Taysha Gene Therapies, Inc. (TSHA) Q1 2026 Earnings Report, Transcript and Summary

Good day, and thank you for standing by. Welcome to the Taysha Gene Therapies First Quarter 2026 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 first speaker today, Hayleigh Collins, Senior Director of Corporate Communications and Investor Relations.

Thank you. Good morning, and welcome to Taysha's first quarter 2026 financial results and corporate update conference call. Earlier today, Taysha issued a press release announcing financial results for the quarter ended March 31, 2026. 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, making regulatory submissions, timing or outcomes of communications with the FDA and 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 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 that we have filed with the SEC, including in our annual report on Form 10-K for the full year ended December 31, 2025, that we filed on March 19, 2026, and our quarterly report on Form 10-Q for the quarter ended March 31, 2026, that we filed today. This conference call contains time-sensitive information that's accurate only as of the date of this live broadcast, May 6, 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, and welcome, everyone, to our first quarter 2026 financial results and corporate update conference call. On today's call, I will begin with an update on our recent regulatory, clinical and commercial readiness activities. Dr. Suku Nagendran, President and Head of R&D, will outline recently published preclinical data that continue to validate our novel TSHA-102 construct design and minimally invasive intrathecal route of administration. Kamran Alam, our Chief Financial Officer, will follow up with a financial update, and I will provide closing remarks and open the call for questions. We entered 2026 focused on a disciplined execution across our regulatory, clinical and pre-commercialization activities for TSHA-102 with the goal of delivering a potentially transformative therapy to a broad population of patients with Rett syndrome who continue to face high unmet need. Over the past several months, we have continued to advance our TSHA-102 clinical development program and made progress towards key clinical milestones anticipated in the second quarter of 2026. On the regulatory front, we recently held an initial breakthrough therapy Type B multidisciplinary meeting with the FDA. During the meeting, we reaffirmed alignment on the planned pathway toward a BLA submission for TSHA-102, covering the pivotal trial design, endpoints and BLA submission scenarios, including the potential to submit for approval based on a 6-month interim analysis from the REVEAL pivotal trial. We believe our consistent constructive dialogue with the FDA continues to support our streamlined path toward a potentially expedited BLA submission. Additionally, in the first quarter of 2026, we held a Type C meeting with the FDA, where the FDA endorsed our proposed Process Performance Qualification or PPQ campaign strategy in support of our planned BLA submission. I am pleased to share that we initiated the BLA-enabling PPQ campaign using our TSHA-102 commercial manufacturing process in April, and we expect to complete execution by the fourth quarter of this year. As a result, we are confident that our CMC activities are on track to support our BLA submission in step with the pivotal data readout. As a reminder, the FDA previously agreed that TSHA-102 material produced from the clinical and final commercial manufacturing processes are comparable, and therefore, they support our ability to utilize the clinical data across all clinical studies in our TSHA-102 development program in our BLA submission. The ability to leverage the totality of evidence to support the long-term clinical benefit of TSHA-102 would strengthen the overall package and support a potentially expedited BLA submission based on the 6-month interim analysis. Turning to our clinical progress. We further advanced dosing in the REVEAL pivotal trial with multiple patients dosed across multiple clinical trial sites. In parallel, enrollment in the ASPIRE trial is ongoing across multiple sites, and we remain on track to complete dosing in both trials this quarter. I am pleased to share that both high and low-dose TSHA-102 continue to be generally well tolerated with no treatment-related serious adverse events or dose-limiting toxicities observed in all patients treated across the REVEAL Phase I/II and REVEAL pivotal trials as of the May 2026 data cutoff. We look forward to reporting longer term data from all 12 pediatric, adolescent and adult patients treated in Part A of the REVEAL Phase I/II trials later this quarter. Our pivotal development strategy is grounded on the rigor of our natural history analysis and Part A data collection and evaluation with trial design, endpoints and statistical analyses developed based on discussions and written feedback from the FDA. Accordingly, developmental milestones in Part A are assessed using 3 structured criteria, all of which must be met in order for a developmental milestone to qualify as a gain or a regain post TSHA-102. First, all caregivers must complete the clinician-administered historical milestone questionnaire used in the natural history study. This allows us to identify milestones eligible for gain or regain by confirming whether a milestone was never previously achieved or was lost long enough ago that the likelihood of a spontaneous gain or regain is less than 6.7%. Establishing a documented time since loss is fundamental to accurately differentiate a true regain from natural variability as each of the 28 milestones has its own determinant. A simple baseline assessment is not sufficient documentation to support a rigorous statistical assessment and is susceptible to false positives. Our approach ensures milestone history is captured accurately so that only true open milestones are counted as gains or regains. Second, the milestone gain must be captured by post-treatment video documentation. This provides evidence of milestone gains that can be objectively reviewed, which brings me to the third criterion. Video evidence must be independently evaluated by multiple external raters using a prespecified definition of achievement for each milestone from our pivotal trial protocol. We believe these criteria are essential for interpreting functional outcomes and provide a reliable assessment of TSHA-102's efficacy as we advance towards registration. We believe our Part A data accurately reflect the outcomes we expect to observe in the pivotal trial as they are evaluated using the same FDA-aligned criteria for the pivotal trial protocol. As a reminder, we presented data from Part A of the REVEAL Phase I/II trials last year, demonstrating an 83% response rate at 6 months post treatment with 5 of the 6 patients treated with the high-dose TSHA-102 gaining or regaining at least developmental milestone. 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 across the 10 patients treated with TSHA-102, patients also demonstrated a total of 165 additional functional skills and improvements across the core domains of Rett syndrome, an average of approximately 19 functional gains per patient. We observed a consistent pattern of early gains that were sustained with additional gains seen over time, demonstrating the deepening of effect. In our upcoming Part A data readout, we expect to report longer term follow-up, including at least 12 months of data from all 12 patients treated with TSHA-102. These results will include functional gains based on natural history-defined developmental milestones and additional functional skills and improvements impacting the activities of daily living that are meaningful to the caregivers and clinicians. We will be hoping to see a consistent pattern of early responses that are sustained and deepen over time across functional gains and clinical outcome measures in the treated patients. We believe this longer term follow-up will provide important context around the durability, deepening of effect and consistency in responses. With FDA alignment on the potential to pool data across the full TSHA-102 development program and our BLA submission, we believe the longer term Part A data has the potential to strengthen the overall BLA package and support an expedited submission. In parallel to our clinical and regulatory execution, we continue to build out our internal commercial infrastructure. We have strategically assembled a strong commercial leadership group, including senior hires who have deep expertise in commercial strategy, pre-commercial and product launch planning as well as payer and health care systems engagement within the gene therapy space. With these key roles now in place, we are focused on developing a strategic commercial strategy to prepare for a potential launch, and we expect to share additional details on our commercial plans in the second half of the year. I would now like to turn the call over to Suku to discuss evidence that further validates the TSHA-102 program and route of administration in more detail. Suku?

Thank you, Sean. We have continued to make meaningful progress advancing TSHA-102 towards registration and remain confident in its differentiated potential. A key design attribute of TSHA-102 is its minimally invasive intrathecal route of administration, which market research shows is strongly preferred by clinicians and caregivers over direct-to-brain central nervous system delivery. This preference is driven by its familiarity, accessibility and scalability, enabling broad access to treatment across institutions from major centers of excellence to regional and local sites. A peer-reviewed article was recently published by Frontiers in Medicine Gene and Cell Therapy, which highlights preclinical data we previously presented at the 2025 International Rett Syndrome Foundation Rett Syndrome Scientific Meeting. The data showed that intrathecal and direct-to-brain intra-cisterna magna administration demonstrated comparable, consistent and widespread distribution of AAV9 vector throughout the brain and spinal cord in non-human primates. We believe this further validates lumbar intrathecal delivery as a potentially safe, effective and minimally invasive approach to deliver a gene therapy to the central nervous system. In addition, on May 14, we plan to present new preclinical data that further validates the construct design of TSHA-102 at the ASGCT 2026 Annual Meeting. Consistent with previously published vector comparisons, the data demonstrated that the self-complementary AAV9 vector enables significantly higher protein expression compared to single stranded AAV9 in neuronal mouse cell models. The 30-fold higher transduction efficiency demonstrated in this study, along with the improved genomic stability of self-complementary AAV9, supports our ability to effectively deliver TSHA-102 to the central nervous system using a minimally invasive lumbar intrathecal administration. In addition, the data showed that the mini MECP2 protein used in our TSHA-102 construct was functionally comparable to the full-length MECP2 protein across molecular and biochemical functions. We believe these data support the strategic TSHA-102 construct design and provides important translational context for the early, sustained and deepening functional gains demonstrated across all patients previously reported in Part A of the REVEAL Phase I/II trials. We believe this supportive evidence, our continued FDA alignment on a registrational path and the clinical data generated to date support the potential for TSHA-102 to provide meaningful benefit to pediatric, adolescent and adult patients with Rett syndrome using a minimally invasive delivery approach that is scalable. Our focus remains on clinical execution and data generation as we work to complete dosing in our REVEAL pivotal and ASPIRE trials and report long-term data from Part A of our REVEAL Phase I/II trial this quarter. I would now like to turn the call over to Kamran to discuss financial results.

Thank you, Suku. Research and development expenses were $33.8 million for the 3 months ended March 31, 2026 compared to $15.6 million for the 3 months ended March 31, 2025. The $18.2 million increase was primarily driven by BLA-enabling PPQ manufacturing initiatives performed during the 3 months ended March 31, 2026 and higher clinical expenses from the REVEAL Part A Phase I/II, Part B pivotal and ASPIRE trials. Compensation expenses, including non-cash stock-based compensation also increased as a result of additional research and development headcount. General and administrative expenses were $9.7 million for the 3 months ended March 31, 2026 compared to $8.2 million for the 3 months ended March 31, 2025. The increase of $1.5 million was primarily due to higher compensation expenses, including non-cash stock-based compensation expense and increases in consulting and professional fees, including commercial launch readiness initiatives. Net loss for the 3 months ended March 31, 2026 was $42.4 million or $0.12 per share compared to a net loss of $21.5 million or $0.08 per share for the 3 months ended March 31, 2025. As of March 31, 2026, Taysha had $276.6 million in cash and cash equivalents. 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. Our confidence in our differentiated TSHA-102 gene therapy candidate continues to strengthen based on the developments highlighted today. And we continue to believe TSHA-102 has the potential to deliver meaningful therapeutic benefit to a broad population of patients with Rett syndrome using a minimally invasive delivery approach. With a favorable tolerability profile demonstrated to date, dosing in the REVEAL pivotal and ASPIRE trials on track for completion in the second quarter of 2026 and a well-defined regulatory and commercial path, we're advancing toward potential registration with clarity as we work to bring a potentially transformative therapy to the Rett community. I will now ask the operator to begin our Q&A session. Operator?

[Operator Instructions] Our first question today comes from Kristen Kluska from Cantor.

Congrats on these updates. So I wanted to ask you a little bit more about some of the data you're going to have at ASGCT. For the work you're doing that supports higher MECP2 protein expression with the self-complementary AAV9, can you tell us why this matters so much versus the obvious of just having more protein expression? Does this allow for a greater orchestra across more neurons? Does it mean a faster onset of action? What would you truly highlight here?

Thanks for the question, Kristen. I think Suku and I can tag team this. But at a high level, I think what we wanted to do was really provide the why as to what the clinical result that we're generating is, right? I mean from a clinical perspective, in every patient treated, whether it's a pediatric patient, adolescent patient, adult patient, everyone has been a responder. We're seeing multiple skills and improvements across all of these patients and they happen quickly and then they improve over time and get deeper. And so the question is why does that occur? And I think what we're highlighting at ASGCT is the fact that the construct, which we purposely utilize self-complementary technology ultimately drives in this data set, a 30x transduction efficiency or protein expression than single strand does. And so that is a reason why you could potentially use a less invasive route of administration like intrathecal versus having to go with a closer to the brain approach. And usually, you have to do that because of a single strand. The other thing, too, is just reinforcing the fact that the mini MECP2 gene continues to show comparability. It's been published for over 15 years that this has been the case. But again, we just wanted to highlight that regardless of the genotype that we're seeing in these 12 patients that we've dosed to date and that we'll report on in a few weeks, they're all responding and they're responding across clinical domains. And the gene, the mini gene is very much a part of that because it essentially equals the full-length gene. And again, the reason we use the mini gene was so we could package the self-comp. So we're just trying to highlight the fact that the reason -- all the reasons that we put into building the construct are being demonstrated clinically and that this allows us to use a particular route of administration that we know is strongly preferred out in the community. Suku, I don't know if there's more you might want to add to that.

Yes, Sean, I have a few more points to add. So Kristen, thanks for that incredibly important question. What we've already shown with our REVEAL Part A program is that a simple lumbar puncture, a self-complementary mini gene construct using TSHA-102 gives you incredibly important clinical results from an efficacy standpoint that translates into a significant improvement in activities of daily living. So the clinical data at the present time from Part A now speaks for itself. So now when we work backwards and continue to further look at preclinical data, whether it's us or from other companies, it is very clear that a self-complementary construct turns on very quickly once given into the central nervous system, i.e., via the CSF. Once it turns on, it has rapid impact on one of the most important components of Rett syndrome, which is the autonomic dysfunction component, where we have impact pretty quickly usually within a couple of weeks post dosing. We've also shown repeatedly now in Part A that we have very positive clinical impact consistently regardless of age, genotype or phenotypic presentation of the patient with Rett syndrome, where there is an improvement in gross motor, fine motor skills or restoration of those skills, which have been lost over time, but also improvement in the ability to communicate as well as when it comes to social activities. So my point here is that a self-complementary stable construct turns on quickly, it persists and it continues to persist and build on top of all the preclinical data that we have that shows that a lumbar puncture with the right product can have a simple but consistent positive clinical response for a post patient population that has significant unmet medical need. And in this case, Rett syndrome. And I think we may have set the stage for an intrathecal lumbar puncture-based platform to treat difficult CNS diseases.

Our next question comes from Salveen Richter with Goldman Sachs.

Regarding the BLA submission pathway for 102, can you walk through the different scenarios here and whether approval based on the 6-month data should be considered the base case assumption? And how you characterize the willingness of the FDA to approve based on 6-month data sets and time lines around this, that would be great?

Yes, Salveen, great question. We've been out talking with the investment community really since the beginning of the year, and this topic has come up. And so I think those that are on the call, this will sound very familiar, but we were very transparent with the FDA. Part of this meeting was trying to gain alignment and we were walking them through various scenarios. And we told them point blank that our preferred scenario would be a full approval at 6 months' worth of data. And the argument for that, right, I mean, generally, they like the precedent of 12 months of data for gene therapy, which is arguably probably pretty arbitrary, to be honest, but that's generally what they've held to. And I think our perspective on that is understood. But if we continue to demonstrate comparability with Part A, we're going to have years of data from those patients that we can use to support the durability. And their answer was essentially, look, ultimately, this is going to come down to the totality of the evidence. And this is something that if the company chooses to do, we will -- we are open to it and we will review that in due course, which is really the best answer you could possibly get, right, which is the door is open, let the data speak for itself. The second derivative of that, in our view, was basically if for whatever reason the FDA decides that let's just say they want to keep it as a precedent at 12 months, we would push hard for a rolling review because the CMC modules would be done, the preclinical modules would be done. And we can have things updated where the 6-month data is packaged in a way that they could look at that and also then there's less to review when you would submit the final 12-month data, and that can pull things forward a couple of quarters. And then obviously, the third scenario would be there may be nothing at all wrong with the data. They just want to see 12 months. So we feel in any of those scenarios, number one, there continue to be a positive and constructive dialogue with the agency. There was no opposition to anything that we put forward. There was an openness to it. Clearly, it's going to come down to the totality of the evidence and their comfort level around the data package that's put forward. But as we've said all along, the nice thing about this 6-month interim is it creates the optionality for us to potentially get this to patients faster. And my personal opinion, I can be wrong, is that almost regardless of what we come back with, I know everyone would prefer it's the fastest time point. And obviously, we're going to do everything we can to facilitate that. But we'll have clarity for the market. And even in the scenario -- and don't read into this, it's just even in the scenario where it's a 12-month ask, we can say that and you know what our 6-month data are and people can judge the probability of success, and then it's an execution story. So for all the reasons that we laid out in this call, we feel that there is strong evidence to push for the 6-month data. The fact that we've got comparability with the FDA on the CMC side is absolutely critical to this. And that opens the door for us to pool the Part A data alongside the pivotal Part B. And in our opinion, really should alleviate any concerns on the durability piece. So ultimately, we'll leave it at that. The nice thing is we've got this option -- these options in front of us, thanks to the data that we've put forward today and also the CMC quality that we've put forward today. So we're in the best possible position we can be. We've got a couple of cards that can fall our way, and we're excited about having this discussion with the FDA at the appropriate time.

Our next question comes from Biren Amin with Piper Sandler.

Recently, the FDA Commissioner announced the real-time clinical monitoring program that enables the FDA to evaluate data real-time. Is that something that the company can leverage for REVEAL given the high unmet need in Rett syndrome, especially Sean, with the 6-month data and the agency potentially following patient data to 12 months during review under this program? So I guess that's the first question. And then second question for REVEAL. Do you expect to stop enrollment at 15 patients or could you potentially over-enroll as is typically the case with clinical trial management and execution? And if that's the case, how does the over-enrollment impact the effect size calculation for the study?

Yes. Just real quickly on the real-time piece, I'll ask Suku to comment on that. But I would say we're always keeping our eyes open for what we could potentially do. Like the other one is the commissioner's voucher, right? Things are so dynamic up there. It can be difficult sometimes to tell what's afforded to you and what's not afforded to you. I think that what I just laid out in terms of scenarios, we feel very good about. If there's an opportunity for us to lever one of these additional pathways, sure, we would try to do that. But again, I don't want to try to make it sound like that's what we're attempting to do out of the gate here just because it's not as formalized and crystallized in terms of the time lines, what you need to meet the hurdle bar, et cetera. I don't know if there's anything you'd add to that, Suku.

Yes, Sean. I mean, Biren, thanks for that very interesting and important question because what the FDA has proposed, I think, could change the way clinical trials are overseen by the FDA with their direct hands-on experience and oversight. But at the same time, as the real-time data pours in, I think the regulators and the sponsors, clinical regulatory teams will have to work very closely to make sure appropriate interpretation is done when it comes to real-time safety data and efficacy data, because especially in the rare disease space, as we know, we are learning not only about the disease, but also the response to the therapeutic intervention at that point in time. And sometimes the real-time decisions versus a more time process-oriented decision could have significant impact and influence on programs. So I hope that helps, because at this time, we are kind of watching the process interestingly. And you mentioned the decision-making governance between the regulators and the sponsors are going to be critical to make sure real-time oversight of clinical trials will pay the dividends that the FDA hopes it will.

Yes. And then the question around the potential for over-enrollment, I would say that you're always trying to balance the -- getting the appropriate patients in screened essentially, understanding that there could potentially be a screen fail. Like one of the criteria we have, right, there's a number of open milestones you must have, right, as an example. You could go through the screening and then find out that, that patient doesn't quite meet it. So you're going to want to have more patients than 15 going through the screening process. And if you do end up in a situation where you dose an extra patient or 2, we would be certainly willing to do that. I can just say that the effects on the statistics are minimal. I mean they would obviously look at the first 15 patients first and do the statistics on that. And then if you had another patient or 2, they would do the statistics on that, but they really don't change much. Anything else you would add there, Suku?

No, the only thing I would add there, Sean, is that as you said, the power and p-values for a patient sample size of 15, if it goes to 16 or 17 based on what Sean just described, it won't have a major impact on power or p-value for the study itself. And as you know, from REVEAL Part A, we already have 100% responder rate at 9 months with a small number of patients. And those observations, I think, are significant. And as you know, all we need is a 33% responder rate for our REVEAL Part B study. So let us see what the eventual data pans out, but I think we are confident that the Part A data hopefully should be reproduced in Part B as well.

Yes. I think the key, Biren, is just simply that the null hypothesis is so low. It's effectively 1 patient spontaneously having an effect. So because of that number being such a low aspect, the overall end doesn't really change things very, very much. But good question. Thank you.

[Operator Instructions] And our next question comes from Tazeen Ahmad from Bank of America.

This is Wesley on for Tazeen. I had a question on sort of the mechanics of the Part B portion of the study compared to the Part A. Are the like assessments being done of the patients, the treated patients being done in the same way in Part B to Part A? Who is doing the video recordings? And with regards to sort of the patients that you are currently screening and plan to dose, are those sort of sites and investigators similar between Part B and Part A? I'm just trying to like look for any color on sort of straight lines we can draw from the 12-month update you're going to share soon to what we can expect and how the Part B is running.

Thanks for the question. And Suku, we can tag team this. Our view is that the read-through from the upcoming data review that we're going to put out should be pretty direct for all of you. And that's why we've put so much emphasis around the rigor of the data collection in Part A. We spent a lot of time on the call talking about that. And it starts with the fact that, number one, what we rate is -- so first of all, all of our milestones for the primary endpoint are prespecified, right? There's clear definitions for those. And those demonstrations are from videos that are conducted in the study itself. So when people -- the way it's been working is that people are doing the hand function test or the RMBA or the Mullen. If we have video of them doing a milestone, that video then goes outside the company and 2 of 3 raters have to adjudicate that as a milestone. So the company has nothing to do with what is declared a milestone. And I think that has been a big part of the reason why the agency has been open to our data set and the interim analysis is that we had rigorous video evidence that was adjudicated outside the company. Now the other side of this coin is that the Mullen, which is another video tape demonstration and the RMBA are also supportive data sets that the agency sees. Again, those are on video. The Mullen also gets centrally adjudicated and the FDA -- and the RMBA is done in the clinic by the physician, right? So there's no real way to be putting your thumb on a scale and making this data subjective. It's very objective. So I think this is a good read-through to Part B. The only difference in Part B is that we're going to have a standalone assessment of all of the milestones. So I would argue that we're probably undercounting milestones in Part A and that we have a better chance of counting more milestones in Part B because there's a standalone test. We spent a lot of time with the FDA developing this test. We have training modules around this test. The test is conducted in the hospital by trained assessors at the hospital. So this is not done at home. The parents aren't doing this. This is very prescriptive and it's done in-house. Those videos then go outside the hospital to the raters where they remain blinded until they break -- until the 6-month time period where they break the blind for all of the 15 patients and review those videos. So the whole point of what we've been trying to emphasize since we began reporting data on milestones is clear definitions, rigorous baseline collection with videos assessed by central raters. It's going to be very similar in Part B, but even more rigorous. And I think there's more ability to capture milestones because we now have a standalone test. So hopefully, that gives you a perspective there, but I think the read-through should be pretty direct when we update you in a few weeks.

Our next question is from Maury Raycroft with Jefferies.

This is James on for Maury. For the 12-plus months of follow-up in the 2Q update, how are you setting expectations for the early milestones and skills deepening versus new more complex milestones and skills appearing between 6 and 12 months? And how do you plan to communicate that in the update relative to the last presentation last year? And also, should we expect a potential safety update from the REVEAL pivotal cohort around IRSF or how should -- or should we expect that update at a later point after IRSF?

Yes. To answer your second question first, I mean, even today, when we said that as of the March safety cutoff, that was inclusive of the REVEAL Part A and also the pivotal trials and ASPIRE. So that's all the studies that we're running right now. You just got a safety update on no treatment-related SAEs and DLTs. And we'll continue to do that on a quarterly basis. And the first part of the question, could you repeat that? I already lost it.

So the 12-plus months follow-up in the 2Q update, how are you setting expectations?

Yes. I mean to be very simple, and I'll turn it over to Suku, what we've seen on the reports that we did last time was that there's early responses. There's more responses that occur as time goes on relative to milestones, relative to skills and improvements. And that the things that you had, you get better at and you're also developing new milestones, new skills and new improvements. That's what we would expect to see at 12 months.

Yes, Sean, as you have emphasized, what we will communicate is the rapid, consistent, persistent clinical impact of TSHA-102 in patients with Rett syndrome regardless of genotype, phenotype or age. And I would also emphasize that we hope that we can continue to show a significant collective improvement in "skills" that per patient could go above the 19 per patient that we disclosed this morning when Sean did his segment of the communication. So just pay attention to that as well because I think a component of reaching developmental milestones in a validated manner, as we've already discussed and described, which the FDA truly likes. And I'm going to emphasize these are done in a blinded reviewer, expert reviewer fashion and not done at home by caregivers, which usually the FDA has questions around. So I hope that our 12-month plus data disclosure further enhances the confidence in what TSHA-102 can contribute potentially in a transformative manner to this patient population.

Yes. I guess last comment there, James, is that we don't expect to see any type of a plateau. We expect to continue to see improvements and new improvements over time based on the historical disclosures.

Our next question comes from Gil Blum from Needham & Company.

Maybe just another one on the 6 months interim, as a clarification, the FDA basically has not given a clear feedback as to what it thinks about this 6-month interim. Would you say that what would dictate the decision here would be the data itself and the 12-month data that you're going to present at IRSF?

Gil, can you repeat that? I honestly didn't quite get the point of the question.

The point is you haven't really gotten clear FDA feedback as it relates to the 6-month interim. They're actually waiting for the data. Is that fair?

Yes. I mean I think that is fair. I think the clear feedback we got is that it's an option for us. And that's all you can ask for at this particular point in time. They've consistently said since we put that disclosure out, I guess it was June '25 where we started talking about that. It's always been something that's enabled. We just confirmed, and we've gotten a lot of questions from investors like, hey, when was the last time you talked to the FDA? It's like, well, we talked twice in the last few months here, once on CMC and once on our first breakthrough meeting. And we went back through, we got confirmation on the design, on the endpoints and our scenarios that I went through. And they're like, yes, I mean that is an option for you. It's going to depend on the data in terms of approvability. So you're never going to get anything better than that, which is why we were so with the outcomes from that meeting.

Okay. So to summarize, they're open to it.

I didn't hear that.

Yes, they are open to the 6-month...

Yes, yes. And it's in writing, by the way. I mean, so it's as good as you can get. There was very much an open-mindedness to this. And it's an open door for us at this point in time, and it's going to be won by the data.

[Operator Instructions] Our next question is from Chris Raymond with Raymond James.

Maybe just 2 here. Just on the Process Performance Campaign or PPQ. You mentioned FDA has agreed on equivalency between the clinical and the commercial manufacturing. Maybe just can you give a little bit more color on what activities, what are sort of the pinch points, I guess, in terms of getting to having something you can submit in Q4 between now and then? And then one of the things that kind of struck us, we've done some KOL work where people seems physician -- the physician community seems very aware that you have a broad range of ages in your data. Maybe just talk a little bit more about the importance of enrolling a broad age range? And how that's being received by the clinical community from your perspective?

Sure. So Chris, starting with the PPQ, we aligned on comparability when we had the clinical lot that was in Part A, and then we ran our, call it, our final commercial process. We ran a lot of that. And so it was 1:1, and the FDA deemed that, that was analytically comparable. And what you have to continue to do as you produce more lots is demonstrate that there's -- those additional lots are also comparable. So at this last meeting, we shared with them multiple additional lots that we'd run, and they continue to say that we're comparable. Now as you go into PPQ, you're generally doing 2 or 3 additional runs and then you share that data with the FDA. So we're in the process of doing those runs right now. Assuming those runs continue to be demonstrating comparability, that's when you're able to pool the data. So the fact that we've been able to do it with multiple runs so far gives us a lot of confidence. There's a strong alignment with the FDA. And then we take that data package and the next time we meet with them, we share that with them, and that's kind of the next step. So we feel like we're in a really good position on the CMC side, and we have been for quite some time. It is not on the critical path to the BLA submission. So that's that. As it relates to the broad ages of enrollment, if you think about the prevalent population, 85% of the prevalent population is over the age of 10. So demonstrating effect across pediatric, adolescent and adults is very, very important, because as we've done market research with both caregivers and with clinicians, they plan on offering it across the age spectrum. And they're planning to offer it because there's demonstrated effect across the age spectrum. So we feel that we're in a good position to serve the broad community who is requesting gene therapy because of the data that we've generated, and that's why we're being thoughtful about making sure that there's representation across the age spectrum in Part B. So our whole goal is to make this available for all patients with Rett syndrome and the data continue to support that. And I can tell you that the demand is high across the age groups based on what we've seen so far.

Our next question is from Jack Allen with Baird.

Congrats on the updates. It sounds great to hear that enrollment is on track to be concluded in the second quarter of this year. I guess my question is pretty simple, and that I was wondering if you could provide any additional color surrounding how far you are as it relates to completing enrollment? How many patients have been dosed in the study? And then maybe if that's a little too direct, if you could just speak to the enthusiasm you're seeing from the patient community and the interest in the trial?

Yes. I think Suku can take the second part of the question. I mean we're not going to give specifics. I would just say the demand is super high. It's high across the age spectrum, multiple sites -- we've got 10 sites that are active. Multiple patients have been dosed across multiple sites. Most of the sites have multiple patients. So I mean, do you want to talk a little bit about the enthusiasm and the demand that we're seeing across the spectrum?

Absolutely. So we have multiple centers of excellence who are part of the clinical trial, and they all have 100, 200-plus patients. Many of the patients' caregivers and parents have been very enthusiastic about being screened and enrolling in our trial. So I would say with confidence that we are over-enrolled and we have more than enough patients to dose to meet the 15 -- the number of 15 or a little bit more. So we should be -- we will be meeting our commitment to complete dosing for both REVEAL Part B and ASPIRE by the end of the second quarter this year.

Our next question is from Whitney Ijem from Canaccord Genuity.

Just thinking about durability, how often are patients assessed in Part A? And I guess I'm just wondering if there's a scenario where later this year, either we or the FDA is getting like an 18-month update on those patients and then potential for longer term updates going forward?

Yes. Thanks for that question, Whitney. That's actually a very important question that you raised. So given that we have a Part B ongoing, and we have an agreement with the FDA that the 6-month interim analysis once all 15 patients in Part B are dosed would be considered based on the efficacy and safety data for potential full approval of our product, the REVEAL Part A long-term data from a clinical standpoint, safety and efficacy, I think could significantly also impact the 6-month interim analysis from Part B collectively driving towards the full approval. And Sean clearly described that the FDA is aligned with us when it comes to the CMC process and the comparability technicalities between the Part A product and the Part B product. So to really answer your question on Part A, the long-term data, I think, up to 18 months being evaluated per the protocol post 12 months every quarter, I think it's going to be also important to the collective 6-month interim analysis. And if the 6-month interim analysis gives very useful clinical data, and Sean described the other scenario for Part B where you might need 12-month data as well, the REVEAL Part A persistence of effect long term will also, I think, influence further the confidence that our product will have immediate, consistent and persistent effect long term as well in this patient community.

Yes. The only thing I would add, Whitney, is when we report the data, we will also report the data that's greater than 12 months. So you should have a real good sense of what's happening over time.

Our next question is from Evan Seigerman with BMO Capital Markets.

Malcolm Hoffman on for Evan. Thinking about potential commercial manufacturing, I just wanted to ask what redundancies exist across TSHA-102 manufacturing chain that could help if there were any disruptions to the process?

Yes. So to answer the question, so we currently are at Catalent, and Catalent's Baltimore, Maryland facility has obviously been inspected and they have extensive gene therapy manufacturing experience. And we feel really confident in the team that's at Catalent and our oversight of the team there. And importantly, as Sean mentioned earlier, we have ensured that based on our lock manufacturing process, CMC is not on the critical path to a potential BLA submission. And as it pertains to downstream potential redundancy in manufacturing, that's something as we get closer to Part B interim data readout. And as we get closer to a potential BLA submission, that's something we will evaluate to mitigate any potential disruption to supply chain. But we feel really confident given Catalent's manufacturing experience in that particular facility in Baltimore that, that facility can meet our ultimate commercial demand.

And Evan, that's where Sarepta is making Elevidys as well. And so it's been FDA inspected, and they're very familiar, as Kamran said, with gene therapy commercial scale. So we feel very confident about that.

Our next question is from Yanan Zhu with Wells Fargo.

This is Jeff on for Yanan. Today and in the last couple of months, market research has been touched on, indicating strong demand for gene therapy in Rett and a clear preference for intrathecal delivery, including mentioning 80% of caregivers and clinicians are seeking gene therapy for their patients. Can you provide any additional color or details on this market research in terms of if you tested any product profiles for TSHA-102 and patient -- physician preference specifically for TSHA-102?

Yes. I mean -- and there'll be more to come in the second half, deeper dives on the commercial aspect of things. But we essentially tested with physicians. So it was about half the physicians were at centers of excellence, half were not at centers of excellence. And then we also separately ran a study with caregivers of Rett patients or children with Rett across the age spectrum. And we kept it pretty simple. I mean we basically -- our product profile was -- our product profile that you've effectively seen, the responder rate, the CGI scores on average with the duration of time that we've been testing these patients. Think about the last data update we gave last year and the deck that we used, it was effectively that on a one pager. And then we just toggle that with is it intrathecal or is it ICV? What would it matter, assuming the same set of data? And so number one feedback consistently in both groups, physicians and the caregivers was very high interest in gene therapy. They realize that you want something that treats the root cause. So there's a very high interest in seeking that out, number one. Number two, what was interesting is it's also -- there's high treatment being sought across the age groups, including those over 30. So that also was encouraging. And then when you distill this down to make it real simple, and again we didn't want to make it too technical at first. I think more has to be shown to get more precise on comparative product profiles. But if all things are equal on safety and efficacy, obviously, there's a preference for the least invasive route, both in terms of perceived safety, but also just in terms of some of the physicians were making the point on throughput in the institutions that it's a lot easier to put -- let's just say you had 100 patients at an institution, it's easier to stage and manage those patients efficiently using intrathecally versus if you have to fight for OR time, neurosurgeon time, et cetera, it's harder to do that. You're going to have more intrusions, you're going to have more emergencies coming in that you're going to have to work to allocate time. So the scalability effect was something that was also quite top of mind for the physician group. So hopefully, that gives you a little flavor for the data.

Our next question comes from Silvan Tuerkcan with Citizens.

I maybe just wanted to follow-up on the intrathecal injection here. So that is not a procedure, right? So that can be done in the outpatient setting versus maybe some of other routes of administrations that may potentially come to the market as well. Can you just speak about that and potentially the cost differential between a full procedure that would require OR time in neurosurgery versus not? And then I don't know if you can comment on this, but do you know the screen fail rate that you currently have? And is that predominantly because of the strictness around the baseline measures?

Yes. In terms of the first question, what we're doing is a 20-minute lumbar puncture administration with mild or no sedation. So the patient can easily have this done and be out of the hospital well within...

Same day.

Yes, same day, well within 24 hours. The ICV approach, obviously, you need to be in the OR for that. You have to have a neurosurgeon do the procedure. And so there is greater time and cost associated with that procedure. In terms of breaking it out, that's something we can talk more about in the second half. But just from an efficiency perspective, the ability to give someone a lumbar puncture, obviously, you can do that in various spots throughout the hospital and do it safely. That's not the case with ICV. I mean there are certain parameters that you're going to have to have, certain staff that you're going to have to have, including neurosurgeons to do the procedure itself. And keep in mind that the OR time is booked in advance. There's only so much OR space. There's only very few neurosurgeons to do these procedures. So my point is that and the point that the physicians were making is that if you have a large number of patients, it would be much more efficient in the institution to be able to dose them on the -- via the intrathecal route for the reasons that I gave. The second question, I didn't quite get. So I don't know if anyone around the table got that or Silvan, if you could repeat that, I didn't get it.

Yes. And obviously, the trial is ongoing. So -- but if you could just speak to the current screen fail rate, just to give a feel of are there -- is there a significant patient population out there that just cannot qualify for this therapy because, let's say, they're too advanced or not advanced enough or do you have any data points in that direction?

So Silvan, you asked actually a very interesting and important question, because remember, Rett syndrome, there are multiple different genotypes. There is a very differentiated phenotypic presentation, meaning multiple phenotypes that present as Rett syndrome. And then you also have the complexity of mosaicism when it comes to central nervous system. So it's a unique combination that eventually results in a complex clinical presentation. And what we've shown in REVEAL Part A is that regardless of genotype or phenotypic presentation or age, our gene therapy given through a simple lumbar puncture consistently provides superior clinical efficacy with no major safety concerns at this point in time. When it comes to screen failure rates, in Part A, as far as I recall, there were no screen failures. In Part B, we have not discussed the screen failures publicly at this point in time. But they are minimal. And given that the common route to the disease is a lack of MECP2 or minimal MECP2 levels that have clinical efficacy or impact on the patient, restoration of MECP2 levels using TSHA-102 in general, addresses the lack of MECP2 and has superior clinical efficacy results up to now. So my assumption here is as we experience and complete Part B REVEAL study and ASPIRE that screen failure or loss of market, I guess, a clinical market access to a large group of patients is not an issue and will not be an issue. I hope that answers your question.

This does conclude our question-and-answer session. I would now like to turn it back to Sean Nolan, Chairman and CEO.

Thanks to everyone who called in. I really appreciate the time and interest in Taysha. Have a great day.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.