Taysha Gene Therapies, Inc. ($TSHA)

Good day, and thank you for standing by. Welcome to the Taysha Gene Therapies Full Year 2025 Financial Results Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Hayleigh Collins, Senior Director, Corporate Communications and Investor Relations. Please go ahead.

Thank you. Good morning, and welcome to Taysha's Full Year 2025 Financial Results and Corporate Update Conference Call. Earlier today, Taysha issued a press release announcing financial results for the full year ended December 31, 2025. A copy of this press release is available on the company's website and through our SEC filings. Joining me on today's call are Sean Nolan, Taysha's Chief Executive Officer; Sukumar Nagendran, President and Head of R&D; and Kamran Alam, Chief Financial Officer. We will hold a question-and-answer session following our prepared remarks. On today's call, we will be making forward-looking statements, including statements concerning the potential of TSHA-102, including the reproducibility and durability of any favorable results initially seen in patients dosed to date in clinical trials, including with respect to functional milestones to positively impact quality of life and alter the course of disease in the patients we seek to treat, our research, development and regulatory plans for our product candidates, including the timing of initiating additional trials, reporting data from our clinical trials and making regulatory [indiscernible] of communication with the FDA on the regulatory pathway for TSHA-102, the potential for the product candidate to receive regulatory approval from the FDA or equivalent foreign regulatory agencies; our ability to realize the benefits of breakthrough therapy designation for TSHA-102, our ability to drive long-term value for stockholders and the market opportunity for our programs. This call may also contain forward-looking statements relating to Taysha's growth, forecasted cash runway and future operating results, discovery and development of product candidates, strategic alliances and intellectual property as well as matters that are not historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the SEC, including in our annual report on Form 10-K for the full year December 31, 2025, that we filed today. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, March 19, 2026. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws. With that, I would now like to turn the call over to our CEO, Sean Nolan.

Thank you, Hayleigh,[indiscernible] 3:20welcome to our full year 2025 financial results and corporate update conference call. On today's call, I will begin with a brief update on our recent clinical, regulatory and commercial readiness activities. Then Dr. Suku Nagendran, our President and Head of R&D, will provide a clinical update on the TSHA-102 program. Kamran Alam, our Chief Financial Officer, will follow up with a financial update, and I will provide closing remarks and then open the call up for questions. 2025 was a year of significant execution for Taysha. We announced compelling REVEAL Phase I/II data across pediatric, adolescent and adult patients with Rett syndrome treated with TSHA-102, received FDA breakthrough therapy designation for TSHA-102 and secured written FDA alignment on our REVEAL pivotal and ASPIRE trial designs, paving the way for a potentially streamlined path toward BLA submission. This progress has set the stage for what we expect to be a transformative year ahead for Taysha as we focus on completing the pivotal development of TSHA-102 and bolstering our commercial readiness efforts as we advance towards potential registration. We've maintained ongoing constructive dialogue with the FDA over the past 2 years, which has enabled alignment on a pathway that we believe reflects the rigorous systematic data collection and well-controlled study design and endpoint selection required by the FDA for a robust data-driven application. In 2025, we finalized alignment with the FDA on our REVEAL pivotal trial protocol and statistical analysis plan in support of our planned BLA submission, and we were pleased to initiate the pivotal trial in the fourth quarter of 2025 with the dosing of our first patient. Multiple patients have now been dosed in the trial with enrollment across -- advancing across multiple sites. We remain on track to complete dosing in the second quarter of 2026. Importantly, both high and low-dose TSHA-102 continues to be generally well tolerated with no treatment-related serious adverse events or dose-limiting toxicities observed in the patients treated in both the REVEAL Phase I/II and REVEAL pivotal trial as of the March 2026 data cutoff. In addition to initiating our REVEAL pivotal trial, we recently received FDA clearance to initiate the safety-focused ASPIRE trial following written FDA alignment on the ASPIRE trial design and data for inclusion in our BLA submission to support a broad label for TSHA-102 for patients aged 2 years and older with Rett syndrome. ASPIRE will enroll 3 females with Rett syndrome aged 2 to less than 4 years, evaluating the safety and preliminary efficacy of a single intrathecal administration of the high dose of TSHA-102 1x10^15 total vector genomes scaled to account for the lower brain volume in the 2 to less than 4-year olds. The written alignment we reached with the FDA outlines that our planned BLA submission will include a minimum of 3 months of ASPIRE safety data, while the efficacy in the 2 to less than 6-year-old population will be extrapolated from the data collected in the REVEAL pivotal trial to support the broad label. We are on track to complete dosing for ASPIRE in the second quarter of 2026. We believe this recent FDA alignment on ASPIRE, together with the alignment on a 6-month interim analysis for our REVEAL pivotal trial, potentially streamlines our path toward BLA submission for TSHA-102. In the first quarter of 2026, we attended a Type C meeting with the FDA and reached written alignment on the CMC requirements for our planned BLA submission. Specifically, we further aligned with FDA on our proposed comparability approach between TSHA-102 material derived from the clinical and final commercial manufacturing processes. The FDA agreed that the approach may support pooling data from the REVEAL Phase I/II trials with data from the ongoing REVEAL pivotal trial and the ASPIRE trial for the planned BLA submission. Importantly, we believe this creates flexibility and will further strengthen the overall data set for the BLA package by including longer-term data and enabling a comprehensive assessment of safety and efficacy data that's been generated across the entire development program. Additionally, the FDA endorsed our proposed process performance qualification or PPQ campaign strategy to support process validation for the BLA submission. This included the stability data package, the potency assay strategy and the execution of BLA-enabling PPQ lots using the commercial manufacturing process, which we expect to initiate in the second quarter of 2026. This feedback aligns with the agency's January 2026 guidance aimed at increasing flexibility and requirements for cell and gene therapies to advance innovation. With this alignment, we are confident that our CMC activities are on track to support our planned BLA submission in step with the pivotal data set readout. We truly appreciate the consistent, constructive and collaborative interaction we have held with the FDA to date and believe our regulatory progress highlights the strength of our data-driven approach and further supports our goal to bring TSHA-102 to patients with Rett syndrome as safely and expeditiously as possible. We will continue to engage with the FDA as we prepare for our planned BLA submission. In addition to our clinical and regulatory progress, we continue to bolster our commercial readiness activities. As a reminder, Rett syndrome is a devastating, rare and progressive neurodevelopmental disease with high unmet need and a profound lifelong burden for patients and caregivers. It is well characterized clinically defined by impairments across multiple clinical domains, including fine and gross motor function, communication, autonomic function and seizures. While Rett syndrome is a heterogeneous condition that presents with different levels of clinical severity based on each patient's distinct genetic background, natural history data show that patients follow a common trajectory regarding the achievement of functional developmental skills with the likelihood of spontaneous gain or regain of developmental milestones falling to approximately 0 after 6 years of age. The multi-domain impairments result in loss of independence with most individuals requiring 24/7 care and lifelong support for daily activities, such as eating or sitting up, severely impacting quality of life for patients and caregivers. This burden and the limitations of currently approved therapies, which focus on symptom management do not address the underlying genetic root cause, have created a strong urgency for new treatment options capable of delivering functional improvements. We believe this urgency, combined with the estimated 15,000 to 20,000 patients with Rett syndrome across the U.S., EU and U.K. underscores the substantial market opportunity for TSHA-102. Within the U.S. specifically, patient estimates range from 6,000 to 9,000 patients based on claims data and epidemiology data. Because Rett syndrome is a neurodevelopmental condition and based on the Phase I/II data we've reported to date across pediatric, adolescent and adult patients, we believe that most patients with Rett syndrome can meaningfully benefit from treatment. TSHA-102 is uniquely designed to address the root cause of Rett syndrome and as such, has the potential to meaningfully alter the natural history of the disease and offer patients the opportunity to achieve functional milestones that would otherwise not be possible according to natural history. Recently completed market research reinforces this opportunity as it demonstrated high anticipated demand from both clinicians and caregivers in the U.S. and a clear preference for intrathecal administration. The research findings are compelling for 2 main reasons. First, the research suggests that clinicians anticipate broad adoption of TSHA-102 across pediatric, adolescent and adult patients with Rett syndrome. Caregivers similarly indicated that they would actively pursue an improved gene therapy with a target product profile consistent with TSHA-102. Caregivers emphasize that improvements in existing function or the achievement of new functional gains would be meaningful for individuals with Rett syndrome as they translate into greater independence in daily living, such as speaking in phrases, walking with support or finger feeding, which we have observed in patients treated with TSHA-102 in REVEAL Part A. Second, clinical outcomes will be the ultimate driver. However, market research indicated that clinicians and caregivers strongly prefer intrathecal administration over direct-to-brain CNS delivery, setting its familiarity, accessibility and scalability, enabling the potential to safely and efficiently treat patients across institutions from large centers of excellence to regional and local institutions. This facilitates broad patient access. Specifically, intrathecal administration as it is used to deliver TSHA-102 is a routine minimally invasive delivery approach that does not require a surgical suite or delivery by a neurosurgery expert. This enables the potential for TSHA-102 to be delivered as an outpatient procedure, which in turn may meaningfully expand the treatment footprint given the administration in the commercial setting will not be limited only to centers of excellence. We believe this broader footprint would enable us to reach patients where they are already receiving care and support, and this is a scalable adoption as demand grows. Finally, as we advance towards registration, we are continuing to build out our internal commercial infrastructure. To that end, we recently appointed Brad Martin as Senior Vice President of Market Access and Value, further strengthening our commercial leadership team. Brad brings over 2 decades of leadership experience in market access and commercial strategy, pre-commercial and product launch planning as well as payer and health system engagement within the gene therapy space. He previously held senior roles at Neurotech Pharmaceuticals, Sarepta Therapeutics and AveXis. At AveXis, he played a crucial role in securing market access for the blockbuster gene therapy, Zolgensma, for the treatment of spinal muscular atrophy. We plan to continue to build out that commercial capability to prepare for potential commercialization, and we expect to share additional details on our TSHA-102 commercial strategy in the second half of the year. I would now like to turn the call over to Suku to discuss progress on the clinical front in more detail. Suku?

Thank you, Sean. As Sean mentioned, we believe we have made significant progress on advancing our TSHA-102 program towards registration. We are encouraged by the data previously shared from Part A of our REVEAL trial and the FDA alignment on a clear pathway to potential BLA submission. As a reminder, we presented data from Part A of the REVEAL Phase I/II trial last year, demonstrating a 100% response rate across our 10 treated patients in both close cohorts. In the high-dose cohort, an 83% response rate was seen at 6 months post treatment with 5 of 6 patients gaining or regaining one or more natural history-defined developmental milestones. By 9 months post treatment, the data demonstrated a 100% response rate across the 6 treated high-dose patients. In addition to the 22 developmental milestones gained, patients also demonstrated a total of 165 other skill gains and improvements across the core domains of Rett syndrome, an average of approximately 19 gains per patient as captured by validated clinical assessments. We have observed a consistent pattern of early gains that were sustained with additional gains over time, demonstrating a deepening [ offset ]. We believe these data enable our alignment with the FDA on the 6-month interim analysis for the REVEAL pivotal trial and supported by the FDA mission to grant breakthrough therapy designation to TSHA-102 in September 2025. We look forward to reporting longer-term safety and efficacy data across all 12 pediatric, adolescent and adult patients treated in REVEAL Part A in the second quarter of this year with all patients having reached a 12-month follow-up time points. We'll be looking to see a consistent pattern of early response that [ deepens ] over time across multiple clinical outcome measures as well as continued well-tolerated safety profile. Recently after Jeff Newell and the investigation of the NIH-funded IRSF Rett syndrome natural history study other publication describing the most comprehensive longitudinal view to date on the trajectory of the gain, loss and regain of developmental milestones in Rett syndrome. We believe this analysis of Rett syndrome milestones provide an important validation of our drug development strategy for TSHA-102 where we are focused on a set of [indiscernible] milestones identified as the most clinically meaningful to caregivers [ as an impact on ] activities of daily living. The publication demonstrates that the combined likelihood of spontaneous milestone gain or regain plus the milestones dropped to 6.3% after age 6 compared to rates as high as 85% between ages of 1 and 5 years. These findings align with our own analysis of the natural history data and provide strong external validation of our 2-study strategy, which allows us to generate data across the broader population while significantly mitigating statistical risk associated with a single-arm study measuring gain or regain of developmental milestones with the natural history derived control. Our FDA aligned REVEAL pivotal trial is enrolling 15 patients aged 6 to less than 22 years in the developmental plateau population of Rett syndrome, the population with the most stable baseline and lowest spontaneous improvement rate. Importantly, this design enables us to test our response rate against the low null hypothesis of 6.7%, requiring a minimum 33% response rate to demonstrate the efficacy. The aim of the ASPIRE trial is to validate the dataset in our patients to support the potential broad label for TSHA-102 in individuals aged 2 years and older with Rett syndrome. As Sean mentioned, we have dosed multiple patients in our REVEAL pivotal trial, Taysha enrollment continues to advance across multiple clinical trial sites. We expect to complete dosing in REVEAL and ASPIRE in the second quarter of 2026. We maintain that the safety and efficacy data we have generated to-date from Part A of our REVEAL trial are differentiating factors and believe our ongoing dialogue with the FDA over the last 2 years supports the potential of TSHA-102 to provide meaningful benefits to patients with Rett syndrome. Looking ahead, we remain focused on our clinical trial execution and data generation as we work to complete patient enrollment and advance toward registration. We believe the thoughtful data-driven approach we've taken in designing and executing our pivotal development strategy position us to deliver as well given broad label for TSHA-102. I would now like to turn the call over to Kamran to discuss financial results.

Thank you, Suku. Research and development expenses were $86.4 million for the year ended December 31, 2025, compared to $66 million for the year ended December 31, 2024. The $20.4 million increase was primarily driven by higher compensation expenses due to increased research and development headcount. Clinical trial and GMP expenses also increased during the year ended December 31, 2025, due to clinical trial activities in the REVEAL studies and BLA-enabling PPQ manufacturing initiatives. General and administrative expenses were $33.9 million for the year ended December 31, 2025, compared to $29 million for the year ended December 31, 2024. The increase of $4.9 million was primarily due to higher compensation expenses and higher legal and professional fees as well as debt issuance costs incurred in connection with the 2025 Trinity Term Loan that are recorded in general and administrative expense under the fair value option. Net loss for the year ended December 31, 2025, was $109 million or $0.34 per share compared to a net loss of $89.3 million or $0.36 per share for the year ended December 31, 2024. As of December 31, 2025, Taysha had $319.8 million in cash and cash equivalents. During the fourth quarter, we raised an additional $50 million in gross proceeds by utilizing our at-the-market or ATM equity offering program with proceeds intended to support a potential commercial inventory build in 2027. We expect that our current cash resources will be sufficient to fund planned operating expenses into 2028. I will now turn the call over to Sean for his closing remarks. Sean?

Thank you, Kamran. The progress we made in 2025 has set the stage for what we expect to be a transformative year ahead as we advance towards registration and our confidence in the differentiated TSHA-102 gene therapy candidate continues to strengthen based on the recent developments highlighted today. With a favorable tolerability profile demonstrated to date, continued patient enrollment and a well-defined regulatory and commercial path, we believe TSHA-102 has the potential to meaningfully address the genetic root cause of this devastating disease and provide meaningful benefit to a broad population of patients with Rett syndrome using a minimally invasive delivery approach. On behalf of the entire Taysha team, we remain committed to bringing a potentially transformative therapy to the Rett syndrome community. I will now ask the operator to begin our Q&A session. Operator?

[Operator Instructions] Our first question comes from the line of Kristen Kluska with Cantor Fitzgerald.

Congratulations on all the progress. So you had a lot of comments about why the community might favor intrathecal administration. I wanted to first ask if you believe the community has a good understanding of why this route of administration gets to the brain. And then also, you listed several reasons why this might be more favorable. I'm curious both from the clinician standpoint as well as the parent or caregiver if there's one item on that list that's standing out more than other.

Yes. Kristen, thanks for the question. I would say that the support for IT, there were manifold reasons why people wanted to go down that route. The most obvious is I think everyone can relate to a lumbar puncture. Right? I mean most of the moms out there have undergone that to some extent. People are familiar with it. They know it's not scary. And I think the most interesting thing is people are taking what I think is a very pragmatic approach. They're basically saying, "Hey, listen, if the data -- the clinical data are going to be the most important thing. And if the data are, let's say, equal, then I'm going to go do the most least invasive approach I can for the person that I love for the very simple reason that it doesn't involve as much drilling bur holes and going to the ICU and having a neurosurgeon involved." As they learn more about that, I think they're just like, "Hey, you know what, if all things are equal here at a minimum, then I'm going to take the safest, what I feel is the safest approach and the easiest approach." I think from the clinical perspective, it's the same kind of a logic set where they're saying, listen, ultimately, it's going to be the clinical data that's going to carry the day. But based on what we know right now, it's easy for us to do this lumbar puncture. And when they start to talk about the practical logistics of the sites, just the throughput necessary for intrathecal delivery done in an outpatient is much easier to manage. You don't have to schedule suite time, surgeon time, things like that. So they're saying in terms of being able to broaden the reach, go to regional and local hospitals and make sure that broadly, the Rett community has access to this therapy, it's a much easier route of administration to administer and provide great care to their patients. Hopefully, that helps.

Okay. Yes. And just on that point, they do understand that this route of administration is getting -- reaching the brain, right?

Yes. Certainly. We didn't get into -- we didn't explain to them the biodistribution. They're basically making the leap that if I administer it that way and the clinical data are good, it's going to where it needs to go. Like they're not -- they don't care about biodistribution. They care about the fact that, "Is my loved one going to get better or not." And they're judging that based on the clinical data, which the product profile is just the data that we've shown to date. So we feel very -- like we weren't surprised by these results at all, frankly. And I think it makes a lot of sense when you take a step back and just digest it all.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

With the appointment of Brad Martin as Head of Market Access and Value, what will the first priorities be in this role? And what are the key aspects of market access that Taysha will be focused on initially? And secondly, can you frame expectations for the update on longer-term safety and efficacy data from Part A? How many patients will we see? What kind of duration of follow-up and what you're looking for in terms of the efficacy profile?

Yes. Thanks, Salveen. To start with the second part of the question first, what you can expect to see is to take a step back, last time we reported data, it was 10 patients. And at the high dose, we had 6 months of data on 5 of the 6 patients. So what we're planning to do in the Q2 update, you'll see data on all 12 Part A patients, and we'll have a minimum of 12 months of data on all patients. The report out will be inclusive of the primary endpoint, which would be milestones. We're also going to give an update on the skills, the improvements. That's the data that we presented at CNS last year. You'll see the CGIs, you'll see the RMBA. So you'll get a very comprehensive picture of the data set. And what we hope to show is what we've been able to demonstrate to date, which is that the early improvements are sustained, and we continue to see deepening of response over the course of time. If you remember, the first patient we dosed by the time we report this data will be out 3 years post dose. So we're starting to generate some nice durability data, which is fantastic. As it relates to what the market access team is doing, there's a lot of steps to take, of course. We generally begin by making sure we're mapping out where the patients are and then what's the mix of the payers. So how much commercial pay is there, how much Medicaid pay is there. And then what we'll do is make sure from a site activation perspective, that we're thinking about the right way to roll this out. So as an example, because of our market research and what we've seen on the route of administration, what's going to be really nice is that we're going to be able to essentially get to the regional and local hospitals. We want to make sure, though, that we roll this out in a very thoughtful manner. And anyone using TSHA-102 is very educated on how to do this, knows how to manage gene therapy patients and that we're comfortable with them and their institution doing that. So part of it is mapping all that out so that we've got a good sequence to the flow. And then beginning to work with the payers and talking to them about the market size, talking to them about the clinical data. And the approach that we've taken historically, Salveen, has been get in early with the payers, be very transparent about what type of -- what's the volume of patients that they could potentially see, educate them on the disease state and educate them on your data set and really just take them along on the journey. So we look to build relationships with the payers. And that's what -- the nice thing about Brad is he has those relationships. He's done this multiple times. And it's never too early to start on this. You really want to get in as early as you can to really pave the road so that there's no surprises on the back end.

Our next question comes from the line of Biren Amin with Piper Sandler.

Congrats on all the progress. Sean, I noticed that the company had a successful Type C meeting with the FDA this quarter on CMC for TSHA-102. So maybe on the BLA, PPQ lots that you're initiating in the second quarter, when would these complete? And if REVEAL interim data are positive, how soon do you think you can file the BLA after the interim data?

Biren, can you repeat the first question?

Yes. So on the BLA enabling PPQ lots that are initiating in the second quarter of this year, when would these complete?

Kamran, do you want to take that?

Yes, sure. Thanks, Sean. So Biren, nice to talk to you. Yes. So the PPQ lots will be completed by end of this year. And in terms of the alignment with FDA, I'll turn it over to Sean.

Yes. I think, Biren, the plan we have would be we can do the analysis, the interim analysis once all patients dosed in the pivotal are at 6 months. That's when the blind would get broken. Obviously, we would -- that's going to be dependent on the last patient dose, right? So that's going to happen sometime in the second quarter based on everything that we're tracking to, which looks good. And then we have to adjudicate all that data. We have to make sure it's correct. The next step, we would sit down with the FDA, go through that data with them and work to align with them on what the next steps could potentially be, right? And so post that and post getting minutes, we would come back to the market and give you the update. The reason we don't want to say what the data are before we meet with the FDA is that, that's only half the story, right? So we think it's important to meet with the FDA. And I think there's a couple of potential avenues that could happen, right? I mean the best case scenario would be the agency is very pleased with the data, and they tell us to proceed to file on the 6-month data set, in which case, we would work to do that immediately. So to be clear, what we're doing in the background, we're writing the CMC modules, the preclinical modules. Those will be in the can and done. So if we get the clearance on the clinical, that would be the only piece that we'd have to write and then we could file the BLA and things would move forward relatively quickly. Another scenario could be the agency says, look, we think the data are good. Historically, we've always liked to see 12 months of data. We'd like to see 12 months of data. In that instance, we would make the case, well, okay, but then let's start the rolling submission because we've got all this other stuff done. You already know the primary endpoint has been met. You're looking for some additional time, okay. Now we would have made the case that the durability from Part A, which we can now pool based on our recent update on CMC, it would help us with that case upfront on the 6-month course of action. But if they want that, I think even in that scenario, again, the only thing that they would have to review would be the clinical module at the end. So that still pulls things up a couple of quarters. And then the last scenario would be they want to do things the traditional way and wait for 12 months. I think even in that scenario, the nice thing about the interim data, and again, we would share this with the market is that I believe what we'd be able to show is that the product works, you've met the endpoint, you've met the statistics of things. Now it's just time and execution, which I think the market would respond very favorably to as well. So the way I look at it is the FDA gave us the option to do the interim analysis. I believe it's based on the data that we showed and the early responses that we showed and the rigor in which the data were collected. So look, we've got a few good cards to play here, and we're looking forward to it as we step through 2026.

Our next question comes from the line of Tazeen Ahmad with Bank of America.

Can you talk about what you think the potential read-through from the recent negative opinion for Daybue from CHMP has for your program? And also what you think that, if at all, it changes what you think the commercial opportunity in Europe is? And related to that, what is your alignment currently with EU regulators on that?

Sure, Tazeen. I don't think there is a read-through based on what happened to Acadia. I think for those of you that have been around since Suku and I joined the management team here, back in the days when everyone talked about CGI and RSBQ, we were on the opposite side of that, if you remember. For gene therapy, you had to be able to demonstrate something that the eye could see that truly had impact on the patient and the caregivers, and it was unequivocal. And so we feel the data that we're generating is very unique. And really, no one has been able to demonstrate restoration of function in a neurodevelopmental disease before. And we're able to do that in multiple patients and across multiple clinical domains. And we've got natural history that is absolutely stellar. It's unequivocal. I think Jeff Newell's paper reinforces everything that we've done from a strategic perspective and supports our thesis on things. And then if we're able to demonstrate, look what's happening with the primary endpoint and people gaining these milestones. But then beyond that, what we're trying to emphasize in the script is, when you look at milestone gains outside the primary endpoint and you look at improvements that people are having, it's almost 20 per patient so far. That's based on what we reported last year. So it's a significant impact that you can't ignore. And the other thing, too, I would point to in the natural history data, there is RMBA data. So we can demonstrate in multiple ways against natural history how we're changing the course of disease and how this is a transformational treatment, which then gives us the power to capture value through price in a very meaningful way and get reimbursed for it. So I mean, if you take a look at what happened with Sarepta up until they had some of the unfortunate safety things, their launch was going great. And I would argue that the data that we're generating is quite demonstrable. We're not having to talk about a scale. We're not having to talk about a 1- or 2-point change in the North Star or a 1-point change in the CGI. The payers don't care. The payers want to see functional gains. They want to see concrete improvements, and that's what's going to lead to getting you approved. I hope that helps.

Yes, Sean. And maybe just a quick follow-up on Europe again, usually, there's a pretty deep discount on price. But again, just given that there would be a lack of therapies available, do you think that strengthens your position on pricing when it comes time to that?

Yes. I mean I think we're going to be in a very strong position on price because of the data that we have and because of the high unmet need in the disease state. So we feel that we're -- obviously, it's early days to get into what the actual price will be. But I think with where we sit and the data that we're capturing and the fact that it's happening across multiple domains and no matter what cohort we're looking at, all the needles are moving in the right direction in a meaningful way. I think we'll be able to capture the appropriate value.

Our next question comes from the line of Maury Raycroft with Jefferies LLC.

Congrats on the progress. For the REVEAL Part A update in first half of this year, do you plan to provide a sub-analysis showing the proportion of patients that achieved more than one developmental milestone by 12 months? And are you planning to show any -- in your data update, are you planning to show any patient level data with vignettes? And if so, how are you setting expectations for a number of patients and milestone gains that you can show in that update?

Thanks, Maury. Yes, to take the second part of your question first, we will likely highlight a couple of patient vignettes. And just to give you some perspective on why we show the data like we do, number one, we're going to have 12 patients worth of data. This drug is going to get approved or not approved in the aggregate, right? The aggregate data is what you get approved on. So I think making sure it's clear, and we'll share every endpoint that we're effectively capturing, you and the investors will get to judge the data and the probability of success in getting approved. So we think that's the most important thing. We think that's where the emphasis should be. I think highlighting a couple of patient vignettes would be helpful to basically show the early improvement and then the sustainability and the deepening of response over time and getting into more specifics about what is actually happening on a patient basis. So if we say that people are effectively gaining about 19 to 20 skills or milestones and improvements, let's tell you the story of what that looks like. Now if I did that for 12 patients, we would be on the call for 5 hours. So that's why we don't want to go through all 12 patients. We just want to highlight a couple of things. And then again, based on the aggregate, you can say, "Hey, I like this data or I don't like this data." But we think that's the right way to go ahead and to portray it. Can you remind me the first part of your question about the Part A?

Yes, just some sort of a formal sub-analysis showing the proportion of patients that achieved more than one developmental milestone by 12 months.

We'll take that into consideration. We're still working on what the ultimate way to portray things. We've got a few ideas on how to get it. We've gotten some feedback from investors on what they'd like to see. So we'll take all that into consideration, and we look forward to that update.

Our next question comes from the line of Gil Blum with Needham & Company.

Allow me also to add my congratulations on the progress. Just a couple of ones from us. So as it relates to your recent update on the ASPIRE study, was this in line with prior expectations? Was it faster? Or this is just run of course here? And our second question, it's good to see submissions using your RMAT designation of the CMC materials, which is a known issue in the space. Are you guys going to receive any feedback on what you've already submitted ahead of completing your filing? Or is this just going to happen later?

Okay. Let's take the ASPIRE. I would say -- and Suk could jump in. I would say we got a pleasant surprise in that initially, what we proposed to the FDA was a study of 2 to less than 6-year olds. And the FDA came back and said, listen, I mean, the brain volumes of a 5-year-old and a 4-year-old are effectively the same as a 6-plus. So we feel that, that data are already being captured and collected. And therefore, they just wanted us to focus on the safety of the 2- and 3-year-old because they do have less brain volume. And so that was the experiment that they wanted us to run. We did recommend the 3 month and they agreed with that. I don't know, Suku, if there's anything else you found interesting about that whole thing.

No what I would add to that, Sean, is that it's clear that the FDA is pretty comfortable with our safety and efficacy data up to the 6-plus age group, and they're going to let that data set to be used for the less than 6 and in that 2- to 3-year old, as you pointed out, because of the brain volume adjustment that's needed, they felt that was the appropriate age group for us to give them a small sample set on safety, and that could potentially be more than adequate for a complete BLA filing.

Yes. And Gil, your question about the CMC, can you just restate that?

Yes. Just wondering because you have an RMAT designation, is there any feedback the FDA could provide you on what you have submitted ahead of completing your filing? Or is that not part of it?

So I mean, I would put it. We've got -- because of breakthrough, -- we've got -- it's an additional way to get access to the FDA. So we do have our first breakthrough meeting with the agency coming up, and there'll be more of those along the way. But we'll use that to have a discussion around potential BLA submission scenarios and working to get at your question, which is you've seen CMC, you've seen our preclinical, just working to gain alignment on the completeness of the packages that we've -- that we're putting together and what we shared with the FDA. So I think we're going to have really good line of sight to where we stand. CMC is a good example. We could not be in a better position right now. So back when we did our first commercial lot, the agency said they deem that the clinical lot and the commercial lot were analytically comparable. Now that we've done more lots, they're continuing to say that. And now they're saying, if you continue to demonstrate this through PPQ, you can pool your data from Part A and from the pivotal and from ASPIRE because the product is the same. So that's the best you can possibly have right now. And I think that's an example of working closely with the agency. I know that they feel like there's nothing more on the preclinical side that needs to get done. It really is just generating that the pivotal data and the ASPIRE data are going to be the last aspects of the submission package.

Our next question comes from the line of Chris Raymond with Raymond James.

Congrats from us on the progress. Just maybe a competitive 2-part question, I guess. And maybe also wanted to drill down a bit on the BLA filing timing question. So Neurogene has made some comments in the past couple of weeks to the effect of the 6-month time endpoint is that they've gotten word from FDA that that's not clinically meaningful. And Sean, I think I've heard you say the difference here is you guys will have 12-month data from Part A to supplement, and that's kind of the difference maker. But I guess, is that the only difference maker? Or is there potentially something else like maybe the risk reward of the therapy or other factors? And then the second point is you got my attention with some of your market research commentary. And I think it's an aspect that could be pretty important. You're talking about intrathecal administration, being able to reach patients outside of large centers of excellence and being able to dose patients at the community center. Do you have any detail around the breakdown of patients between these centers of excellence and out in the community and from just sort of the setup there commercially, just assuming like both therapies are on the market at some point?

Yes. I can say that the research we've done to date show that about 50% of the Rett patients are associated with a center of excellence. That means that over the course of 1 year, there's one visit to the center of excellence. So that doesn't necessarily mean that it's the most convenient place for them to get the therapy. And put another way, there's 50% more patients outside of the COEs. So we think it's very important to make sure that there is a network of care that gets to where the patients are. And so with the data we have, we're able to map where are the patients, and then we're going to take a very thoughtful approach about working through access to care and making sure that the people that are using this are well trained, the facility has the right mechanisms in place to support gene therapy and things of that nature. But what's nice about the intrathecal route is it allows us to broaden that footprint in a relatively straightforward manner. And getting access to patients is the most important thing. Suku will tag team the question on the meaningfulness of 6 months. I mean I can just say the FDA never said that to us. So every case is unique. I guess the simplistic way I would answer that question is it depends what data you're generating in the first 6 months. And I think if those data are compelling from a clinical perspective, then the agency is going to take note.

Yes. What I would add to that, Sean, is that I haven't seen any data from Neurogene's initial studies that show that they have actual clinical efficacy in the first 6 months post dosing. And most of their clinical, in fact, appears to come much later, maybe 10 months post dosing. And usually, the FDA looks at proof of concept before they agree to an earlier analysis. And we have 6 month interim analysis from our Part A data that is more than convincing that allows them to say, yes, we can evaluate and bring that data set in for actual review and approval if necessary. And then the second component is they always point back to the construct because Neurogene's construct is single stranded and single-stranded constructs usually take much longer to come together in the nucleus of the cell of interest and actually become efficacious from a protein production standpoint. So I think that may have played a role in also the 6-month interim analysis being given to us, while in their case, there may have been some pushback.

Yes. The other thing, too, just to highlight, Chris, Daybue got approved on 12-week data. So I think it's really just what is being demonstrated at a certain point in time, right? Hope that helps?

[Operator Instructions] Yes. Our next question comes from the line of Jack Allen with Baird.

On the progress made over the course of 2025. I wanted to ask briefly about how enrollment is going in the pivotal studies and what aspects you're looking to, I guess, screen these patients on the basis of? Can you talk a little bit about the pre-dosing period in the trial and how you're identifying patients that are really apt for the clinical studies that you're enrolling right now?

Suku, we can tag team this. I would say, number one, Jack, there's consistency between Part A and Part B in that the severity of the patients is still a CGI-S between 4 and 6, right? We did -- one of the things we did -- we haven't provided the number, but one of the things we did put in the pivotal protocol is that of the 28 milestones, there needs to be a certain number of open milestones to get into the study from a screening perspective. So that's probably the most interesting aspect of things that you're looking at. Suku, do you want to talk about the enrollment and the progress that we're making?

Yes. So Jack, I mean, we have dosed multiple patients already. Multiple sites are active, and we are, frankly, I would say, have the potential to have more patients than we need to actually screen and dose. And we are well on time lines when it comes to dosing all 15 patients and actually having results, hopefully, for the 6-month interim analysis by the end of this year. I think that's where things are progressing at the present time.

Yes, Jack, I think one thing that's really important is that the training at the sites is super important, meaning we've created a stand-alone DMA, right? That's -- the Developmental Milestone assessment is our name for that. So it's a new cohort that we developed to standardize the data collection of the milestones. And the FDA was -- that was really where they spent the most of their time with us was how are you going to systematize and make sure that the data collection are rigorous to make sure that we understand at baseline what a patient could and couldn't do and then you replicate that in a consistent manner every single time you conduct the DMA. So that's really -- Suku's team has done a stellar job in activating the sites and training the sites and getting them up and running. But that really is in our discussions with the agency, a fundamental aspect that we wanted to make sure we had our hands tightly around.

Our next question comes from the line of Yanan Zhu with Wells Fargo.

I wanted to follow up on the pooling of data between the Phase I/II and the pivotal study, given that, that sounds like something why you did -- that's why you did the manufacturing comparability study. So in what form will the data be pooled? Are we talking about a supportive dataset separate from the top primary endpoint analysis? Or could the 2 study combine into one and give one number in the label? And then I have one additional question.

At a high level, I would say what the pooling allows you to do is multiple types of analysis, looking at the totality of your data. So you can pool for safety, you can pool for efficacy, you can pool for age distribution, you can pool for a lot of different things. And the agency is going to do all those things anyway. The fact that you've got the ability to do that, though, does create the ability for you to support further your package because you've got different and, I would say, additive analytics that you can utilize to support the package that you're making. I don't know what else you'd add to that, Suku?

Well, Sean, I wouldn't add much else other than to say it gives us a comprehensive large data set in this rare disease of Rett syndrome that allows us to look at, as you said, multiple analysis, but also duration of efficacy, but also impact on multiple milestone achievements over time. So I think it's pretty comprehensive strategy that we've come up with. And frankly, the FDA appears to agree with us, given that they agree that from a technical aspect, the clinical lots and the commercial lots that we are studying are both equitable. So I think it's a huge win for us to move this forward in a rapid manner.

Right. Congrats for the ability to do that. And my follow-up question is on expectation for the upcoming data update now with 12 months data on the milestones. What is the expectation for patients continuing to gain milestones between 6 and 12 months? And is there any chance to observe a loss of milestones? Or is that captured in the data so that we have a sense of true durability?

Yes, Yanan, we would expect that there are continuous gains that happen, continuous improvements that occur over the course of time. So that's what we would anticipate seeing in this dataset. I would say in terms of loss of gains and things like that, it's not what you would anticipate. I can say that sometimes, you can see something may not be demonstrated. Like if one of the girls has the flu or a UTI, it's very possible that they're not feeling well and they're not going to demonstrate something. It doesn't mean they lost it. And we -- I can just say in what we've reported on to date, we've never seen a loss of any gain. So we'll work to highlight that when we give the update in the first half.

Our next question comes from the line of Whitney Ijem with Canaccord Genuity.

I'm going to ask one ASPIRE question in 2 parts. First is -- just to double check on the language around the extrapolation. Is there any nuance there or like math involved? Or is it just that the REVEAL efficacy will be assumed for the ASPIRE population? And then the second question is just on dosing in ASPIRE. I think there was mention of a scaling based on brain volume. So can you -- any color you can give on that?

Yes, Whitney, there's really no math on the extrapolation. It was really just whatever you see in the 6 plus, that's going to get extrapolated into the younger age group. So that's where the alignment is with the agency. It's at a macro level. And then on the second part of the question on the scaling, yes, I mean, it's a very consistent mathematical equation that you use from the preclinical to get to your human equivalent dose. And we'll be using that same calculation in the 2- to 3-year old. So Suku, I don't know if there's anything more you'd add to that?

All I would add, Sean, is that the calculation for the 2- to 4-year olds is essentially equivalent to the 1x10^15 dose from an efficacy standpoint when you look at our preclinical models.

Right. So in terms of what they're getting.

Exactly. Yes, exactly.

Does that make sense? So a 2-year-old, even though they're getting less of a dose, it's equal to the 1x10^15 in a larger person. So they're getting the same therapeutic effect.

This concludes the question-and-answer session. I would now like to hand the call back over to Sean Nolan for closing remarks.

We appreciate everyone taking the time to listen to our 2025 update and corporate update as well and look forward to making progress throughout the year and providing an update in Q2. Take care, everyone.

This concludes today's conference. Thank you for your participation. You may now disconnect.