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

Welcome to Taysha Gene Therapies' TSHA-102 program update webcast. [Operator Instructions] As a reminder, this webcast is being recorded today, June 18, 2024. I will now turn the call over to Hayleigh Collins, Director of Corporate Communications and Investor Relations. Please go ahead.

Thank you. Good morning, and welcome to Taysha's TSHA-102 program update webcast. Earlier this morning, Taysha issued a press release announcing positive clinical data in adult and pediatric patients from the low-dose cohort in the ongoing REVEAL Phase I/II trials evaluating TSHA-102 in Rett syndrome. 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 CEO, who will begin with a brief overview of the program and recent progress; and Dr. Sukumar or Suku Nagendran, President and Head of R&D of Taysha, who will then discuss the clinical data from the first 2 adult and first 2 pediatric patients treated with TSHA-102. Sean will provide closing remarks before we hold a question-and-answer session, where Kamran Alam, Chief Financial Officer, will join us. Please note that on today's call, we will be making forward-looking statements including statements relating to our strategy, future operations, prospects, plans and objectives of management, the therapeutic and commercial potential of TSHA-102, including the reproducibility and durability of any favorable results initially seen in the patients dosed in the REVEAL trial, to positively impact quality of life and alter the course of disease in the patients we seek to treat in our research, development and regulatory plans for our product candidates, including time lines for our clinical trials and reporting results therefrom, and the trial design of TSHA-102 REVEAL trials and our current cash resources supporting our planned operating expenses and capital requirements into 2026. These statements may include the expected timing and results of clinical trials for our product candidates and other clinical and regulatory plans and the market opportunity for those 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. These risks include uncertainties related to the timing and results of clinical trials and regulatory interactions for our product candidates, our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activities. For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the Securities and Exchange Commission, including in our annual report on Form 10-K for the full year ended December 31, 2023, and our quarterly report on Form 10-Q for the quarter ended March 31, 2024. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, June 18, 2024. 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 TSHA-102 program update. We are pleased to share positive longer-term data from our REVEAL adolescent and adult trial as well as initial data from our REVEAL pediatric trial, each evaluating TSHA-102, our lead gene therapy program in clinical evaluation for the treatment of Rett syndrome. We are highly encouraged by the safety profile and broad clinical response observed across multiple domains in both adult and pediatric patients with different genetic mutation severity treated with the low dose of TSHA-102. Recall, there are 2 ongoing Phase I/II REVEAL trials evaluating TSHA-102, an adult and adolescent trial taking place in Canada and the U.S., where patients aged 12 and older with Stage 4 Rett syndrome, the most advanced stage of the disease, and a pediatric trial taking place in the U.S. with clearance in the U.K. for patients aged 5 to 8 years old with Stage 3 Rett syndrome. Across all patients treated to date, TSHA-102 has been generally well tolerated, with no serious adverse events related to TSHA-102 or dose-limiting toxicities in adult patients up to 52 weeks and pediatric patients up to 22 weeks. In both adult patients, the longer term follow-up data from week 52 and 25, respectively, indicate a durable response was sustained in new improvements across multiple clinical domains, including motor skills, communication and socialization, autonomic function and seizures. Importantly, both pediatric patients showed initial improvements across the same clinical domains we observed in the adult patients, with early evidence of developmental gains post treatment at week 12 and 8, respectively. Suku will discuss this in more detail. There is a high heterogeneity among patients with Rett syndrome due to the broad spectrum of genetic backgrounds that result in a variable phenotype in phenotypic symptoms and the severity of disease. Therefore, the patients dosed with TSHA-102 across both trials have different genetic mutations and associated disease severity ranging from mild to severe. We believe the improvements observed across consistent clinical domains, regardless of baseline disease severity, support the broad treatment potential of TSHA-102 across patients of different ages and genetic mutation backgrounds. The unmet need and burden of care for Rett syndrome is high, given there are no approved disease-modifying therapies that treat a genetic root cause of the disease. Rett syndrome is a rare neurodevelopmental disorder that affects an estimated 15,000 to 20,000 patients in the United States, European Union and the United Kingdom. It is caused by mutations in the X-linked MECP2 gene encoding methyl-CpG-binding protein 2 or MECP2 protein, which is essential for regulating neuronal and synaptic function in the brain. The disorder is characterized by loss of communication and hand function, slowing and/or regression of development, motor and respiratory impairment, seizures, intellectual disabilities and shortened life expectancy. Disease progression is divided into 4 key stages, beginning with early onset developmental stagnation at 6 to 18 months of age, followed by rapid regression, plateau and late motor deterioration. Our adolescent and adult trial includes late motor deterioration, Stage IV patients, which is the most advanced stage of the disease. And our pediatric trial includes patients with pseudo-stationary Stage III Rett syndrome. While our pediatric trial captures an earlier stage of the disease, it is important to understand that most patients with Stage III Rett syndrome have already developed the hallmark symptoms of the disease and present with many advanced manifestations. Patients typically approach Stage III after a period of deterioration and rapid regression of learn skills, particularly related to language and hand movement. The regression period is characterized by partial or complete loss of acquired purposeful hand skills and spoken language, gait abnormalities and stereotypic hand movements, which results in loss of independence and in most cases, leads to lifelong caregiver dependence. Many patients with Stage III Rett syndrome also suffer from seizures that can significantly impact their quality of life. Importantly, for our protocol for Part A of the REVEAL pediatric trial, the Stage III patients must have demonstrated stable disease for 6 months in order to be enrolled. TSHA-102 is a self-complementary intrathecally delivered AAV9 gene therapy and clinical evaluation for Rett syndrome that is intended to be a onetime treatment designed to address the underlying cause of the disease. In Rett syndrome, the random X-inactivation and subsequent mosaic pattern of MECP2 expression results in a mixture of cells that are either deficient MECP2 protein or express MECP2 protein normally, which makes Rett syndrome challenging to treat with traditional small molecule and gene therapy approaches. We believe our TSHA-102 gene therapy candidate, equipped with the novel miRNA-responsive auto-regulatory element or miRARE technology, has the potential to appropriately address this challenge by mediating MECP2 expression in the central nervous system on a cell-by-cell basis to overcome the risks associated with both under and overexpression of MECP2. Ultimately, TSHA-102 was designed to enable the necessary function of MECP2 protein in cells lacking MECP2, while protecting against toxic overexpression of MECP2 in healthy sequencing. This allows for a more precise cellular MECP2 mediation to enable targeted expression in cells with insufficient MECP2 levels, which may allow for positive clinical effect at much lower total dose exposure for patients. Clinical and preclinical data continue to support the ability of TSHA-102 to produce and maintain safe transgene expression levels in the central nervous system. I will now turn the call over to Suku to provide more in-depth [indiscernible] of the clinical data across our TSHA-102 program. Suku?

Thank you, Sean, and good morning, everyone. I'm pleased to share long-term clinical data from the adult patients and initial data from the pediatric patients treated with the low dose of TSHA-102. We will start with the REVEAL Phase I/II adolescent and adult trial, assessing the safety and preliminary efficacy of TSHA-102 in females aged 12 years and older with Stage IV Rett syndrome. We are currently enrolling patients in Part A, the dose escalation portion of the trial, which is evaluating a low dose and a high dose of TSHA-102 sequentially. Two patients have been dosed to date in cohort 1, evaluating the low dose of TSHA-102 of 5.7E14 total vector genomes. Cohort 1 is now complete. The Independent Data Monitoring Committee or IDMC approved our request to proceed to an early dose escalation, and we dosed the first patient in Cohort 2, evaluated the high dose of 1E15 total vector genomes in the second quarter of 2024. As Sean mentioned, we've seen an encouraging safety profile and improvements across consistent clinical domains through longer-term assessments in both adult patients treated in the low-dose cohort. TSHA-102 has been generally well tolerated, with no serious adverse events related to TSHA-102 or dose-limiting toxicities as of the week 52 assessment for patient 1 and the week 36 assessment for patient 2. Both patients demonstrated sustained and new improvements across multiple efficacy measures at week 52, following the completion of the steroid and sirolimus taper for the first adult patient and at week 25, following completion of the steroid taper for the second adult patient. At this rate of follow-up assessments, the principal investigator reported sustained and new improvements in both patients across multiple clinical domains including motor skills, communication, socialization, autonomic function and seizures. We believe these continued improvements observed in both adult patients, with different genetic mutation severity and phenotypic expression, support the durable response and potential of TSHA-102 to be transformative across multiple genotypes of Rett syndrome. As Sean mentioned, the baseline status of the 2 adult patients is quite different due to their distinct MECP2 mutations, which manifests in dramatically different phenotypes and clinical severity. Patient 1, who was dosed with TSHA-102 at age 20, has a large deletion within her MECP2 gene that manifests as a highly severe phenotype. The disease severity is reflected in her baseline score across efficacy measures, including Clinical Global Impression Severity or CGI-S, which is a 7-point scale with regard to signs and symptoms of Rett syndrome that rates the severity of patient's illness relative to the clinician experience with participants who have the same diagnosis. At baseline, the patient's CGI-S score was 6, indicating severely ill. Prior to treatment for the first adult patient was in a constant state of hypertonia with complete loss of ambulation and was wheel-chair bound. She had lost her ability to sit or stand by age 8 years old as documented in the patient's medical history. Additionally, the patient had limited body movement, require constant back support and had lost fine and gross motor function early in childhood. She had very little hand function, with essentially no function of her nondominant hand by age 6. She also became non-verbal around this time. She experienced frequent apnea and hyperventilation episodes and had a history of seizures, and 2 to 4 seizures per year at baseline. In contrast, the second patient was dosed with TSHA-102 at 21 years old, has a missense mutation in MECP2 gene that manifests in a milder form of disease. Her baseline CGI-S score was 4, indicating moderately ill. Prior to treatment, she had partial loss of ambulation, could walk with prompting partially impaired gait and balance developed at age 18. Hand stereotypies appeared at 3 years old following regression, and she mostly held her hands firmly together, with weak ability to reach and grasp objects. She also became non-verbal around the same time. Additionally, the patient experienced frequent hyperventilation episodes and had a history of frequent seizures, 2 to 4 seizures per week at baseline. While the disease severity differed between the 2 patients, we saw a consistent pattern of improvement across multiple clinical domains and efficacy measures as early as 4 weeks post treatment in both adult patients. We will now show pre and post treatment video evidence of some of the improvements that were reported. Please note that we will only be showing the videos today from patients whose families and caregivers provided consent for the company to share publicly. Also patient videos from Canada require facial blurring technology to de-identify the patients, whereas U.S. videos do not at this time. You are not permitted to record video shared during today's webcast or otherwise use these images and audio for any reason without the prior written consent of Taysha and the patient's caregiver. One of the most striking improvements, the first adult patient experienced post treatment was the restoration of gross motor skills. The patient had lost the ability to sit unassisted and became wheelchair-bound at age 8 as documented in her medical history. Further, the patient was very socially withdrawn and minimally interactive pretreatment. We will now show video evidence of these observations from her baseline assessment. [Presentation]

In the baseline video, the 20-year patient was seated in an upright position on the hospital bed with the full support of the backrest and she was wearing a back brace. As a reminder, she had lost the ability to sit unassisted at age 8. At 6 weeks post treatment, the patient gained the ability to sit unassisted for the first time in over a decade, and had restored movement in her legs. She also displayed an increase in social interaction communication through vocalization. There appeared to be awakening from the previously withdrawn state observed at baseline. We will now show video evidence from week 6 post treatment, supporting these improvements. [Presentation]

As seen in the 6-week post-treatment video, the patient was able to sit unassisted without the support of the hospital bed backrest. She was not wearing her back brace and she displayed restoration of movement. Additionally, the patient increased social interest and communication through vocalization was evident in the post-treatment video, and there appeared to be awaking from a previously withdrawn state. She sustained these improvements, including the ability to sit unassisted through later follow-up assessments. We will now show video evidence from week 35 post treatment. [Presentation]

We believe in gross motor gains coupled with the patient's increased social interest observed in the video at week 6 and 35 following treatment are highly encouraging and reinforce the potential of TSHA-102 to have a transformative impact for adults with the most advanced stage of Rett syndrome. In addition to these improvements observed in the videos, the principal investigator reported that both patients showed sustained and new improvements at week 52 and 25, respectively, compared to baseline across multiple clinical domains, impacting activities of daily living. Per the protocol, patient 1 began prophylactic immunosuppressant therapy, 7 days prior to TSHA-102 administration. Her steroid taper was completed by week 36, and her sirolimus taper was completed by week 43. At week 52 post-treatment, the first adult patient demonstrated sustained improvements in multiple clinical domains after completion of her immunosuppression taper, including the fine motor skills and hand function at week 52, with the gained ability to grasp objects with a nondominant hand and transfer them to her dominant hand for the first time since infancy. Additionally, she could open her hands, dissociate her fingers, stretch her nose and touch a screen following treatment. These sustained improvements in hand function, which are not typically observed in the natural history of Rett syndrome, are very encouraging and support the potential of TSHA-102 to bring meaningful therapeutic benefit to patients and caregivers. Further, the principal investigator reported sustained improvements in communication and socialization at week 52 post treatment. The patient was more alert and socially interactive, with increased communication using vocalization. Caregivers reported an enhanced ability to use an eye-gaze driven communication device at week 25, which she had expressed interesting before treatment. Difficulty in communication including loss of speech, is one of the prominent symptoms of Rett syndrome and a key area of concern for caregivers as it directly interferes with the patients' ability to communicate their needs and express their interest. These sustained improvements are highly encouraging, as we believe that the ability to communicate could give patients a sense of control and greater independence. The first patient also demonstrated sustained improvements in autonomic function at week 52, with improved breathing patterns and reduced breathing dysrhythmias including infrequent hyperventilation and less breath holding spells compared to before treatment. Additionally, she experienced a sustained improvement in sleep quality and duration. Caregivers reported that following treatment, the patient sleeps through the night for the first time in 20 years and therefore, she's a lot much more alert during the day. Additionally poor perfusion of the extremities is a characteristic sign in patients with Rett syndrome that is thought to result from dysautonomia. The efforts are encouraging that the first patient also showed a sustained improvement in circulation at week 52 post treatment, with the patient's hands and feet restored the normal temperature and color, whereas before treatment, her hands and feet are usually cold and blue based on the principal investigator's critical observations. The principal investigator also reported that the first patient's seizures overall well control through week 52 following treatment at lower levels of anti-seizure medication relative to baseline, and the patient no longer was experiencing unprovoked seizures. Before treatment, the patient had 2 to 4 seizures per year. Now turning to the second adult patient, similarly the principal investigator reported that the second adult patient demonstrated sustained improvements across multiple clinical domains following completion of steroid taper at week 25 post treatment as well as new improvements compared to baseline. Specifically, she sustained improvements in fine motor skills, with the reduction in hand stereotypies particularly purpose less hand movements and a diagnostic hallmark of Rett syndrome. Before treatment, the patient mostly held her hands firmly together. Her hand stereotypies have improved for the first time since regression at age 3 at the initial 4 and 6-week assessment. The sustained improvement in hand stereotypies was encouraging and may provide new opportunities for fine motor skill learn. The second patient also sustained improvements in communication and socialization through week 25, with increased interest in social communication activities including increased response to spoken words and eye contact. The principal investigator also reported sustained improvement in autonomic function with improvements in breathing dysrhythmias including hyperventilation and reduced apneic spells. The patient also showed a sustained improvement in circulation at week 25 post treatment, evident by the restoration of the patient's hands and feet to normal temperatures and color compared to the cold and blue appearance before treatment based on the principal investigator's clinical observations. Additionally, the second adult patient demonstrated new improvements in gross motor skills at week 25 post treatment, with improved posture and stability. Notably, she also demonstrated pronounced improvements in seizure frequency, with a significant reduction in seizures at 25% lower levels of anti-seizure medication relative to the baseline seizure frequency of 2 to 4 seizures per week. Since treatment with TSHA-102, the patient had a single seizure event, with 8.5 months reported seizure-free as of week 36 post treatment. The timeline depicts when both adult patients lost skills and develop disease manifestations across multiple clinical domains, which is supported by the medical records and documented patient medical history. These symptoms of Rett syndrome appeared as early as age 3 for the first patient and in age 2 for the second patient. And the key takeaway is that only after treatment with TSHA-102 are we seeing improvement and signs of restoration of function across key areas of disease in adults with the most advanced stage of Rett syndrome. Both adult patients demonstrated continued improvement across multiple clinician and caregiver reported efficacy measures compared to baseline based on the 52-week assessment following the completion of the steroid and sirolimus taper for the first patient, and the week 25 assessment for the second patient following the completion of the steroid taper. Patient 1 showed sustained improvements in Clinical Global Impression Severity or CGI-S and Clinical Global Impression Improvement or CGI-I compared to baseline. She also demonstrated new improvements in Parental Global Impression Improvement or PGI-I, the Rett Syndrome Behavior Questionnaire, RSBQ, which was driven by improvements in hand behaviors, general mood, breathing, repetitive face movements, body rocking and expressionless face, nighttime behaviors and fear and anxiety as well as the Revised Motor Behavior Assessment R-MBA, which was driven by improvements in motor dysfunction, functional skills, social skills and respiratory behaviors. The Rett Syndrome Hand Function Scale or RSHFS week 52 assessment has not been completed yet. Patient developed improvement at the late assessment at week 25 compared to baseline. Patient 2 showed sustained improvement in CGI-S and PGI-I at week 25 compared to baseline and new improvements in R-MBA, which was driven by improvements in social skills, respiratory behaviors, seizures, functional skills, motor dysfunction, aberrant behavior, truncal rocking and stereotypic hand movements. Patient 2 did not show a change in CGI-S at 25 weeks post treatment compared to baseline, and there was a slight increase in RSBQ total store reported at week 25. The critical takeaway is that collectively, the early improvements shown in the 2 adult patients across multiple efficacy measures have been sustained through longer-term assessments. It is encouraging that we continue to see improvements across multiple clinical domains in the longer-term assessments with no diminution of effect according to the principal investigator. Overall, we believe the safety profile and continued improvements across multiple clinical domains, even following a steroid taper in both adult patients with advanced Stage IV Rett syndrome treated with the low-dose of TSHA-102 support the durability and potential of TSHA-102 to be transformative across multiple genotypes of Rett syndrome and further validates our construct. Now, let's turn to the pediatric trial. Our ongoing REVEAL Phase I/II pediatric trial evaluate the safety and preliminary efficacy of TSHA-102 in female patients with Stage III Rett syndrome, age 5 to 8 years old. Enrollment criteria require patients to be post regression and have entered the stage of stabilization meaning, there have not been any identified loss of skills in the last 6 months. We are currently enrolling patient in Part A of the dose escalation portion of the trial, which is evaluating a low dose and a high dose of patient 1 or 2 sequentially. Two patients have been dosed to date in cohort 1, evaluating the low dose of TSHA-102 of 5.7E14 total vector genomes, and cohort 1 is now complete. The IDMC approved our request to proceed to an early dose escalation, and we expect to dose the first pediatric patient in cohort 2, following IDMC review of the initial 6-week data from the first patient treated in the high dose cohort of the adolescent and adult trial. Turning to the data. We are pleased to see an encouraging safety profile, an initial clinical improvement across multiple domains in the first 2 pediatric patients dosed in low-dose cohort. TSHA-102 was generally well tolerated with no serious adverse events related to TSHA-102 or dose-limiting toxicities as on the week 22 assessment for patient 1 and week 11 assessment for patient 2. There were 2 SAEs reported in the second pediatric patient that were not the treatment related. Both were related to underlying disease, and one was also attributed to immunosuppression, and both have resolved. Both patients showed early improvement across multiple efficacy measures at week 12 for patient 1 and week 8 for patient 2 compared to baseline. Additionally, the principal investigator reported improvements across multiple clinical domains, including motor skills, communication and socialization, autonomic function and seizures due to early evidence of developmental gains. Important to both pediatric patients with different genotypes, treated with a low dose of TSHA-102 showed a similar safety profile improvements across consistent clinical domains. Those that we observed in the 2 adult patients treated with a lower dose. Importantly, we believe this supports the broad treatment potential of TSHA-102. Similar to adult patients, the pediatric patients have different genetic background and the sophisticated disease severity. Patient 1, the 6-year-old female has deletion within MECP2 gene that manifests as a moderate phenotype. At baseline the patient CGI-S score of 5, indicating markedly ill. Prior to treatment, the patient was completely non-ambulatory and had limited gross motor function. She could sit unassisted for up to 30 seconds and stand with support by age 3, but she was never able to walk independently. Additionally, the patient had very little hand function and lost the ability to use eating utensils at 1.5 years of age and loss of [indiscernible] by age 2. She has been mostly nonverbal since the age of 1, and the ability to use her eye-gaze during communication device and speak 3 words inconsistently at baseline. She experienced a total spells and had her history of seizures with approximately 1 seizure every 3 months at baseline. In contrast, patient 2, a 7-year-old female, had a missense mutation within her MECP2 gene that manifests as a milder phenotype. Her baseline CGI-S score was 4, indicating moderately ill. Prior to treatment, she had a partial loss of ambulation, could stand and walk independently. She developed a mildly ataxic gait at 1.5 years of age, impacting her gait and balance. Additionally, the patient had impaired hand function since the age of 1 and could reach, swipe and transfer objects between her hands at baseline, but her ability to reach and grasp objects was weak. The patient had been nonverbal since she was 1 and could use her eye-gaze driven communication device at baseline. Additionally the patients experienced frequent hyperventilation episodes, and had a history of seizures, with approximately 2 to 4 seizures daily at baseline. Importantly, we observed a similar pattern of response across consistent clinical domains impacting activities of daily living in both pediatric patients treated with the low dose of TSHA-102 despite their genetic -- despite the differences in generic background. We will now show video evidence supporting some of these initial improvements. Following treatment, the first pediatric patient's hand function improved for the first time since she was 1.5 years old, when she had lost the ability to use eating utensils, and her grasping improved for the first time since she was 2 years of age, when she lost [indiscernible]. Based on medical records and caregiver reports, the patient was able to hold an object for up to 12 seconds and would drop the object when moving her arm. We will now show video evidence of the first pediatric patient's hand function and grasping skills at baseline. [Presentation]

In the baseline video, the patient held an object for around 1 second, showing evidence of a very limited hand function ability pretreatment, which limited independence and activities of daily living. At week 12 following treatment, the patient held a spoon for up to 40 seconds and maintained her grasp while moving her arm. She was unable to do this pretreatment. We will now show a snapshot of the video evidence of this improvement. [Presentation]

As seen in the week 12 post treatment video, the patient held a spoon for up to 40 seconds, and she maintained her grasp while moving her arm. At the weak 12 post-treatment assessment, the patient also held a pen for up to 3 minutes, and she maintained her grasp while moving her arm. We will now show a snapshot of the video evidence of this improvement. [Presentation]

Progressive loss of hand function is a hallmark characteristic of Rett syndrome that impedes daily activities, communication and independence. As I mentioned, the patient had lost the ability to use eating utensils at 1.5 years of age and lost [indiscernible] by age 2. We believe the patient's improvements at hand function and grasping, which are not typically observed in the natural history of Rett syndrome, are very encouraging and support the potential of TSHA-102 to bring meaningful therapeutic benefit to patients and caregivers. The second pediatric patient also showed improvements across multiple clinical domains following treatment, including breathing patterns. Breathing disturbances are a prominent feature of Rett syndrome that impacts up to 80% of patients and impact quality of life. Patients with Rett syndrome often display bouts of hypoventilation that alternate with irregular breathing or hyperventilation, which can be associated with significant dysregulation in the cardiorespiratory coupling. Prior to treatment, the second pediatric patient experienced frequent hyperventilation episodes. We will now show video evidence from the patient's baseline assessment capturing this. [Presentation]

In the baseline video, the second pediatric patient displayed frequent hyperventilation following -- followed by breath holding. Per the patient's medical history, these breathing abnormalities appeared at age 4. At week 8 post treatment, the patient showed improvement in breathing patterns for the first time since age 4 during the R-MBA assessment. We will show video evidence supporting this improvement. [Presentation]

As seen in the video at 8 weeks post treatment, the patient displayed improved breathing patterns, including a significant reduction in hyperventilation per the R-MBA assessment. Breathing disturbances are a prominent feature of Rett syndrome, and notably, all 4 patients treated with low-dose TSHA-102 experienced improvement in breathing patterns post treatment, based on caregiver and clinician assessments. We believe the consistent improvements observed in autonomic function is very encouraging and further supports the potential of TSHA-102 to have a meaningful impact on patients with Rett syndrome. In addition to these improvements observed in the videos, the principal investigator reported initial improvements across multiple clinical domains in both pediatric patients and early evidence of development gains following TSHA-102. Let's start with the first pediatric patient. As of 12 weeks post treatment, the principal investigator reported improvements across multiple clinical domains and early evidence of developmental gains, including gross motor skills, as the truncal stability improved with the ability to sit unassisted up to 1 minute at week 12 post treatment, whereas before treatment, she was only able to sit unassisted for 30 seconds. She also showed improvements in balance and stability when standing, and she gained the ability to move her leg on her own to better take a step with assistance. In addition, the first pediatric patient showed improvement in overall motor and autonomic function with improved swallowing and oral intake relative to the use of a gastrostomy tube for feeding at week 12 post treatment. Swallowing requires a combination of voluntary function including the cranial nerves in the central nervous system, which are involved with the coordination and movements involved in chewing and swallowing and involuntary functions under control of the autonomic nervous system. Importantly, this indicates that the TSHA-102 impacts both motor and autonomic function in a coordinated manner to further improve functional capabilities for patients with Rett syndrome, impacting activities of daily living. The principal investigator reported that the first patient's communication and socialization also improved, with enhanced use of an eye-gaze driven communication device, including use of new words and gained the ability to string multiple words together and identify object functions for the first time. The patient also gained new skills in visual reception and receptor language, including the ability to identify an object from memory, follow 2 unrelated commands and identifying the function of objects and action words, which she was unable to do pretreatment. Further the first pediatric patient showed improvement in autonomic function with improved breathing patterns as well as improvement in seizures, with stable seizure events reported at week 12 relative to the baseline seizure frequency of one seizure every 3 months. Now let's turn to the second pediatric patient. As of week 8 post treatment, the PI, our principal investigator reported improvements across multiple clinical domains and early evidence of developmental gains included fine motor skills and hand function. With the ability to reach more quickly compared to baseline. She also showed improvements in gross motor skills as her gait, speed and stability when walking improved as well. Importantly she gained new skills following treatment, including the ability to stand from a chair and walk up a stair, both she was unable to do at baseline. The principal investigator also reported improvement in the patient's socialization and communication, including improved social interest and eye contact. Further, the second pediatric patient showed improvements in autonomic function, with improved breathing patterns, including less hyperventilation and breath-holding episodes, as seen in the video. The second pediatric patient also had an increase in days reported seizure-free post treatment relative to baseline, which is one of the most severe aspects of the disease impacting the patient and her caregiver's quality of life prior to treatment. Pretreatment, the patient had approximately 2 to 4 seizures per day since the age of 3, with a medical history of hospitalization for seizure control. Two weeks post TSHA-102, the patient demonstrated a reduction in seizure frequency, with several days reported as seizure-free. The patient experienced episode of seizures during the week 4 post-treatment assessment, resulting in hospitalization, which was deemed unrelated to TSHA-102 and related to the underlying disease, a concurrent urinary tract infection, propofol sedation for protocol requirement of having an MRI brain. Although her seizures resolved prior to discharge a new antiseizure medication was then added to the patient's regimen as a result, which was maintained through week 11 post treatment. The timeline depicts when both pediatric patients lost skills and developed disease manifestations across multiple clinical domains. These milestone losses and clinical manifestations are reported and supported by the medical records documented in the patient's medical history. These symptoms of Rett syndrome appeared as early as age 1 for both pediatric patients. Similar to the adult patients after treatment with TSHA-102, we have seen improvements and early signs of developmental gains across these clinical domains. Both pediatric patients demonstrated improvements across key clinician and caregiver reported efficacy measures following treatment with TSHA-102, which support the clinical observations reported by the principal investigator. The first pediatric patient showed improvements in CGI-I, PGI-I, R-MBA, which was driven by an improvement in respiratory behaviors, aberrant behaviors and motor dysfunction. The patient also showed improvement in the Adapted Mullen Scales for Early Learning at week 12 post treatment. We will go more in depth on the Mullen Early Learning skills shortly. At week 12, there was a slight increase in RSBQ total score for the first pediatric patient compared to baseline. The second pediatric patient demonstrated improvement in CGI-I, PGI-I and R-MBA, which was driven by improvements in respiratory behaviors, seizures and truncal rocking at week 8, following treatment relative to baseline. Although the RSBQ was not assessed at baseline, she also demonstrated an improvement in RSBQ in week 8 relative to week 4, which was driven by improvements in breathing, repetitive facial movements, nighttime behaviors and fear and anxiety. Collectively, the early improvements observed in the 2 pediatric patients treated with the low dose of TSHA-102 across multiple efficacy measures further reinforce the potential for TSHA-102 to be transformative across a broad population of patients with diverse genetic backgrounds, and we believe further validates our construct. The Adapted Mullen Scales for Early Learning is a standardized cognitive developmental assessment adopted for use in patients with Rett syndrome. The MSEL-A functionally evaluates skills compared to developmental milestones across 4 subscales, including visual reception, which is one's ability to visually interpret the surrounding; receptive language, one's ability to comprehend spoken language; fine motor, one's ability to use their hands to manipulate an object and communicate; and expressive language, one's ability to produce language and communication. The MSEL-A is administered by trade psychologist or psychometrician, and the scores are reviewed by a certified central [indiscernible]. The assessment evaluates where patients with Rett syndrome fall under the developmental curve compared to a standard developmental milestone. Each domain assess the patient's developmental age equivalence is captured or calculated based on standardized developmental norms. At week 12, following treatment with TSHA-102, which is the first post-treatment assessment of the Mullen Scale, the first pediatric patient showed an improvement in the age equivalence of skills she was able to demonstrate across multiple domains compared to baseline, including visual reception, receptive language and fine motor and new developmental gains demonstrated as depicted in the chart. Before treatment, the patient was able to identify objects from a picture, resulting in an age equivalent baseline score of 25 months of visual reception. At week 12 post treatment, she gained the ability to identify an object from memory based on 3 choices, resulting in an improvement in the age equivalent score of 26 months. Additionally, before treatment, the patient was able to follow one unrelated command and comprehend question from a picture, resulting in an age equivalent base months for potential months of receptive language. At week 12 post treatment, she gained the ability to follow 2 unrelated commands and identify the function of objects and action words such as eating, sleeping or washing, resulting in an improvement in our age equivalent score of 24 months. Further, the patient lost her ability to grasp at age 2 and displayed limited hand function at baseline, resulting in an age equivalent baseline score of 3 months for fine motor. At 12 weeks post treatment, she gained her ability to use refined thumb grasp resulting in an improvement in the age equivalent score of 5 months. The patient was not able to demonstrate these skills before treatment, further Mullen evaluation at baseline, medical history and caregiver reports. These developmental gains suggest clinically meaningful improvements for the patients that she has generalized these newly gained skills beyond, demonstrating them during the MSEL-A assessment. Specifically for the principal investigator assessment administrating psychometrician, the patient uses her eye-gaze driven communication device to identify object functions while using the device at home, and she held an object up to three minutes at week 12 compared to 12 seconds pretreatment, which supports her hand grasping improvements captured under Mullen evaluation. Overall, we believe the early improvements observed across multiple clinical domains in both pediatric patients treated with a low dose of TSHA-102 are very encouraging. I will now turn the call back to Sean to discuss the next steps of the program. Sean?

Thanks, Suku. Rett syndrome is a highly complex symptomatic disease. And overall, we are encouraged by the safety profile and improvements observed across consistent clinical domains in the adult and pediatric patients with different genetic mutation severity treated with the low dose of TSHA-102. We believe the improvements seen across consistent areas of the disease in all 4 patients as well as the durable response reported in the longer-term data from both adult patients further reinforce the potential of TSHA-102 to be transformative for a broad range of patients with Rett syndrome. Importantly, we believe the encouraging safety profile and clinical response reported in all 4 patients supports our continued clinical evaluation, as we now set to the high dose in both patient populations. With cohort 2 now complete in both REVEAL trials, we are focused on moving to the high-dose cohort and collecting data across a broad spectrum of patients to further inform the next phase of our studies. For our adolescent and adult trial, we dosed the first patient in the high-dose cohort in the second quarter of 2024, following IDMC approval of our request to dose escalate early, which is a critical step that accelerates our ability to further inform our clinical development and regulatory plan for Part B, the dose expansion portion of the studies. The IDMC also approved our request for early advancements of cohort 2 and in our REVEAL pediatric trial, following review of available clinical data from the first 2 adult and two pediatric patients treated with the low dose of TSHA-102. With dosing of the first pediatric patient in cohort 2 to follow IDMC review of initial safety data from the first patient dosed in cohort 2 in the adolescent adult trial. As a reminder, TSHA-102 has received numerous designations from the FDA, EMA and U.K. MHRA, most recently, which was RMAT designation, that we believe will help expedite the development of TSHA-102 through increased interactions with regulatory authorities to support our goal of bringing the potentially disease-modifying treatment to the Rett syndrome community. As such, we are focused on completing dose escalation for both REVEAL trials and collecting data, and we'll continue to look for similar patterns of improvement in adult, adolescent and pediatric patients. We have multiple clinical milestones expected in the second half of 2024. In the third quarter of this year, we expect to dose the first pediatric patient in cohort 2, evaluating the high dose of TSHA-102. In the second half of the year, we expect to report initial available safety and efficacy data from the high-dose cohort in both adolescent, adult and pediatric REVEAL trials. We look forward to a productive second half of 2024 as we continue to evaluate the therapeutic potential of TSHA-102, and work to generate critical clinical data that will guide the next phase of our studies. With that, I will now ask the operator to begin our Q&A session. Operator?

[Operator Instructions] With that, we'll go ahead and take the first question from Kristen Kluska at Cantor.

Congrats on these very strong data, and thank you to the caregivers for sharing children's smiles with all of us. I wanted to ask, now that your four patients worth of data and recognizing they're all unique in themselves, are there any early trends you're able to identify in terms of timing or even domains where you're seeing some of the initial effects and which ones may take a little longer?

Thanks, Kristen. I appreciate it. And again, we also want to recognize and thank the caregivers that allowed us to utilize those videos. I'll give a high-level remarks and turn it over to Suku. But essentially, I think you're talking about based on the four patients that we've treated, are there early trends that we're seeing in terms of clinical response. And I think at a high level, we see early response within the first few weeks, but do you want to kind of step through the progression that you think we observed?

Yes. So thanks for that question, Kristen, because it's a very important one. And again, I would remind the audience that we are still with the low dose, right? And we haven't reported high dose data yet. But as a clinician, I'm very encouraged by what we are seeing. And what I would state is that what we've noticed consistently between the two adults and the two pediatric patients is that the initial positive impact of our gene therapy appears to be in the autonomic domains of abnormalities. So for example, the respiratory abnormalities like the apneic spells and the hyperventilation episodes, you tend to see a positive response of resolution in the first 7 to 10 days or a [indiscernible] resolving. The impact on the abnormal sleep happened actually in the first 7 days in the adult patient one. Based on her on motor abnormalities, which all patients had, that was a very quick response within the first 10 days, et cetera. So I guess what I'm getting at is that's a very promising signal because that could be very useful for us as we develop our Part B trial design. And I don't want to get into details of why I say that, but I think just stay tuned that as we put the data together. The seizure aspect of the disease at which 90% of patients appeared to have seizures by the time they reach the age of 5. They seemed to have, in general, consistent impact on reduction of the number of seizures, the use of the antiepileptic meds, et cetera, which is also very encouraging because, obviously, for the patients, you can reduce seizures significantly or actually frankly resolve some of the episodes and reduce how much meds they have to use the dosages, you improve the activities of daily living for them for their caregivers. But frankly, a lot of these anti-epileptic meds come also with side effects. So that could be huge from a clinical management standpoint. Now, then you get to the gross motor side and the fine motor skills, with the low dose, there are consistent signals regardless of the type of developmental milestone these patients lose over time. So let's say, ability to sit and ability to stand and maybe ability to walk properly, depending on the stage of presentation, all stages there is an impact clinically. So patients are getting the ability to sit longer unassisted, getting the ability to stand, maybe walk the staircase even if it's one step, get better stability. So again, low dose, right? So my hope is at the high dose, we get a much stronger response, which could make a significant difference in these patients. Social withdrawal, all these patients are completely socially withdrawn. But following the gene therapy, I mean, I'm very surprised how quickly they kind of open up or wake up or whatever the right terms is, yes Sean?

Yes. I think just to summarize that, the view that we have is what's encouraging across the four patients in two different populations, right, pediatrics as well as adults at the low dose is that, honestly, within about 12 weeks, everything that Suku said is what we're observing. We're seeing improvements in autonomic aspects, improvements in gross and fine motor function, improvements in their socialization and communication as well as seizures. And hopefully, that continues to improve as they get stronger and the connections are made within the neuro network. So thanks a lot, Kristen. Appreciate that.

The next question comes from Salveen Richter of Goldman Sachs.

Congratulations on the data. Could you speak to the regulatory pathway from here and how you're thinking about the pivotal endpoint? And also, how young you can go, whether you could go into babies at this point?

Thanks for the question, Salveen. In terms of the regulatory pathway, the way that we're thinking about it has been relatively consistent. We've always thought about utilizing Part A to inform Part B of the study. And so I think what's encouraging thus far is it's reinforcing our strategy, that even at the low dose across patients, across genotypes, across ages, we're seeing relatively consistent improvements across these clinical domains, which is quite informative. And the next step in the strategy has always been, let's get to the high dose and see if we see further improvements in patients that can potentially put a little bit of a finer point on what potentially could be final trial design and endpoints. So we're going to move to the high dose. We've dosed the first adolescent adult patient at this particular point in time. And our hope is that essentially, let's call it fourth quarter this year, first quarter next year, we're able to have discussions with the FDA about what does Part B look like, both in terms of trial design and endpoints. And I think we're on track to do that. We also are going to leverage the RMAT designation that we were granted, which again, I think -- it's difficult to obtain. It's facilitated by the fact that you have preliminary evidence of clinical benefit in a very difficult-to-treat disease with high unmet need. And so as part of that, we have granted a Type B meeting, and we're planning for that right now. We'll have discussions with the agency about I should say, continued discussions with the agency about our thinking on endpoints and trial design. But we're not going to go there right now with everything written in stone. I think it's shaping up nicely in our minds. I think we're seeing that there could be multiple avenues we could go down if clinically meaningful and objective end points, but we want to collect more data before we make that final decision. Hopefully, that makes sense.

The next question comes from Whitney Ijem at Canaccord.

I'll add my congrats on the data. Just a quick question. Can you remind us where you are on manufacturing in terms of the process, whether that's locked or any changes that need to happen? And I guess, in particular, regarding the ongoing discussions with the FDA, are there additional questions or things that need to be ironed out on the manufacturing front that you'll be talking about over the coming months?

Yes, Whitney, great question. We feel like we're in a good position on the CMC side. So essentially, we use a relatively straightforward suspension culture, triple transfection process. It's relative, it's been the same with the clinical doses, the pharm tox lots. We've used the same partner at Catalent to help with that. The internal group came up with the process and refinements along the line. We have made, I would say, a refined process that has now taken us to scale. It's the process that we intend to use commercially. So we're at scale from that perspective. We're with the same supplier that we've used or partner that we've used along the way. We've worked to further improve, I would say the empty-to-full ratio. It was in a good place to begin with. We just wanted to make it as good as possible, and we feel that we've done that. We've had a Type B meeting on CMC with the agency in the spring time. And we feel like we're in very good alignment around next steps, comparability and where we want to use the product. So we've already made the product that we would use for Part B. That's in the freezer at this particular point in time. We're working through release of that and kind of last steps with the agency, but we're optimistic that we're in a good place and that we can use that in the pivotal trial, which has been part of our strategy all along. Hopefully, that makes sense.

The next question comes from Chris Raymond at Piper.

Congrats from us as well on the data. This might be an early question to ask, but as you guys continue to engage with regulators, what kind of durability questions are they asking? Again, it's an early question to ask, but what kind of follow-up are you expecting at least to provide, at least pre-commercially?

To be totally frank, Chris, there hasn't been a specific discussion about durability. The agency hasn't come to us and said, we want to see X amount of data over Y amount of time. I would say that when you look at historic norms, generally, the ask is for 12 months of data. I think we're in a situation that's about as good as it can get in that we're not dealing with cells that turn over, right? We're talking about target cells of the neurons. And so there's less of a concern, I would say, about due to cell turnover, you might have diminution of effect. So our base case is that it's likely a 12-month ask from the agency. Again, we'll work to do everything we can that would be clinically justified around is there a case to be made for something shorter. What is encouraging is that we're seeing response as Suku had mentioned at very early time points. You do have Trofinetide that was approved with 12 weeks of data, albeit it's not a gene therapy. But we'll see what we can do. I think, again, getting to the high dose will further elucidate our view on that. But right now, I think 12 months is a reasonable estimation.

The next question is from Gil Blum at Needham.

Congrats on the update here. So definitely some pretty striking changes, especially in the adult patient #1 and the pediatric patient #1. Could you provide us with -- maybe contextualize for us what these kind of improvements would mean to average caregiver or physician, because I know most people don't have children with this kind of disability at home.

Yes. I mean, I'll turn it over to Suku to answer that question.

Gil, that's an important question. And depending on the spectrum of the phenotype, these patients presented, whether they're pediatric patients or adult patients, it's very important to note the clinical aspects of the disease that they present with, right? So if you take adult patient 1, as an example, she couldn't sit unassisted. She needed a back brace. She was socially withdrawn, wouldn't really do much for herself. What you saw in the video post treatment, we have 2 time points in the timeline, where the patient was very socially engaging, was trying to move her hands, was able to sit unassisted, she appears to be doing a lot more and intellectually is able to communicate. So my clinical assessment is that her activities of daily living, she's progressing slowly towards independence or some independence, which I think would also relieve her parental pressure she puts on her parents to look after. Actually she's the patient who have the sleep challenges. And if you think about this, that the dad had told the PR that he hasn't slept for 10 years because he sleeps usually with -- in the daughter's room. But after the gene therapy, I mean, again, this was a rapid response. Within 7 to 10 days, the sleep abnormality disappeared. The daughter start sleeping through the night, and the dad's now reporting, I'm finally sleeping every night. It has made a huge impact on his quality of life. So that's one classic example. In pediatric patients, you saw the improvements in hand function skills, right? The ability to use the spoon, et cetera, the ability to use right arm. She also had an autonomic dysfunction around breathing. Some of the seizures obviously are well controlled. So I know I'm getting into seizures, but if you look at all 4 patients across, right, the ones that have more severe seizures or even a few seizures a year, if you get those seizures completely under control and reduce the dose of the medicine, again, you have a lot of improvement in activities of daily living, quality of life, et cetera, and frankly, for the patient and the caregiver as well. So those are very strong ADL biomarkers, in my opinion, that show that this -- our gene therapy could make hopefully a remarkable difference in this patient population.

Yes. And Gil, I guess I would just add to that. When you talk to the caregivers, at the top of the list of their concerns is the communication and socialization aspect. And I think if you look at the videos that we showed, the fact that those children, they had -- they were definitely more withdrawn pretreatment. And you can just see that they were interacting, their eyes were more open, they were trying to socialize. And I think it's apparent that's something that would be so meaningful to you because you knew that they were in there before, you just couldn't really get to them. And I think that, that ability to communicate, that ability for the child to point to what might hurt or scratch and itch or something like that, but also communicate with the parent is so important. I think the hand function aspect again allows for, hopefully, down the road, the ability to feed oneself, et cetera. I think the other thing, too, I'd point to on the video is when you think about it, again, as a parent, watching some of the breathing difficulties is hard to watch, right? And that happens all day long. And if you can ameliorate that and make just everybody more comfortable, again, I think that absolutely is something that's going to be meaningful. And then I think it's obvious on the gross motor function aspect of things that you are starting to regain things you haven't had, it's further encouraging. So again, across the board, I think this is going to be well received by caregivers, but I think those are the ones that kind of always rise to the forefront. I hope that helps.

The next question comes from Maury Raycroft at Jefferies.

I'll add my congrats. I was just going to ask a logistical question. I guess, when will we see updates from the MSEL-A and all the other clinical endpoints for the pediatric patients? And do you plan on reporting an update at your quarterly update? Or would there just be one complete update second half of this year with a high dose data?

Yes. So I mean, just to be clear, on the Mullen, the first time point -- so it's conducted at baseline, and then the first time point that it's conducted is 12 weeks. So that was the only Mullen score we have just to be clear, in the pediatric population. As it relates to updates, right now, the plan is to give a wholesome update on the available patients that we dosed at the high dose in both patient populations at sometime later in the second half of the year. I would just -- like that's the plan. I would say we'd always reserve the right along the way to potentially give an update on patients previously dosed. But again, I don't want to commit to that at this point in time. So we'll try to give more guidance when it's time for the next earnings call, but that's the current plan at this particular juncture.

The next question is from Mahdi Goudarzi at Truist.

This is Mahdi for June, and congrats on the data. So 2 quick questions. What sort of improvements you expect in -- for RSBQ specifically with higher doses. And given that your competitor using a full-length MECP2, wouldn't you have expected like or wanted to see better improvement using full-length versus the miniMECP2?

Thanks, Mahdi. So again, I'll take the RSBQ question first. Look, we've been pretty consistent. RSBQ is not a good scale to measure therapeutic effect. You can take a look at -- I think one of the reasons we put the charts together like we did is to show that it can be variable. And particularly in the pediatric population, the steroids, in our opinion, mask some of the benefit. Like when you look at what's happening in later time points, most of the improvements are around general mood, ability to sleep, irritability, things of that nature because of the steroids. They're hungry. It just makes it more difficult. So in our view, and what we're trying to communicate here is through the videos, is what's more important are the clinically meaningful aspects of what's improving from a gross motor perspective. What's happening with hand function. Are milestones being recovered. Are we seeing improvements in the breathing and the sleep, seizure reduction. Those are more tangible clinically meaningful endpoints that the agency certainly would like to see. We've been pretty consistent in our view about how good RSBQ is. And I think that's consistent with the KOLs as well. I think they would agree that that's not the best scale. So our view is that at best, in a pivotal trial, RSBQ is likely an exploratory, possibly a secondary end point. So hopefully, that's clear in terms of our position with RSBQ. As it relates to full length versus mini-gene, again, I think there's plenty of preclinical work that's been done to demonstrate in the disease model from surgery and [indiscernible], there's no difference in effect in either the mini-gene or the full-length gene. I mean essentially the functional aspects. The whole point of the mini-gene is the functional aspects of the gene, the key domains are included in it. So when you take a look at our preclinical work and you compare it, the [indiscernible] are looking to mice are probably the best comparator, with all the caveats around don't compare across studies, but it's the same age of mice and you're measuring the same things. I would say that to the vast majority of people, the data look very consistent in mice model. And the dose that we use were significantly less. So I think preclinically, I think there's clear evidence that the mini-gene is fully functional. And I think more importantly, when you take a look at what we've reported out over the last 12 months and in particular, demonstrated with the video evidence across the domains ranging from autonomic to motor function, to socialization and communication, to seizures, all aspects of the disease, all stemming from different regions of the brain, we're seeing an effect. So I think that the mini-gene clearly is demonstrating it's very effective. And I guess we'll have to see when others put out their data, how does that look like? And again, there's differences in the routes of administration and things of that nature. So right now, our view very strongly is that the mini-gene is absolutely stellar in what it's doing.

The next question comes from Yanan Zhu at Wells Fargo.

Congrats on the update. So I was wondering, looking at CGI-I for patient #1 in the adult study. CGI-I went from 2 to 3 between the last 2 updates, and whereas the PGI-I and RSBQ both got better. I wonder what drove the CGI-I change in that patient? And also a very quick question. Are you measuring hand functions using the Rett Syndrome Hand Function Scale in the pediatric study? Will we see that data at some point?

Okay. I'll take the first one and turn it to Suku on the hand function. But again, I think I don't want to get Suku wound up, but I think that's one of the reasons we really try to focus on, the clinical outcomes and milestone improvements and actually the clinically relevant data because there's an inherent challenge in the scales. So Yanan, you bring up a great point. Why does everything look like it's improving on the scales, it's all about points in time, right? I mean so RSBQ can be done over a matter of days, it's not done specifically on one day. It could even be broken out over the course of a couple of different days depending upon how the caregivers have time allocated. The PGI is also done by the caregivers and they're not done on the same day. What I can't tell you is when the CGI was done, it was basically in the clinic. It's done in the span of one hour where they're seeing the physician, and the patient actually had influenza and was sick when she went in there. So I think that's one of the reasons that what we shared in the release was the fact that the -- clearly, the caregivers think that there's a significant improvement that's been demonstrated over the course of time, and the principal investigators indicating that there's been no diminution of effect. So I wouldn't read too much into one scale at one point in time. Suku, what about the hand function?

Yes. And Sean, I just want to emphasize that CGI-I, as you said, one point in time, but it's always compared to baseline.

Correct. Yes.

So you don't see them. So remember, Yanan, in the pediatric trial, like the adult/adolescent trial is -- it's a first-in human trial, a safety trial, obviously, with hypothesis generating for efficacy measures, right? So when the pediatric trial was initially designed, hand function scale was not put in because there are multiple other measures that they were trying to figure out which ones we could use. And then Mullen was also thrown in there just to assess how the Mullen would respond to this patient -- in these patients at baseline in 12 weeks post treatment. But my team has been talking about actually potentially adding the Rett Hand Function Scale back into the pediatric trial so we can get further assessments with the low dose and high dose, and then that could give us signals on whether or not we want to use it in the confirmatory trial. So that's kind of where we are right now, okay?

The next question comes from Jack Allen at Baird.

Congratulations on the data update here. I wanted to ask just generally how you're thinking about these data in the context of the genetic or the genotypic severity of these patients? It seems like in the adult cohort, you saw a more robust effect in the patient with a higher more severe disease. And then in the pediatric cohort, I know there are a number of different markers here, but it seems like the -- on some of the specific CGI-I and RSBQ, and I know you just made some comments around RSBQ and the volatility of that end point. But it seems like the less severe pediatric patient is having a more robust response in some regards. I'd love to hear how you're thinking about that aspect of the data set here. I know it's very small patients as well.

Yes. Look, again, I guess I'll start and turn it over to Suku. But I would continue to point people to the clinical observations and the clinical data, right? I mean, part of what we highlighted, Jack, was like, in the adult patient 1, as an example, her biggest, I would say, the impact of the disease was on socialization and gross motor function, right? And we demonstrated that in the video that those who are certainly appear to be impacted, in fact, by the treatment. The second adult patient, one of the worst aspects of her disease was actually seizures. And we've seen basically that she's been seizure-free for 8.5 months, which is certainly an incredible aspect of the therapy. Peds patient 1 right, I mean, her biggest deficit was like the hand function and the ability to grasp which she lost at age 2, and again, what we're trying to indicate is that, that's coming back in a rapid fashion and encouraging. I mean, hopefully, over time, she's able to feed herself. And ped patient 2, I would just say, it's 8 weeks in, the breathing is a really significant aspect of things that we wanted to highlight. You can see the quality of life and the stress that, that would cause both for the patient and the caregiver. But beyond that, she's been able to stand from a sitting position and begin to move her legs like up a step essentially. So we're seeing signs of encouragement. I think you also have to look at where we are post dosing from a temporal perspective and what's really the most bothersome aspects for each patient. But Suku, I don't know if there's anything else you might want to add to that to help Jack.

So I have 2 things to add Jack. One is that, given it's still early days, but we have 2 adults and 2 pediatric patients, so there is one large deletion in the adult, one smaller deletion in the pediatric patient 1 and 2 different missense mutations. But what's very interesting is on the clinical stuff, right? So all the clinical features of this disease, the seizures and the autonomic dysfunction, we are seeing consistent impact with the low dose. So that's very encouraging. The second comment I had was about -- you said -- I think you said something about RSBQ at the beginning. I just want to remind everybody, I mean, I've dealt with scales before, but I think the RSBQ is very complex, incredibly subjective. And if you go back to the FDA notes, when see the review Trofinetide. Even the FDA had a hard time assessing how to use the RSBQ scores in the Trofinetide trial. So that's how they added CGI-I to give it some concreteness and then they could use the p value for the clinical utility evaluations and an approval. But I guess my point here is when you have hopefully a gene therapy that has hopefully relevant clinically meaningful impact on clinical domains that are absolutely important to address and fix in the patients, when the RSBQ becomes, as Sean pointed out earlier, truly an exploratory or frankly, we may not even need it in a trial given that we have other measures that actually allow us to assess the utility of our product, pre-and-post treatment, okay?

Got it. So, if I could just slip in a really quick one. Could you just elaborate on the SAEs in the second pediatric patient? I know they weren't related to study drug, but any comment?

Yes. So if you remember, Peds patient 2 had a lot of seizures. I mean, pretreatment, if I recall it's 2 to 4 seizures a day. And then she was on the steroids, just part of the immunosuppressive regimen, had severe reflux, irritability, sleepless nights, had a UTI, was sedated to get, if I recall, an MRI, which basically dropped her seizure threshold, and therefore, she started having cluster of seizures that resulted in her being sent to the emergency room and then being admitted to hospitals. So that was the first SAE that was not treatment-related, but enough other reasons for her to have seizures. The second episode was where she appeared to be very uncomfortable and in significant discomfort, which resulted in her being seen by the physician or the PI and then being seen in the hospital ER or admitted. And she had kidney stones, pancreatitis, appendicitis, gallstones, et cetera, everything you could worry about ruled out and also had some other nerve evaluations done which were normal. So overall, it was well, the etiology was unclear but she was sent back home and as far as I know she's back to her baseline and she is comfortable as far as I know, because that's post follow-up period for her. Sean?

She also was impacted.

Yes. Thanks for reminding me. Yes, I forgot the most important point on the CAT scan. She had a significant stool and I think some impaction. So when that was resolved, a lot of her symptoms went away. And that's an important point that Sean just reminded me that these patients tend to have significant motility disorders. So when we have motility disorders, obviously the gut moves very slowly, and she also had a viral infection. And that made things worse. So she just had a very complex presentation.

Yes. I guess, Jack, one of the things, just going back to the seizures. It seems like this patient, she's got a history of similar type things happening. And it appears like when she has a [ hormone ] situation, right? I mean she had multiple things going on. She had a urinary tract infection. She was sedated. She was very, very sensitive to the anesthesia. And I think those things kind of threw her into a bit of a difficulty. But fortunately, things appear to be in a good spot based on the timeline that we reported, and we're pleased that she's doing better.

So this is all the time that we have. And this concludes our question-and-answer session. So I'll now turn the call back to Mr. Nolan for final remarks.

We want to thank everyone for taking the time to hear the data this morning, and we're always happy to talk after the fact. Have a great day, and thank you.

Thank you. Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation. You may now go ahead and disconnect your lines.