Taysha (TSHA) Q3 2026 Earnings Call Transcript

DATE

Thursday, Nov. 12, 2026

CALL PARTICIPANTS

• Chief Executive Officer - Sean Nolan
• President and Head of R&D - Sukumar Nagendran
• Chief Financial Officer - Kamran Alam
• Chief of Staff and Technical Operations Officer - Fred Porter

TAKEAWAYS

• Cash and Cash Equivalents -- $422.8 million as of Sept. 30, 2026, which management expects will support planned operating expenses and capital requirements into the second half of 2028.
• Net Loss -- $39.1 million for the third quarter, compared to $32.7 million in the prior-year period.
• Research and Development Expenses -- $28.8 million, an increase of $3.1 million year over year primarily driven by clinical activity in the REVEAL and ASPIRE trials and increased headcount.
• General and Administrative Expenses -- $13.1 million, reflecting a $4.8 million increase driven by commercial launch readiness initiatives and compensation expenses.
• Total Patients Dosed -- 33 participants treated with TSHA-102 across three trials as of the November 2026 data cutoff, all of whom have cleared the acute post-dosing safety monitoring period.
• Pivotal Trial Milestone -- 17 patients dosed in the REVEAL pivotal trial, with the last patient dosed more than four and a half months prior to the call.
• ASPIRE Trial Status -- four patients dosed in the pediatric study, with the final patient dosed more than three months prior to the report.
• Manufacturing Purity -- single-digit empty capsid percentage achieved across commercial-scale batches, intended to improve product quality and patient safety by reducing vector load.
• Clinical Safety Profile -- zero reports of severe treatment-related serious adverse events or dose-limiting toxicities across the 33-patient dataset as of the latest data cutoff.
• High-Dose Level -- 1x1015 total vector genomes (vg) administered in clinical evaluations, which management reported as generally well tolerated.
• Low-Dose Level -- 5.7x1014 total vector genomes (vg) administered in clinical evaluations, showing a consistent safety profile across broad patient ages and genotypes.
• Potential BLA Submission Timeline -- first half of 2027 for reporting six-month interim pivotal analysis data and obtaining FDA feedback on the regulatory pathway.
• Pipeline Expansion -- nomination of an additional gene therapy candidate for a central nervous system disorder with high unmet medical need expected in the first half of 2027.
• Payer Engagement -- ongoing pre-approval information exchange discussions with payers conducted since 2025 to support potential market access.
• Manufacturing Yields -- production of finished good doses from Process Performance Qualification batches that management expects will result in favorable cost of goods sold.
• Net Loss Per Share -- $0.10 for the third quarter, compared to $0.09 in the three months ended Sept. 30, 2025.
• Payer Strategy Duration -- two years of advance planning performed by the market access team to coordinate with centers of excellence and distribution partners.
• Pivotal Trial Primary Endpoint -- a statistical requirement for approximately one-third of patients to respond at six months to achieve significance in the interim analysis.
• ASPIRE Safety Cohort -- inclusion of pediatric patients as young as 2 and 3 years of age with no treatment-related serious adverse events reported to date.
• Manufacturing Validation -- successful completion of commercial-scale batches at the Harmans facility in Maryland to support the potential Biologics License Application.
• Potency Release Strategy -- alignment with recently finalized FDA guidance on cell and gene therapy to solidify the commercial potency release plan.

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RISKS

• Nagendran reported that a patient experienced a Grade 2 peripheral neuropathy event, which was classified as a serious adverse event because the patient "had to be admitted for treatment and was discharged in less than 18 hours post-treatment" per hospital protocol.

SUMMARY

Taysha Gene Therapies, Inc. (NASDAQ:TSHA) reported the completion of critical clinical and manufacturing milestones for its lead program, TSHA-102, as it prepares for potential regulatory submission in 1H 2027. Management indicated that all 33 patients dosed across current trials have cleared the acute safety window, and the company successfully completed its commercial-scale manufacturing validation campaign. The company stated that its current cash position provides a runway into the second half of 2028, supporting both the Rett syndrome program and the planned nomination of a new central nervous system gene therapy candidate. Management reported that commercial readiness activities, including payer engagement and site readiness at medical institutions, are advancing in parallel with clinical development to support a potential market launch.

• CEO Nolan indicated the management team will suspend public discussions in January 2027 while preparing for the FDA Type B meeting and analyzing interim data.
• Nolan stated that the construct design excludes introns to theoretically mitigate the risk of vector integration, distinguishing it from other gene therapy approaches.
• Fred Porter noted that the commercial manufacturing process at the Maryland facility demonstrated comparability to clinical material, supporting the inclusion of earlier Phase I/II data in the planned regulatory filing.
• Nagendran reported that spontaneous milestone gains are negligible in patients over 6 years of age according to natural history data, suggesting that clinical responses observed in the trial are attributable to the therapy.
• Management confirmed the interim analysis will involve a blinded review of five videos per patient, including two baseline and three post-dosing assessments, to evaluate primary endpoint success.
• Nolan stated that single-digit empty capsid percentages are intended to minimize total vector load exposure for patients while simultaneously improving manufacturing efficiency.

INDUSTRY GLOSSARY

• AAV9: Adeno-associated virus serotype 9, a viral vector used to deliver genetic material to the central nervous system.
• BLA: Biologics License Application, the request for permission to introduce a biologic product into interstate commerce.
• CMC: Chemistry, Manufacturing, and Controls; the body of information that defines the manufacturing process and quality control.
• DLT: Dose-Limiting Toxicity, a serious side effect that prevents increasing the dosage of a drug.
• IRSF: International Rett Syndrome Foundation.
• MECP2: The gene that provides instructions for making the MeCP2 protein, which is essential for brain function.
• miRARE: miRNA-Responsive Auto-Regulatory Element technology, designed to regulate protein expression levels.
• PPQ: Process Performance Qualification, a series of manufacturing runs to demonstrate that a process can consistently produce a quality product.
• Rett syndrome: A rare neurodevelopmental disorder caused by mutations in the MECP2 gene.
• SAE: Serious Adverse Event, a medical occurrence that results in hospitalization or other significant medical intervention.
• vg: Vector genomes, a unit of measurement for the concentration of a gene therapy.

Full Conference Call Transcript

Operator: Thank you for standing by, and welcome to Taysha Gene Therapies Third Quarter 2026 Financial Results Conference Call. [Operator Instructions] I would now like to hand the call over to Stephanie Webster. Please go ahead.

Unknown Executive: Thank you. Good morning, and welcome to Taysha's Third Quarter 2026 Financial Results and Corporate Update Conference Call. Earlier today, Taysha issued a press release announcing financial results for the quarter ended September 30, 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, 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 foreign regulatory agencies, our ability to realize the benefits of Breakthrough Therapy designation for TSHA-102, our ability to drive long-term value for stockholders, and the market opportunity for our program.

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, including our potential nomination of an additional gene therapy candidate in the first half of 2027, manufacturing and commercial readiness activities, strategic alliances, and intellectual property, as well as matters that are not historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements.

For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the SEC, including in our annual report on Form 10-K for the full year ended December 31, 2025, that we filed on March 19, 2026. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, November 12, 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.

Sean Nolan: Thank you, Stephanie, and welcome everyone to our Third Quarter 2026 Financial Results and Corporate Update Conference Call. On today's call, I will begin with an update on our recent clinical, manufacturing, and commercial readiness activities. Dr. Sukumar Nagendran, President and Head of R&D, will then provide an update on the TSHA-102 program. Kamran Alam, our Chief Financial Officer, will follow up with a financial update. Finally, I will provide closing remarks before opening the call up to questions. During the Q&A, Fred Porter, Chief of Staff and Technical Operations Officer, will also be available for questions.

The third quarter marked another period of strong execution for Taysha, during which we made meaningful progress across our clinical, manufacturing, and commercial readiness activities, supporting a potential BLA submission and the potential future commercialization of TSHA-102. As we round out the year, we remain focused on building upon the robust dataset generated thus far in preparation for a potentially catalyst-rich period ahead, including top-line data from the REVEAL pivotal trial six-month interim analysis and potential FDA feedback on the BLA submission pathway expected in the first half of 2027. I'll first touch on our clinical progress, which Sukumar will elaborate on later on the call.

Following the completion of dosing in both the REVEAL Pivotal and ASPIRE trials, we are pleased to announce that all 33 patients dosed with TSHA-102, 29 in the REVEAL Phase I/II and pivotal trials, and four in the ASPIRE trial, have cleared the acute post-dosing safety monitoring period associated with AAV gene therapies. The last pivotal trial patient was dosed over four and a half months ago, and the last ASPIRE patient was dosed over three months ago. We are very encouraged by our clearance of the acute safety window, which continues to demonstrate that TSHA-102 is well tolerated in all patients.

This represents a key milestone for our program and gives us further confidence in the favorable safety profile observed to date and the continued advancement of TSHA-102 toward a potential BLA submission and potential future commercialization. As a reminder, once all patients in the REVEAL pivotal trial complete six months of follow-up, we will conduct an interim analysis, which may serve as the basis of our planned BLA submission and potentially accelerate our submission timeline by at least two full quarters relative to filing on the 12-month data.

We continue to expect to report full top-line data from the interim analysis and potential feedback from the FDA on next steps in the BLA submission pathway in the first half of 2027. Both high and low-dose TSHA-102 continue to be generally well tolerated. Notably, across the broader TSHA-102 clinical program, which began over three years ago, 33 patients spanning a broad range of ages, genotypes, and disease severities have been treated, with no severe treatment-related serious adverse events or dose-limiting toxicities reported as of the November 2026 data cutoff, supporting a favorable and consistent safety profile for trial participants across the program.

I also want to touch on our commercial readiness efforts and the achievement of a major manufacturing milestone in the fourth quarter of 2026, with successful completion of our BLA-enabling process performance qualification, or PPQ, manufacturing campaign for TSHA-102. Recall, following a Type C meeting in January 2026, we aligned with the FDA on our proposed PPQ strategy, including the production of commercial-scale drug product batches required to validate our final TSHA-102 commercial manufacturing process in support of our planned BLA submission. We have now completed the BLA-enabling PPQ manufacturing campaign for TSHA-102, with all process parameters and analytical results meeting the predefined product specifications, as well as comparability criteria for commercial product and clinical material.

In addition, our assessment of comparability between PPQ commercial product and the clinical trial material conducted under the FDA-aligned strategy supports the potential inclusion of the REVEAL Part A data in the planned BLA submission, further supporting the potential for a BLA submission based on the pivotal six-month trial interim analysis. We are also very pleased with the yield and the number of finished good doses manufactured from each of our PPQ batches, which we believe should translate to efficient and favorable cost of goods sold to support our potential commercial launch. Additionally, the commercial manufacturing process consistently achieved a single-digit empty capsid percentage, an important indicator of product quality that contributes to patient safety.

These results demonstrate our ability to consistently manufacture high-quality product at the scale required to support the potential commercial demand and potential commercialization. We look forward to sharing these data and finalizing our CMC plan with FDA at a Type B meeting expected later in this fourth quarter. Beyond manufacturing, we also continue to advance our broader commercial readiness efforts during the third quarter, further building out our commercial organization and advancing key market access initiatives, including expanding our payer team, conducting pre-approved information exchange discussions with payers, progressing site readiness activities at institutions, and advancing trade and distribution readiness activities to support the potential launch of TSHA-102.

We believe the progress made across clinical manufacturing and commercial readiness efforts has positioned us well for multiple key upcoming regulatory interactions. In the fourth quarter, we plan to discuss the manufacturing data with the FDA to further strengthen the CMC package. Thereafter, we plan to engage with the FDA on next steps in a potential BLA submission pathway, and we will share the feedback from this meeting, along with the top-line data from the six-month interim pivotal trial analysis in the first half of 2027. With multiple potential milestones on the horizon for Taysha's Rett program, we continue to leverage our expertise in CNS genetic medicines as we begin to position Taysha as a broader genetic medicines franchise.

We expect to nominate an additional gene therapy development candidate targeting a CNS disorder with high unmet medical need and robust commercial opportunity and commence preclinical development activities in the first half of 2027. With that, I'll turn the call over to Sukumar.

Sukumar Nagendran: Thank you. As Sean highlighted, we achieved several important milestones this quarter that we believe further strengthen the foundation of TSHA-102 and its path towards potential registration. As a reminder, 33 patients have been treated with TSHA-102 in the REVEAL Phase I/II, REVEAL pivotal, and ASPIRE trials. Across studies, dose levels, and broad patient population, TSHA-102 continues to be generally well tolerated, with no severe treatment-related serious adverse events or dose-limiting toxicities observed as of the November 2026 data cutoff. Notably, this favorable safety profile includes the ASPIRE trial, where no treatment-related serious adverse events have been reported amongst all participants as young as two and three years of age.

As Sean mentioned, all patients in the REVEAL and ASPIRE trials have now cleared the acute post-dosing safety monitoring period commonly associated with AAV gene therapy. With all patients in the REVEAL pivotal and ASPIRE trials now beyond this period, and no severe treatment-related serious adverse events or dose-limiting toxicities identified across all 33 patients. The growing safety dataset continues to support the favorable and consistent safety profile observed across our TSHA-102 program, and the benefit-risk profile continues to remain highly favorable. In the third quarter, we further highlighted the scientific foundation supporting TSHA-102 through multiple encore presentations at the 55th Child Neurology Society Annual Meeting.

Taysha's oral presentation and three poster presentations featured data previously presented at the International Rett Syndrome Foundation Scientific Meeting, highlighting longer-term REVEAL Part A data, natural history analysis, and psychometric validation work, all of which support the clinical and regulatory foundation for TSHA-102. Taken together, the growing safety dataset, durability, and consistency of clinical responses observed to date, along with continued progress across the TSHA-102 scientific foundation, further strengthen our confidence in the TSHA-102 program and our potential regulatory pathway. I will now turn the call over to Kamran.

Kamran Alam: Thank you, Sukumar. Research and development expenses were $28.8 million for the three months ended September 30, 2026, compared to $25.7 million for the three months ended September 30, 2025. The $3.1 million increase was primarily driven by higher clinical expenses from the REVEAL Part A Phase I/II, REVEAL Part B Pivotal, and the 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 $13.1 million for the three months ended September 30, 2026, compared to $8.3 million for the three months ended September 30, 2025.

The increase of $4.8 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 three months ended September 30, 2026, was $39.1 million, or $0.10 per share, compared to a net loss of $32.7 million, or $0.09 per share, for the three months ended September 30, 2025. As of September 30, 2026, Taysha had $422.8 million in cash and cash equivalents. We expect that our current cash resources will support planned operating expenses and capital requirements into the second half of 2028. I will now turn the call over to Sean for his closing remarks. Sean?

Sean Nolan: Thank you, Kamran. We believe the progress made this quarter further strengthens the clinical, manufacturing, and regulatory foundation supporting the TSHA-102 as we advance toward a potential BLA submission and work to bring this potentially transformative therapy to the Rett syndrome community. With all patients in the REVEAL trial and ASPIRE trials dosed and past the acute post-dosing monitoring period, and the BLA-enabling PPQ campaign complete, we remain focused on generating a rigorous dataset and preparing for upcoming FDA interactions.

Next year, we expect FDA feedback following our CMC Type B meeting in the first quarter, and plan to report topline data from the REVEAL Pivotal six-month interim analysis, along with FDA feedback on the planned BLA submission pathway in the first half of 2027. We continue to see a potential path to a BLA submission based on either the six-month interim or the 12-month pivotal trial data, and expect to provide greater clarity on the planned submission pathway in the first half of 2027. In parallel, we plan to continue to advance our long-term vision of building a broader CNS genetic medicines franchise with the nomination of an additional gene therapy candidate in the first half of 2027.

I would like to recognize the expertise and vigilance of our participating principal investigators, the rigorous training and oversight provided by our clinical development and clinical operations teams, as well as our CRO and CDMO partners, and importantly, the commitment of the patients and caregivers whose participation in the trials and dedication help ensure the best possible outcome for the Rett syndrome community. With that, I will now ask the operator to begin our Q&A session.

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

Kristen Kluska: Thanks for taking my question. The question I had for you is, we understand what the bar needs to be for the upcoming readout in order for the trial to be deemed significant and successful, but how are you thinking about the clinical bar, perhaps to make this competitive at a six-month analysis? Assuming you are in a position where you can file, will we still get to see the 12-month data at some point? Thank you.

Sean Nolan: Yeah, I think we'll start with your second part of your question. The short answer is yes. I mean, we would definitely share the 12-month data. That would ultimately become part of the product label. I don't see that there's any competitive challenges with leading with the six-month data. In fact, I think getting to market first is critically important, and if we're able to do that, I think that positions us well. If our six-month data are strong enough for us to be able to submit on that, based on the discussions we've had with payers thus far, things are lining up nicely in terms of reimbursement broadly.

I think that will only be strengthened as we then augment the label with the 12-month data. But so far on our discussions with the payers, there's no impediment to going with six months with the full approval versus waiting for the 12 month in terms of securing proper reimbursement. Again, we see the six month as all upside and the potential to get to market even faster.

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

Elizabeth Webster: This is Elizabeth on for Salveen. You mentioned that you will nominate an additional candidate targeting a CNS disorder and start preclinical activities in the first half of next year. Wanted to see if you could give us any more color on where you think Taysha's capabilities and expertise in this space would be best suited in terms of an indication or using your delivery platform. Thank you.

Sean Nolan: Appreciate the question. I will take that and then certainly open up to Sukumar to give his perspective as well. I think, number one, we are going to focus on CNS genetic medicines. I think that is our core expertise. Sukumar himself has a steeped history in CNS gene therapy development. The team that he is surrounded himself on, both by the MDs on our staff as well as the medical affairs teams and the clinical operations group, are all very experienced in CNS, and in particular, CNS genetic medicine. So, I think that is directly in our wheelhouse.

The other thing I would highlight is, I think one of our core competencies, in addition to the clinical and regulatory strengths we have, is on the CMC side. The work that Fred Porter, Gretchen Smith, the whole team have done is truly outstanding.

I think those of you that have known us over the course of the last decade or so, we have really worked to put a premium around the quality of the CMC, and the fact that we are at a commercial scale and single-digit empty-to-full ratio is something that Fred really set as a goal and drove the team, and Gretchen drove the teams to get there, which we think is going to be It reduces the amount of dose that the patients are exposed to, and hopefully that improves and enhances the safety profile.

So, I think the combination of those things, along with the relationships on the regulatory side that we have developed with the CNS team in genetic medicines at FDA, and the credibility that we have built, are reasons why we want to continue to expand our footprint in that particular space. Sukumar, I'm not sure if there's anything else you might want to add to that.

Sukumar Nagendran: Yeah, Sean, what I would emphasize is basically, as you said, we have a very strong team on the CMC and translational research side under Fred Porter, and we have a very strong regulatory team. I would remind the folks that when we were at AveXis, the work we did with the FDA helped set the draft guidance for neurodegenerative disorders for the FDA. I would also say that the work we've done at Taysha in the neurodevelopmental neural network disorder space with Rett syndrome has also helped mature the neurodevelopmental guidance that has come out from the FDA in draft form.

Furthermore, we also have significant clinical experience in taking a CMC product where the empty capsids are now in the single digits, which translationally could have significant potential clinical impact for us across the board. We look at commercial opportunities with large patient populations, hopefully for the future, where we can use our preclinical experience on the translational side, looking at animal models of proper disease state that translate to the CNS rare disorder space with large commercial populations that can not only help pivot Taysha beyond the lead program of Rett syndrome to other relevant commercial opportunities and clinical opportunities in the CNS space.

We are looking forward to doing what we have to do to further progress our pipeline.

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

Biren Amin: On the FDA meeting where you discussed the interim data at six months, I think that's going to happen early next year. How much data will be shared with FDA from the Part A patients and the correlation of activity from six months to longer-term follow-up that allows FDA read-through on the duration of response with the six-month interim? On the CMC Type B meeting, FDA recently finalized CMC guidance 10 days ago on cell and gene therapy. How does your PPQ campaign align with that final guidance? Thank you.

Sean Nolan: Yeah, so on the first question, we will update the FDA on the Part A data that we have. I think it would be a data cut post, certainly well beyond 12 months. I know that. We will share any safety data that we have over the course of time with them, which is like the update you just got with no severe treatment-related SAEs or DLTs. That will continue to get updated for the FDA from a safety perspective as well. So they will definitely see the Part A data.

We will share all of the primary endpoint and secondary endpoint data with them at that meeting as well, so they can get a fulsome look at the totality of the evidence and how things are lining up at six months. It is our belief that if the Part B data continue to move forward and resemble what we saw in Part A, the combination of the pivotal data plus the long-term Part A data is going to be very helpful and very well may facilitate us being able to file on the six-month data set.

As it relates to CMC, I think the best person to answer how the guidance from the FDA stacks up against our PPQ results is Fred Porter. So Fred, would you mind taking that question, please?

Fred Porter: Yes, Sean, I am happy to, thanks for the question. Yes, the recent guidance that got finalized around potency assay strategy is kind of a key part of the conversation we intend to have with the agency later this year. We have been talking to the agency over the course of this program about our potency assay strategy, really leveraging that matrix approach. What we hope to do on this final meeting ahead of our BLA submission is really solidify our final commercial potency release strategy, leveraging all the elements of that guidance.

So we are very well aligned with the finalized guidance that just came out and really look forward to sharing that data with the agency and getting their feedback. Thanks for the question.

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

Wesley Yon: This is Wesley on for Tazeen. Thanks for the updates today. I had a question on the sequence of events coming for the second half of next year. When you do the six-month interim, do you plan to announce I know you're not going to share the data before the FDA meeting, but do you plan to announce when that interim analysis is finished, or will you sort of hold everything for one release with the FDA interaction information as well as the primary endpoint data? Thank you.

Sean Nolan: Wesley, the way we're thinking of this is, the trigger for the interim analysis is going to be the last patient hitting their six-month assessment, right? And right now, that's scheduled within the month of December. Once that occurs, there's a whole process that takes place where the blind gets broken. Then all the videos have to be reviewed by the blinded raters, so there's time around that. Then we'll get the top-line data followed by the secondary endpoints. We'll request the Type B meeting with the FDA.

If things hold on the timeline, again, assuming nobody gets the flu and has to have their appointment delayed or something like that, we would be thinking the FDA meeting would likely occur later in the first quarter, and then the minutes coming either that same quarter or into early in the second quarter. That's why we guided to the first half, was just to give flexibility because some of its outside of our control, both in terms of the patient's visits and then ultimately the timing of the FDA minutes, which is normally 30 days, but sometimes it can extend. So we just wanted to make sure we had the flexibility on that.

Once we have the data, sometime in the month of January, the management team will go dark, right? We're going to have to stay out of public discussions until we have that meeting with the FDA and get back. That's the sequence of events. The logic behind it, again, is we felt if we put the data out ahead of the FDA feedback, I think we're going to have a lot of Everyone's going to have their own opinion of how good it is. Should it receive the six-month review or what have you? We just felt really the opinion that matters the most here is going to be the FDA's, and we want to be respectful of them.

Therefore, we thought it was best to keep it out of the public eye and then have that discussion with them and then come back and say, "Look, here's the data, here's how the FDA sees the data, and here's the next steps." Hopefully, in any scenario there, Wes, we're in a situation where we're providing clear line of sight to the market, and hopefully, it's the six-month review, which would be breaking precedent for the FDA. I mean, we feel strongly that if the data are similar to what we saw in Part B, that there's an absolute case for that.

If they want to stick to their precedent and go with 12 months, we could explain that to people, but you'd also get to look at the data. It really becomes an execution and a timing situation, but the probability of approvability would be high, and then that's the focus on the commercialization efforts, which our team is well advanced on. Hopefully that gives you a little color as to how we're stepping through this.

Operator: Our next question comes from the line of Maurice Raycroft of Jefferies.

Maurice Raycroft: Just checking, besides potency release strategy, is there anything else that you need to clarify in the CMC front in the Q4 Type B meeting? You expanded the Catalent partnership to commercial supply at Harmans in Q2, the same quarter when the PPQ tests began. Were the PPQ batches made at Harmans?

Sean Nolan: Yeah, again, the best person here would be Fred. Do you mind taking both of those questions, Fred?

Fred Porter: Sure, I don't mind at all. Yeah, great questions around the topics of this meeting are around a few things. One is we wanted to share the results from that PPQ campaign, the performance results, the analytical testing results, and the comparability data. Like Sean mentioned in the intro, that's going to be a key discussion with them. We feel like this is the data we're going to share aligns with our pre-aligned strategy with them around comparability. We also want to look forward and position ourselves really strongly for our BLA filing to try to get ahead of any area of uncertainty before we start building our BLA for submission next year.

So that's really the plan, including final specifications, some other key activities that would help enable our commercial readiness and BLA readiness as well. In terms of where the batches were manufactured, you're right, we signed our commercialization agreement last year ahead of our PPQ campaign, and we have manufactured our lots at the commercial Harmans facility in Maryland. So, thank you for the question.

Operator: Our next question comes from the line of Gil Blum of Needham.

Gil Blum: Just one from us. I am sure you guys heard some of the reported cases of malignant transformations with Zolgensma. I mean, this is kind of a longer-term safety question. Given it is a similar strategy as it relates to CNS indications, just wondering how you guys are thinking of that as a risk, and whether you think this is related to just total dose effect of AAV or vector or whatever you guys think could be the cause here. Thank you.

Sean Nolan: Yeah, Gil, I will take a real high-level stab at that and then turn the call over to Sukumar. I think right now, with the amount of information that is publicly available, it is difficult, right? I mean, it looks like there are nine cases that have been reported. One of the cases was unrelated with a benign tumor. The two others looks like there was some mutagenesis that had happened. I think the story, more to tell there, right? What we do not know is some of the background rate on some of these tumors and things of that nature in each of the disease states. So, there is more to come.

I think we have to just be patient for that. I would say at a very high level, in our preclinical and clinical data with TSHA-102, we have had no evidence of any type of tumor formation. I think you all know we use MRIs at baseline and then at times throughout the study. So, I think we are in a good situation there, and it would have flagged something if we would have seen it thus far. I can report on the 33 patients that we have dosed to date, we have not had any indication of that kind of situation. The other thing that seems to be playing out here, you mentioned total dose, right?

I mean, this was from an IV dose administered versus a fixed dose directly into the CNS. So, that could potentially be a bit of a contributing factor here. Also the construct. I think it is important, we do not use a widely acting promoter. We use something that is very focused in the CNS, as opposed to a ubiquitous promoter. Our construct does not have any introns in it, which can potentially, theoretically lead to some type of vector integration. I think for all those reasons, right now our view is this is more likely a program-specific kind of a situation.

I think we will have more data unfold as it occurs, but we do not see any read-through directly to us. It does not seem to be an AAV9 phenomenon. It may be unique to, again, construct design and potentially biology of the disease itself. Let me pause there and turn it over to Sukumar to see if he may have additional perspective to share.

Sukumar Nagendran: Yeah. Thanks, Sean. Hey, Gil. That is a good question. I mean, keep this in mind though, with gene therapy, usually when you treat the root cause of the disease, especially with lethal central nervous system disorders, such as what Zolgensma was approved for, SMA type 1. SMA type 1 kids, usually by 20 months of age, 95% of these children are either not alive or they are on permanent respiratory support. So if you consider that lethality and you look at the number of patients dosed with Zolgensma IV, I think Novartis reported over 6,000 patients have been dosed so far since its approval in 2019.

Out of those 6,000 patients dosed, there were nine cases of tumors reported, I mean, nine patients by Novartis. Out of those nine patients, six patients, the actual history of the disease or the tumors are unclear because Novartis has not given us the details yet. But the three patients of whom the details are somewhat clear, one of those was a benign astrocytoma tumor, I think in the spinal cord, and there was no evidence of insertional mutagenesis.

The other two cases were thought to be malignant, and there seems to be evidence of insertional mutagenesis of the associated promoter, which I think was a CAG chicken beta-actin promoter, and it appears that the GLI1 tumor suppressor gene may have been activated. But the issue is this, what the product has done, Zolgensma, is it has changed the epidemiologic course of SMA type 1 by now allowing these children to live much longer and potentially healthier lives. In presymptomatic children, it appears that it is preventing the disease from occurring from at least the data that I have seen.

So basically, the epidemiology of the disease has been altered with SMA type 1, and given that Zolgensma is being used to treat the disease, and we are not sure what the predisposition of this patient population is to tumors, whether benign or malignant. So collectively speaking, the benefit I think far outweighs the risk for this patient population with Zolgensma, and frankly, ITVISMA, which is approved for over two years of age. The number needed to treat for a positive outcome, I think, is far greater than the number needed to harm in this specific population.

So, I would say as a physician and a clinician, I am pretty comfortable with Zolgensma and ITVISMA continuing to do what it does in this highly lethal risk, high-risk patient population. I hope that it helps answer your question, Gil.

Operator: Our next question comes from the line of Jack Allen of RW Baird.

Jack Allen: I wanted to ask about the patients enrolled in REVEAL Part B. I was curious if we get any additional incremental color ahead of the first half of 2027 update from the six-month data there. I believe there had been previous discussion of potentially having more open milestones in the REVEAL Part B patients. Any context you can provide as it relates to the differences between Part A and Part B patients would be very helpful here.

Sean Nolan: Yeah, Jack, I can take a stab at that and turn it to Suku as well. In general, there's a lot of similarities, right? I mean, the baseline severity scores of the CGI-S are in the four to six range. The ages are going to be six years to 21 years of age, so that's very consistent. The distribution of ages is, it's a nice distribution. We've got a good mix of pediatric kids, adolescent kids, and then young adults. So, I think we've got a good spectrum there. We've got a good spectrum of severities at baseline, like we talked about, and we took all genotypes again. So, I'd say there's a lot of consistencies there.

Your point about the open milestones is a good one, which is, in Part A, we didn't have a threshold of the number of open milestones you had to have, right? Obviously, the more open milestones you have, the greater the probability that you might actually hit one. In Part B, we haven't said what it was, but we did keep a number of There was a threshold of open milestones that you had to have open. So, our hope there is that it gives patients more opportunity to demonstrate benefit potentially than what we saw in Part A. Sukumar, I don't know in terms of any other baseline characteristics or is there any other color you want to provide?

Sukumar Nagendran: Yeah, Sean, what I would add and just remind folks on the call is that Part A was a first-in-human safety study with efficacy measurements being hypothesis-generating. Essentially, we were evaluating multiple different efficacy parameters, which included milestones versus the natural history from the IRSF database to allow us to choose appropriate efficacy milestones to be the primary endpoint. Obviously, we have developmental milestones based on the IRSF database for the ages above six, and also based on CDC guidelines.

Having said that, the number of open milestones are actually truly clinically relevant for the Part B study because it also enables us to evaluate more accurately and more concisely the global impact of our product across the age range studied, which is pretty broad and adequately represented, but also regardless of genotype or phenotype, hopefully reproduce the results that we saw in Part A, which was basically 100% responder rate.

Also, the baseline characteristics between Part A and Part B is that we have accurate baseline evaluations in Part B that are even more consistent than Part A, which I think further increases our confidence in hitting the primary endpoint with success, and hopefully bring this product to the patients who deserve it based on the six-month interim analysis from Part B.

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

Yanan Zhu: Was wondering about, for the discussion with FDA on the interim data, what aspects of the data could inform the agency's decision to whether allow filing or not on the six-month data? I think you've mentioned in the past the bar on response rate. Can you comment on if that's the main factor, or could there be other layers of the data that could increase or decrease the likelihood of filing on interim? Thank you.

Sean Nolan: Yanan, good question, and Sukumar and I can also tag team this one. You are correct. The statistics at six months and 12 months are the same. It is essentially that about a third of patients need to respond to make sure that from a statistical perspective, you have hit that particular threshold. I would say in general, the FDA is going to look, as they always do, at the totality of the evidence. Really, that is why we did submission primary and we wanted to share with them the secondary endpoints so they had that perspective as well. You know, certainly the natural history and the milestone progression during the natural history.

We also have the CGI-S and the CGI-I, and all those secondary endpoints we have shared, would improve the additional skills and improvements that we have shared over the course of time. The FDA would have the ability to follow those. They would have a later time point cut from the Part A data. I cannot tell you, and I think the FDA, I can say from our experience, they never really tell you exactly what you need to do. They are giving you the ability, and you have an alignment around a trial that is run and endpoints that they have agreed to, an SAP that they have agreed to.

Now, we are asking them to do something that they have not done before. We are basically saying, "I know that you generally wanted to look at 12 months of data before, but we think six months is sufficient." Obviously, our case for that, assuming that we continue to demonstrate the comparability from Part A, is that we do have long-term Part A data to show durability. If the Part B data at six months looks encouraging, we know from Part A that it generally should just get better over the course of time. We have a logic. The FDA understands our logic.

I think the question is going to come down to the totality of the evidence, and does the FDA want to look at potentially changing precedents, and how comfortable are they with that? I think that is why we are having the meeting, to get their perspective on things. That is where, again, I feel from a market perspective, we really believe if the data are good at six months, we have a great case for the six-month full approval and submission. We have shared that with the FDA.

They clearly understand our view on that, and they have said, "Let us have that discussion when we see the data." I think things have lined up as well as they could, and then ultimately it is going to be looking at the TLVs and then getting comfortable with, again, potentially changing precedent. I just go back to a comment earlier. We think six months is right if the data are strong for the community and the patients and getting things out sooner rather than later, particularly if safety has been demonstrated. If the FDA is concerned about a precedent, and to be very clear to everybody, they have never expressed this to us. They have not.

I am just giving you my opinion because we are asking them to do something different. If they want to stick with 12 months, my view is at least we share that with you along with the data, and you can definitely get a sense of the probability of success and the strength of the label. I see that as a positive scenario too. We are going to put our best foot forward on the six month. Again, they are very open-minded to it. It is just going to be a function of everything they see and how they feel about precedent. Sukumar, I am not sure if there is anything else you might want to comment on there.

Sukumar Nagendran: Yeah. Thanks, Sean. One thing I would again remind the audience here is that when you look at the natural history, which helped us set the stage for the Part A design, what you would remember is the age group we studied in Part A was six to 21 years of age, and in Part B, it was six to 22 years of age. Any spontaneous gain of a milestone that was never achieved above the age of six, or a spontaneous regain after a loss of a milestone, is literally negligible. We also ran Monte Carlo simulations of 15 patients times 10,000 sequences.

I guess that point I am emphasizing is the clinical response that you see in every patient in Part B after the age of six, post TSHA-102 dosing, has to be due to the product. Even a 30% responder rate is not a statistical number. It is a truly clinically meaningful number. The question is, can we reproduce a 30% response rate in Part B, given that we had 100% responder rate in Part A? I think if you do the statistical odds, I think we should be able to hit the statistical number needed for the Part B primary endpoint.

Also clinically meaningful is the fact that in Part A, we have shown that TSHA-102 gene therapy given intrathecally works very quickly, within two weeks. It helps address autonomic dysfunction, which is consistent almost amongst all patients dosed, and also it helps address communication, loss of social skills very quickly, as well as achievement and growth and fine motor milestone dysfunction. It is consistent across the age groups studied, and the genotypes identified, as well as severity of disease. If you can reproduce all of that from Part A in Part B, the six-month interim analysis, I think will truly be clinically meaningful for the FDA to seriously consider changing the paradigm from a regulatory process for gene therapy approval.

Operator: Our next question comes from the line of Jack Allen of Baird. Your line is open, Jack.

Jack Allen: Thanks so much for taking the follow-up question. I just wanted to ask one more briefly on the design of the REVEAL study. I know you have the more robust baseline measures. I think there are as many as two video assessments at baseline. But when we think about the number of video assessments within the six-month period, I am just curious how many on-study video assessments there might be. Then as it relates to the six-month analysis, is it going to be the first six months of data from all these patients, or will it be at least six months of data from each patient when you take that data cut, potentially in December, January timeframe?

Sean Nolan: Yeah, Jack. The first question would be, so you are right, there is two videos that are done pre-dosing to set the baseline, and then there are three videos done post-dosing in the first six months. So those five videos for each patient are what is going into the, call it the blinded review. At six months, when we do the interim, we are only going to look at six months of data for all patients. So anyone who is at nine months or 12 months or whatever, we are not looking at that data. That is going to continue to be blinded for the 12-month assessment. Hope that makes sense.

Operator: Our next question comes from the line of Evan Seigerman of BMO.

Evan Seigerman: Sean, you said something earlier interesting about the commercial batches in terms of the quality with single-digit empty vectors and a potential kind of safety benefit for patients. Have you actually seen that kind of in the real world, and are you able to demonstrate that or include that in labeling or use that as kind of a marketing component in your messaging? That's a very interesting thing and I think could be very important. Love for you to expand on that.

Sean Nolan: Yeah, I mean, I think it is critically important if you're able to do it, right? I mean, if you just make it real simple, there's gene therapies out there that could be 50% empties or more, right? In the case of 50% empties, you're doubling the dose to get the therapeutic effect. So number one, you've got from a patient safety perspective, you're exposing patients to more dose because you have such a percentage of empty capsids, and there's obviously a potential risk associated with that based on the total vector load that one may be giving.

Now, we think we're mitigating that by our route of administration and giving a fixed dose as opposed to using a systemic dose, but even getting into the single digits, which has been a goal of ours internally, we feel is the right thing from a product purity perspective that can potentially translate into, again, less exposure to the patients. The other benefit to that is the cost of goods, right? I mean, you're more efficient in your process, your yields are going to be better, and that obviously is a benefit as well.

Whether that gets into the label, I would say probably doesn't, but I think if we're able to continue to sustain that, and we have every reason to believe we would, as we've run multiple batches at commercial scale at this point, I think it is something from a messaging perspective, we would definitely want to share with the clinicians so that they have that information and they can use that to inform their patients as they talk about benefit risk. Hope that makes sense.

Operator: Our next question comes from the line of Silvan Tuerkcan of Citizens.

Silvan Tuerkcan: I just had two quick ones. Maybe could you just give us maybe a follow-on that reported grade two peripheral neuropathy event that you had seen in one of the girls here? I know it resolved, but how's that girl been doing? I do not know if you can comment on that. And then on ESGCT, there was a poster by one of your competitors and the ability of the transgene expression control via the regulatory element, right? The data in that poster seems to show that with miRARE, there is some dampening of overall expression levels. What do you make of that preclinical data? Thank you.

Sean Nolan: Yeah, I mean, I would say look, at a high level, at this point in development, to be talking about the preclinical data seems like we are missing the forest through the trees. To be very specific on your question, Silvan, I would say the following. We have published data on our miRARE, all the preclinical work we did, the non-human primate work we did, and that has been published in peer-reviewed journals, and it clearly shows the ability to manage expression on a cell-by-cell basis. Keep in mind, too, that the non-human primate data, those are all wild-type animals, and the safety profile was fantastic. That was all submitted to the FDA.

They never asked us a question about it. They did ask for a cell-based assay to confirm the in vivo work, which we did. The cell-based assay clearly shows the control with and without miRARE. That data is all with the FDA. They have never asked us another question around expression control. I cannot speak to the work that others have done, but it is certainly not the work that we have done with our own construct. As it relates to your first question on the PNS patient, I guess, Sukumar, you are the best person to take this, if you do not mind.

Sukumar Nagendran: Yeah, thanks, Sean. So, just to refresh everyone's memory, when it comes to Rett syndrome, it's thought that 50%-70% of Rett patients don't have peripheral neuropathies that already pre-exist. This patient did have evidence of underlying clinical evidence of sensory neuropathy. If you recall, this patient had some worsening of symptoms, and per hospital protocol, had to be admitted for treatment and was discharged in less than 18 hours post-treatment, which obviously, per the FDA guidance, made this an SAE. This patient started recovering pretty quickly post-treatment, I think within 24 to 48 hours. I would say is now getting pretty close to getting back to her baseline prior to treatment, although she's not exactly there yet. Thanks.

Operator: Our next question comes from the line of Whitney Ijem of Canaccord.

Angela Qian: This is Angela on for Whitney. Just thinking through again, assuming success with the six-month endpoint, how are you guys thinking about commercial readiness to potentially capitalize on the market lead there? Can you also just give us a sense of how many doses you would plan to have available at launch, whether that be if you were filing on six months or 12 months? Thank you.

Sean Nolan: Yeah, Angela. On the doses, Fred and his team and Kamran have worked out with Catalent a commercial supply agreement. We have a good estimate range of what we think demand's going to be in the first 12 months, and we've worked through that with Catalent. We don't see that there's going to be any supply constraint to the market. I think that's an important piece. As it relates to getting ready, we've built a very experienced commercial team. I would say over the last year, I mean, if you want to think about the basics of, what is the marketing strategy? What's the go-to-market strategy look like? We've got that complete. You're talking about the messaging.

What are the strategic imperatives that we have to accomplish? What are the targets that we're going to go after first, both in terms of centers of excellence, and how do we broaden the reach over the course of time? We've been through that. What's the target audience of physicians that we want to work through? How do we coordinate with the advocacy groups and make sure from a disease education campaign and gene therapy education that we've got the right materials in place and we can stage that accordingly? All of that has been ongoing, and we feel very, very good about that. What's the sales force sizing look like?

All of that, working with the SP, selecting your 3PL, all those kinds of things, we've either done or are almost completed with. The market access piece, we've really invested heavily in both bringing on an experienced team in gene therapy, which is critically important. We've been, as I mentioned in the call, we've been doing a lot of work with the payers in terms of pre-approval, information sharing, talking with them about profiles, potential. We've been doing pricing work. I tell you, the feedback we've gotten is great. They like the conversations to begin as early as we're doing them. We started them actually in 2025.

They like them a couple years in advance so they can plan for it. They just want no surprises, and they want to do the right thing. We've had very good interface with them. We've got a very good plan in place for how we're stepping through it. You can see on our expense side, some of the SG&A bump has been on the commercial and medical affairs teams. I would just say that we're very confident about where we are and how we're going to position the product, which is why we really want to be first to market, and we're going to be ready to do that should the opportunity arise.

Operator: Ladies and gentlemen, this concludes our question and answer session. I'll turn the call back to Mr. Nolan for his final remarks.

Sean Nolan: Thank you very much. We appreciate everyone's time this morning and look forward to providing updates in the first half of next year. Take care, everyone. Have a good day.

Operator: Thank you. Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation. You may now disconnect your line.

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