match the Embolden skill list at this early time point of 6 months, which is well before the 12-month definition in the Embolden trial. This data is consistent with the previously dosed patients. Based on the current data set in totality, with additional follow-up to go, 6 of 8 patients meet these requirements to be a responder for Embolden, well above the 35% threshold required for a successful outcome in Embolden.

This slide shows the breadth of skill gains across multiple domains per patient. Hand function, gross motor function and communication with increasing skill gains over time. As one of our principal investigators recently told us after reviewing all of this data, each of these skills are meaningful under themselves, but when you put them all together, they alter the course of disease in a significant way.

So for the next set of slides, I'm going to take you through each of the patients with a response. And we see continued acquisition of new skills and durability of previously gained milestones. Please note that the complexity of the skill gains is also a significant differentiator. For example, this is patient one who has gained 11 skills in total. Most recently, she added the new skill of sitting up from a lying down position independently. Notably, she has not plateaued even 24 months after her treatment. Perhaps more remarkably, not shown on this slide, but while at baseline, she could not hold objects and now she's holding a hand shopping basket at CVS while shopping with her mom.

Moving on to patient 2, who has gained 10 skills in total. She gained the new skill of drinking from a cup independently and climbing stairs with assistance. This is remarkable progress from baseline in both hand function and gross motor planning. This is our second patient starting to climb the stairs.

Patient 3, who has gained 6 skills in total. She added hand function and executive function skills. At baseline, she couldn't eat solid foods. And now she is using her hands to grab a pancake from grandma to feed herself. She is also following instructions to pick up the right puzzle pieces while playing with her grandma.

Patient 4, who has gained 4 skills in total, gained independent drinking from a cup and the ability to follow instructions. At the encouragement of her mom, after multiple attempts, she was able to successfully coordinate her arm and hands to turn off the lights on her own, something she was absolutely determined to accomplish.

Moving on to patient 7, who gained 1 skill just 6 months post treatment, she progressed from palm feeding to using a fork for the first time to feed herself. This is yet another example of a complex skill gain.

And patient 8, who gained 3 skills just 6 months post treatment, including using words in an exchange back and forth with her dad for the first time since her disease regression, pleasantly surprising her father. She also kissed her mom for the first time ever.

As you can see from this data, the skills are complex, layering one on top of the other as gains remain durable over time, truly setting a new standard for what to expect in gene therapy for Rett syndrome. Shown on this slide is just kind of a composite in summary of what matters to families, and you are seeing some real activities of daily living, improvements in health-related quality of life that we haven't gone through, and I will keep my remarks short, so I won't go through all of these and multi-domain improvements.

These are just some caregiver testimonials, so you have them. I'm not going to read them for you, but just know that they are in a slide deck, so you can get a sense of the kinds of improvements that families are experiencing firsthand.

Moving on to safety. NGN-401 remains well tolerated at the 1E15 dose. All NGN-401 related events have been mild, grade 1 or moderate grade 2. The majority are known potential risks of AAV and are resolved or are resolving. There is no evidence of a hyperinflammatory syndrome at this dose. Most liver events were mild and consistent with data we have presented previously.

A quick note on patient 5. She had abnormal nerve conduction findings and areflexia. The abnormal nerve conduction has returned to the normal range. Unrelated to NGN-401, this patient broke her leg while playing with her dad on the playground. This confounded her 12-month gross motor assessment. So looking ahead, we expect to complete the Embolden trial enrollment in the next 3 to 6 months and share additional Phase I/II data in 2026. And finally, we have sufficient cash to fund operations through the first quarter of 2028.

And with that, I am going to open it up to the fireside chat, and you can ask me your questions.

Okay. Thanks, Rachel. We have time for a bunch, so this should be good. Maybe just to start, let's ask the obvious cross-trial comparison question, like how do you now stack up your data versus Taysha's data? How should we compare? What are the caveats of the comparison?

Yes. Look, I think it's really simple. We're seeing more skills over fewer patients. We have durability. We have more complex skills over multiple domains in multiple individual patients. We've really gone to great lengths to share data on an individual patient level data -- on an individual patient level, we're providing baseline characteristics so everyone can get the full picture of these durable multi-domain multiple skill for patient data and across the disease severity. Unfortunately, for TSHA-102, we don't have baseline data that has not been presented. The patient level data has not been presented. The durability data has not been presented.

But even if we ignore all of that and just do our best to try to compare like-for-like, if you look at the Embolden task list and look at the REVEAL task list, we have 31 developmental milestones achieved with NGN-401 over 8 patients. We believe this represents approximately 50% more skills gained in fewer patients than TSHA-102. The skills are complex. We didn't talk through all of them, but think about pincer grasp, drinking from a cup, using utensils to eat, climbing the stairs, following instructions, and this is in multiple patients. We just haven't seen those kinds of skills from TSHA-102. We believe our strong results are consistent with our approach to unlock efficacy using local brain delivery with ICV administration and the full-length MECP2 gene.

Okay. Great. And then on the Phase III design, right, I think one question you've been getting regularly is kind of this whole dynamic of your primary outcome being at 12 months, not doing a 6-month interim whereas Taysha is. And so maybe just help clarify that and your engagement with the FDA. And within that, you said, I think, at the outset of your presentation, you think you can be best and first. This whole interim difference, I think, has led some to view Neurogene being second. So why do you think that's not the case?

Yes. So look, just very high level, the trial designs are pretty similar in that they're both baseline controlled studies, single arm with a primary endpoint of 12 months, right? Importantly, we have one registrational trial that encompasses ages 3 years and older. Based on our current enrollment projections, we expect to complete enrollment in the next 3 to 6 months. This is before Taysha anticipates starting its second registrational study, which is not planned until mid-2026.

We learned last week that Taysha has not yet determined what this study design actually looks like. It's under discussion with the FDA. We don't know the protocol. We don't know if it's a safety or efficacy study. We don't know how large the sample size is. We don't actually know the dose yet. And as I mentioned, their guidance is to start that study in mid-2026. So what we know is that we have initiated dosing, right? We announced our first patient dosing. We expect to complete enrollment in 3 to 6 months. And our design allows for patients ages 3 years and above in one study.

Great. And then methodologically, can you talk about how benefit in this Phase I/II study is codified, specifically like milestones and how this is all kind of counted? And are there any differences between the way it's done here versus the pivotal study?

Versus the pivotal study. So very similar. So we have video evidence in both Phase I/II and the Embolden trial. The main difference is that the videos in Embolden will be rated by blinded central raters and blinded to time to ensure that bias is mitigated.

Okay. Okay. Like what's your expectation on how that could influence this at all?

Well, because we have independent validation of the videos that we've seen.

For the Phase I/II.

For the Phase I/II, I think we have significant confidence in the outcome here. And again, with a threshold, and I think you might even have a question on this, but from a threshold perspective of requiring 7 out of 20 patients to be successful. We have 6 out of 8 responders today that maybe even changes with time. I think we're feeling very good. And really what we're talking about now is what is the market share of the products and what will that look like and what really matters to families. So I think we're feeling very confident in the design and the product profile that's being generated to date.

Yes. Okay. Yes. Maybe let's talk a little bit about the regulatory piece because I feel like there's nothing like more topical right now than like gene therapy regulatory. Before we even ask just specifically, maybe just go back through like your engagement with the FDA over the past, I don't know, 9 months and like your confidence in the context of what we've just kind of seen with uniQure that this single-arm registrational study is like fully aligned and the right path [indiscernible] to take.

Yes. So let's point out there's a number of key differences. And I think when people see headlines and they see single-arm study, external control gene therapy, they just sort of throw a baby in bathwater and it gets thrown away. So what's different between Neurogene's Embolden study and what's going on with uniQure, quite different. So first of all, unlike uniQure, we are not seeking approval on the basis of a Phase I/II trial. A major limitation for filing for approval on a Phase I/II trial is that the key elements involved in the statistical analysis are not prespecified. So we are not seeking approval on our Phase I/II, right, which we've just presented some of that data today.

So for Embolden specifically, we have prespecified all of the necessary elements required to be in place prior to dosing. And we've confirmed these aspects of the protocol with the FDA very recently to ensure alignment. In terms of sort of the general tenor and how we've been interacting to get to that point, under the START program, we have quarterly meetings. So every quarter, there's a stipulated meeting. But frankly, I'll tell you that we are interacting with them much more frequently than that because there's an opportunity for ad hoc. And so there's a lot of back and forth. And we're doing that across leadership changes. So that was true before, and that has continued to be true.

So I think it's just a really incredible opportunity. I have somebody on my leadership team who has a wealth of regulatory experience and has made very clear comments that in her 25-year career, she's never seen the kind of regulatory engagement in terms of back and forth and being able to communicate with FDA as we have under the START program.

Okay. Okay. And then as it relates to the Phase III bar, so I think this is the first time you're sharing the statistical bar. It's kind of an impossible question to answer. But what do you think the like actual regulatory bar is?

Well, look, let me just tackle that in 2 pieces, statistics and then what does it take? So look, on statistics, just to be really clear, there's an assumed noninterventional response rate or we'll call it "placebo rate" just to make it simple. And then there's a drug treatment response that you're assuming. Given our treatment effect in the Phase I/II to date and our sample size of 20 patients, we believe that we are well powered to see a treatment effect. So that's just sort of a statement on the stats. But beyond meeting the statistical threshold, we believe we are setting a new standard for Rett syndrome gene therapy with multiple skills across multiple domains, durable over time with no plateau up to 24 months post treatment. And we think those factors are really going to matter to regulators and to everybody else.

Yes. Makes sense. Can we go back maybe to the safety slide for a second? Or I can just also ask a question too, if you don't want to jump around the slides. I think you made one comment that most events are mild. There's some moderate. They've all resolved or are resolving. How would you -- like can you just expound upon that a little bit? Like what does like are resolving mean? Like anything else or other details you can share?

Yes. I mean this is pretty standard for AAV treatment. So when you think about liver enzyme elevations, for example, the majority of patients do experience liver enzyme elevations. They tend to be grade 1. They tend to be transient. Can you have a patient where if they have some medication changes with the -- whatever is going on with them because they have a lot of other treatments that are ongoing, that can certainly interact and you have a bump in liver enzyme. So there's simple things like that, that have resolved in most patients, but maybe are not fully resolved because it's something that's ongoing. So certainly, there's nothing here.

Nothing that's evidence of like broader inflammation.

No, no. So -- and just going back to that question because I think just to educate on inflammation, when we saw that hyperinflammatory response in a totally different, much higher dose, a threefold higher dose, that happened immediately, right, within days. So this cohort here, and we're announcing that we have no evidence in any patient. So that is not something that we are seeing. But we feel very comfortable with the safety profile and mentioning here, again, that this is grade 1 or grade 2 events. pretty standard for gene therapy.

Yes, makes sense. Sure. Yes, please go ahead.

[indiscernible].

So the question, just for people listening in on the webcast is communication is severely impaired in the treatment -- in Rett syndrome generally. It's one of the core hallmarks of disease, and we are showing improvements in communication across a number of patients. And what do we think that means over the long term. I mean, you're exactly right. I mean we're seeing improvements in executive function in order to turn off a light switch, for example, right? It's not only coordinating your body to like make your arm go up and hit the switch, but you have to want to do it. And you have to recognize that your mom is saying, hey, give it one more try, give it one more try. And it's just -- it's really incredible.

Other types of executive function being able to see something that you want and reach out for it and grab it and feed yourself, like these are skills that it's not just about like an isolated hand function, right? There's this whole neural network. And so maybe just take a big step back, what is the gene that we're even talking about, MECP2. This is a gene that is responsible for the maintenance of neurons and neuronal health. And it's required lifelong. It's not like it's only required for a certain period of time during development. It's -- you could give an adult Rett syndrome if you pulled away their MECP2. So we're restoring that function, and we're restoring neural networks and as a result of that, these restored neural networks over time, we believe the data are showing us that you're starting to learn and gain skills and then -- and that's why we're not seeing a plateau. So I think we're optimistic. Obviously, we have more data to collect as we continue to follow patients with time. But we think this is a real altering of the trajectory of the disease.

Any other questions? For me, from a timing perspective, so just talk about the pivotal, like the number of sites. I think you said fully enrolled in 3 to 6 months. Have you identified all the patients at this point?

Yes. So we've been certainly working very hard behind the scenes over the last number of months to get us to the place where we are now. We have initiated the clinical trial sites, 12 of 13 planned. And as we mentioned the other week, we have already dosed our first patient, and sites are very excited, enthusiastic to enroll their patients. So I think we feel very confident in the enrollment projections.

in terms of the time lines and you said, oh, have you identified all the patients, sorry, my brain is -- I need a booster. Are we -- have we identified? To be honest with you, there are certain sites that could supply all 20 patients with their own sites. So obviously, we're not going to do that, right? We're enrolling across multiple sites. So we don't think that patient identification by itself is going to be really rate limiting.

So as you think about the time lines, just keep in mind that both companies, as we initiate trials, we're not only headed into the holidays, but more importantly, we're headed into flu and cold season. And any of you who have young children, they get sick. And if you get sick, your dosing date is going to get pushed out, right? It's just you're not going to dose somebody with a viral infection, for example, that would be something that would delay. So those are the kinds of things that end up being more relevant to dosing time lines. It's not necessarily the patient identification process itself. There's a lot of patients out there. It's a huge market opportunity with a huge unmet need and a lot of excitement.

Have you learned anything? So you have like not heterogeneous, but you have patients with variable baseline impairment in the study. Like have you learned anything for the types of patients that might respond better or might not respond better? And like what's your expectation for the pivotal cohort?

Yes. Look, it's a really important question because I remember sitting on this stand with you probably like 1.5 years ago, something like not this one, but maybe at a different conference in venue and you were saying, Rachel, do you expect patients with more mild disease to be better responders or somebody with more moderate or more severe disease? Do you remember that question?

Yes, I think so. Yes.

So you asked me that question. And I said, well, we don't know. And we started talking about what are the kinds of things that could improve more quickly. But I think what the data are showing us is that we're actually seeing improvements across that. That, by the way, was also a question among our principal investigators. If you have a little bit of residual functional protein, are you going to do better? Or like will we be more concerned with those patients? And actually, we're showing that all of these patients are seeing benefits.

Obviously, if you have more impaired hand function, it might take you longer to be able to use a utensil, but we're seeing that. If you're not ambulatory, you're not flying out of a wheelchair, so we need to set expectations appropriately, but we are seeing the non-ambulatory girls continue over time to gain strength, require less support for the ability to stand and move their feet and moving along. So when you watch the series and time -- over time, you're seeing these benefits. And it really is regardless of mutation, regardless of presentation.

Obviously, some skills are gained more quickly than others. Age doesn't seem to be -- we can't say like, well, geez, like the 4-year-olds did so much better than the 8-year-old. I mean I just showed you an 8-year-old with 3 skills gained within 6 months, who did -- who gained more skills than 1 of our 4-year-olds. So I think it's really about the presentation of disease, not being driven by mutation, but also thinking about like where is MECP2 going and how long does it take to kind of restore those neural networks in that individual.

Yes. Yes. Okay. Maybe one last quick question on the safety side. I think the slide mentioned something about like a nerve conduction finding. Can you just like clarify that for people? Like what happened there? And how comfortable are you?

Yes. So nerve conduction abnormalities are actually part and parcel of AAV administration. So this is something that we've seen certainly with a number of other drugs. Typically, there's no clinical symptoms associated with it. And you do occasionally, we pointed out for one of our patients that there was areflexia that was associated and the nerve -- underlying nerve conduction findings have moved to the normal range. So I think in the grand scheme of a treatment for Rett syndrome and the kind of benefits that we're seeing, I think we're not too concerned about this. Obviously, we want to manage any type of side effects as anybody would do who is seeing side effects with any treatment, but we feel very, very comfortable with the overall profile.

Great. Any last questions from the audience? Rene, yes.

[indiscernible].

Yes. So I can answer that question a little -- I think we're out of time on the webcast, but I'll follow up with you and explain that a little further.

Okay. Thank you, Rachel. Appreciate it.

Thank you.

Thanks.