Taysha Gene Therapies Inc Aktie

Hello, and welcome to the Taysha Gene Therapies Second Quarter 2026 Financial Results Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

It is now my pleasure to introduce Vice President of Corporate Communications and Investor Relations, Hayleigh Collins.

Thank you. Good afternoon, and welcome to Taysha's second quarter 2026 financial results and corporate update conference call. Earlier today, Taysha issued a press release announcing financial results for the quarter ended June 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 product candidate to receive regulatory approval from the FDA or equivalent foreign regulatory agencies. Our ability to realize the benefits of breakthrough therapy designations for TSHA-102, our ability to drive long-term value for stockholders, and the market opportunity for our programs.

This call may also contain forward-looking statements relating to Taysha's growth, forecasted cash runway, and future operating results, discovery and development of product candidates, strategic alliances and intellectual property, as well as matters that are not historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. For a list and description of the risks and uncertainties that we face, please see the reports we filed with the SEC, including 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, August 11, 2026. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws.

With that, I would now like to turn the call over to our CEO, Sean Nolan.

Thank you, Hayleigh, and welcome everyone to our second 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. Suku Nagendran, President and Head of R&D, will then discuss data presented at the recent IRSF Rett Syndrome Scientific Meeting, which strengthens the clinical and scientific foundation of the TSHA-102 program. Kamran Alam, our Chief Financial Officer, will follow up with a financial update, and I will then provide closing remarks before opening the call up for questions.

The second quarter of 2026 was a highly productive period for Taysha. We continued to execute against our clinical development strategy while advancing key manufacturing and commercial readiness initiatives as we move toward a potential BLA submission for TSHA-102. We achieved several important milestones, including the completion of dosing in both the REVEAL pivotal and ASPIRE trials, as well as the presentation of compelling longer-term Part A data from the REVEAL Phase I/II trials. Beyond the clinical development, we expanded our partnership with Catalent to include future commercial manufacturing support for TSHA-102, completed payer research to inform further market access planning initiatives, continued to build our leadership team, and strengthened our balance sheet through a successful follow-on financing that is expected to support our planned activities into the second half of 2028 and through potential BLA approval. Collectively, we believe these accomplishments place us in a position of strength as we approach the planned 6-month interim analysis from the REVEAL pivotal trial, continue our engagement with the FDA, and advance commercial readiness activities.

I will begin with a clinical update. We continue to execute with discipline across our REVEAL pivotal and ASPIRE trials and are pleased with the significant progress made to date. In June, we announced the successful completion of dosing in the over-enrolled REVEAL pivotal trial with a total of 17 patients dosed with TSHA-102. Importantly, similar to our REVEAL Part A trials, we enrolled a well-balanced distribution of ages across pediatric, adolescent, and adult patients that's reflective of the broader Rett syndrome population. We believe this allows us to generate a comprehensive data set that may support a broad label for TSHA-102.

Once all 17 patients in the pivotal trial complete 6 months of follow-up, we will conduct a 6-month interim analysis, which may serve as the basis for our planned BLA submission and potentially accelerate our submission time line by at least 2 full quarters relative to filing on the 12-month data. Given our longer-term Part A data substantially exceeded the FDA-aligned 33% minimum efficacy threshold established for the pivotal trial, we believe this further strengthens the potential for regulation based on the most current trial analysis.

I also want to share that as of July, we have completed dosing in our ASPIRE trial, where we treated 4 patients aged 2 to less than 4 years old with TSHA-102. ASPIRE is primarily a safety-focused and to support a broad label for patients aged 2 years and older with Rett syndrome as part of our planned BLA package. In addition to generating supportive safety data, ASPIRE is designed to provide insight into the impact of early intervention, including the potential to reverse disease manifestations and restore function while also preventing further disease progression in younger patients.

With dosing now complete in both trials, we are laser-focused on preparing for the pivotal trial interim analysis and subsequent discussions with the FDA to inform next steps toward a BLA submission. We expect to provide an update on both fronts in the first half of 2027. We continue to believe the increasingly robust body of evidence generated across the program strengthens the rationale for this potentially expedited submission plan.

Turning to safety, both high and low dose TSHA-102 continue to be generally well-tolerated. There have been no severe treatment-related serious adverse events or dose-limiting toxicities observed since the clinical trial began over 3 years ago across the 33 patients treated in the REVEAL Phase I/II pivotal and ASPIRE trials as of the August 2026 data cutoff, supporting a favorable and consistent safety profile. In early July 2026, over the holiday weekend, 1 patient in the REVEAL pivotal trial experienced a single moderate Grade 2 treatment-related adverse event of peripheral sensory neuropathy, an expected AAV-associated risk approximately 6 weeks after treatment. Consistent with the treating institute's policy, the patient was admitted overnight for management and observation, thus resulting in a technical classification of the Grade 2 event as serious adverse event. The patient was discharged the following day, and importantly, rapidly demonstrating substantial recovery.

Clinical trial dosing is now complete, and we have surpassed 3 years since the first patient received TSHA-102. To date, 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. The safety profile of TSHA-102 has remained encouraging with a consistent benefit to risk profile throughout the program.

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 operation teams, as well as our CRO partner, and importantly, the commitment of the patients and caregivers whose participation in the trials and dedication to help ensure the best possible outcomes for the Rett syndrome community. Based on the totality of the data generated to date, including the favorable safety profile and compelling efficacy data from the longer-term follow-up from the REVEAL Part A, we continue to believe TSHA-102 has the potential to be a differentiated and transformative therapy for a broad population of patients with Rett syndrome who continue to face high unmet medical need.

The strengthened body of evidence supporting TSHA-102 was highlighted at this year's IRSF Rett Syndrome Scientific Meeting, where we presented data that collectively reinforced the clinical and scientific foundation of our development program and registrational strategy. Suku will discuss the data in greater detail shortly, but before I turn the call over, I wanted to touch on our ongoing commercial readiness efforts.

We have continued to make meaningful progress in preparation for a potential launch. This past quarter, we completed payer market research, which demonstrated strong support for TSHA-102's value proposition and reimbursement potential. Specifically, the research demonstrated that TSHA-102 was viewed as a high-value therapy due to its transformative disease-modifying potential in a population with significant unmet need. Coupled with the convenience of a onetime intrathecal administration that is less invasive than other direct-to-CNS approaches and can be administered in a broadly accessible outpatient setting.

Importantly, payer willingness to provide coverage was primarily driven by the potential for TSHA-102 to deliver durable, clinically meaningful benefits. Payers consistently emphasized the importance of demonstrating durable functional gains and improvements that translate into real-world benefit for patients and caregivers, areas where we believe the growing body of clinical evidence supporting TSHA-102 is particularly compelling and differentiating.

Finally, the research demonstrated that strong efficacy, safety, and durability are expected to be the primary drivers of coverage and support reimbursement, with durable functional improvements serving as the most important determinant of value. These findings reinforce our confidence in TSHA-102's commercial potential and reimbursement outlook. We are leveraging these insights to further refine our market access strategy and support a successful potential commercial launch. In tandem with our market access strategy, we have also expanded our longstanding partnership with Catalent, the leading global contract development and manufacturing organization. Catalent will serve as our primary commercial manufacturing partner following potential FDA approval of TSHA-102. This expanded agreement secures a long-term commercial manufacturing capacity and establishes a scalable supply framework intended to support TSHA-102's potential launch and future demand. Under the agreement, manufacturing will be conducted at Catalent's FDA-licensed gene therapy campus in Harmans, Maryland, which is an established AAV manufacturing facility with significant commercial expertise. Catalent will leverage its experience across more than 90 gene therapy programs, including multiple commercial products.

With BLA-enabling process performance qualification activities underway, we believe we have established a strong manufacturing foundation necessary to support the anticipated significant demand for TSHA-102 following its potential launch and commercialization.

Finally, we continue to strengthen our organization through the key leadership hires that position us for the next phase of growth. This includes the recent appointment of Mike Johannesen as Chief Legal Officer. Mike brings more than 3 decades of experience across corporate law, governance, compliance, and strategic transactions, including extensive leadership experience in the gene therapy space. His tenure at Advanced Medicine Partners, Jaguar Gene Therapy, and AveXis will be instrumental as we execute on our strategic priorities and continue to evolve the organization.

I would now like to turn the call over to Suku to dive deeper into our recent data presentations at the IRSF Scientific Meeting.

Thank you. As Sean highlighted, we've achieved several important milestones supporting the advancement of TSHA-102 towards potential registration, including the successful completion of dosing in both the REVEAL and ASPIRE trials, as well as multiple data presentations at the IRSF Scientific Meeting supporting TSHA-102. Importantly, these data sets reinforce our confidence in the program and collectively support the transformational potential of TSHA-102 to deliver durable real-world benefits to patients. We presented longer-term REVEAL Part A data, where all 12 patients treated had at least 12 months of follow-up data as of the May 2026 data cutoff, enabling a more comprehensive assessment of the durability, depth, and consistency of treatment effect over time.

The data continue to demonstrate broad multi-domain functional impact that deepened over time through greater than 12 months post TSHA-102. We're particularly encouraged by the durability and deepening of the treatment effect. Notably, we have not observed evidence of plateau effect with data continue to trend upwards over time. Using the FDA-aligned developmental milestone assessment criteria that serves as the primary endpoint in the REVEAL pivotal trial, results from Part A far exceeded our FDA-aligned pivotal response rate threshold of 33%, with a 75% response rate seen as early as 3 months and increasing to 83% at 6 months. By 12 months, 100% of the 12 patients were responders. These results further bolster our confidence going into the upcoming 6-month interim analysis of the REVEAL pivotal trial.

We have observed a consistent and clinically meaningful treatment effect across the pediatric, adolescent, and adult patients treated. Across the 6 pediatric patients evaluated, 16 total developmental milestones were achieved. And among the 6 adolescent and adult patients, 15 developmental milestones were achieved. Together, patients achieved a total of 31 developmental milestones. Given that over 85% of the prevalent Rett syndrome population is older than 10 years of age, we are particularly encouraged by the consistency observed regardless of age or disease severity that supports the commercial opportunity for TSHA-102.

In addition to the consistent treatment effect across age groups, we've observed broad functional impact across core disease domains of Rett syndrome. At 12 months and beyond, patients demonstrated a total of 310 functional gains across communication, fine motor, gross motor, and autonomic domains, averaging 26 gains per patient. These gains included both naturally defined developmental milestones as well as additional skills and improvements that meaningfully impact daily life, such as enhanced motor skills and hand use, the ability to respond to questions, reduced seizure activity, and decreased hand stereotypies, to name just a few. Collectively, these findings reinforce our belief that TSHA-102 has the potential to provide meaningful therapeutic benefit across the broad Rett syndrome population and deliver tangible gains in independence and quality of life for patients and caregivers.

We continue to be encouraged by the favorable safety profile of TSHA-102, with no severe treatment-related SAEs or DLTs across the 33 patients treated as of the August 2026 data cutoff. The safety profile of TSHA-102 has remained encouraging, the consistent benefit to risk profile throughout the program. To that end, I would like to recognize our participating principal investigators for their clinical expertise and diligence in patient care, and thank our clinical development and clinical operations teams and CRO partner for their exceptional training, proactive monitoring, and commitment to maintain the highest standards of patient safety and trial execution throughout the study.

In addition to the clinical data, we also presented analysis from the Rett syndrome natural history study supporting the design of the REVEAL pivotal trial. The data demonstrated a clear developmental plateau after 6 years of age, with the likelihood of gaining or regaining a developmental milestone that was lost after a defined number of years declining sharply to less than 6.7%. These results support the minimum inclusion age of 6 years in our well-controlled, single-arm interventional trial evaluating gain and regain of developmental milestones. We also further strengthen our confidence that the developmental gains observed in REVEAL are meaningful and distinguishable from the expected natural history of the disease in patients 6 years and older.

We also presented methods evaluation study data supporting the developmental milestone assessment, DMA for short, as a psychometrically valid and FDA-supported primary endpoint for single-arm interventional studies. Prior to initiating REVEAL, the DMA was evaluated in a multi-site, noninterventional study to assess its applicability as a clinical outcome measurement in a registrational study. These findings were shared with and reviewed by the FDA as part of the trial protocol developmental discussion and strengthen our confidence in the integrity and interpretability of the data set we expect to generate from the REVEAL pivotal trial.

Finally, we presented previously reported preclinical data supporting the design of the TSHA-102 construct. The data demonstrated that Taysha's miniMeCP2 is functionally comparable to full-length MECP2 across molecular and biochemical functions. In addition, Taysha's self-complementary AAV9 vector enables superior MECP2 expression compared to a single-stranded AAV9. This supports our construct design and ability to achieve broad effective delivery to the central nervous system through the minimally invasive intrathecal administration approach, which as Sean Nolan referenced earlier, is of particular importance to care. Taken together, the durability and breadth of the clinical responses observed to date, consistency in response across patient populations, supportive natural history analysis, and psychometric validation of the DMA pivotal trial endpoint, together with a favorable safety profile, continue to position TSHA-102 as a potentially transformative therapy.

I'll now turn the call over to Kamran Alam to review our financial results.

Thank you, Suku. Research and development expenses were $38.6 million for the 3 months ended June 30, 2026, compared to $20.1 million for the 3 months ended June 30, 2025. The $18.5 million increase was primarily driven by BLA-enabling PPQ manufacturing initiatives performed during the 3 months ended June 30, 2026, and higher clinical expenses from the REVEAL and ASPIRE trials. Compensation expenses, including noncash stock-based compensation, also increased as a result of additional research and development headcount.

General and administrative expenses were $12.1 million for the 3 months ended June 30, 2026, compared to $8.6 million for the 3 months ended June 30, 2025. The increase of $3.5 million was primarily due to higher compensation expenses, including noncash stock-based compensation expense, and increases in consulting and professional fees, including commercial launch readiness initiatives.

Net loss for the 3 months ended June 30, 2026, was $46.6 million or $0.13 per share compared to a net loss of $26.9 million or $0.09 per share for the 3 months ended June 30, 2025.

As of June 30, 2026, Taysha had $455.4 million in cash and cash equivalents. This reflects the gross proceeds of $230 million from the June 2026 follow-on financing, including full exercise of the underwriter's option to purchase additional shares. 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?

Thank you, Kamran. We believe the growing body of evidence supporting TSHA-102 further strengthens its path toward potential registration and our commitment to bringing this potentially transformative therapy to a broad population of patients with Rett syndrome. We believe the continued progress across our clinical manufacturing and commercial readiness initiatives, combined with our strengthened balance sheet, positions us well as we approach the REVEAL pivotal 6-month interim analysis, continue our engagement with the FDA, and prepare for the potential BLA submission and commercialization. We remain on track to complete the BLA-enabling PPQ campaign in the fourth quarter of 2026, and we anticipate reporting top line data from the REVEAL pivotal trial 6-month interim analysis and FDA feedback on the BLA submission pathway in the first half of 2027.

I will now ask the operator to begin our Q&A session. Operator?

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

The one I wanted to ask was on your payer research. Obviously, they see the potential of this therapy and the unmet need, but you made some comments around the onetime IT administration procedure in particular. Curious if there was anything specific they said about that kind of procedure and the outpatient that was important in the payer discussions. And yes, how we should be thinking about the specifics behind that?

Yes, Kristen, thanks for the question. There will be more to come on this. I would say this is the second step in our payer discussions. More to come later this fall, and hopefully, we can provide more updates as time goes on. But the number one in terms of high value, as you would expect, the focus was primarily on the potentially transformative data set that we have. And they really like this idea of the milestones and being able to demonstrate functional gains and improvements that have never been demonstrated before. So this also highlighted the strength and the robustness of the natural history analysis that we did because it really contextualized for the payers what they were getting for the money that would be spent on the therapy.

The second thing was around the durability and the fact that, at this point, we could share with them that we have at least 3 years' worth of data in our patients. By the time we get to market, that's going to be closer to 4-plus, 5 years, things of that nature. And obviously, that meant a lot to them.

And the safety aspect was another one, too. And they liked the fact that we've continued to demonstrate that overall, this is a well-tolerated gene therapy. So that combination of the product offering really resonated in the context of a high unmet need, rare disease with nothing that has been demonstrated to truly transform outcomes in patients.

The IT piece was something they definitely anchored to because of the fact that they realized that this is a much less invasive route of administration versus other ways to go direct to the CNS. They know that because of this administration aspect, that the reimbursement is going to be on the outpatient side, and so those are going to be attractive margins for those folks. And they also realize that when you start thinking about the scalability of it, you can get to more patients with this. So as they thought about the economics, they can see how the outpatient reimbursement could be quite attractive to them, relative to other potential administrations with other gene therapies that are out there. Hope that helps.

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

Can you help us further understand the Grade 2 SAE? You noted that this is an expected AAV-associated risk, but how do you mitigate this risk going forward, and how frequent are these type of events for gene therapies that leverage AAV9?

Yes, Salveen, great question. I think a few things for context here. Number one, the Rett population in general, there's data on this. Over 50% of Rett patients have peripheral neuropathies as part of the disease course. Number two, as you stated that AAV9 does have a -- it's a known effect of AAV9 that you can see peripheral neuropathies, and there's multiple product labels where that's indicated. It's not unexpected here. In this particular case, it was a Grade 2, which is a moderate event.

I would say that in terms of the management of this, I would ask Suku to comment on that. But from what we see from the product profile, the balance between risk and benefit really tilts heavily on the benefit side here, without question. We were hoping to get through the whole clinical trial program without any type of situation like this, but the fact that it's a Grade 2 is certainly encouraging. It was not severe. And I'll turn it to Suku, but I just want to highlight that this team really worked hard with the PIs in terms of monitoring and then managing. And this will get at your question, is how do you mitigate these type of things because they are expected to occur. Suku?

Yes, Sean and Salveen, thanks for the question. So as Sean highlighted, with AAV9 programs, you do see sensory neuropathy, so it's not uncommon. And it is usually easily managed with immunomodulatory agents if the clinical consequences need that kind of intervention. And as Sean highlighted, in our program, we've looked at this carefully, and the benefit significantly continues to -- the benefit is significantly more than any risk to this patient population. And there is very good data that in Rett syndrome patients that you do get peripheral neuropathies. So at times, the peripheral neuropathy and the clinical features of the disease itself can sometimes mask or be the main reason that you have the sensory neuropathy.

And in this specific case, we worked very closely with the investigator and followed the institutional treatment protocols to work with them and to have appropriate immunomodulatory agents to treat the clinical presentation, and this patient recovered pretty quickly. There was substantial recovery post discharge from the hospital within 24 hours. So overall, we are quite pleased with the outcome for this patient.

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

Maybe just a follow-up. Have you discussed these events with FDA? Have they provided any kind of feedback on any kind of change to monitoring requirements, or changes just in general to outpatient administration? Have you seen any similar neurological symptoms in other treated patients?

Yes. Tazeen, thanks for the question. Let me give a little bit of context on this one, too, because I think it really does matter. Every situation is a little bit unique and in this particular instance, again, keep in mind, this is a Grade 2 moderate [Audio Gap] Grade 4 is considered life-threatening. Grade 5, obviously, is the worst outcome possible. So this is a mild to moderate type of a finding. It happened on the July 4 holiday. So the PI's out of town, sub-PI is managing things. A patient has a presentation and we very much supported this. They did exactly what Suku and his team have trained them to do, which is monitor closely and then treat very quickly. And so, as a result of that, the policy at the hospital was an overnight administration and monitoring, and that's what led to this being deemed a serious adverse event.

Suku, you want to comment on that?

Yes. I was also going to address Tazeen's question about the FDA. So we did send this case report into the FDA, and so it has been disclosed to them. At this point, they have not had any questions. We've also disclosed this to the IDMC, and they felt it was part of the usual process of AAV9 therapy, and they raised no concerns either, and did not suggest anything different from what we have done up to now.

Right. So the reason I was giving you the background, Tazeen, is to give you the context that I think had there not been some of these circumstances that I mentioned, very likely we would not even be talking about this. So it was a unique set of circumstances that contributed, which is why, as Suku mentioned, we feel very comfortable in our ability to manage this going forward. It's not unexpected in the disease or with AAV9, and obviously the IDMC felt that way. And it's been several weeks since we have corresponded with the FDA and again, nothing from them, which we frankly wouldn't expect anyway. Hope that helps.

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

I was going to focus on just the seizure data that you are collecting. For Part A, wondering if EEG data were collected, and if so, are you seeing any objective changes in EEG activity that correspond with the higher level improvements in seizures that were reported at IRSF? And how will seizure activity be assessed more rigorously in the pivotal versus Part A? Are you going to have enough patients and baseline data to evaluate benefit on seizures and potentially include that in the label?

Maury, that's a very interesting and important question. So as you probably know, when it comes to Rett syndrome, 80% to 90% of Rett syndrome patients do have a history of seizures, especially once they are 3 to 4 years of age. That's when they first start showing features of different types of seizures, whether it's generalized tonic-clonic or partial complex absence, et cetera. We do have seizure data from the Part A data set that we are evaluating. Overall, as Dr. Elsa Rossignol also disclosed in her presentation, there appears to be an overall decrease in seizure frequency and severity, and maybe even in the combination of meds dose. We are evaluating that data further in depth, and we may disclose some of that data at a major medical meeting, hopefully either late this year or maybe early next year.

In the Part B data set, there are EEG data at baseline that occur, the patient's medical history, the medication history, et cetera, that includes anticonvulsant medications that are used. There are EEGs being done as a part of the protocol, but it's not a primary or secondary endpoint. It's probably more going to be exploratory. So at this point, it will give us a signal potentially on hopefully the beneficial effects of TSHA-102 when it comes to seizure control as well. But all I can say at this point is stay tuned, and we will update you further as we get that information. One thing that's reassuring at this point in time as of today is, we don't see worsening of seizures, which is important as well.

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

This is Stanley on for Chris Raymond. Maybe just one more follow-up on the safety event. I know that this is related to AAV exposure, but do you think that there also could have been related to the intrathecal administration? And was there anything about the patient such as age, dose exposure, or any other risk factors that might have predisposed them to the event?

I'll turn this over to Suku, but I can say at a high level, there was nothing relative to the administration that was noted by the PI. As you know, this is done very commonly. Again, the age of the patient really had no bearing on this circumstance. And things essentially can happen, and I think that's what we have here. So I don't believe there's any read-through, but Suku, you should certainly comment on this.

Yes, Sean, I agree that I don't think the lumbar puncture procedure itself puts the patient at high risk for this kind of incident. With AAV9, as we said earlier, you do sometimes see peripheral sensory neuropathies develop, and that could be one of the reasons that this occurred. But also, an important point we made earlier was that Rett syndrome patients do have their own features of peripheral and polyneuropathies, and that also develops over time. So sometimes could they have both concurred at the same time? Maybe, but we will not know at this point in time. But the most important thing is the patient responded and is doing much better now, and that obviously assures us as well on the overall safety profile for the product.

Our next question comes from the line of Jack Allen with Baird.

Congrats on the progress made over the course of the quarter. Two quick ones from our end. I was hoping you could add some more color on when the dosing of ASPIRE completed. I think you guys were targeting July, and I'm just curious if you have any more precision about when in July that may have completed.

And then as it relates to the more recent disclosure around the sensory neuropathy, it's great to hear the patient is on the mend. Any more color you can provide on the immunomodulatory agents that were given to that patient and the time course to recovery would be very helpful as well.

Yes, Jack, thanks for the questions. I think we haven't been super precise in terms of dates on the dosing just historically. I would say it's been several weeks since the last ASPIRE patient was dosed. This event that we're talking about here happened 6 weeks post dosing. So all the people in the pivotal trial are beyond that, obviously. So that's probably the most clarity that we can provide on that. I don't know, Suku, if there's anything more to add?

Well, what I would add, Sean, is that, the patient started recovering pretty quickly after the treatment was given. And we haven't got into details around what the specific therapies were or what the details were behind the patient, because that could be disclosing the patient's potential protected health information as well. So we are not going to get into that at this point in time.

But you did mention, Suku, that the way to manage these types of things is with immunosuppression or immunomodulatory agents.

Correct. Because that's what's relatively standard.

Yes, it's pretty forward. Very standard. Hope that helps, Jack.

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

Just on the safety event, was wondering, is it the expectation that patients who might have peripheral neuropathy could have a full recovery upon immunomodulatory treatment? And then also, I was wondering the role of prophylactic immunosuppression and how that might have -- could have impacted on this kind of event. I believe patients do have prophylactic steroid, although whether they had -- I wasn't sure whether steroid was also used prophylactically.

So, Yanan, you had multiple questions in your question there, so let me try to answer all of them in a very simple manner. So the prophylactic immunomodulation given for protocol, overall, I think, does have very positive impact on the occurrence of these peripheral neuropathies post-AAV9 gene therapy. So that is why they're not overwhelmingly seen, but they are seen common. Okay? So if you know what I mean.

Second is the peripheral neuropathies that may or may related to AAV9 gene therapy, regardless of route of administration. If the recovery to the immunomodulatory intervention is rapid, we observe that the patient is going to get much better quicker over time. So that is a positive signal clinically. So hopefully that's what we see eventually with this patient.

And what was the other -- there was another question. You had 3 questions. Did I answer your question, Yanan?

Sorry, I didn't quite hear whether prophylactic treatment could play a role in preventing this or...

Yes. Prophylactic treatment will play a role, not in preventing, but in reducing the incidence. Does that make sense?

Okay. Yes.

Yes. So what I'm saying is, if you didn't give any prophylactic treatment, you might see a few more cases, but it won't be overwhelming. But prophylactic treatment reduces the incidence.

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

This is Jonathan on for Gil. I just had a quick question, if you guys could provide any color around the over-enrollment, it looks like for your ASPIRE and pivotal trials. It seems like you guys got an extra patient in the ASPIRE and 2 in the pivotal.

Yes, Jonathan. The rationale behind that was because we didn't want to leave any patient behind. So we made a commitment that if you went into screening and you screened into the study, that we would treat you. And so, one of the reasons that you have to consider doing that is that, if you do get a screen fail and you don't have more patients than you're planning for in the process of being screened, you could end up delaying your enrollment. So we made a conscious decision to work that way as a clinical operations organization, and we work very closely with the PIs and the potential caregivers so that they understood that and they understood the commitment that we made. So that's why there is a few more patients in the REVEAL pivotal and one additional patient in the ASPIRE trial.

Our next question comes from the line of Angela Qian with Canaccord Genuity.

This is Angela on for Whitney. First question is on the safety. You guys mentioned that Rett patients typically get peripheral neuropathy. Does that present normally more like acute events, or is that more chronic when it happens in the population?

And then separately, have you guys talked about potential sales size for us and what the commercial organization would need to look like to support a launch?

Just on that last question, did you ask about the size of the commercial organization?

Yes, just like have you said anything about how many salespeople you might need to support the launch?

How many salespeople?

Oh, no. You know what, I'll take that part first. I would say more to come on that, Angela. It's a relatively discreet SG&A, and I think what you're going to see is a combination of a relatively small amount of "sales representatives." You're going to have a group of people that are very focused on working to secure kind of reimbursement for the families, and that's going to be a big part of what we do. Patient services is going to be another group that's instrumental in working with the families to make sure that everything gets navigated from the time the prescription gets written to them, getting to the institution and treated to them working with the insurance companies to make sure that reimbursement occurs.

So we're going to put the resources in play to make sure that it's the most optimal situation and journey for the families going through this. So there'll definitely be more to come later this year, beginning of next year, as we further refine our details around the go-to-market strategy and what that organization looks like. We've done a lot of work thus far, and at this point, it's, again, doing more market research and work to make sure we really understand the patient journey and flow. And we have a good idea right now. I would say we're 80% of what we -- I think we have 80% line of sight of what this is going to look like, but I think before we give more detail, I'd like to get additional information, and then we can give you a very fulsome report on that.

And you had another question on the neuropathy. Patients with Rett syndrome do develop peripheral sensory and at times, a mixed neuropathy, and it becomes chronic over time. So if your question is it sudden acute, and does it resolve on its own? Usually not. It's more of a chronic process.

Our next question comes from the line of Evan Seigerman with BMO Capital Markets.

I wanted to touch on some of the manufacturing and CMC work that you are working on. Beyond the completion of the PPQ runs, what CMC activities remain kind of on the critical path to the BLA? Are we talking assay validation, process validation reports, shipping hold time validation, or other kind of components of that?

And just as a follow-up, when you say the FDA has agreed with the comparability approach, kind of can you just drill into what that actually means in terms of the process in getting to commercial product?

Yes, great question. I would say, in terms of -- if we start with the comparability, the first time we hit a line with the FDA on comparability was when we compared the clinical lot, so that was the lot in Part A, with our first commercial lot, which is the part in Part B, right? And so it was kind of a 1-to-1 comparison. And we went through all the different analytics and product characterization parameters with the FDA [Audio Gap] analytically comparable.

Subsequent to that, we've run more batches of the commercial process, and they've continued, and I think we disclosed this a few quarters ago, that they continue to deem us analytically comparable to the clinical lot. So the next step is that, when we complete the PPQ runs, if those 2 are comparable from an analytical perspective, which we fully expect, that then allows us to utilize the Part A data, both in terms of efficacy and safety to support the regulatory submission. So we're in a really good spot there.

You asked about assay validations and things of that nature, we're in a really good spot there with the FDA. So really what's on the critical path is us completing the PPQ runs and then having that discussion with the FDA after we submit all the data around what the comparability looks like.

So I would say in a nutshell, we're very pleased where we are on the CMC side, and at this point in time, CMC is not a critical path item for us.

Our next question comes from the line of [ Joshua Woodman ] with Citizens.

Congrats on the update. Maybe just going back to IRSF, you presented a really great poster outlining the establishment of the [ RSDMA ], the development milestone assessment. I was hoping you guys could just reiterate the key points there and highlight how this provides confidence in the reliability of essential raters and confidence in the validity and interpretability of the data from a regulator's perspective.

We can tag team this, but I think it starts with the fact that we're creating, via the milestone strategy, a novel pathway for approval in Rett syndrome, right? I mean, to date, the only thing that has been approved has been approved based on CGI and RSBQ. And we knew that for a gene therapy, that was not going to be sufficient to garner capturing the value we think would be commensurate with the product. The payers would not have paid with that as your 2 endpoints, essentially. So we struck out on an endeavor to figure out what would be a clinically meaningful, very robust endpoint that's unequivocal that demonstrated the value of the product. And fortunately for us, we found the milestone plateau and then began to work on what's the construct of the actual tool that we'll use as the instrument to capture this data.

And so, what we were able to do with the DMA is do exactly that. And so, it's a very systematized way to go through the assessment of the milestone. So keep in mind, there's 28 milestones, so you're going to want to put in place a process that's very systematic and very rigorous. So as an example, the sequence of the milestones is tested the same way every time. Any implements used in the study are consistent from baseline throughout the study, so it's very easy to, again, measure what you're seeing there.

The angles of the cameras, as an example, is something that was tested. The manuals for the training. All of this took a lot of time. So it took 18 months from the concept to us being able to lock it down with the FDA, and fortunately for us, we ran a pilot in the background. We haven't talked too much about it, but we call it the [indiscernible] trial. And so, we were able to do the DMA in an nontreated population that was also, for the most part, sites in the clinical trial. So you knew like that was going to be a good index against then the ultimate final version of this, and that was also part of the submission that we made to the FDA. And that's how when we say that it is psychometrically validated, that pilot helped us validate that. We shared all that with the FDA, and that's what got them comfortable around taking this approach in an open label study, was how rigorous you're going to be able to collect that data and ensure that you had a clear baseline.

So, I mean, we can go chapter and verse deeper on that, but at a very high level, that's what happened, and it took a lot of hard work from the team, and it took a lot of time. It wasn't something you could just jump into, and it was something the FDA was very concerned around, was the rigor and the systemization of that data collection.

I don't know, Suku, if there is any more you might want to add?

No. All I would add, Sean, is the process and rigor of the collection and validation of the data set for the DMA was what was done in that study, and that was what was disclosed in the poster. And interestingly, there was an FDA representative at the IRSF meeting who actually presented to the audience and talked about the need for this kind of rigor, and also made a point that just because a patient population being studied is potentially highly variable, that doesn't -- cannot be used as an excuse for a poorly designed trial for approval of a product. It was a very interesting discussion that was raised. So this is a review of what also may be more relevant space with a currently approved product as well. So it was pretty timely, our data disclosure as well as the other presentations that occurred at IRSF.

And I'm showing no further questions. So with that, I'll hand the call back over to Chairman and CEO, Sean Nolan, for any closing remarks.

We appreciate everyone taking the time to hear our update, and we look forward to speaking with everyone in the future. Have a good night. Take care.

Ladies and gentlemen, thank you for participating. This does conclude today's program, and you may now disconnect.

Good day, and thank you for standing by. Welcome to the Taysha Gene 102 Rett syndrome Program Update Conference Call. [Operator Instructions] Please note that today's conference is being recorded. I would now like to hand the conference over to your speaker host for today, Hayleigh Collins, Senior Director, Corporate Communications and Investor Relations. Please go ahead.

Thank you. Good morning, and welcome to Taysha's TSHA-102 Rett Syndrome Program Update Conference Call. Earlier this morning, we issued a press release announcing the completion of dosing in the REVEAL pivotal trial and longer-term clinical data from Part A of the REVEAL Phase I/II trial evaluating TSHA-102 for the treatment of Rett syndrome.

A copy of this press release is available on the company's website. Joining me on today's call are Sean Nolan, Chief Executive Officer; and Su Nagendran, President and Head of R&D. Kamran Alam, Chief Financial Officer, will join us for a question-and-answer session following our prepared remarks.

On today's call, we'll 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, supporting 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 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 we face, please see the reports we filed with the SEC, including in our annual report on Form 10-K for the full year ended December 31, 2025, that we filed on March 19, 2026, and our quarterly report on Form 10-Q for the quarter ended March 31, 2026.

This conference call contains time-sensitive information that's accurate only as of the date of this live broadcast, June 22, 2026. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws.

With that, I would now like to turn the call over to our CEO, Sean Nolan.

Thank you, Hayleigh, and thank you, everyone, for joining us this morning. I will begin today's call with a brief overview of Rett syndrome, an update on our REVEAL pivotal trial and review the longer-term Part A data. Dr. Suku Nagendran will discuss the data in greater detail. I will conclude with next steps and then open the call for questions.

Rett syndrome is a devastating rare and progressive neurodevelopmental disease with high unmet need and a profound lifelong burden for patients and caregivers. It is well characterized clinically defined by impairment across communication, fine and gross motor, autonomic function and seizures.

These impairments result in loss of independence, with most individuals requiring 24/7 care and lifelong support for daily activities. This burden and the limitations of currently approved therapies have created strong urgency for new treatment options capable of delivering functional improvements.

We believe this urgency, combined with the estimated 15,000 to 20,000 patients with Rett syndrome across the U.S., EU and U.K., underscores the substantial market opportunity for TSHA-102. Consistent with the FDA's 2025 guidance on innovative trial designs for gene therapies targeting small populations, a single-arm registrational trial relies on robust, well-characterized external and baseline data to distinguish treatment effects from natural disease progression.

Therefore, we conducted a rigorous analysis of longitudinal data from the Rett syndrome natural history study to inform our pivotal trial design. The natural history study captured longitudinal data on the gain, loss and regain of developmental milestones across communication, fine motor and gross motor function.

Our analysis across 28 clinically meaningful milestones showed that before the age of 6, there was up to a 97% likelihood of spontaneous milestone gain. This can cause -- this can confound the ability to distinguish treatment effects from natural developmental variability in patients younger than 6 years old.

In contrast, after age 6, the likelihood of gaining a new or regaining a developmental milestone that was lost after a defined number of years declined sharply to less than 6.7%. These results support the minimum inclusion age of 6 years in a well-controlled single-arm interventional trial evaluating gain and regain of developmental milestones.

We're pleased to share that we have completed dosing in our over-enrolled REVEAL pivotal trial with 17 patients in the developmental plateau population of Rett syndrome treated with TSHA-102. We enrolled a well-balanced age distribution across pediatric, adolescent and adult patients, similar to the broad age range seen in Part A. We're encouraged by the significant interest and demand from caregivers and clinicians, and we sincerely thank the Rett community for their support, trust and participation as we reach this important milestone.

TSHA-102 continues to be generally well tolerated with no treatment-related serious adverse events or dose-limiting toxicities reported as of the June 2026 data cutoff. The single-arm open-label trial is evaluating a single intrathecal administration of high-dose TSHA-102, 1 E to the 15 total vector genomes in patients with Rett syndrome 6 to less than 22 years of age, who are not expected to gain or regain developmental milestones.

The primary endpoint is response rate, defined as the percentage of patients who gain or regain 1 or more of the 28 naturally -- natural history-defined developmental milestones with each patient serving as their own control. A response rate of 33% is the minimum threshold for success sufficient to reject the natural history established null hypothesis of 6.7%.

We plan to conduct a 6-month interim analysis once all 17 patients complete 6 months of follow-up. Earlier this year, we reaffirmed alignment with the FDA that the interim analysis has the potential to serve as the basis of our planned BLA submission, which may expedite our submission by at least 2 full quarters. We believe our longer-term REVEAL Part A data further supports the potential for the BLA submission based on the pivotal trial interim analysis.

Now let's turn to the Part A data, which includes 2 additional high-dose patients since our last data update in 2025. All 12 treated patients have at least 12 months of follow-up as of the May 2026 data cutoff, enabling a more comprehensive assessment of the durability, depth and consistency of treatment effect over time. We will focus on the 6- and 12-month time points, which are the SAP-defined primary analysis landmarks for our pivotal trial as well as data beyond 12 months to assess the durability and continued accumulation of functional gains.

There are several key highlights in this data set. First, the data demonstrated a 100% response rate according to the pivotal trial primary endpoint with all 12 patients achieving one or more natural history-defined developmental milestones. Second, longer follow-up across all patients demonstrated a durable and deepening treatment effect with additional functional gains accumulating over time through 12 months post TSHA-102 and beyond.

There has been no plateau effect observed with an upward trend in the data over time. Wonderful to see. In fact, developmental milestones increased by 69% from month 6 to month 12 and by 94% from month 6 to greater than 12 months. Third, we observed broad functional impact across core disease domains among pediatric, adolescent, and adult patients.

Importantly, this is regardless of age, disease severity or genotype. At greater than or equal to 12 months post TSHA-102, a total of 310 functional gains were observed across the patients, averaging 26 gains per patient across communication, fine motor, gross motor and autonomic domains. The functional gains include natural history-defined developmental milestones and additional skills and improvements, which we will discuss in more detail later.

Fourth, and importantly, the robust and clinically meaningful response at both 6 and greater than or equal to 12 months exceed the FDA aligned minimum threshold for efficacy and in our view, robustly support the potential for a BLA submission based on the REVEAL pivotal trial 6-month interim analysis. Finally, from a safety standpoint, TSHA-102 continued to be generally well tolerated with no treatment-related serious adverse events or dose-limiting toxicities.

Collectively, these data build on previously disclosed data and further support the potential for TSHA-102 to transform the lives of pediatric, adolescent and adult patients suffering from Rett syndrome. Understanding our approach to data collection and evaluation is essential for interpreting the results we are sharing today. Our FDA-aligned pivotal development strategy is grounded in the rigor of our natural history analysis, Part A data collection, and video evidence evaluation.

The functional gains that we will discuss today fall into 2 categories: developmental milestones and additional skills and improvements. Developmental milestones are defined as a functional gain of 1 or more of the 28 milestones defined in the natural history. This is the primary evidence of efficacy that will support our planned BLA submission and the FDA's review of efficacy in the pivotal trial. Developmental milestones in Part A are assessed using 3 criteria, all of which must be met for a developmental milestone to qualify as a gain or regain post TSHA-102.

First, all caregivers must complete a clinician-administered historical milestone questionnaire used in the natural history study to identify milestone eligible for gain or regain based on each patient's unique history. The milestone gain must be captured post treatment via video documentation, which is then evaluated independently by multiple external central raters using prespecified definitions of achievement. This ensures objective assessment. We believe our Part A data accurately reflects the outcomes we expect to see in the pivotal trial as they are evaluated using the same FDA aligned criteria for the pivotal trial protocol.

We also measure additional skills and improvements, which are defined as a functional gain or improvement in a core disease characteristic beyond the 28 natural history defined developmental milestones. They are assessed via rigorous video evidence evaluation and validated scales. These gains serve as supportive evidence of functional gain. The 12 patients treated in REVEAL Part A range from 6 to 21 years of age of dosing with post-treatment follow-up spanning 12 to 30 months.

4 patients were treated with the low dose and 8 were treated with the high dose of TSHA-102. We enrolled patients across a broad spectrum of disease severity as assessed by the Clinical Global Impression Severity or CGI-S scale, a 7-point clinician-rated assessment of illness severity ranging from 1, which is normal or not at all ill to 7 among the most extremely ill. Baseline scores range from 4 to 6, reflecting moderately to severely ill patients.

Despite the broad range in age and disease severity, 100% of the 12 pediatric adolescent and adult patients treated with TSHA-102 achieved one or more developmental milestones, which is less than the 6.7 likelihood of spontaneously occurring in this population based on natural history. We observed a rapid and robust response, supporting the pivotal trial is well powered to establish efficacy.

Part A results far exceeded our FDA-aligned pivotal response rate threshold of 33%, with a 75% response rate seen as early as 3 months and increasing to 83% at 6 months. By 12 months, 100% of the 12 patients were responders. Importantly, we believe these results further support the potential of our FDA aligned 6-month interim analysis in the REVEAL pivotal trial to serve as the basis for a BLA submission.

A total of 31 developmental milestones were achieved across the 12 patients, spanning the core functional domains of Rett syndrome, communication, fine motor and gross motor function. These achievements represent the breadth of response demonstrated and reflect meaningful improvements in daily living that are important to caregivers, families and clinicians. Starting with communication, milestones achieved included speaking in phrases and using words with meaning and following commands.

These important skills enable patients to express their needs, preferences and emotions and foster social connections. Fine motor milestones achieved included using utensils to eat and finger feeding, which are important self-care skills. Lastly, gross motor milestones achieved included walking with support and climbing down the stairs, which enable independence and reduce the physical burden of caregiving.

We observed a consistent and clinically meaningful treatment effect across pediatric, adolescent and adult patients treated with TSHA-102. Specifically, 16 of the 31 total developmental milestones were achieved across the 6 pediatric patients and 15 were achieved across the 6 adolescent adult patients. This highlights the consistent treatment effect seen regardless of age or disease severity, which is important given over 85% of the prevalent patient population is older than 10 years of age.

Bottom line, based on these outcomes, we believe that most patients, regardless of age and baseline severity can meaningfully benefit from TSHA-102. Our market research indicates that clinicians anticipate broad adoption of TSHA-102 across pediatric adolescent and adult patients and caregivers report they would actively pursue an approved gene therapy with a profile consistent with TSHA-102.

I would now like to turn the call over to Suku to discuss the data in greater detail.

Thank you, Sean. Looking at developmental milestone achievements from a temporal lens, many patients achieved milestones as early as 3 months post TSHA-102. These gains were persistent and patients continued to accumulate additional milestones over time across all 3 core disease domains. The total number of developmental milestones achieved across the patients increased from 16 at 6 months to 27 at 12 months, a 69% increase, and 31 to greater than 12 months, a 94% increase.

You can see here the continued accumulation of functional abilities over time. The majority of patients achieved multiple developmental milestones with 75% of high-dose patients achieving 2 or more post TSHA-102. We also observed clinically meaningful skill gains and improvements in core disease characteristics beyond the 28 natural history defined developmental milestones, which, as Sean mentioned, were assessed through rigorous video evidence evaluation and validated scales.

Together, the developmental milestones and additional skills and improvements reflect the totality of functional gains seen post TSHA-102 that impact activities of daily living. At greater than equal to 12 months post TSHA-102, a total of 310 functional gains were observed, translating to an average of 26 per patient. We believe these durable multi-domain functional gains that accumulated over time reflect the broad functional impact of TSHA-102.

It is important to note that we believe that these numbers are conservative as only approximately 60% of patients had Mullen and ORCA data available, which were both added in later study protocol versions, while 100% had R-MBA and developmental milestone data. The 310 functional gains observed across the patients included 31 developmental milestones, which Sean discussed earlier and 279 additional skills and improvements.

These additional skills and improvements span communication, motor, autonomic and behavioral domains such as improved gross and fine motor skills and hand use the ability to respond to questions, and reduced our absence seizure activity. I would now like to hand the call back over to Sean to speak to the impact of these functional gains.

Thanks, Suku. To help put these functional gains into perspective, here we've highlighted a handful of caregiver testimonials from patients treated in Part A that illustrate the meaningful impact across core disease domains and overall quality of life. We will now share 2 high-dose patient vignettes to further demonstrate how these outcomes translate into meaningful improvements in daily life for patients and their caregivers.

The 2 patients represent opposite ends of the age spectrum among those treated in Part A, a 21-year-old woman and a 6-year-old girl to demonstrate the broad treatment effect. Jane is a 21-year-old woman living with Rett syndrome. Before treatment, she was unable to speak and often appeared disconnected from her surroundings and withdrawn from social interactions. This meant she could not express even basic needs or preferences. She rarely made choices and was unable to follow simple commands, leaving her parents to constantly anticipate what she might need.

Jane had no purposeful hand function and only rarely finger-fed, relying on our parents to feeder meals and assist with daily tasks. Mobility was also a significant challenge. Jane could walk independently, but only for short distances, about 20 steps with a slow unsteady gate. She was unable to climb stairs and therefore, had to be carried by her dad.

Her mobility had declined over time and require constant supervision and hands-on support from her parents throughout the day. Jane also suffered from refractory epilepsy and experienced daily to weekly seizure episodes. She had feeding difficulties that resulted in feeding taking over 30 minutes. Taken together, these challenges meant that nearly every aspect of Jane's day from basic communication to movement, and meals required significant caregiver support, limiting her independence and her ability to engage meaningfully with the world around her.

Jane, who is 21 years old at dosing achieved sustained meaningful functional gains following TSHA-102. At 18 months post treatment, she now regularly uses words and speaks and phrases with meeting such as "Okay. Bye mom." She recently discovered root beer and quickly learned the word to request for her new favorite treat. She is now consistently engaged in social interactions, initiates behaviors like giving high-fives and is described as joyful, playful and a teasing young adult who loves interacting with others and spending time with her dog.

Jane can now clearly express her needs and preferences. She points to what she wants, makes choices and follows commands. She consistently uses fingers to self-feed and can be found feeding herself a bowl of chips. She now holds a juice box in her hands and turns the light switch on and off when entering or leaving the room. Jane's gate mobility have also improved. And now she walks independently throughout the home, moving from room to room and coming to the table at meal times.

She can also now climb the stairs with support by holding the railing, no longer requiring her dad to carry her. Her seizure frequency has reduced from daily or weekly to now monthly, and she no longer has feeding difficulties. According to the principal investigator, Jane has strongly benefited from TSHA-102. She has gained more autonomy and her quality of life has improved. She is now able to interact purposely with her environment and with her loved ones.

Jane's mom said, we would never go back to the way things were before. This has been a miracle. Sarah is a 6-year-old girl living with Rett syndrome. Prior to treatment with TSHA-102, she was severely impacted across multiple aspects of daily life. She spoke just one word with meaning and was rarely responsive when spoken to, often appearing disconnected from the world around her. This made it difficult for her to engage with others or communicate even basic needs.

She had constant hand stereotypes, leaving her very limited function in terms of use of her hands. She was unable to eat using eating utensils. At the gross motor level, she could take a few steps with support, but she required assistance from her parents for positional transfers, and she was limited in her overall mobility and independence. Sarah had a severe breathing dysrhythmia characterized by frequent episodes of breath-holding and hyperventilation with cyanosis and periods of limpness, along with cold, blue extremities.

Taken together, these challenges meant that nearly every aspect of Sarah's day from basic communication to movement meals required significant caregiver support, limiting her independence and her ability to engage meaningfully with the world around her. Sarah, who is 6 years old at dosing achieved sustained meaningful functional gains following treatment with TSHA-102.

At 12 months post treatment, she now uses multiple words with meeting such as "encore," which is French for more. When she wants more of something, she says, "Mama." Now she's now using the AAC device to communicate, expressing her needs and makes requests such as asking her parents for food or to play a specific song she likes. She is now actively engaged with her surroundings, paying attention to those around her, localized to participate in conversations and showing a clear interest in social interaction.

Sarah experienced a reduction in hand stereotypes and now uses her hands in a purposeful functional way. She can pick up toys and actively engage with them, shaking or banging them together to create sounds with great joy. She gained independence and feeding and is now using utensils without assistance. She enjoys meals on her own, especially strawberries dipped in whipped cream.

Sarah gained the ability to pull herself to a standing position and maintains a standing position with support, requiring less assistance from her parents for positional transfers. Her breathing has improved considerably with reduced breath holding and hyperventilation and her cyanosis has improved, with her extremities now warm and normal in color. Overall, the principal investigator shared that Sarah has strongly benefited from TSHA-102 and her ability to communicate and interact with her environment has improved notably.

Sarah's dad said, "if we were given the choice to receive this therapy again, we would definitely do it again. This has all been worth it." Zooming out, these examples highlight the breadth and real-world significance of the functional gains across core disease domains seen with TSHA-102 treated patients. Despite differences in age and baseline severity, patients consistently demonstrated improvements that meaningfully change how they interact with the world.

For example, patients who are nonverbal gained the ability to speak in phrases, make choices more consistently, participate in conversations and engage and play with others. Patients who once required caregiver assistance for feeding gained the ability to feed themselves and play with toys and experienced reduction in hand stereotypies, supporting greater autonomy in daily activities.

Non-ambulatory patients gained the ability to walk with support and climb down the stairs with support. Patients who required caregiver assistance for positional transfers have gained the ability to pull themselves to a standing position and stand by holding on, reducing caregiver burden. And patients who relied on G2 for feeding have gained the ability to eat and drink by mouth. And we've seen a consistent reduction in the frequency of seizures and breathing dysrhythmia post TSHA-102.

I will now turn the call back to Suku to discuss -- for him to discuss additional supportive data.

Thank you, Sean. Let's turn to the supporting efficacy scale. The R-MBA is a clinician-assessed scale that measures symptom severity across several domains. It has been well characterized within natural history and was collected at 6- and 12-month intervals throughout the natural history study. R-MBA demonstrated a consistent and robust treatment effect across all 12 patients at both 6 and 12 months post TSHA-102.

Looking at the average change relative to baseline, we see statistically significant improvement at both time points, which is a sharp contrast to the minimal change in natural history, suggesting a reversal of the expected disease trajectory. Notably, the treatment effect shows greater statistical separation from natural history at 12 months from 6 months, as reflected by a lower p-value.

Beyond 12 months, the treatment effect continues to deepen with a clear dose-dependent separation. High-dose patients achieve a mean improvement of 15.7 points compared to 7.8 points in the low-dose cohort. Overall, the results further reinforce our conviction in the treatment potential of TSHA-102.

Now let's look at the CGI-I, or Clinical Global Impression Improvement, a clinician assessed scale that assesses improvements from baseline to provide an overall global impression of a patient. The scale ranges from 1 to 7 with lower scores indicating a higher degree of improvement. TSHA-102 drove early sustained global improvements in CGI-I with dose-dependent effects that deepened over time.

100% of the patients demonstrated an improved CGI-I score of 3 or less at a multi post-treatment assessment. Notably, mean CGI-I scores in the high-dose cohort were less than 3 at all assessments and improved over time, reaching 1.7 in the high-dose cohort at 18 months post treatment.

Turning to safety. TSHA-102 continues to be generally well tolerated at both low and high doses as of the May 2026 data cutoff. No treatment-related serious adverse events or dose-limiting toxicities were observed among the 12 patients in Part A. Treatment-emergent adverse events related to TSHA-102 were mild to moderate in severity, the most common being elevated liver enzymes, CSF protein increase and pyrexia.

Seizures have been generally well controlled. We are pleased to report that across the 29 patients treated in the REVEAL Part A and pivotal trials, there have been no treatment-related serious adverse events or dose-limiting toxicities as of the June 2026 data cutoff. Overall, this favorable safety profile, combined with the breadth and durability of improvement further supports the continued advancement of TSHA-102 towards a potential BLA submission.

I'll turn the call back over to Sean for concluding remarks.

Thanks, Suku. Our confidence in the differentiated potential of TSHA-102 continues to strengthen based on today's updates, which we believe further support the potential 6-month interim analysis registrational strategy and a clear path to a broad label for patients aged 2 years and older.

With dosing in the REVEAL pivotal trial now complete, we are focused on the upcoming 6-month interim analysis as we advance towards potential registration. Dosing of the safety-focused ASPIRE trial, which is enrolling patients aged 2 to less than 4 years old, is ongoing with enrollment exceeding the initial target of 3 patients.

We remain on track to complete dosing of 3 patients in June 2026 and expect to dose 1 additional patient in July 2026, further strengthening the potential BLA submission for TSHA-102. We believe the REVEAL Part A data provides proof of concept and strong support for a potential BLA submission based on the pivotal trial interim analysis, given TSHA-102 demonstrated robust, clinically meaningful responses at both 6 and 12 months and beyond across multiple key outcome measures.

Importantly, we observed an 83% response rate at 6 months and a 100% response rate at 12 months, exceeding the FDA-aligned minimum threshold for the pivotal trial, which further bolsters our confidence in our 6-month -- in our pivotal trial 6-month interim analysis. Our confidence is further bolstered by total functional gains observed, R-MBA and CGI-I data, all demonstrating significant and consistent response at 6 months, 12 months and beyond.

In addition, the CGI-S scale was not designed as a clinical outcome measure and is not sensitive to incremental changes, requiring a dramatic improvement to detect a shift in score. Therefore, it is encouraging that 25% of patients showed a CGI-S total score improvement at 6 and 12 months post TSHA-102, which then improved to 57% of patients at the 18 months or greater follow-up.

As a reminder, the FDA has agreed that our clinical and final commercial manufacturing processes are considered comparable, which means this REVEAL Part A data can be included in our BLA to support the totality of evidence. This alignment further supports the possibility of a BLA submission based on the pivotal trial interim analysis. With an estimated 15,000 to 20,000 patients with Rett syndrome across the U.S., EU and U.K., compelling Part A clinical data across pediatric, adolescent, and adult patients and a minimally invasive, commercially advantageous delivery approach, we see a significant opportunity to address the profound unmet medical need.

In the coming quarters, we look forward to completing key BLA-enabling activities, including completing dosing in the ASPIRE trial in July 2026 and the BLA-enabling PPQ campaign in the fourth quarter of this year. We expect to report top line data from REVEAL pivotal trial 6-month interim analysis, along with the FDA feedback on the BLA submission pathway in the first half of 2027.

The updates shared today strengthen our confidence in the differentiated potential of TSHA-102 to transform the treatment landscape for Rett syndrome and our readiness to advance toward a BLA. We believe the early, durable and deepening treatment effect consistently observed across multiple outcome measures and our longer-term data further support our path to a potential submission based on the 6-month interim analysis.

We would like to thank the entire Rett syndrome community as well as our clinical investigators and dedicated team at Taysha for their unwavering support, trust and participation as we work to bring this potentially transformative therapy to patients.

With that, I will now ask the operator to begin the Q&A session. Operator?

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

Congrats on all the positive updates you provided today. I was a little intrigued by some of the anecdotes you shared around seizure reduction. So I was hoping from a high level, you could tell us what you are seeing in terms of seizure activity in these patients. And then as we just think about the fact that some of these patients have several seizures, do you think the impact to reduce them could help with other milestones just given that they exhaust the brain cells when they occur?

I'd ask Suku to take that question.

Thanks for that very intriguing question, Kristen. So as you probably know, when it comes to patients with Rett syndrome, it's thought that 80% to 90% of these patients do have seizures. They can be generalized tonic-clonic, partial, complex or absence seizures, or a combination of the above. What is also important to note, I think, as you were hinting at, when patients have seizures, such as patients with Rett syndrome and neurodevelopmental disorders, it literally stuns the brain and essentially gets in the way of these patients reaching or gaining new milestones.

So if you have a therapeutic that even impacts seizures in a positive manner, this could also open the floodgates, hopefully, to gaining new milestones or regaining lost milestones over time. And in our case, we have looked at seizure history from a preliminary analysis standpoint and the signals are that the severity of seizures and the frequency of seizures appear to decrease in some patients and also the combination of antiepileptics. Many of these patients tend to be on 2, 3 or 4 antiepileptics.

And in some cases, the doses are reduced or the need for more than 3 antiepileptics may be reduced. So all I can say is stay tuned because we are further analyzing this data in great detail. And I hope that we can present this data sometime in the future that further highlights the broad clinical impact of TSHA-102 in patients with Rett syndrome, given, as you know, by lumbar function. So thank you.

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

As we think about the REVEAL Part B study being derisked here, could you help us understand any differences in the assessments between Part A and Part B?

Thanks, Salveen. Suku, we can tag team this. But I think what gives us a lot of confidence right now, and we were trying to highlight throughout the call is that there's a great deal of consistency in terms of the COAs or the scales that we used in Part A. So we're evaluating milestones. We're evaluating additional skills and improvements. We're evaluating the R-MDA, the CGI, the ORCA and the CGI-S.

All that is going to be also done in Part B. And one of the things that is important to note is that we think the data in Part A is underestimating the potential benefit demonstrated because as we talked about in the script, only 60% of the patients had both the Mullen and the ORCA because those were added later in the protocol. So we would anticipate that there's even potentially stronger gains observed across the board in these patients. Suku, I don't know if there's anything else you'd add to that.

Yes, Sean, I agree with you. And what I would also add is that Part A started off as a safety study with multiple efficacy parameters being evaluated as hypothesis generating. It was pretty clear, very early, we started picking up on strong efficacy signals in some components that we were evaluating, which then led to us formulating the rigor that we've now translated into the Part B REVEAL study.

So our developmental milestone assessment in Part B is very rigorous, blinded using multiple independent raters at the 6-month and 12-month time point that the FDA likes and has already commented in writing that they're quite complementary of such a rigorous process that enables us to do a very simple open-label single-arm study. Keep in mind, our primary endpoint is blinded. So that gives a lot of rigor and further credibility to our study in Part B.

Also, as Sean highlighted, the ORCA, which is patient assessed or not the patient actually, the caregiver assessed and also the Mullen, which is an expert evaluation with videos was done only in 60% of the patients when it comes to having baseline and post-treatment evidence via videos in the Part A REVEAL study. In Part B, all the patients do have that. So collectively, I would anticipate, given the success we've seen 100% responder rate in Part A, that hitting a 33% responder rate in Part B and the probability of success for Part B should, from an actuarial standpoint, be quite high.

And the total clinical impact of our product when it comes to developmental milestone achievement, which is the primary endpoint, plus skills, plus improvements, which come from all the other measures and physician notes in CGI-I and CGI-S should be hopefully much greater than what we've seen in Part A. And if all of that holds true, that further enables us to submit a BLA for full approval potentially with the 6 months interim in Part B because the totality of clinical evidence should be overwhelming for any regulator to look at, especially in a disease like Rett syndrome where there is significant unmet medical need globally.

Yes. And maybe just to put a capstone on all this, Again, when you think about the key secondaries like the R-MDA, the CGIs, the Mullen, et cetera, those are all conducted the same way in Part A, they are in Part B. And we think that's going to translate very well and can derisk things for the investors and also the caregivers thinking about potential benefits. But just to highlight on the primary endpoint side, keep in mind that the definitions of the 28 developmental milestones are prespecified.

The evaluation of the data in Part A was based on video evidence and was centrally adjudicated with multiple raters. And in Part B, yes, it's going to be blinded, but the process is the same. And we've now created a stand-alone DMA, which creates more likelihood that you'll be able to capture developmental milestones in a systematic way. So from our perspective, we see Part A as very derisking to Part B. Thanks, Salveen.

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

Congrats on the update. I'd like to get your view regarding to what degree will long-term data from Part A be part of FDA's consideration and accepting the 6-month interim from Part B? And then given these data updates on long-term durability, will you be applying for CNPV?

Yes. Suku, let's tag to this. But the ability to use your Part A data is driven by whether or not the product used in Part A is comparable to the product used in Part B and is your commercial process, right? And so initially, in our interactions with the FDA, we had our clinical lot that was used in Part A, and we had a lot that we had done from a commercial process. And that one-to-one comparison was deemed analytically comparable in our discussions and written correspondence with the FDA.

Subsequently, we've run several more batches. And in our last meeting with the agency on CMC, they continue to deem things analytically comparable. So the last step to that is completing the PPQ runs. And if those continue to demonstrate comparability, which we have every reason to believe they would, that allows you to then use your Part A data to support the BLA filing. And we think exactly as you're asking, Biren, that's going to be very helpful to us because we're going to have at the time of the BLA submission, 2 to 4 years on a lot of patients that will support the concept of durability and continued progress over the course of time. I don't know if there's more you'd add to.

Yes. What I would emphasize, Sean, as you did, is that the product is considered comparable between Part A and Part B. So the clinical product we used in Part A, the research grade product and the commercial product in Part B as of today is probably comparable by the FDA. But the Part A long-term data further highlights the fact that the clinical effect of TSHA-102 continues to be persistent, deepens over time and additional clinical components again that include developmental milestones, skills and improvements.

So everything persists long term, and it continues to add on for patients. So this is also critical to show not just the immediate rapid efficacy of our product, but additional accumulation and long-term consistency of our product as well, which I think hopefully will be convincing enough to regulators to seriously consider the Part B 6-month interim for full BLA approval.

And Biren, one last thing. I think that the question is important on several levels. One of the things we're trying to emphasize is that when you look objectively at the primary endpoint, at the R-MDA, at the CGIs, at the total functional gains and improvements at 6 months versus 12 months, which are the landmarks in the SAP for approval, they're exceptionally strong. They're all above the threshold of success.

So there's no reason in our view to wait for 12 months. If someone wanted to make the case, they'd like to see more durability. Now we can point to the Part A data because we're -- the 2 processes are comparable allows us to support that argument as well. So we right now have a lot of confidence in our ability to potentially move forward here with as much alacrity as possible with that 6-month interim and move towards a BLA and get this to market and to patients as soon as possible. Thank you.

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

I just wanted to clarify on time lines. In your press release, you stated again in early '27, you plan to engage with the FDA to review the interim data and the next steps towards submitting your BLA. Is there any way that you think that could happen earlier than that? And what would be rate limiting?

I'm glad you asked that question because we want to be very clear about that. The likelihood is we would be evaluating our data in December, right? We would start the analysis of the 6-month interim. You've got to clean that data up, request the meeting with the FDA. So we think the meeting with the FDA is going to happen in the first quarter.

And the reason we put first half is we just -- I can't -- I don't have perfect line of sight right now to is that mid-first quarter, later first quarter because we want to come back to the market after we've cut the data, after we've met with the FDA and after we have the minutes -- so that's what's leading us to this first half update. We're pushing to do things as soon as we can. We just want to make sure everything as tight as possible and that we have those minutes before we come back to the Street. Hopefully, that makes sense.

And our next question coming from the line of Maury Raycroft with Jefferies.

Congrats on the update. You've overenrolled Part B by 2 patients. Can you confirm when the last patient in Part B was dosed and how much follow-up you have on safety for all patients? And talk about the risk related to a treatment-related SAE arising at this point in the study?

Yes. I'll take the first question. I can tell you the vast majority of patients were dosed before the end of May. There was a couple of patients in June. And we've obviously, at this point in time, dosed 29 patients with TSHA-102 and the safety profile continues to look very, very encouraging. Suku, I don't know more to add about the second part of Maury's question there.

Yes, Maury, what I would add is that when you look at the different routes of administration for any type of gene therapy, intrathecal route in my experience, continues to be the safest as of today. And if you look at the data out there, whether it's ZOLGENSMA, our data set and others, and there are usually no concerning safety signals even in the first 4 weeks because as you probably know, in gene therapy, you tend to want at least 2 to 4 weeks of safety data usually to see if there's a signal.

But in the intrathecal space, though, usually, any changes that you normally see, especially with enzymes, they tend to be mild to moderate, and they're usually very well controlled with steroid regimens as long as you monitor the patients carefully over time. So as Sean said, at this point, we haven't seen any treatment-emergent SAEs related to product or any dose-limiting toxicities. So I feel quite comfortable. We have a very safe program where the benefit as of today far outweighs the risk.

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

Congrats from us as well on the update. So just a couple of questions. So you have a dose response using CGI-I and R-MBA. Any color as to milestones gained by dose? And then I guess I just wanted to understand a little bit more, Sean, and clarify what -- how you're communicating on Part B. Did I hear correctly that you're not going to share the data until after you get the minutes back from the FDA having met with them on the Part B data? Or would you provide that data to the market first?

Yes, Chris, on the second question, we would want to get the data, meet with the FDA get the minutes and then come back to the market. And the reason for that is we think that the Street would be unsatisfied if we just simply put the data out because the other part of the equation is, okay, so what's the next steps and how does the FDA feel about that? So that's the rationale for the pathway that we plan on taking there. As it relates to milestones by dose, I think we reported the last time, really, what we're seeing is the fact that the speed to the milestone is faster in the high dose. So to get to the higher numbers, the 100% responder rate, I think we did in 9 months at the high dose versus 12 months at the low dose.

Our next question in queue coming from the line of Jack Allen with Baird.

On the update, very impressive data. I wanted to ask about the REVEAL Part B enrollment. It seems like you've overenrolled this study. It was 17 patients versus the target enrollment of 15. I was curious if you could provide any additional context surrounding the amount of engagement you're seeing from the community here. Are there even additional patients that don't meet the clinical trial criteria that are interested in gene therapy? I'm just curious from a commercial perspective, what kind of demand we could expect here.

I mean, Jack, I'll go first and Suku can jump in here. But the demand was significant. I mean we could have had double the amount of patients in the study. And really, what we were trying to do is really give a lot of credit to the clinical development team and clinical operations team at Taysha because you're trying to balance out speed of enrollment because you could potentially have somebody screen fail.

And for us, the screen fail was generally -- we set a threshold of a number of open milestones to have. And so that's something that you want to make sure you've got effectively more patients than you might need on paper in case someone did a screen fail and you didn't lose time. So that's the reason for it. And we felt if the patients went through the screening process, there was an obligation on our part to go ahead and then treat them. And so that's why we had a couple of additional patients in the study.

Yes. And Sean, I was also going to add for your benefit, Jack, that given the broad significant clinical efficacy that we've seen in Part A, we have fairly good power and a p-value for regulatory standards now set up for Part B. So essentially, by -- so I guess my point is the statistical one that when you have broad clinical separation between an intervention and the comparator where which is the plateau Phase II natural history, the increase in power by over-enrolling 2 patients actually technically reduces the number of patients you need to hit 33% responder rate for statistical analysis. I just thought you might find that interesting to know.

And Jack, one last thing I would say is that clearly, in the data and in the script, we're excited about the fact that we're seeing broad efficacy regardless of patient age, baseline severity and genotype -- and that actually manifested itself in Part B enrollment as well because when you look at the age distribution, there's a good representation of the pediatric population, the adolescent and adult population, which is very consistent with the market research that we're doing right now and seeing that there's going to be strong demand across the age groups. And very fortunately, based on the data that we're generating, there's an impact and a very significant one, and we step through a couple of those vignettes regardless of age. So I think the demand for this TSHA-102 is going to be very, very high in the community.

Our next question coming from the line of Jonathan Hsu with Needham & Company...

This is Jonathan on for Gil today. Congratulations on all the progress. I had a question around some of the milestone gains. Specifically, did you guys see any acceleration of milestone gains with additional supportive therapy? Or were there any losses of milestones as well?

Part of our protocol, we did not recommend additional physical therapy or services beyond what the families were already doing. And so I think you're getting a true representation of the effect of the drug versus trying to influence outcomes by external factors. I think it's a practical matter, each family is going to be able to do more or less with external resources in a commercial setting.

I certainly think if you're able to use those types of services, it could potentially be beneficial to you. But I think what you're seeing in the real world in Part A data, and you'll see in Part B data, hopefully, is the effect of the drug. And I think that's what we're clearly demonstrating there.

Yes, not much to add, Sean. So we didn't add anything above and beyond what standard of care at that point in time in the patients were enrolled in the trial.

Our next question coming from the line of Whitney Ijem with CG.

Congrats on the update and all the progress. Just to follow through on the commercialization question and thinking through demand, particularly in the adult population. I guess first part of the question, you mentioned 85% of patients, I think, over the age of 10. Are there any additional and particularly thinking about the older patients, any like age cohorts you can break out in terms of percent prevalence?

And then how are you thinking about balancing what feels like it could be a lot of demand in the older patients, as you said, and kind of being able to capitalize on a potential kind of lead relative to competitors versus trying to control and pace the launch and make sure everything goes well.

So from the distribution perspective, the average lifespan of Rett patients is into their 50s and 60s and so you'd expect some type of a bell curve distribution there. What I can tell you from our market research is that both the clinicians and the caregivers like the parents were basically saying, regardless of age, they would be very interested in seeking out TSHA-102.

And I think that adult data is really motivating people. And as it continues to get out and we publish on it, I think that's going to further occur. I think when we build our own models, we would expect that as the patients get older, there may be less share in a particular age cohort, but the demand is still going to be there to seek treatment. So I think that's an important piece is that a large percentage of the prevalent population are going to be seeking treatment for gene therapy in TSHA-102. And the second part of the question -- I'm trying to remember. Do you remember the second part of the question? If you're on, you can...

Yes, I can add. Am I still live?

Thanks, Whitney.

Yes. No, sorry for the multi-parter. But just how are you thinking about demand and kind of rollout and setting yourselves up for success in terms of capitalizing on a potential lead versus competitors, but also presumably trying to pace and make sure initial treatments go well, et cetera. So just how you're thinking about that at this point?

Look, the thing that's going to be at the forefront of what we do is going to be patient safety. So we're going to make sure that we roll this out in a very thoughtful manner and that the physicians and the sites that use TSHA-102 understand the product characteristics, understand the appropriate monitoring and care for the patients. Unfortunately, most of the -- most of the sites in the study are centers of excellence and obviously places where you would want to start.

The nice thing for us is that the route of administration lends itself to being able to do a couple of things. One is, let's just say, within an institution that could be very well trained, your ability to scale intrathecal dosing is much more straightforward and manageable for that institution versus other types of directive to brain procedures where you've got to get the surgical suite, neurosurgeon time and things of that nature.

So just the throughput and footprint that you can grow in an institution is significant. We think that's a major opportunity for us. And we do have and we're continuing to refine the plan in which we would then step things through out into the community so that we can get the reach as more institutions come online. So we think we're going to be able to balance things. But the first and foremost thing is that the places that use the therapy are trained and know how to use the therapy.

Ladies and gentlemen, that's all the time we have for our Q&A session. I will now turn the call back over to Mr. Sean Nolan for any closing comments.

We just appreciate everyone taking the time this morning to listen to the data update. We're very excited about the progress we're making and look forward to sharing more with you in the future. Have a good day, everyone.

Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect.

Good day, and thank you for standing by. Welcome to the Taysha Gene Therapies First Quarter 2026 Financial Results Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Hayleigh Collins, Senior Director of Corporate Communications and Investor Relations.

Thank you. Good morning, and welcome to Taysha's first quarter 2026 financial results and corporate update conference call. Earlier today, Taysha issued a press release announcing financial results for the quarter ended March 31, 2026. A copy of this press release is available on the company's website and through our SEC filings.

Joining me on today's call are Sean Nolan, Taysha's Chief Executive Officer; Sukumar Nagendran, President and Head of R&D; and Kamran Alam, Chief Financial Officer. We will hold a question-and-answer session following our prepared remarks.

On today's call, we will be making forward-looking statements, including statements concerning the potential of TSHA-102, including the reproducibility and durability of any favorable results initially seen in patients dosed to date in clinical trials, including with respect to functional milestones to positively impact quality of life and alter the course of disease in the patients we seek to treat, our research, development and regulatory plans for our product candidates, including the timing of initiating additional trials, reporting data from our clinical trials, making regulatory submissions, timing or outcomes of communications with the FDA and the regulatory pathway for TSHA-102, the potential for the product candidate to receive regulatory approval from the FDA or equivalent foreign regulatory agencies; our ability to realize benefits of breakthrough therapy designation for TSHA-102, our ability to drive long-term value for stockholders and the market opportunity for our programs.

This call may also contain forward-looking statements relating to Taysha's growth, forecasted cash runway and future operating results, discovery and development of product candidates, strategic alliances and intellectual property as well as matters that are not historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. For a list and description of the risks and uncertainties that we face, please see the reports that we have filed with the SEC, including in our annual report on Form 10-K for the full year ended December 31, 2025, that we filed on March 19, 2026, and our quarterly report on Form 10-Q for the quarter ended March 31, 2026, that we filed today.

This conference call contains time-sensitive information that's accurate only as of the date of this live broadcast, May 6, 2026. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws.

With that, I would now like to turn the call over to our CEO, Sean Nolan.

Thank you, Hayleigh, and welcome, everyone, to our first quarter 2026 financial results and corporate update conference call. On today's call, I will begin with an update on our recent regulatory, clinical and commercial readiness activities. Dr. Suku Nagendran, President and Head of R&D, will outline recently published preclinical data that continue to validate our novel TSHA-102 construct design and minimally invasive intrathecal route of administration. Kamran Alam, our Chief Financial Officer, will follow up with a financial update, and I will provide closing remarks and open the call for questions.

We entered 2026 focused on a disciplined execution across our regulatory, clinical and pre-commercialization activities for TSHA-102 with the goal of delivering a potentially transformative therapy to a broad population of patients with Rett syndrome who continue to face high unmet need. Over the past several months, we have continued to advance our TSHA-102 clinical development program and made progress towards key clinical milestones anticipated in the second quarter of 2026.

On the regulatory front, we recently held an initial breakthrough therapy Type B multidisciplinary meeting with the FDA. During the meeting, we reaffirmed alignment on the planned pathway toward a BLA submission for TSHA-102, covering the pivotal trial design, endpoints and BLA submission scenarios, including the potential to submit for approval based on a 6-month interim analysis from the REVEAL pivotal trial. We believe our consistent constructive dialogue with the FDA continues to support our streamlined path toward a potentially expedited BLA submission.

Additionally, in the first quarter of 2026, we held a Type C meeting with the FDA, where the FDA endorsed our proposed Process Performance Qualification or PPQ campaign strategy in support of our planned BLA submission. I am pleased to share that we initiated the BLA-enabling PPQ campaign using our TSHA-102 commercial manufacturing process in April, and we expect to complete execution by the fourth quarter of this year. As a result, we are confident that our CMC activities are on track to support our BLA submission in step with the pivotal data readout.

As a reminder, the FDA previously agreed that TSHA-102 material produced from the clinical and final commercial manufacturing processes are comparable, and therefore, they support our ability to utilize the clinical data across all clinical studies in our TSHA-102 development program in our BLA submission. The ability to leverage the totality of evidence to support the long-term clinical benefit of TSHA-102 would strengthen the overall package and support a potentially expedited BLA submission based on the 6-month interim analysis.

Turning to our clinical progress. We further advanced dosing in the REVEAL pivotal trial with multiple patients dosed across multiple clinical trial sites. In parallel, enrollment in the ASPIRE trial is ongoing across multiple sites, and we remain on track to complete dosing in both trials this quarter. I am pleased to share that both high and low-dose TSHA-102 continue to be generally well tolerated with no treatment-related serious adverse events or dose-limiting toxicities observed in all patients treated across the REVEAL Phase I/II and REVEAL pivotal trials as of the May 2026 data cutoff. We look forward to reporting longer term data from all 12 pediatric, adolescent and adult patients treated in Part A of the REVEAL Phase I/II trials later this quarter.

Our pivotal development strategy is grounded on the rigor of our natural history analysis and Part A data collection and evaluation with trial design, endpoints and statistical analyses developed based on discussions and written feedback from the FDA. Accordingly, developmental milestones in Part A are assessed using 3 structured criteria, all of which must be met in order for a developmental milestone to qualify as a gain or a regain post TSHA-102.

First, all caregivers must complete the clinician-administered historical milestone questionnaire used in the natural history study. This allows us to identify milestones eligible for gain or regain by confirming whether a milestone was never previously achieved or was lost long enough ago that the likelihood of a spontaneous gain or regain is less than 6.7%. Establishing a documented time since loss is fundamental to accurately differentiate a true regain from natural variability as each of the 28 milestones has its own determinant. A simple baseline assessment is not sufficient documentation to support a rigorous statistical assessment and is susceptible to false positives. Our approach ensures milestone history is captured accurately so that only true open milestones are counted as gains or regains.

Second, the milestone gain must be captured by post-treatment video documentation. This provides evidence of milestone gains that can be objectively reviewed, which brings me to the third criterion. Video evidence must be independently evaluated by multiple external raters using a prespecified definition of achievement for each milestone from our pivotal trial protocol. We believe these criteria are essential for interpreting functional outcomes and provide a reliable assessment of TSHA-102's efficacy as we advance towards registration. We believe our Part A data accurately reflect the outcomes we expect to observe in the pivotal trial as they are evaluated using the same FDA-aligned criteria for the pivotal trial protocol.

As a reminder, we presented data from Part A of the REVEAL Phase I/II trials last year, demonstrating an 83% response rate at 6 months post treatment with 5 of the 6 patients treated with the high-dose TSHA-102 gaining or regaining at least developmental milestone. By 9 months post treatment, the data demonstrated a 100% response rate across the 6 treated high-dose patients. In addition to the 22 developmental milestones gained across the 10 patients treated with TSHA-102, patients also demonstrated a total of 165 additional functional skills and improvements across the core domains of Rett syndrome, an average of approximately 19 functional gains per patient.

We observed a consistent pattern of early gains that were sustained with additional gains seen over time, demonstrating the deepening of effect. In our upcoming Part A data readout, we expect to report longer term follow-up, including at least 12 months of data from all 12 patients treated with TSHA-102. These results will include functional gains based on natural history-defined developmental milestones and additional functional skills and improvements impacting the activities of daily living that are meaningful to the caregivers and clinicians. We will be hoping to see a consistent pattern of early responses that are sustained and deepen over time across functional gains and clinical outcome measures in the treated patients.

We believe this longer term follow-up will provide important context around the durability, deepening of effect and consistency in responses. With FDA alignment on the potential to pool data across the full TSHA-102 development program and our BLA submission, we believe the longer term Part A data has the potential to strengthen the overall BLA package and support an expedited submission.

In parallel to our clinical and regulatory execution, we continue to build out our internal commercial infrastructure. We have strategically assembled a strong commercial leadership group, including senior hires who have deep expertise in commercial strategy, pre-commercial and product launch planning as well as payer and health care systems engagement within the gene therapy space. With these key roles now in place, we are focused on developing a strategic commercial strategy to prepare for a potential launch, and we expect to share additional details on our commercial plans in the second half of the year.

I would now like to turn the call over to Suku to discuss evidence that further validates the TSHA-102 program and route of administration in more detail. Suku?

Thank you, Sean. We have continued to make meaningful progress advancing TSHA-102 towards registration and remain confident in its differentiated potential. A key design attribute of TSHA-102 is its minimally invasive intrathecal route of administration, which market research shows is strongly preferred by clinicians and caregivers over direct-to-brain central nervous system delivery. This preference is driven by its familiarity, accessibility and scalability, enabling broad access to treatment across institutions from major centers of excellence to regional and local sites.

A peer-reviewed article was recently published by Frontiers in Medicine Gene and Cell Therapy, which highlights preclinical data we previously presented at the 2025 International Rett Syndrome Foundation Rett Syndrome Scientific Meeting. The data showed that intrathecal and direct-to-brain intra-cisterna magna administration demonstrated comparable, consistent and widespread distribution of AAV9 vector throughout the brain and spinal cord in non-human primates. We believe this further validates lumbar intrathecal delivery as a potentially safe, effective and minimally invasive approach to deliver a gene therapy to the central nervous system.

In addition, on May 14, we plan to present new preclinical data that further validates the construct design of TSHA-102 at the ASGCT 2026 Annual Meeting. Consistent with previously published vector comparisons, the data demonstrated that the self-complementary AAV9 vector enables significantly higher protein expression compared to single stranded AAV9 in neuronal mouse cell models. The 30-fold higher transduction efficiency demonstrated in this study, along with the improved genomic stability of self-complementary AAV9, supports our ability to effectively deliver TSHA-102 to the central nervous system using a minimally invasive lumbar intrathecal administration.

In addition, the data showed that the mini MECP2 protein used in our TSHA-102 construct was functionally comparable to the full-length MECP2 protein across molecular and biochemical functions. We believe these data support the strategic TSHA-102 construct design and provides important translational context for the early, sustained and deepening functional gains demonstrated across all patients previously reported in Part A of the REVEAL Phase I/II trials.

We believe this supportive evidence, our continued FDA alignment on a registrational path and the clinical data generated to date support the potential for TSHA-102 to provide meaningful benefit to pediatric, adolescent and adult patients with Rett syndrome using a minimally invasive delivery approach that is scalable. Our focus remains on clinical execution and data generation as we work to complete dosing in our REVEAL pivotal and ASPIRE trials and report long-term data from Part A of our REVEAL Phase I/II trial this quarter.

I would now like to turn the call over to Kamran to discuss financial results.

Thank you, Suku. Research and development expenses were $33.8 million for the 3 months ended March 31, 2026 compared to $15.6 million for the 3 months ended March 31, 2025. The $18.2 million increase was primarily driven by BLA-enabling PPQ manufacturing initiatives performed during the 3 months ended March 31, 2026 and higher clinical expenses from the REVEAL Part A Phase I/II, Part B pivotal and ASPIRE trials. Compensation expenses, including non-cash stock-based compensation also increased as a result of additional research and development headcount.

General and administrative expenses were $9.7 million for the 3 months ended March 31, 2026 compared to $8.2 million for the 3 months ended March 31, 2025. The increase of $1.5 million was primarily due to higher compensation expenses, including non-cash stock-based compensation expense and increases in consulting and professional fees, including commercial launch readiness initiatives.

Net loss for the 3 months ended March 31, 2026 was $42.4 million or $0.12 per share compared to a net loss of $21.5 million or $0.08 per share for the 3 months ended March 31, 2025. As of March 31, 2026, Taysha had $276.6 million in cash and cash equivalents. We expect that our current cash resources will be sufficient to fund planned operating expenses into 2028.

I will now turn the call over to Sean for his closing remarks. Sean?

Thank you, Kamran. Our confidence in our differentiated TSHA-102 gene therapy candidate continues to strengthen based on the developments highlighted today. And we continue to believe TSHA-102 has the potential to deliver meaningful therapeutic benefit to a broad population of patients with Rett syndrome using a minimally invasive delivery approach. With a favorable tolerability profile demonstrated to date, dosing in the REVEAL pivotal and ASPIRE trials on track for completion in the second quarter of 2026 and a well-defined regulatory and commercial path, we're advancing toward potential registration with clarity as we work to bring a potentially transformative therapy to the Rett community.

I will now ask the operator to begin our Q&A session. Operator?

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

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

Thanks for the question, Kristen. I think Suku and I can tag team this. But at a high level, I think what we wanted to do was really provide the why as to what the clinical result that we're generating is, right? I mean from a clinical perspective, in every patient treated, whether it's a pediatric patient, adolescent patient, adult patient, everyone has been a responder. We're seeing multiple skills and improvements across all of these patients and they happen quickly and then they improve over time and get deeper.

And so the question is why does that occur? And I think what we're highlighting at ASGCT is the fact that the construct, which we purposely utilize self-complementary technology ultimately drives in this data set, a 30x transduction efficiency or protein expression than single strand does. And so that is a reason why you could potentially use a less invasive route of administration like intrathecal versus having to go with a closer to the brain approach. And usually, you have to do that because of a single strand.

The other thing, too, is just reinforcing the fact that the mini MECP2 gene continues to show comparability. It's been published for over 15 years that this has been the case. But again, we just wanted to highlight that regardless of the genotype that we're seeing in these 12 patients that we've dosed to date and that we'll report on in a few weeks, they're all responding and they're responding across clinical domains. And the gene, the mini gene is very much a part of that because it essentially equals the full-length gene.

And again, the reason we use the mini gene was so we could package the self-comp. So we're just trying to highlight the fact that the reason -- all the reasons that we put into building the construct are being demonstrated clinically and that this allows us to use a particular route of administration that we know is strongly preferred out in the community.

Suku, I don't know if there's more you might want to add to that.

Yes, Sean, I have a few more points to add. So Kristen, thanks for that incredibly important question. What we've already shown with our REVEAL Part A program is that a simple lumbar puncture, a self-complementary mini gene construct using TSHA-102 gives you incredibly important clinical results from an efficacy standpoint that translates into a significant improvement in activities of daily living. So the clinical data at the present time from Part A now speaks for itself.

So now when we work backwards and continue to further look at preclinical data, whether it's us or from other companies, it is very clear that a self-complementary construct turns on very quickly once given into the central nervous system, i.e., via the CSF. Once it turns on, it has rapid impact on one of the most important components of Rett syndrome, which is the autonomic dysfunction component, where we have impact pretty quickly usually within a couple of weeks post dosing.

We've also shown repeatedly now in Part A that we have very positive clinical impact consistently regardless of age, genotype or phenotypic presentation of the patient with Rett syndrome, where there is an improvement in gross motor, fine motor skills or restoration of those skills, which have been lost over time, but also improvement in the ability to communicate as well as when it comes to social activities.

So my point here is that a self-complementary stable construct turns on quickly, it persists and it continues to persist and build on top of all the preclinical data that we have that shows that a lumbar puncture with the right product can have a simple but consistent positive clinical response for a post patient population that has significant unmet medical need. And in this case, Rett syndrome. And I think we may have set the stage for an intrathecal lumbar puncture-based platform to treat difficult CNS diseases.

Our next question comes from Salveen Richter with Goldman Sachs.

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

Yes, Salveen, great question. We've been out talking with the investment community really since the beginning of the year, and this topic has come up. And so I think those that are on the call, this will sound very familiar, but we were very transparent with the FDA. Part of this meeting was trying to gain alignment and we were walking them through various scenarios. And we told them point blank that our preferred scenario would be a full approval at 6 months' worth of data.

And the argument for that, right, I mean, generally, they like the precedent of 12 months of data for gene therapy, which is arguably probably pretty arbitrary, to be honest, but that's generally what they've held to. And I think our perspective on that is understood. But if we continue to demonstrate comparability with Part A, we're going to have years of data from those patients that we can use to support the durability. And their answer was essentially, look, ultimately, this is going to come down to the totality of the evidence. And this is something that if the company chooses to do, we will -- we are open to it and we will review that in due course, which is really the best answer you could possibly get, right, which is the door is open, let the data speak for itself.

The second derivative of that, in our view, was basically if for whatever reason the FDA decides that let's just say they want to keep it as a precedent at 12 months, we would push hard for a rolling review because the CMC modules would be done, the preclinical modules would be done. And we can have things updated where the 6-month data is packaged in a way that they could look at that and also then there's less to review when you would submit the final 12-month data, and that can pull things forward a couple of quarters.

And then obviously, the third scenario would be there may be nothing at all wrong with the data. They just want to see 12 months. So we feel in any of those scenarios, number one, there continue to be a positive and constructive dialogue with the agency. There was no opposition to anything that we put forward. There was an openness to it. Clearly, it's going to come down to the totality of the evidence and their comfort level around the data package that's put forward.

But as we've said all along, the nice thing about this 6-month interim is it creates the optionality for us to potentially get this to patients faster. And my personal opinion, I can be wrong, is that almost regardless of what we come back with, I know everyone would prefer it's the fastest time point. And obviously, we're going to do everything we can to facilitate that. But we'll have clarity for the market. And even in the scenario -- and don't read into this, it's just even in the scenario where it's a 12-month ask, we can say that and you know what our 6-month data are and people can judge the probability of success, and then it's an execution story.

So for all the reasons that we laid out in this call, we feel that there is strong evidence to push for the 6-month data. The fact that we've got comparability with the FDA on the CMC side is absolutely critical to this. And that opens the door for us to pool the Part A data alongside the pivotal Part B. And in our opinion, really should alleviate any concerns on the durability piece. So ultimately, we'll leave it at that. The nice thing is we've got this option -- these options in front of us, thanks to the data that we've put forward today and also the CMC quality that we've put forward today. So we're in the best possible position we can be. We've got a couple of cards that can fall our way, and we're excited about having this discussion with the FDA at the appropriate time.

Our next question comes from Biren Amin with Piper Sandler.

Recently, the FDA Commissioner announced the real-time clinical monitoring program that enables the FDA to evaluate data real-time. Is that something that the company can leverage for REVEAL given the high unmet need in Rett syndrome, especially Sean, with the 6-month data and the agency potentially following patient data to 12 months during review under this program? So I guess that's the first question.

And then second question for REVEAL. Do you expect to stop enrollment at 15 patients or could you potentially over-enroll as is typically the case with clinical trial management and execution? And if that's the case, how does the over-enrollment impact the effect size calculation for the study?

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

I don't know if there's anything you'd add to that, Suku.

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

So I hope that helps, because at this time, we are kind of watching the process interestingly. And you mentioned the decision-making governance between the regulators and the sponsors are going to be critical to make sure real-time oversight of clinical trials will pay the dividends that the FDA hopes it will.

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

Anything else you would add there, Suku?

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

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

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

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

Thanks for the question. And Suku, we can tag team this. Our view is that the read-through from the upcoming data review that we're going to put out should be pretty direct for all of you. And that's why we've put so much emphasis around the rigor of the data collection in Part A. We spent a lot of time on the call talking about that. And it starts with the fact that, number one, what we rate is -- so first of all, all of our milestones for the primary endpoint are prespecified, right? There's clear definitions for those. And those demonstrations are from videos that are conducted in the study itself.

So when people -- the way it's been working is that people are doing the hand function test or the RMBA or the Mullen. If we have video of them doing a milestone, that video then goes outside the company and 2 of 3 raters have to adjudicate that as a milestone. So the company has nothing to do with what is declared a milestone. And I think that has been a big part of the reason why the agency has been open to our data set and the interim analysis is that we had rigorous video evidence that was adjudicated outside the company.

Now the other side of this coin is that the Mullen, which is another video tape demonstration and the RMBA are also supportive data sets that the agency sees. Again, those are on video. The Mullen also gets centrally adjudicated and the FDA -- and the RMBA is done in the clinic by the physician, right? So there's no real way to be putting your thumb on a scale and making this data subjective. It's very objective. So I think this is a good read-through to Part B.

The only difference in Part B is that we're going to have a standalone assessment of all of the milestones. So I would argue that we're probably undercounting milestones in Part A and that we have a better chance of counting more milestones in Part B because there's a standalone test. We spent a lot of time with the FDA developing this test. We have training modules around this test. The test is conducted in the hospital by trained assessors at the hospital. So this is not done at home. The parents aren't doing this. This is very prescriptive and it's done in-house. Those videos then go outside the hospital to the raters where they remain blinded until they break -- until the 6-month time period where they break the blind for all of the 15 patients and review those videos.

So the whole point of what we've been trying to emphasize since we began reporting data on milestones is clear definitions, rigorous baseline collection with videos assessed by central raters. It's going to be very similar in Part B, but even more rigorous. And I think there's more ability to capture milestones because we now have a standalone test. So hopefully, that gives you a perspective there, but I think the read-through should be pretty direct when we update you in a few weeks.

Our next question is from Maury Raycroft with Jefferies.

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

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

And the first part of the question, could you repeat that? I already lost it.

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

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

Yes, Sean, as you have emphasized, what we will communicate is the rapid, consistent, persistent clinical impact of TSHA-102 in patients with Rett syndrome regardless of genotype, phenotype or age. And I would also emphasize that we hope that we can continue to show a significant collective improvement in "skills" that per patient could go above the 19 per patient that we disclosed this morning when Sean did his segment of the communication.

So just pay attention to that as well because I think a component of reaching developmental milestones in a validated manner, as we've already discussed and described, which the FDA truly likes. And I'm going to emphasize these are done in a blinded reviewer, expert reviewer fashion and not done at home by caregivers, which usually the FDA has questions around. So I hope that our 12-month plus data disclosure further enhances the confidence in what TSHA-102 can contribute potentially in a transformative manner to this patient population.

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

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

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

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

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

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

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

I didn't hear that.

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

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

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

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

Sure. So Chris, starting with the PPQ, we aligned on comparability when we had the clinical lot that was in Part A, and then we ran our, call it, our final commercial process. We ran a lot of that. And so it was 1:1, and the FDA deemed that, that was analytically comparable. And what you have to continue to do as you produce more lots is demonstrate that there's -- those additional lots are also comparable. So at this last meeting, we shared with them multiple additional lots that we'd run, and they continue to say that we're comparable.

Now as you go into PPQ, you're generally doing 2 or 3 additional runs and then you share that data with the FDA. So we're in the process of doing those runs right now. Assuming those runs continue to be demonstrating comparability, that's when you're able to pool the data. So the fact that we've been able to do it with multiple runs so far gives us a lot of confidence. There's a strong alignment with the FDA. And then we take that data package and the next time we meet with them, we share that with them, and that's kind of the next step. So we feel like we're in a really good position on the CMC side, and we have been for quite some time. It is not on the critical path to the BLA submission. So that's that.

As it relates to the broad ages of enrollment, if you think about the prevalent population, 85% of the prevalent population is over the age of 10. So demonstrating effect across pediatric, adolescent and adults is very, very important, because as we've done market research with both caregivers and with clinicians, they plan on offering it across the age spectrum. And they're planning to offer it because there's demonstrated effect across the age spectrum. So we feel that we're in a good position to serve the broad community who is requesting gene therapy because of the data that we've generated, and that's why we're being thoughtful about making sure that there's representation across the age spectrum in Part B. So our whole goal is to make this available for all patients with Rett syndrome and the data continue to support that. And I can tell you that the demand is high across the age groups based on what we've seen so far.

Our next question is from Jack Allen with Baird.

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

Yes. I think Suku can take the second part of the question. I mean we're not going to give specifics. I would just say the demand is super high. It's high across the age spectrum, multiple sites -- we've got 10 sites that are active. Multiple patients have been dosed across multiple sites. Most of the sites have multiple patients.

So I mean, do you want to talk a little bit about the enthusiasm and the demand that we're seeing across the spectrum?

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

Our next question is from Whitney Ijem from Canaccord Genuity.

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

Yes. Thanks for that question, Whitney. That's actually a very important question that you raised. So given that we have a Part B ongoing, and we have an agreement with the FDA that the 6-month interim analysis once all 15 patients in Part B are dosed would be considered based on the efficacy and safety data for potential full approval of our product, the REVEAL Part A long-term data from a clinical standpoint, safety and efficacy, I think could significantly also impact the 6-month interim analysis from Part B collectively driving towards the full approval. And Sean clearly described that the FDA is aligned with us when it comes to the CMC process and the comparability technicalities between the Part A product and the Part B product.

So to really answer your question on Part A, the long-term data, I think, up to 18 months being evaluated per the protocol post 12 months every quarter, I think it's going to be also important to the collective 6-month interim analysis. And if the 6-month interim analysis gives very useful clinical data, and Sean described the other scenario for Part B where you might need 12-month data as well, the REVEAL Part A persistence of effect long term will also, I think, influence further the confidence that our product will have immediate, consistent and persistent effect long term as well in this patient community.

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

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

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

Yes. So to answer the question, so we currently are at Catalent, and Catalent's Baltimore, Maryland facility has obviously been inspected and they have extensive gene therapy manufacturing experience. And we feel really confident in the team that's at Catalent and our oversight of the team there. And importantly, as Sean mentioned earlier, we have ensured that based on our lock manufacturing process, CMC is not on the critical path to a potential BLA submission.

And as it pertains to downstream potential redundancy in manufacturing, that's something as we get closer to Part B interim data readout. And as we get closer to a potential BLA submission, that's something we will evaluate to mitigate any potential disruption to supply chain. But we feel really confident given Catalent's manufacturing experience in that particular facility in Baltimore that, that facility can meet our ultimate commercial demand.

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

Our next question is from Yanan Zhu with Wells Fargo.

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

Yes. I mean -- and there'll be more to come in the second half, deeper dives on the commercial aspect of things. But we essentially tested with physicians. So it was about half the physicians were at centers of excellence, half were not at centers of excellence. And then we also separately ran a study with caregivers of Rett patients or children with Rett across the age spectrum. And we kept it pretty simple. I mean we basically -- our product profile was -- our product profile that you've effectively seen, the responder rate, the CGI scores on average with the duration of time that we've been testing these patients. Think about the last data update we gave last year and the deck that we used, it was effectively that on a one pager. And then we just toggle that with is it intrathecal or is it ICV? What would it matter, assuming the same set of data?

And so number one feedback consistently in both groups, physicians and the caregivers was very high interest in gene therapy. They realize that you want something that treats the root cause. So there's a very high interest in seeking that out, number one. Number two, what was interesting is it's also -- there's high treatment being sought across the age groups, including those over 30. So that also was encouraging. And then when you distill this down to make it real simple, and again we didn't want to make it too technical at first. I think more has to be shown to get more precise on comparative product profiles.

But if all things are equal on safety and efficacy, obviously, there's a preference for the least invasive route, both in terms of perceived safety, but also just in terms of some of the physicians were making the point on throughput in the institutions that it's a lot easier to put -- let's just say you had 100 patients at an institution, it's easier to stage and manage those patients efficiently using intrathecally versus if you have to fight for OR time, neurosurgeon time, et cetera, it's harder to do that. You're going to have more intrusions, you're going to have more emergencies coming in that you're going to have to work to allocate time. So the scalability effect was something that was also quite top of mind for the physician group. So hopefully, that gives you a little flavor for the data.

Our next question comes from Silvan Tuerkcan with Citizens.

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

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

Same day.

Yes, same day, well within 24 hours. The ICV approach, obviously, you need to be in the OR for that. You have to have a neurosurgeon do the procedure. And so there is greater time and cost associated with that procedure. In terms of breaking it out, that's something we can talk more about in the second half. But just from an efficiency perspective, the ability to give someone a lumbar puncture, obviously, you can do that in various spots throughout the hospital and do it safely.

That's not the case with ICV. I mean there are certain parameters that you're going to have to have, certain staff that you're going to have to have, including neurosurgeons to do the procedure itself. And keep in mind that the OR time is booked in advance. There's only so much OR space. There's only very few neurosurgeons to do these procedures. So my point is that and the point that the physicians were making is that if you have a large number of patients, it would be much more efficient in the institution to be able to dose them on the -- via the intrathecal route for the reasons that I gave.

The second question, I didn't quite get. So I don't know if anyone around the table got that or Silvan, if you could repeat that, I didn't get it.

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

So Silvan, you asked actually a very interesting and important question, because remember, Rett syndrome, there are multiple different genotypes. There is a very differentiated phenotypic presentation, meaning multiple phenotypes that present as Rett syndrome. And then you also have the complexity of mosaicism when it comes to central nervous system. So it's a unique combination that eventually results in a complex clinical presentation. And what we've shown in REVEAL Part A is that regardless of genotype or phenotypic presentation or age, our gene therapy given through a simple lumbar puncture consistently provides superior clinical efficacy with no major safety concerns at this point in time.

When it comes to screen failure rates, in Part A, as far as I recall, there were no screen failures. In Part B, we have not discussed the screen failures publicly at this point in time. But they are minimal. And given that the common route to the disease is a lack of MECP2 or minimal MECP2 levels that have clinical efficacy or impact on the patient, restoration of MECP2 levels using TSHA-102 in general, addresses the lack of MECP2 and has superior clinical efficacy results up to now. So my assumption here is as we experience and complete Part B REVEAL study and ASPIRE that screen failure or loss of market, I guess, a clinical market access to a large group of patients is not an issue and will not be an issue. I hope that answers your question.

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

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

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

Good day, and thank you for standing by. Welcome to the Taysha Gene Therapies Full Year 2025 Financial Results Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Hayleigh Collins, Senior Director, Corporate Communications and Investor Relations. Please go ahead.

Thank you. Good morning, and welcome to Taysha's Full Year 2025 Financial Results and Corporate Update Conference Call. Earlier today, Taysha issued a press release announcing financial results for the full year ended December 31, 2025. A copy of this press release is available on the company's website and through our SEC filings.

Joining me on today's call are Sean Nolan, Taysha's Chief Executive Officer; Sukumar Nagendran, President and Head of R&D; and Kamran Alam, Chief Financial Officer. We will hold a question-and-answer session following our prepared remarks.

On today's call, we will be making forward-looking statements, including statements concerning: the potential of TSHA-102, including the reproducibility and durability of any favorable results initially seen in patients dosed to date in clinical trials, including with respect to functional milestones to positively impact quality of life and alter the course of disease and 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 programs.

This call may also contain forward-looking statements relating to Taysha's growth, forecasted cash runway and future operating results, discovery and development of product candidates, strategic alliances and intellectual property, as well as matters that are not historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the SEC, including in our annual report on Form 10-K for the full year December 31, 2025, that we filed today.

This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, March 19, 2026. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws.

With that, I would now like to turn the call over to our CEO, Sean Nolan.

Thank you, Hayleigh [Audio Gap] to our full year 2025 financial results and corporate update conference call. On today's call, I will begin with a brief update on our recent clinical, regulatory and commercial readiness activities. Then Dr. Suku Nagendran, our President and Head of R&D, will provide a clinical update on the TSHA-102 program. Kamran Alam, our Chief Financial Officer, will follow up with a financial update, and I will provide closing remarks and then open the call up for questions.

2025 was a year of significant execution for Taysha. We announced compelling REVEAL Phase I/II data across pediatric, adolescent and adult patients with Rett syndrome treated with TSHA-102, received FDA Breakthrough Therapy designation for TSHA-102 and secured written FDA alignment on our REVEAL pivotal and ASPIRE trial designs, paving the way for a potentially streamlined path toward BLA submission. This progress has set the stage for what we expect to be a transformative year ahead for Taysha as we focus on completing the pivotal development of TSHA-102 and bolstering our commercial readiness efforts as we advance towards potential registration. We've maintained ongoing constructive dialogue with the FDA over the past 2 years, which has enabled alignment on a pathway that we believe reflects the rigorous systematic data collection and well-controlled study design and endpoint selection required by the FDA for a robust data-driven application.

In 2025, we finalized alignment with the FDA on our REVEAL pivotal trial protocol and statistical analysis plan in support of our planned BLA submission. And we were pleased to initiate the pivotal trial in the fourth quarter of 2025 with the dosing of our first patient. Multiple patients have now been dosed in the trial, with enrollment across -- advancing across multiple sites. We remain on track to complete dosing in the second quarter of 2026. Importantly, both high- and low-dose TSHA-102 continues to be generally well tolerated with no treatment-related serious adverse events or dose-limiting toxicities observed in the patients treated in both the REVEAL Phase I/II and REVEAL pivotal trial as of the March 2026 data cutoff.

In addition to initiating our REVEAL pivotal trial, we recently received FDA clearance to initiate the safety-focused ASPIRE trial following written FDA alignment on the ASPIRE trial design and data for inclusion in our BLA submission to support a broad label for TSHA-102 for patients aged 2 years and older with Rett syndrome. ASPIRE will enroll 3 females with Rett syndrome aged 2 to less than 4 years, evaluating the safety and preliminary efficacy of a single intrathecal administration of the high dose of TSHA-102, [ 1 ] of the 15 total vector genomes, scaled to account for the lower brain volume in the 2 to less than 4-year olds. The written alignment we reached with the FDA outlines that our planned BLA submission will include a minimum of 3 months of ASPIRE safety data, while the efficacy in the 2 to less than 6-year-old population will be extrapolated from the data collected in the REVEAL pivotal trial to support the broad label. We are on track to complete dosing for ASPIRE in the second quarter of 2026. We believe this recent FDA alignment on ASPIRE, together with the alignment on a 6-month interim analysis for our REVEAL pivotal trial, potentially streamlines our path toward BLA submission for TSHA-102.

In the first quarter of 2026, we attended a Type C meeting with the FDA and reached written alignment on the CMC requirements for our planned BLA submission. Specifically, we further aligned with FDA on our proposed comparability approach between TSHA-102 material derived from the clinical and final commercial manufacturing processes. The FDA agreed that the approach may support pooling data from the REVEAL Phase I/II trials with data from the ongoing REVEAL pivotal trial and the ASPIRE trial for the planned BLA submission. Importantly, we believe this creates flexibility and will further strengthen the overall data set for the BLA package by including longer-term data and enabling a comprehensive assessment of safety and efficacy data that's been generated across the entire development program.

Additionally, the FDA endorsed our proposed process performance qualification or PPQ campaign strategy to support process validation for the BLA submission. This included the stability data package, the potency assay strategy and the execution of BLA-enabling PPQ lots using the commercial manufacturing process, which we expect to initiate in the second quarter of 2026. This feedback aligns with the agency's January 2026 guidance aimed at increasing flexibility and requirements for cell and gene therapies to advance innovation. With this alignment, we are confident that our CMC activities are on track to support our planned BLA submission in step with the pivotal data set readout.

We truly appreciate the consistent, constructive and collaborative interaction we have held with the FDA to date and believe our regulatory progress highlights the strength of our data-driven approach and further supports our goal to bring TSHA-102 to patients with Rett syndrome as safely and expeditiously as possible. We will continue to engage with the FDA as we prepare for our planned BLA submission.

In addition to our clinical and regulatory progress, we continue to bolster our commercial readiness activities. As a reminder, Rett syndrome is a devastating, rare and progressive neurodevelopmental disease with high unmet need and a profound lifelong burden for patients and caregivers. It is well characterized clinically, defined by impairments across multiple clinical domains, including fine and gross motor function, communication, autonomic function and seizures. While Rett syndrome is a heterogeneous condition that presents with different levels of clinical severity based on each patient's distinct genetic background, natural history data show that patients follow a common trajectory regarding the achievement of functional developmental skills, with the likelihood of spontaneous gain or regain of developmental milestones falling to approximately 0 after 6 years of age.

The multi-domain impairments result in loss of independence, with most individuals requiring 24/7 care and lifelong support for daily activities such as eating or sitting up, severely impacting quality of life for patients and caregivers. This burden and the limitations of currently approved therapies which focus on symptom management do not address the underlying genetic root cause, have created a strong urgency for new treatment options capable of delivering functional improvements.

We believe this urgency, combined with the estimated 15,000 to 20,000 patients with Rett syndrome across the U.S., EU and U.K., underscores the substantial market opportunity for TSHA-102. Within the U.S. specifically, patient estimates range from 6,000 to 9,000 patients based on claims data and epidemiology data. Because Rett syndrome is a neurodevelopmental condition and based on the Phase I/II data we've reported to date across pediatric, adolescent and adult patients, we believe that most patients with Rett syndrome can meaningfully benefit from treatment.

TSHA-102 is uniquely designed to address the root cause of Rett syndrome, and as such, has the potential to meaningfully alter the natural history of the disease and offer patients the opportunity to achieve functional milestones that would otherwise not be possible according to natural history. Recently completed market research reinforces this opportunity, as it demonstrated high anticipated demand from both clinicians and caregivers in the U.S. and a clear preference for intrathecal administration.

The research findings are compelling for two main reasons. First, the research suggests that clinicians anticipate broad adoption of TSHA-102 across pediatric, adolescent and adult patients with Rett syndrome. Caregivers similarly indicated that they would actively pursue an improved gene therapy with a target product profile consistent with TSHA-102. Caregivers emphasize that improvements in existing function or the achievement of new functional gains would be meaningful for individuals with Rett syndrome as they translate into greater independence in daily living, such as speaking in phrases, walking with support or finger feeding, which we have observed in patients treated with TSHA-102 in REVEAL Part A.

Second, clinical outcomes will be the ultimate driver. However, market research indicated that clinicians and caregivers strongly prefer intrathecal administration over direct-to-brain CNS delivery, citing its familiarity, accessibility and scalability, enabling the potential to safely and efficiently treat patients across institutions, from large centers of excellence to regional and local institutions. This facilitates broad patient access. Specifically, intrathecal administration, as it is used to deliver TSHA-102, is a routine minimally invasive delivery approach that does not require a surgical suite or delivery by a neurosurgery expert. This enables the potential for TSHA-102 to be delivered as an outpatient procedure, which in turn may meaningfully expand the treatment footprint, given the administration in the commercial setting will not be limited only to centers of excellence. We believe this broader footprint would enable us to reach patients where they are already receiving care and support, and this is a scalable adoption as demand grows.

Finally, as we advance towards registration, we are continuing to build out our internal commercial infrastructure. To that end, we recently appointed Brad Martin as Senior Vice President of Market Access and Value, further strengthening our commercial leadership team. Brad brings over 2 decades of leadership experience in market access and commercial strategy, pre-commercial and product launch planning, as well as payer and health system engagement within the gene therapy space. He previously held senior roles at Neurotech Pharmaceuticals, Sarepta Therapeutics and AveXis. At AveXis, he played a crucial role in securing market access for the blockbuster gene therapy Zolgensma for the treatment of spinal muscular atrophy. We plan to continue to build out that commercial capability to prepare for potential commercialization, and we expect to share additional details on our TSHA-102 commercial strategy in the second half of the year.

I would now like to turn the call over to Suku to discuss progress on the clinical front in more detail. Suku?

Thank you, Sean. As Sean mentioned, we believe we have made significant progress on advancing our TSHA-102 program towards registration. We are encouraged by the data previously shared from Part A of our REVEAL trial and the FDA alignment on a clear pathway to potential BLA submission. As a reminder, we presented data from Part A of the REVEAL Phase I/II trial last year, demonstrating a 100% response rate across our 10 treated patients in both dose cohorts. In the high-dose cohort, an 83% response rate was seen at 6 months post treatment, with 5 of 6 patients gaining or regaining [ 1 natural history defined ] developmental milestones. By 9 months post treatment, the data demonstrated a 100% response rate across the 6 treated high-dose patients.

In addition to the developmental milestones gained, patients also demonstrated a total of 165 other [ still gains ] and improvements across the core domains of Rett syndrome, an average of approximately 19 gains per patient, as captured by validated clinical assessments. We have observed a consistent pattern of early gains that were sustained with additional gains over time, demonstrating a deepening [ of effect ]. We believe these data enable our alignment with the FDA on the 6-month interim analysis for the REVEAL pivotal trial and supported by the FDA [ mission ] to grant Breakthrough Therapy designation to TSHA-102 in September 2025. We look forward to reporting longer-term safety and efficacy data across all 12 pediatric, adolescent and adult patients treated in REVEAL Part A in the second quarter of this year, with our patients developing [ 12-month follow-up time points ]. We'll be looking to see a consistent early response that over time across multiple clinical outcome measures, as well as continued well-tolerated safety profile.

Recently, [indiscernible] of the NIH funded [indiscernible] study, part of a publication describing the most comprehensive [ long ] view to date on the trajectory of the gain, loss and regain developmental milestones in Rett syndrome. We believe this analysis across [indiscernible] milestones provide an important validation of our development strategy for TSHA-102, where we are focused on a set of 28 milestones identified as the most clinically meaningful to caregivers [indiscernible].

The publication demonstrates that the combined likelihood of spontaneous milestone gain or regain [indiscernible] milestones dropped to 6.3% [indiscernible] compared to record high of [ 85% ] between the ages of 1 and 5 years. These findings align with our own analysis of the natural history data and provide strong external validation of our 2-study strategy, which allows us to generate data across the broader population while significantly mitigating statistical risk associated with a single-arm study measuring gain or regain of developmental milestones in the natural history derived control.

Our FDA aligned REVEAL pivotal trial is enrolling 15 patients aged 6 to less than 2 years in the developmental plateau population of Rett syndrome, the population with the most stable baseline and spontaneous improvement rate. Importantly, this design enables us to test our response rate against the [ known ] hypothesis of 6.7%, requiring a minimum 33% response rate to demonstrate efficacy. The aim of our ASPIRE trial is [indiscernible] patients to support the potential broad label for TSHA-102 in individuals aged 2 years and older with Rett syndrome.

As Sean mentioned, we have dosed multiple patients in our REVEAL pivotal trial. Additional enrollment continues to advance across multiple clinical trial sites. We expect to complete dosing in REVEAL and ASPIRE in the second quarter of 2026. We maintain that the safety and efficacy data we have generated to date from Part A of our REVEAL trial are differentiating factors and believe our ongoing dialogue with the FDA over the last 2 years supports the potential of TSHA-102 to provide meaningful benefits to patients with Rett syndrome.

Looking ahead, we remain focused on our clinical trial execution and data generation as we work to complete patient enrollment and advance toward registration. We believe the thoughtful data-driven approach we've taken in designing and executing our pivotal developmental strategy position us to deliver as well as broad label on TSHA-102.

I would now like to turn the call over to Kamran to discuss financial results.

Thank you, Suku. Research and development expenses were $86.4 million for the year ended December 31, 2025, compared to $66 million for the year ended December 31, 2024. The $20.4 million increase was primarily driven by higher compensation expenses due to increased research and development headcount. Clinical trial and GMP expenses also increased during the year ended December 31, 2025 due to clinical trial activities in the REVEAL studies and BLA-enabling PPQ manufacturing initiatives.

General and administrative expenses were $33.9 million for the year ended December 31, 2025, compared to $29 million for the year ended December 31, 2024. The increase of $4.9 million was primarily due to higher compensation expenses and higher legal and professional fees, as well as debt issuance costs incurred in connection with the 2025 Trinity term loan that are recorded in general and administrative expense under the fair value option. Net loss for the year ended December 31, 2025, was $109 million or $0.34 per share compared to a net loss of $89.3 million or $0.36 per share for the year ended December 31, 2024.

As of December 31, 2025, Taysha had $319.8 million in cash and cash equivalents. During the fourth quarter, we raised an additional $50 million in gross proceeds by utilizing our at-the-market or ATM equity offering program, with proceeds intended to support a potential commercial inventory build in 2027. We expect that our current cash resources will be sufficient to fund plant operating expenses into 2028.

I will now turn the call over to Sean for his closing remarks. Sean?

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

I will now ask the operator to begin our Q&A session. Operator?

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

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

Yes. Kristen, thanks for the question. I would say that the support for IT, there were manyfold reasons why people wanted to go down that route. The most obvious is I think everyone can relate to a lumbar puncture, right? I mean, most of the moms out there have undergone that to some extent. People are familiar with it. They know it's not scary.

And I think the most interesting thing is people are taking what I think is a very pragmatic approach. They're basically saying, hey, listen, if the data -- the clinical data are going to be the most important thing. And if the data are, let's say, equal, then I'm going to go do the most least invasive approach I can for the person that I love for the very simple reason that it doesn't involve as much drilling Burr holes and going to the ICU and having a neurosurgeon involved. As they learn more about that, I think they're just like, hey, you know what, if all things are equal here at a minimum, then I'm going to take the safest, what I feel is the safest approach and the easiest approach.

I think from the clinical perspective, it's the same kind of a logic set where they're saying, listen, ultimately, it's going to be the clinical data that's going to carry the day. But based on what we know right now, it's easy for us to do this lumbar puncture. And when they start to talk about the practical logistics of the sites, just the throughput necessary for intrathecal delivery done in an outpatient is much easier to manage. You don't have to schedule suite time, surgeon time, things like that. So they're saying in terms of being able to broaden the reach, go to regional and local hospitals and make sure that broadly, the Rett community has access to this therapy, it's a much easier route of administration to administer and provide great care to their patients. Hopefully, that helps.

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

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

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

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

Yes. Thanks, Salveen. To start with the second part of the question first, what you can expect to see is, to take a step back, last time we reported data, it was 10 patients. And at the high dose, we had 6 months of data on 5 of the 6 patients. So what we're planning to do in the Q2 update, you'll see data on all 12 Part A patients, and we'll have a minimum of 12 months of data on all patients.

The report out will be inclusive of the primary endpoint, which would be milestones. We're also going to give an update on the skills, the improvements. That's the data that we presented at CNS last year. You'll see the CGI-S, you'll see the R-MBA. So you'll get a very comprehensive picture of the data set. And what we hope to show is what we've been able to demonstrate to date, which is that the early improvements are sustained, and we continue to see deepening of response over the course of time. If you remember, the first patient we dosed, by the time we report this data, will be out 3 years post-dose. So we're starting to generate some nice durability data, which is fantastic.

As it relates to what the market access team is doing, there's a lot of steps to take, of course. We generally begin by making sure we're mapping out where the patients are and then what's the mix of the payers. So how much commercial pay is there, how much Medicaid pay is there. And then what we'll do is make sure from a site activation perspective, that we're thinking about the right way to roll this out.

So as an example, because of our market research and what we've seen on the route of administration, what's going to be really nice is that we're going to be able to essentially get to the regional and local hospitals. We want to make sure, though, that we roll this out in a very thoughtful manner. And anyone using TSHA-102 is very educated on how to do this, knows how to manage gene therapy patients and that we're comfortable with them and their institution doing that. So part of it is mapping all that out so that we've got a good sequence to the flow. And then beginning to work with the payers and talking to them about the market size, talking to them about the clinical data.

And the approach that we've taken historically, Salveen, has been get in early with the payers, be very transparent about what type of -- what's the volume of patients that they could potentially see, educate them on the disease state and educate them on your data set and really just take them along on the journey. So we look to build relationships with the payers. And that's what -- the nice thing about Brad is he has those relationships. He's done this multiple times. And it's never too early to start on this. You really want to get in as early as you can to really pave the road so that there's no surprises on the back end.

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

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

Biren, can you repeat the first question?

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

Kamran, do you want to take that?

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

Yes. I think, Biren, the plan we have would be -- we can do the analysis, the interim analysis once all patients dosed in the pivotal are at 6 months. That's when the blind would get broken. Obviously, we would -- that's going to be dependent on the last patient dose, right? So that's going to happen sometime in the second quarter based on everything that we're tracking to, which looks good. And then we have to adjudicate all that data. We have to make sure it's correct.

The next step, we would sit down with the FDA, go through that data with them and work to align with them on what the next steps could potentially be, right? And so post that and post getting minutes, we would come back to the market and give you the update. The reason we don't want to say what the data are before we meet with the FDA is that, that's only half the story, right? So we think it's important to meet with the FDA. And I think there's a couple of potential avenues that could happen, right? I mean, the best case scenario would be the agency is very pleased with the data and they tell us to proceed to file on the 6-month data set. In which case, we would work to do that immediately.

So to be clear, what we're doing in the background, we're writing the CMC modules, the preclinical modules, those will be in the can and done. So if we get the clearance on the clinical, that would be the only piece that we'd have to write, and then we could file the BLA and things would move forward relatively quickly. Another scenario could be the agency says, "Look, we think the data are good. Historically, we've always liked to see 12 months of data. We'd like to see 12 months of data." In that instance, we would make the case, well, okay, but then let's start the rolling submission because we've got all this other stuff done. You already know the primary endpoint has been met. You're looking for some additional time, okay. Now we would have made the case that the durability from Part A, which we can now pool, based on our recent update on CMC would help us with that case upfront on the 6-month course of action. But if they want that, I think even in that scenario, again, the only thing that they would have to review would be the clinical module at the end. So that still pulls things up a couple of quarters.

And then the last scenario would be they want to do things the traditional way and wait for 12 months. I think even in that scenario, the nice thing about the interim data -- and again, we would share this with the market -- is that I believe what we'd be able to show is that the product works, you've met the endpoint, you've met the statistics of things. Now it's just time and execution, which I think the market would respond very favorably to as well.

So the way I look at it is the FDA gave us the option to do the interim analysis. I believe it's based on the data that we showed and the early responses that we showed and the rigor in which the data were collected. So look, we've got a few good cards to play here, and we're looking forward to it as we step through 2026.

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

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

Sure, Tazeen. I don't think there is a read-through, based on what happened to Acadia. I think for those of you that have been around since Suku and I joined the management team here, back in the days when everyone talked about CGI and RSBQ, we were on the opposite side of that, if you remember. For gene therapy, you had to be able to demonstrate something that the eye could see that truly had impact on the patient and the caregivers, and it was unequivocal.

And so we feel the data that we're generating is very unique. And really, no one has been able to demonstrate restoration of function in a neurodevelopmental disease before. And we're able to do that in multiple patients and across multiple clinical domains. And we've got natural history that is absolutely stellar. It's unequivocal. I think Jeff Newell's paper reinforces everything that we've done from a strategic perspective and supports our thesis on things.

And then if we're able to demonstrate, look what's happening with the primary endpoint and people gaining these milestones. But then beyond that, what we're trying to emphasize in the script is when you look at milestone gains outside the primary endpoint and you look at improvements that people are having, it's almost 20 per patient so far. That's based on what we reported last year. So it's a significant impact that you can't ignore.

And the other thing, too, I would point to in the natural history data, there is R-MBA data. So we can demonstrate in multiple ways against natural history, how we're changing the course of disease and how this is a transformational treatment, which then gives us the power to capture value through price in a very meaningful way and get reimbursed for it.

So I mean, if you take a look at what happened with Sarepta up until they had some of the unfortunate safety things, their launch was going great. And I would argue that the data that we're generating is quite demonstrable. We're not having to talk about a scale. We're not having to talk about a 1- or 2-point change in the North Star or a 1-point change in the CGI. The payers don't care. The payers want to see functional gains. They want to see concrete improvements, and that's what's going to lead to getting you approved. I hope that helps.

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

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

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

Congrats on the progress. For the REVEAL Part A update in first half of this year, do you plan to provide a sub-analysis showing the proportion of patients that achieved more than 1 developmental milestone by 12 months? And are you planning to show any -- in your data update, are you planning to show any patient level data with vignettes? And if so, how are you setting expectations for a number of patients and milestone gains that you can show in that update?

Thanks, Maury. Yes, to take the second part of your question first, we will likely highlight a couple of patient vignettes. And just to give you some perspective on why we show the data like we do. Number one, we're going to have 12 patients' worth of data. This drug is going to get approved or not approved in the aggregate, right? The aggregate data is what you get approved on. So I think making sure it's clear, and we'll share every endpoint that we're effectively capturing, you and the investors will get to judge the data and the probability of success in getting approved. So we think that's the most important thing. We think that's where the emphasis should be.

I think highlighting a couple of patient vignettes would be helpful to basically show the early improvement and then the sustainability and the deepening of response over time and getting into more specifics about what is actually happening on a patient basis. So if we say that people are effectively gaining about 19 to 20 skills or milestones and improvements, let's tell you the story of what that looks like.

Now if I did that for 12 patients, we would be on the call for 5 hours. So that's why we don't want to go through all 12 patients. We just want to highlight a couple of things. And then again, based on the aggregate, you can say, "Hey, I like this data," or "I don't like this data." But we think that's the right way to go ahead and to portray it. Can you remind me the first part of your question about the Part A?

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

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

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

Allow me also to add my congratulations on the progress. Just a couple of ones from us. So as it relates to your recent update on the ASPIRE study, was this in line with prior expectations? Was it faster? Or this is just run of course here?

And our second question, it's good to see submissions using your RMAT designation of the CMC materials, which is a known issue in the space. Are you guys going to receive any feedback on what you've already submitted ahead of completing your filing? Or is this just going to happen later?

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

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

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

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

So I mean, I would put it [Audio Gap] we've got -- because of Breakthrough, we've got -- it's an additional way to get access to the FDA. So we do have our first Breakthrough meeting with the agency coming up, and there'll be more of those along the way. But we'll use that to have a discussion around potential BLA submission scenarios and working -- to get at your question, which is you've seen CMC, you've seen our preclinical, just working to gain alignment on the completeness of the packages that we've -- that we're putting together and what we shared with the FDA. So I think we're going to have really good line of sight to where we stand.

CMC is a good example. We could not be in a better position right now. So back when we did our first commercial lot, the agency said they deem that the clinical lot and the commercial lot were analytically comparable. Now that we've done more lots, they're continuing to say that. And now they're saying, if you continue to demonstrate this through PPQ, you can pool your data from Part A and from the pivotal and from ASPIRE because the product is the same.

So that's the best you can possibly have right now. And I think that's an example of working closely with the agency. I know that they feel like there's nothing more on the preclinical side that needs to get done. It really is just generating that the pivotal data and the ASPIRE data are going to be the last aspects of the submission package.

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

Just maybe a competitive 2-part question, I guess. And maybe also wanted to drill down a bit on the BLA filing timing question. So Neurogene has made some comments in the past couple of weeks to the effect of the 6-month time endpoint is that -- they've gotten word from FDA that that's not clinically meaningful. And Sean, I think I've heard you say the difference here is you guys will have 12-month data from Part A to supplement, and that's kind of the difference maker. But I guess, is that the only difference maker? Or is there potentially something else, like maybe the risk/reward of the therapy or other factors?

And then the second point is you got my attention with some of your market research commentary. And I think it's an aspect that could be pretty important. You're talking about intrathecal administration being able to reach patients outside of large centers of excellence and being able to dose patients at the community center. Do you have any detail around the breakdown of patients between these centers of excellence and out in the community and from just sort of the setup there commercially, just assuming like both therapies are on the market at some point?

Yes. I can say that the research we've done to date show that about 50% of the Rett patients are associated with a center of excellence. That means that over the course of 1 year, there's 1 visit to the center of excellence. So that doesn't necessarily mean that it's the most convenient place for them to get the therapy. And put another way, there's 50% more patients outside of the COEs. So we think it's very important to make sure that there is a network of care that gets to where the patients are.

And so with the data we have, we're able to map where are the patients, and then we're going to take a very thoughtful approach about working through access to care and making sure that the people that are using this are well trained. The facility has the right mechanisms in place to support gene therapy and things of that nature. But what's nice about the intrathecal route is it allows us to broaden that footprint in a relatively straightforward manner. And getting access to patients is the most important thing.

Suku, let's tag team the question on the meaningfulness of 6 months. I mean, I can just say the FDA never said that to us. So every case is unique. I guess, the simplistic way I would answer that question is it depends what data you're generating in the first 6 months. And I think if those data are compelling from a clinical perspective, then the agency is going to take note.

Yes. What I would add to that, Sean, is that I haven't seen any data from Neurogene's initial studies that show that they have actual clinical efficacy in the first 6 months post dosing. And most of their clinical, in fact, appears to come much later, maybe 10 months post dosing. And usually, the FDA looks at proof of concept before they agree to an earlier analysis. And we have 6 month interim analysis from our Part A data that is more than convincing that allows them to say, yes, we can evaluate and bring that data set in for actual review and approval if necessary.

And then the second component is they always point back to the construct because Neurogene's construct is single-stranded, and single-stranded constructs usually take much longer to come together in the nucleus of the cell of interest and actually become efficacious from a protein production standpoint. So I think that may have played a role in also the 6-month interim analysis being given to us, while in that case, there may have been some pushback.

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

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

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

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

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

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

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

I wanted to follow up on the pooling of data between the Phase I/II and the pivotal study, given that, that sounds like something why you did -- that's why you did the manufacturing comparability study. So in what form will the data be pooled? Are we talking about a supportive data set separate from the top primary endpoint analysis? Or could the 2 study combine into 1 and give 1 number in the label? And then I have one additional question.

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

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

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

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

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

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

Yes, Whitney, there's really no math on the extrapolation. It was really just whatever you see in the 6 plus, that's going to get extrapolated into the younger age group. So that's where the alignment is with the agency. It's at a macro level.

And then on the second part of the question on the scaling, yes, I mean, it's a very consistent mathematical equation that you use from the preclinical to get to your human equivalent dose. And we'll be using that same calculation in the 2- to 3-year old. So Suku, I don't know if there's anything more you'd add to that?

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

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

Exactly. Exactly. Yes.

That make sense. So a 2-year-old, even though they're getting less of a dose, it's equal to the 1 into the 15 in a larger person. So they're getting the same therapeutic...

Effect.

Effect. Right.

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

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

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

Good day, everyone and welcome to The Taysha Gene Therapies Third Quarter 2025 Earnings Call. [Operator Instructions] 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 Haley 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 the prospectively aligned by -- that by prospectively aligning with FDA on the statistical analysis plan for our pivotal trial helps 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 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. Suku?

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. Kamran?

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 that 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. Sean?

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. Operator?

[Operator Instructions] 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 occur 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 time line parameters around when we expect enrollment could potentially take.

Thanks for that question, Kristen. So as Sean highlighted, we have multiple sites -- more than 15 sites identified for our clinical trials program Part B. All of these sites are at centers of excellence. And very interestingly, many of these sites have 100-plus patients per site who have the diagnosis of Rett syndrome. And many of these patients could qualify for a Part B trial. And this includes pediatric, adolescent, and adult patients who will be part of the process.

Now furthermore, let me highlight that in the best case scenario, we could potentially enroll and recruit all 15 patients within a 3-month time period, and a more conservative time line could be between 3 to 6 months. And as I said, many of these sites already have multiple patients identified. And there's significant interest in our gene therapy program due to the efficacy already and safety already disclosed in the Part A trial and the ease of route of administration that we have to deliver a gene therapy that already shows 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 time line 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.

Thanks for the question, Salveen. For the first part of the question, relative to what updates will we give in the first half of next year, I think it'll be consistent with what you've seen. As the data matures, we've tried to look at things as a full cohort. So ultimately we want to get to, we have all 12 patients at 12 months, and I think that'll be very important data to look at relative to the 6-month time point, where are we at 12 months with these patients. And so we'll do that.

In addition to that, I think it's important to continue to provide updates relative to the safety profile. So we want a little bit of flexibility here that we could potentially give an update in the first quarter with almost 12 months of data, we could do -- we could wait for the second quarter, but we want to -- we just want to make sure that the market is aware of the fact that we do plan to give further updates both in terms of safety and efficacy that we think will be very enlightening and informative relative to the predictability of the approval of the pivotal trial. So that's number one.

Number two, as it relates to FDA alignment, we highlighted in the script and I think it's really important that back in September the FDA put out guidance that's very consistent with everything we've done to date in our interactions with them, which is very specifically, they want alignment on your SAP before you start your clinical trial. Like that is the highly recommended path to take. And that's exactly what we've done. We submitted the SAP going back as far as January. When we got the okay to go ahead and submit the final SAP and the clinical protocol by the end of the second quarter without an end-of-phase meeting, we did that. We've answered all the then subsequent queries from the statistical analysis plan question and clinical questions. And we actually even reached out to the FDA because we had believed we'd answered all their questions, and we sent them a note and said, "We just want to confirm that there's no other outstanding statistical or clinical questions." And they said, "Confirmed."

So we feel everything that we've just presented with the [ NF15 ], the threshold of a responder being the gain or regain of 1 milestone and crossing the threshold of having a 33% response rate, all ties to the statistical plan that we've submitted. So we feel we're very much in alignment with the FDA. And the other thing I would just note is that per the FDA's internal SOPs, these milestone meetings where you're talking about the final protocol, the SAP internally, the Directors are at those meetings. So I can't give you specific names who are there, but that is the protocol. So we feel, again, supremely confident at this particular point in time. We've done everything that this FDA has asked us to do. We've been in full alignment with them the entire way. And I would argue, we were in full alignment with the Peter Marks regime as well. And I think that's all because of the integrity of the data and the quality and rigor of the data collection that we've put forward. So we think we've checked all the boxes, we've double checked, and we're told we're good to go. And that's why it's full steam ahead on patient enrollment right now.

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 dialog 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's 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?

Yes, Gil, I would say in our experience, the most time we spent in dialog with the FDA was around the rigor of the data collection for the primary endpoint. They were very much focused on how we were going to do that, that there was high fidelity in the data, and that there was high inter-rater reliability. And in fact, what we did to further bolster our case with the FDA is we actually ran a pilot at multiple sites testing the DMA with multiple central raters, and we submitted that as part of our data package to get the protocol approved and also in the Breakthrough Therapy package as well.

And so all I can say is that like anything, you're as good -- in our space, you're as good as the data that you're collecting. FDA was super focused on that. So I'm assuming anyone going into a pivotal trial would be held to the standard of a minimum of video evidence and having it centrally adjudicated. I think the question is have you run the experiment and do you know that the methodology you're employing is going to give you the result that you anticipate. And what we feel good about is we've run that result. We've collected the data from our Part A study, and we've done central raters with that. But then the pilot study, which you really haven't talked too much about, but we ran that in the background again at multiple sites, and that gives us the confidence, and hopefully gave the FDA confidence that what we're putting forward is highly rigorous, high-end fidelity, and high-end inter-rater reliability.

Our next question comes from Biren Amin with Piper Sandler.

This is [ Michael ] on for Biren. 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, 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 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 number of patients you could potentially have enrolled by 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, it's a great question. I think we can provide more information in either Q1 or sometime in the springtime, I think, as we have better line of sight. Again, just from how we're stepping through it, we've submitted protocol to the FDA, we've got a -- waiting for their feedback on that. That'll certainly inform things. We're doing -- I would say, contextually, we're doing for the pivotal trial, 15 patients. This is a smaller subset of patients. So we would anticipate the number of patients to be less than 15 in this study. I think that from a IRB perspective, it will be a new protocol.

So it'll have to go through the process of contracting IRB approval, ethics, all the things that you have to do. I can tell you that there are, as you would anticipate, multiple sites, of course, that want to be a part of this. So I don't think that's going to be an issue. We just want to make sure that, number one, we get alignment first and foremost with the FDA on the protocol and the associated statistical plan that we're putting forward. And then number two, that from an operational perspective, we're doing things in a manner that is most efficient and doesn't by any way impede the enrollment of the 6-plus population.

So the way we see this, based on the fact that the primary endpoint in the little kids study, is safety -- we think the 2 trains are going to come back together. And again, just to make the point that we do anticipate including that data along with the 6-plus pivotal data in the BLA submission with the goal of getting a broad 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's going to be 1x10 15 total vg, but we're going to adjust for brain volume. So we want to make sure that none of those younger kids get any more dose on a per-kilogram basis than anyone we've dosed so far safely. So we've given that a lot of thought. The clin dev team has done a super job. Again, we've got that in front of the FDA. So we're being very thoughtful about that safety perspective. So more to come on that once we have the protocol finalized.

As it relates to the FDA, what we can point to is a couple of things. And I said this earlier. We had good alignment with Nicole Verdun. Nothing that we've changed -- we've done nothing since the new regime's been in that's different in terms of our natural history assessment, our proposed endpoints, et cetera. And I've used this term before, but no one has pushed us off the ball. And the reason we believe that is because we have levered data collected in a very rigorous manner to make our case with the FDA.

Number two, the approach that we're taking is exactly what the FDA wants. So that's why we referenced this FDA guidance from September where they're basically saying, "Hey, [indiscernible] for gene and cell therapies, we want alignment on your protocol and your SAP before you start the study."

So what are we doing? We've taken our first-in-human study. We've learned from that. We've done the natural history analysis. And now what we're saying is, based on what we've learned, we're going to propose a prospective pivotal trial with the following endpoint and the following statistical analysis plan. And we've worked with the FDA to get that into a situation where they've signed off on that. So we've done exactly what they wanted.

Our understanding is any of these milestone meetings like signing off on a protocol or Breakthrough designation, which I can talk about in a second. But internally the Directors are in those meetings. So we've checked and double-checked to make sure we're not misinterpreting things. We've gotten confirmation of that. We feel like we've done everything that the FDA has asked us to do.

And more importantly, we're not asking them to do something that's out of course. What we're not doing is we're not taking the Part A data and saying, "Oh, you know what, we want you guys to go back and we're going to propose now that we're doing a DMA, and we're going to do these developmental milestones. So we want you to approve our data based on a statistical plan we put in front of you after the fact." That is not something that we've done. We're taking a more traditional approach and starting a new study. Suku wants to add some information?

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

Yes, I mean, Jack, one last thing on Breakthrough to the point Suku is making. The internal SOP at FDA for Breakthrough is that when a Breakthrough request comes in, the Directors are made aware of it. They then send it to the review team and assign them to review it and let them know the recommendation. And so that means that eyes are on things. And again, we've done the best that we can to be data driven in all of our requests.

And therefore, again, we feel the fact that the Breakthrough was granted in September under this current regime in the manner that they like. We've followed their guidance that they've issued in September in terms of protocol for pivotals as well as SAP. We've tried to step through it in exact manner that they want and, I would argue, the exact manner based on data that any administration would want. So that's why I went back into the Wayback Machine with the Peter Marks' group. But it is important, and I do think it's relevant, to say they agreed with what we were doing as well, based on the way that we were going through it. So I've always said data drives -- is the currency of the realm. And we believe that's the case.

We're just going to keep moving forward and be as transparent as we can with the agency. And as a result of having Breakthrough, we now can set up even additional meetings with them, which we've already done, to start to talk about BLA submission process and things of that nature.

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. I think to start with your second question, all of the 28 milestones that we selected, we did in concert with KOLs and with the advocacy community. So if you were talking to some of the KOLs, they would talk about higher order milestones. So there's 51 milestones, Chris, in the natural history database. You'll hear like that language, because these are the milestones that, from a clinical and from a functional perspective, really do matter across the 3 different domains. So I wouldn't say anyone rises to the level more than anyone else. It's all relevant to the particular situation of each individual patient. I will say that when you talk to the parents communication is top of mind with them.

They want to know what hurts, what do they want, are they hungry, how can they make them feel better, those kinds of things, which make a lot of sense. But that's why we feel we've reached that agreement with the FDA that any 1 of those 28 is relevant. And I think what we're also trying to show is that over time, not only are there more milestones being gained of the 28, but the whole purpose of the supplemental analysis was to show that outside of that -- the 28 are a mechanism for us to get approval, but outside of that, in multiple scales, whether it be done from the clinicians or rated independently like the Mullen or the ORCA, which is the parents and what they're saying that they're noticing. The point of that was to say, beyond the 28 that we've talked about, there's a lot of other things happening that are great. And we're seeing good things, the parents are seeing things, the clinicians are seeing improvements in function, and all of that is going to be what we put forward to the FDA in the final package and would also be part of what we discuss with payers. Suku?

Yes, thanks, Sean. And one more thing I would add is that -- Chris, is that as our trial design is patient as their own control, every milestone matters. So it doesn't matter what the milestone is out of the 28, to the patient, to the parent, or the caregiver, all of them actually matter, and all of them have impact on activities of daily living. And given our Part A data set, my hope as a physician and clinician is that there will be no patient left behind over time as we gather more data from Part B.

Yes. And then the first part of your question, Chris, about commercial, I'd say a couple 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 (sic) [ CGI-I ] and RSBQ and those type of scales is going to mean absolutely nothing to the payers. They do not care what a CGI (sic) [ CGI-I ] 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 (sic) [ CGI-I ]. 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 you can start filing for BLA?

Yes, thanks for that question. So this is Suku, and I'll respond to that question because it's -- thanks because it's important that it's clearly defined and the audience understands what it means. So remember again, natural history, once patients with Rett syndrome reach the age of 6 and above, they do not regain a lost milestone. So I'll give you an obvious one.

Let's assume a patient before 6 years of age with Rett syndrome can sit up without support and they lose it completely and now cannot sit up without support. Post treatment with TSHA-102, our gene therapy through lumbar puncture, if that patient now again is able to sit without support, that is a regain of a lost milestone. A gain of a new milestone is something where the patient before the age of 6, for example, can never use their fingers due to significant stereotactic movements and therefore cannot pick up a teaspoon or a cup to feed themselves. Post treatment, this milestone is now achieved where the patient can actually use their fingers, which they've never done before, can pick up a spoon or a cup and feed themselves. That is the gain of a new milestone.

So it's very almost black and white, which actually makes it very easy both for the clinicians who are evaluating the patients, the video reviewers who are blinded, as well as when the FDA hopefully sees our videos, it will make it obvious that our product actually works. And keep in mind that this entire process of video recording, central raters, blinding, et cetera, came from our AveXis experience many years ago. And we have most of the team here at Taysha that will continue to execute on this program and hopefully reproduce what we were able to do for SMA population using AVXS-101, which is now 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.