Taysha Gene Therapies, Inc. Q3 FY2025 Earnings Call

Good day, everyone and welcome to The Taysha Gene Therapies Third Quarter 2025 Earnings Call. Please note, this call may be recorded and I will be standing by if you should need any assistance. It is now my pleasure to turn the conference over to Hayleigh Collins. Please go ahead.

Thank you. Good morning and welcome to our Third Quarter 2025 Financial Results and Corporate Update Call. Earlier today, Taysha issued a press release announcing financial results for the third quarter ended September 30, 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 submissions; timing or outcomes of communications 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 regulatory agencies; our ability to realize the benefits of Breakthrough Therapy designation for TSHA-102; 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 December 31, 2024, that we filed February 26, 2025, and our quarterly report on Form 10-Q for the quarter ended September 30, 2025, that we filed today. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, November 4, 2025. 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 third quarter conference call. I will begin with an update of our recent corporate activities and progress across our TSHA-102 Rett syndrome program. Suku will then discuss the new supplemental analysis from Part A of our REVEAL Phase I/II trials. Kamran will follow up with a financial update, and I will provide closing remarks before opening the call to questions. In the quarter, we believe we made meaningful progress that sets the stage for what could be a transformative period ahead for Taysha. The recent regulatory clarity and progress we've achieved, which was enabled by the strength of our REVEAL Part A data set, rigorous data evaluation methodology, and our natural history data analysis, allows us to focus on executing our REVEAL pivotal trial and advancing towards BLA submission with clarity and confidence. A major milestone was the receipt of FDA Breakthrough Therapy designation for TSHA-102 at the end of September. This designation is designed to expedite the development and review of therapies for serious conditions that have demonstrated preliminary clinical evidence of substantial improvement over available treatments in one or more clinically meaningful endpoints. TSHA-102 received Breakthrough Therapy designation based on the FDA's review of available safety and efficacy data from all 12 pediatric, adolescent, and adult patients treated with TSHA-102 in Part A of our REVEAL Phase I/II trials, including clinical data from the previously disclosed May 2025 data cutoff. Receiving Breakthrough designation highlights the FDA's recognition of both the significant unmet medical need among the 10,000 patients suffering from Rett syndrome in the U.S. and the therapeutic potential of TSHA-102 to redefine the treatment paradigm for this devastating disease. Notably, over 80% of programs with Breakthrough Therapy designation that proceeded to file for approval have ultimately received FDA approval. We look forward to continued engagement with the FDA as we advance toward potential registration. In September, we finalized alignment with FDA on our REVEAL pivotal trial protocol and statistical analysis plan in support of our planned BLA submission for TSHA-102, following resolution of remaining clinical and statistical queries. Importantly, our previously aligned-upon key design elements remain unchanged. In line with FDA's guidance for cell and gene therapy programs that was issued in September, we believe that by prospectively aligning with FDA on the statistical analysis plan for our pivotal trial, we help ensure that the data set collected will be considered reliable and suitable for BLA submission. We are enrolling 15 patients in the developmental plateau population of Rett syndrome with a primary endpoint of response rate, which is defined as the percentage of patients who gain or regain one or more of the 28 natural history-defined developmental milestones. A response rate of 33%, equivalent to 5 out of 15 patients, is the minimum threshold for success sufficient to achieve our primary endpoint. Notably, we've observed a 100% response rate across the 10 patients in Part A of our REVEAL trials. Additionally, we aligned with the FDA on a 6-month interim analysis that may serve as the basis for BLA submission, potentially accelerating our planned BLA submission by at least 2 quarters. As previously disclosed, the data from Part A of the REVEAL trials demonstrated an 83% response rate at 6 months post-treatment, with 5 of the 6 patients treated with the high-dose TSHA-102 achieving a developmental milestone. We observed a consistent pattern of sustained milestone gains with a deepening of effect or additional milestone gains over time. By 9 months post-treatment, the data demonstrated a 100% response rate across the 6 treated high-dose patients in Part A. We believe these data support both the suitability of the 6-month time point to demonstrate clinically meaningful efficacy and that the 6-month efficacy data may be representative of treatment effects at 12 months. We believe this enabled our alignment with FDA that a 6-month interim analysis may serve as the basis for BLA submission. It's important to understand that we believe we received Breakthrough Therapy designation and achieved FDA alignment largely due to the results of the rigorous clinical evaluation methodology applied to our video-evidenced developmental milestone data from Part A of the REVEAL Phase I/II trials. In Part A, videos were centrally rated by multiple independent reviewers using milestone definitions from the pivotal trial protocol to ensure an objective, consistent evaluation of milestone gain and regain in the developmental plateau population where these gains are not expected to spontaneously occur. By adhering to rigorous milestone evaluation criteria based on natural history, this approach minimizes bias and avoids overcounting milestones by ensuring the milestones are truly eligible for gain or regain. As a result, this provides a reliable reflection of TSHA-102's disease-modifying therapeutic effect and ensures that the pivotal trial is well-powered to demonstrate efficacy. We will continue to have frequent and consistent interactions with the FDA. We presented our REVEAL Part A data from the May 2025 data cutoff, including the new supplemental analysis, which provides supportive evidence that further reinforced TSHA-102's consistent, multidomain impact on activities of daily living at the Child Neurology Society Annual Meeting in October. Suku will discuss these results shortly. With the strength of our Part A clinical data and a clear FDA-aligned path to potential registration, we believe we are strongly positioned to initiate our REVEAL pivotal trial and accelerate execution towards BLA submission. Dosing of the first patient in our REVEAL pivotal trial is scheduled and on track for this quarter, with additional patient enrollment expected to continue across multiple sites this quarter. On the heels of our strong clinical and regulatory progress, we are thrilled to have regained full global rights to our TSHA-102 Rett syndrome program. We regained these rights in October following the expiration of our 2022 option agreement with Astellas, which had granted Astellas an exclusive option to enter into a negotiation period to license TSHA-102 and certain rights with respect to change in control transactions. We appreciate the collaborative relationship we've had with Astellas and the unencumbered rights to TSHA-102 that we now hold, which enable us to focus on driving long-term value with full strategic flexibility and optionality. We continue to build out our infrastructure to support advancing TSHA-102 toward late-stage development and potential commercialization, if approved. This September we strengthened our commercial leadership team with the appointment of David McNinch as Taysha's Chief Commercial Officer. David brings over 2 decades of experience in global commercialization and strategic market development across multiple therapeutic areas. Most recently, he served as Chief Business Officer at Encoded Therapeutics, where he led the commercial and partnering strategy across the company's gene therapy portfolio. He previously held senior commercial roles at Prothena as well as InterMune, where he led the launch of Esbriet, the first FDA-approved treatment for idiopathic pulmonary fibrosis, and supported the company's acquisition by Roche. David reports to Sean McAuliffe, Taysha's Chief Business Officer. Previously at AveXis, Sean led the development and execution of the commercial launch of Zolgensma for spinal muscular atrophy, the first FDA-approved gene therapy for the treatment of a monogenic CNS disease, which has reached blockbuster status. With an estimated 15,000 to 20,000 patients with Rett syndrome across the U.S., EU, and U.K., compelling clinical data from Part A of our REVEAL trials, and a minimally invasive, commercially advantageous delivery approach, we see a significant opportunity to address a profound unmet medical need and drive long-term value. We believe our strong balance sheet, team with proven gene therapy experience, and the clear path to registration strongly position us to initiate our REVEAL pivotal trial and accelerate execution toward BLA submission. I will now turn the call over to Suku to discuss our clinical progress in more detail.

Thank you, Sean. As Sean mentioned, the regulatory progress we've achieved to date was enabled by the strength of our REVEAL Part A data and our natural history data analysis that allows us to objectively measure developmental milestone gain and regain in the developmental plateau population using each patient as their own control. At the Child Neurology Society Annual Meeting in October, we presented a comprehensive review of our Part A data set using the evaluation frame point and endpoints of our pivotal trial. As previously reported, 100% of the 10 patients in Part A achieved 1 or more natural history-defined developmental milestones following treatment with TSHA-102, with a consistent pattern of early gains that are sustained and new achievements continuing to emerge over time following TSHA-102 treatment. These milestones were all video evidenced and assessed by independent central raters according to the definition of milestone achievement from our pivotal trial protocol. These criteria enabled a reliable, objective, and consistent assessment of TSHA-102's efficacy, and importantly, show that our pivotal trial is well-powered to establish the therapeutic impact of TSHA-102. Additionally, we presented a new supplemental analysis of REVEAL Part A data that captured supportive evidence of additional skill gains and improvements outside of the 28 natural history-defined milestones. These gains are derived from the Adapted Mullen Scales of Early Learning, the Revised Motor Behavior Assessment or RMBA, and the observer-reported communication ability assessment, which are Rett-validated, structured assessments that evaluated prespecified skills and quantifiable improvements. The results show that in addition to the developmental milestones achieved across the treatment cohort in Part A, patients consistently gained multiple additional skills and improvements in core disease characteristics across the domains of autonomic function, communication, fine motor, and gross motor areas. We believe these findings reinforce the consistent, broad therapeutic impact of TSHA-102 on activities of daily living that are important to caregivers and clinicians. As we continue to prioritize safety, I am pleased to share that TSHA-102 continues to be generally well tolerated, with no treatment-related serious adverse events or dose-limiting toxicities across the 12 pediatric, adolescent, and adult patients treated with the high and low doses of TSHA-102 in Part A of our REVEAL trials as of the October 2025 data cutoff. We are encouraged by the data we've collected from Part A of our REVEAL trials, which we believe support the potential of TSHA-102 to provide meaningful benefit to children, adolescents, and adults living with Rett syndrome. We look forward to reporting longer-term Part A clinical data in the first half of 2026. I will now turn the call over to Kamran to discuss financials.

Thank you, Suku. Research and development expenses were $25.7 million for the 3 months ended September 30, 2025, compared to $14.9 million for the 3 months ended September 30, 2024. The increase was driven by BLA-enabling process performance qualification, or PPQ, manufacturing initiatives, REVEAL clinical trial activities, and higher compensation expenses as a result of increased headcount during the 3 months ended September 30, 2025. General and administrative expenses were $8.3 million for the 3 months ended September 30, 2025, compared to $7.9 million for the 3 months ended September 30, 2024. The increase of $0.4 million was primarily due to debt issuance costs incurred in connection with the refinancing of our existing loan and security agreement with Trinity Capital, which are recorded in general and administrative expense under the fair value option, and was partially offset by lower legal and professional fees. Net loss for the 3 months ended September 30, 2025, was $32.7 million, or $0.09 per share, compared to a net loss of $25.5 million, or $0.10 per share, for the 3 months ended September 30, 2024. As of September 30, 2025, Taysha had $297.3 million in cash and cash equivalents. We expect that our current cash resources will support planned operating expenses and capital requirements into 2028. I will now turn the call over to Sean for his closing remarks.

Thank you, Kamran. With Breakthrough Therapy designation and finalized FDA alignment, together with our strong balance sheet and full strategic control of TSHA-102, we believe we are entering the pivotal phase of development with focus and confidence in our ability to redefine the treatment landscape for Rett syndrome while driving long-term value. We remain on track to dose the first patient in our REVEAL pivotal trial, with additional enrollment expected at multiple sites this quarter. Additionally, we expect to report longer-term clinical data from Part A of our REVEAL Phase I/II trials in the first half of 2026. We look forward to providing further updates as we initiate our REVEAL pivotal trial and advance TSHA-102 towards BLA submission. I will now ask the operator to begin our Q&A session.

We'll take our first question from Kristen Kluska with Cantor.

Just curious, this time around in the pivotal trial, you have a lot more evidence going for you. So can you talk about the pipeline of interest and demand for being in this trial and then your thoughts about how long it could take to fully enroll?

Kristen, thanks for the question. I would say unequivocally that the demand to be in the trial is exceptionally high. I think the fact that we've been relatively consistently putting out both safety and efficacy data as we have maturation in the study and keeping close contact with the advocacy group, centers of excellence, and KOLs has led to a strong demand. So with that as a backdrop, let me just turn it over to Suku to give a little bit more flavor and then maybe just give timeline parameters around when we expect enrollment could potentially take.

Thanks for that question, Kristen. As Sean mentioned, we have identified over 15 sites for our clinical trials program Part B, all of which are centers of excellence. Notably, many of these sites have more than 100 patients diagnosed with Rett syndrome, and many of these individuals may qualify for a Part B trial, including pediatric, adolescent, and adult patients. In the best-case scenario, we could potentially enroll all 15 patients within a 3-month timeframe, while a more conservative estimate could range from 3 to 6 months. Many of these sites have already identified multiple patients, and there is significant interest in our gene therapy program due to the previously disclosed efficacy and safety in the Part A trial, along with the ease of administration of the gene therapy that has already demonstrated significant clinical impact. Thank you.

Yes. And maybe just one more thing to add. We highlighted it in the press release. But to Suku's point, we've got dosing schedules for the first patients already scheduled this quarter, and we expect other patients to enroll at multiple sites this quarter as well. So I think that speaks to both the demand and the alacrity at which the sites have worked to initiate the pivotal trial.

And Kristen, one more point I should emphasize is many of these sites may be able to dose more than 1 patient in a staggered parallel fashion. So we might be able to get 1, 2, or 3 patients 2, 3 weeks apart at some of these sites, which would further accelerate our timelines and hopefully make the submission of the BLA timeline even shorter and make this product available to deserving patients who have Rett syndrome.

Our next question comes from Salveen Richter with Goldman Sachs.

I was just wondering if you could touch on expectations for the longer-term data in the first half of next year and also help us understand in the context of your discussions with the FDA what they have signed off on in terms of that minimum threshold for success here that's sufficient for filing.

Thank you for the question, Salveen. Regarding updates in the first half of next year, they will align with what we've previously shared. As our data develops, we're looking at the full cohort of patients. Our goal is to have data on all 12 patients at the 12-month mark, which will be critical for comparison with the 6-month results. We also aim to continue updating information about the safety profile. We might provide an update in the first quarter with nearly 12 months of data, or we could wait until the second quarter, but we want to ensure the market knows we plan to deliver more updates on safety and efficacy that we believe will clarify the likelihood of pivotal trial approval. On FDA alignment, we emphasized in our script that the guidance released by the FDA in September aligns with our previous interactions. Specifically, they recommend achieving alignment on your Statistical Analysis Plan (SAP) before starting the clinical trial, which we have done. We submitted our SAP back in January, and after receiving approval to submit the final SAP and clinical protocol by the end of the second quarter without needing an end-of-phase meeting, we proceeded. We've addressed all follow-up questions related to the statistical analysis and clinical matters. We also reached out to the FDA to confirm there were no remaining statistical or clinical questions, and they confirmed that. We're confident that the completed threshold of a responder—defined by achieving or regaining one milestone and crossing the 33% response rate—aligns with our submitted statistical plan. We believe we're closely aligned with the FDA. Additionally, during milestone meetings about the final protocol and SAP, the Directors are present, supporting our process. We're very confident because we've complied with everything the FDA has requested. Our data's integrity and quality assurance throughout the collection process have been paramount. We've thoroughly reviewed our steps and received confirmation that we’re on the right track, which is why we are moving forward with patient enrollment.

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

I wanted to get a little bit more color on how you're thinking about the way we should all be thinking about the data from the younger patients, meaning the 2- to 6-year-olds, relative to the 6-plus-year-olds as it relates to efficacy in particular. And then on safety, should we be expecting to see a staggered release of safety data on that younger population relative to the older population? Basically, when could we expect to see data start to come in from that cohort base?

Thanks for the questions, Tazeen. Number one, I think the headline is our goal is to ensure that by the time we submit the BLA under any circumstance that these 2- to 5-year-old population is included in that, so that we would have a very broad 2-plus label effectively. And so the way we're stepping through that is this quarter we'll be having dialogue with the FDA. We've submitted the protocol to them, so we'll be getting some feedback on that. It is a safety-focused study. We have had discussions with the FDA, formal meetings with the FDA, where we've basically made the following request, that for this population, we want to establish safety, number one. We will collect some efficacy data, of course, but what we proposed was that we could extrapolate efficacy from the 6-plus population and that that would be sufficient for getting this younger group into the label. And the FDA agreed to that. So that's how we're going to step through it. We would anticipate beginning to dose these patients once we have alignment with the FDA, probably towards the middle of 2026. Again, because it's safety, we think the trains will align on time in terms of BLA submissions, and then we'll follow efficacy over the course of time in this patient population to see if there are things that are unique there. And if appropriate, we could certainly update the label with any new data we have. But again, to just restate the primary goal is that, at approval, you would have a label of 2-plus with no specific constraints relative to efficacy that's been collected. It's the full population that you're getting approval on.

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

So maybe just another one on protocols here. How much leeway do you think the agency provides regarding the method of video review and is it fair to assume that all companies in the space receive the same guidance on that?

In our experience, the most time spent in discussions with the FDA centered around the rigor of data collection for the primary endpoint. They were very concerned with our approach to ensuring high fidelity in the data and strong inter-rater reliability. To strengthen our case with the FDA, we conducted a pilot study at multiple sites testing the DMA with various central raters, which we included in our data package for protocol approval and the Breakthrough Therapy submission. Essentially, in our field, the quality of your work is determined by the data you collect, and the FDA was particularly focused on this aspect. Therefore, I believe that any organization entering a pivotal trial would be expected to provide at least video evidence and have it centrally adjudicated. The key question is whether you have conducted the experiment and if your methodology will yield the expected results. We feel confident because we have gathered data from our Part A study and employed central raters. Additionally, we executed a pilot study at multiple sites in the background, which reinforces our confidence and hopefully also reassures the FDA that our submission is robust, with high fidelity and inter-rater reliability.

Our next question comes from Biren Amin with Piper Sandler.

Are there any updates on your plans in Europe or discussions with the EMA on the applicability of Part B? And separately, is the bar for the interim analysis similar to that for the final 12-month analysis?

Thanks, Michael. Thanks for the question. First and foremost, our focus has been and will be on the U.S., number one, two, and three. That's the biggest market out there. We've been historically resource constrained, both financially as well as human resource capital wise. We're in a better position now, but we've really worked to make sure that we are as aligned as possible, with the highest probability possible to get things approved as safely and as quickly as we can in the U.S. We will continue, and what we've been doing, Michael, with Europe and the U.K. is working to enable them, so stepping through regulatory dialogs and things of that nature. We think that as we further generate data in Part A and also get into Part B, that will further inform those discussions and will give us an even clearer line of sight to what the options we have. We know we're going to have multiple options to go into Europe. There's some that we've taken in the past that would be the most efficient and make the most sense for all parties involved. We want to see if we can work to enable that. The other thing too is from a policy perspective, I think, we all know the challenges on both sides of the pond. We want to make sure we focus here at home and lock in those things. And we can also take the time while we're collecting the data to see how policy also shakes out from an ex-U.S. perspective as well. So the long-term goal is to enable Europe for sure. It's just a question of stepping through it in a very thoughtful manner.

Our next question comes from Maury Raycroft with Jefferies.

Congrats on the progress. Wondering if you'd tell us anything additional about timelines for IRB approval for the additional 2 to 5 sites that you'll need for the pivotal. And just when thinking about enrollment for this study, is there anything more you could say about the number of patients you could potentially have enrolled by the end of this year? Just helping provide some line of sight to potentially getting to data from the pivotal by the end of next year.

Yes, Maury, that's a great question. We can likely provide more information in either Q1 or sometime in the spring, as we gain better clarity. We've submitted the protocol to the FDA and are awaiting their feedback, which will definitely guide us. For the pivotal trial, we are planning to include 15 patients, although we expect the actual number to be less than that. From an IRB standpoint, this will be a new protocol, so it will go through the required process for IRB approval and ethics review. There are multiple sites interested in participating, so I don’t foresee that being a challenge. Our priority is to align with the FDA on the protocol and the statistical plan. Additionally, from an operational standpoint, we aim to do things efficiently to avoid hindering the enrollment of the 6-plus population. Our expectation is that since safety is the primary endpoint in the younger children's study, the two data streams will eventually converge. We also plan to include this data alongside the 6-plus pivotal data in the BLA submission, aiming for a broader label.

Our next question comes from Jack Allen with Baird.

Congrats on all the progress made over the course of the quarter. I guess my first one was on the broader sentiment of the FDA. There was quite a bit of news over the weekend and Monday morning driving CBER and some changes outside CDER. And I just wanted to get a sense for any thoughts that the team has as it relates to management interactions with the agency, whether the agency is functioning as expected and what your plans are going forward to interact. And then briefly on the younger patient cohort, I also wanted to ask about how you're thinking about dose. As you go into younger patients, you could theoretically increase the relative exposure if you're treating smaller patients with a fixed dose. I'm just curious if you have any plans to address that potential issue.

Yes, Jack, let me start with the second part of your question on dose. It will be 1x10^15 total vg, and we will adjust for brain volume. We want to ensure that younger children do not receive a higher dose per kilogram than anyone we have previously dosed safely. We have considered this carefully, and our clinical development team has done an excellent job. We have presented this to the FDA, and we are being very mindful of safety. We will provide more details once we finalize the protocol. Regarding the FDA, we have a few points to share. Previously, I mentioned that we had good alignment with Nicole Verdun. We have not made any changes since the new administration took over concerning our natural history assessment or proposed endpoints. I have mentioned this before, but no one has deterred us from our course. We believe this is due to the robust data we have gathered to support our case with the FDA. Moreover, our approach aligns perfectly with what the FDA is looking for. This is reflected in the FDA guidance from September, which emphasizes the need for alignment on protocols and statistical analysis plans before starting the study. We have learned from our first-in-human study and conducted a natural history analysis. Based on those insights, we are proposing a prospective pivotal trial along with the associated endpoint and statistical analysis plan and have worked with the FDA to ensure their approval. We have complied with their requests and confirmed that we are on the right track. Notably, we are not asking for things outside the standard processes. We are not taking Part A data and proposing changes that would require the FDA to approve based on a statistical plan presented after the fact. We are implementing a more conventional approach and initiating a new study. Suku, do you have any additional information to share?

Yes, one thing I would add, Sean, is that under Dr. Vinay Prasad and Vijay Kumar's current leadership of CBER, their team has followed the spirit of the RMAT designation in CBER and the Breakthrough designation that we have achieved. Our interactions have been very fluid, constructive, and useful. I just wanted to emphasize that.

Yes, Jack, I want to mention one last thing regarding Breakthrough. The internal standard operating procedure at the FDA for Breakthrough requests is that when a request is submitted, the Directors are notified. They then forward it to the review team, who reviews the request and provides recommendations. This process ensures that there is oversight. We have made every effort to base our requests on data, which is why we believe that the Breakthrough designation granted in September aligns with the current guidelines in the way they prefer. We have adhered to their September guidance concerning the protocol for pivotal studies and statistical analysis plans. We have approached it precisely as they would like, which is also consistent with what any administration would expect based on data. That's why I referenced the Peter Marks' group. It's important to note that they concurred with our approach based on how we proceeded. I have always maintained that data is crucial, and we stand by that. We will continue to progress and maintain transparency with the agency. As a consequence of receiving the Breakthrough designation, we can also arrange additional meetings with them, which we have already initiated, to discuss the Biologics License Application submission process and other related matters.

Our next question comes from Chris Raymond with Raymond James.

Just a couple of commercial questions here maybe. So you're starting the commercial buildout now with the hiring of a Chief Commercial Officer. Maybe talk about the footprint you'll need, how it will look, and maybe the milestones that we should expect in terms of, I guess, access progress. And then maybe a related question. Of the 28 developmental milestones, are there any that you think matter more, be it communication, fine motor, or gross motor milestones in terms of clinical acceptance among the physician community, or in terms of ease of access that we should be thinking about?

Yes. To address your second question, we selected all 28 milestones in collaboration with key opinion leaders and the advocacy community. If you speak to some of the key opinion leaders, they might mention higher order milestones, noting that there are 51 milestones in the natural history database. This terminology reflects the milestones that are clinically and functionally significant across the three different domains. I wouldn't say that any particular milestone is more important than the others; each one is relevant to the individual circumstances of each patient. When talking to parents, communication is a major concern for them. They want to know what their child is feeling, what they need, are they hungry, and how they can help them, which is understandable. That's why we believe we've established a consensus with the FDA that any one of those 28 milestones is significant. Additionally, we aim to demonstrate that, over time, not only are more of the 28 milestones being achieved, but the supplementary analysis was intended to highlight that, beyond these 28 milestones—which serve as a mechanism for our approval—there are numerous other positive developments occurring, as noted by clinicians and parents through independent assessments like the Mullen or the ORCA. The intention of this is to show that there is much more happening that is positive. We are witnessing improvements in function, as acknowledged by both parents and clinicians, and all of this will be included in our submission to the FDA as well as in discussions with payers.

Yes, thank you, Sean. I want to emphasize that since our trial design has patients serve as their own controls, each milestone is significant. Every milestone, whether it's one of the 28 we discussed or not, is important to the patient, their parents, and caregivers, as they all influence daily living activities. Given our Part A data set, I hope that as a physician and clinician, we will ensure that no patient is overlooked as we collect more data from Part B.

Yes. And then the first part of your question, Chris, about commercial, I'd say a couple of things. First, you're definitely on the leading edge of the curve here. We think starting in the first quarter, we really are going to put more color around how we see the commercial opportunity. I think, for starters, it really is underappreciated how large the patient population is. So we're doing a lot of work relative to claims data analysis and things of that nature to put finer points on things. We're also looking at the launch of Daybue. That's going to be a good surrogate for potential uptake. And the more that we're digging into things, the more robust we think the opportunity truly is, particularly in a situation where the data set that we're going to be able to discuss with payers and also get the treating clinicians and the families hopefully excited about what they're seeing is that no one's been able to demonstrate functional gains before in a neurodevelopmental disease, even in adults. So that opens up a really significant opportunity. And we also have known from the get-go that using CGI and RSBQ and those types of scales is going to mean absolutely nothing to the payers. They do not care what a CGI score actually is. They want to know what they're paying for. And what they're going to be paying for is going to be improvements in function or gains of function that haven't been demonstrated, which is why we feel so strongly that this endpoint for a gene therapy is the right way to go. An example is in Canada, the HTA denied Daybue being reimbursed because they couldn't determine the clinical relevance of a 0.3 change in CGI. So again, I think we're going to be on really strong ground with the data set that we're putting forward in a very significant patient population. And the other thing I'll say just in terms of the team, David McNinch is our new Chief Commercial Officer. He's got a ton of experience. He and I work together at InterMune on the launch of Esbriet, which was a big success. David was also recently at Encoded. He knows gene therapy very well. He reports to Sean McAuliffe, who's our Chief Business Officer. Sean was on the Zolgensma launch team. So we've got a very stacked group internally and, I would say, on the Medical Affairs team, our Head of Medical Affairs, Alain, ran Med Affairs in Canada for Acadia. So we feel like the field team and the commercial team, call it, the external-facing group, we've got just a stellar all-star team, and we'll continue to put out more perspective on that as we generate the data and move towards the BLA submission. Great question.

Our next question comes from Yanan Zhu with Wells Fargo Securities.

Wanted to dig into the statistical plan a little bit. Thanks for all the color so far on the call regarding alignment and the FDA. Given that the trial design is novel and there is not an external control arm, per se, wonder how the p-value is derived. And also in terms of the interim analysis, how unambiguous or subjective the threshold is for triggering filing based on interim? In other words, do you run any risk if you file on interim? Just wondering with regard to the actual data and the p-value in making that decision.

So that's a good question. I'll try to answer that for you in very simple, straightforward terms. So the evaluations are not subjective, they're actually quite objective, because remember, we have a natural history that is very tightly analyzed and the FDA accepted our natural history analysis. But it's very clear once these patients get above 6 years of age, they do not gain new milestones, or they do not regain milestones. And our evaluation process for achievement of new milestones or regain of milestones is video recorded. And as Sean has pointed out earlier, it's very rigorously evaluated by blinded central reviewers. And there are different reviewers for the 6-month interim analysis as well as the 12-month interim analysis. So you have to keep that in mind as well. Now remember, also the 6-month interim analysis, all 15 patients dosed have to reach that 6-month time point before we break the blind on the video evaluations and before we share the information or the data with the FDA for potentially filing on the BLA as we complete the study at 12 months. And that data set will also be available at the final filing of the BLA. So what we do is by the 6-month interim analysis process, we have the opportunity to shorten the time line of filing of the BLA by two quarters more. So again, the 6-month interim analysis also does not really have significant impact on the p-value nor the power of the study, given that the loss of the alpha is actually minimal, and it's a 33% responder rate is all that's needed really to meet our primary endpoint, whether it's a 6-month or 12-month analysis. And keep in mind that usually none of these patients at 6 months reach a new milestone or regain a lost milestone. Therefore, any milestone gained even by 1 patient is miraculous. So I will leave it at that. From a clinician's perspective, I think we have something that I hope that we can gather the data quickly and get our data set to the FDA so that we can make this therapy available to patients as soon as possible. I hope that answers your question, Yanan.

Our next question comes from Joon Lee with Truist Securities.

This is Mahdi on for Joon. So the question is, I just wanted to ask you to please remind us what is the actual definition of regaining again. And assuming that at the 6-month interim data is positive, how soon can you start filing for BLA?

Thank you for that question. This is Suku, and I will address it because it's important to clearly define what it means. Remember that once patients with Rett syndrome reach age 6 and older, they do not regain lost milestones. For example, if a patient under 6 years old can sit up without support and then loses that ability, post-treatment with TSHA-102, if that patient can sit up again without support, that is considered a regain of a lost milestone. On the other hand, a gain of a new milestone is where a patient under 6 could never use their fingers due to significant movements and could not pick up a spoon or cup to feed themselves. After treatment, if the patient is now able to use their fingers to pick up a spoon or cup and feed themselves, that represents a new milestone gained. This distinction is quite clear, which makes it straightforward for the clinicians evaluating the patients and the blinded video reviewers. It should also be evident to the FDA when they view our videos that our product works. Keep in mind that our video recording process, central raters, and blinding were developed from our AveXis experience years ago, and most of the team here at Taysha is dedicated to executing this program, hoping to achieve similar success for the SMA population as we did with AVXS-101, now known as Zolgensma.

It appears we have no further questions at this time. I'll turn the program back to the speakers for any additional or closing remarks.

We appreciate everyone taking the time this morning to join us. Have a good day. Thank you.

This concludes today's program. Thank you for your participation and you may disconnect at any time.