Taysha Gene Therapies, Inc. (TSHA) Earnings Call Transcript & Summary

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 Sukumar 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. Sukumar 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, spine 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 of 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 two 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 two 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 three 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 group. 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 Global 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 continue to accumulate additional milestones over time across all three 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 two 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 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 OCA data available, which were both added in later study protocol versions, while 100% had RMBA 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 reduce 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 two high-dose patient vignettes to further demonstrate how these outcomes translate into meaningful improvements in daily life for patients and their caregivers. The two 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, hi 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-5s 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 breathing and hyperventilation with cyanosis and periods of lymphness, 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, momma. 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 strawberry dipped and 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 stereotypes, 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 RMBA 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. RMBA 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 achieved 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 the 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, RMBA 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 [ key ] 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 chronic, 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 CA 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 RMBA, the CGI-I, 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.

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 development 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 RMBA, the CGI-S, 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.

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 the data updates on long-term durability, will you be applying for [ CMPV ]?

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 RMBA, at the CGI-S, 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 two 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.

Our next question coming from the line of Susan 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 Maurice Raycroft with Jefferies.

Congrats on the update. You've overenrolled Part B by two 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? [ 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 Maurice question there.

Yes, Maurice, 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 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 RMBA. 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 [ there ], which is the plateau Phase II natural history, the increase in power by over-enrolling two 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.

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 Su ] 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 enrolled in the trial.

Our next question coming from the line of Whitney Ijem with [ CGM ]

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...

I can add.

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 direct 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.