Welcome to Taysha Gene Therapies' TSHA-102 Program Update Webcast. At this time, all participants are in a listen only mode. Following Management's prepared remarks, we will hold a brief question and answer session. As a reminder, this webcast is being recorded today, June 18th, 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 1/2 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 CEO, who will begin with a brief overview of the program and recent progress, and Dr. Sukumar Nagendran, President and Head of R&D of Taysha, who will then discuss the clinical data from the first two adult and first two 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 timelines 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 TSHA'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 TSHA'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 31st, 2023 and our Quarterly Report on Form 10-Q for the quarter ended March 31st, 2024. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, June 18th, 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 two ongoing phase 1/2 REVEAL trials evaluating TSHA-102, an adult and adolescent trial taking place in Canada and the U.S.
for patients age 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 with sustained and 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 eight 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 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 the genetic root cause of the disease. Rett syndrome is a rare neurodevelopmental disorder that affects an estimated 15,000-20,000 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 four key stages, beginning with early onset developmental stagnation at 6-18 months of age, followed by rapid regression plateau and late motor deterioration.
Our adolescent and adult trial includes late motor deterioration Stage 4 patients which is the most advanced stage of the disease, and our pediatric trial includes patients with pseudostationary Stage 3 Rett syndrome, while our pediatric trial captures an earlier stage of disease. It is important to understand that most patients with Stage 3 Rett syndrome have already developed the hallmark symptoms of the disease and present with many advanced manifestations. Patients typically approach Stage 3 after a period of deterioration and rapid regression of learned 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 3 Rett syndrome also suffer from seizures that can significantly impact their quality of life. Importantly, per our protocol for Part A of the REVEAL Pediatric trial, the Stage 3 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 one-time 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 in 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 autoregulatory 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 sites. 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 nervous system.
I will now turn the call over to Suku to provide more in-depth discussion of the clinical data across our T102 program.
Sukumar,
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 1/2 adolescent and adult trial assessing the safety and preliminary efficacy of TSHA-102 in females aged 12 years and older with Stage 4 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 5.7 E14 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 dose the first patient in Cohort 2 evaluating 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 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 two adult patients is quite different due to their distinct MECP2 mutations which manifest in dramatically different phenotypes and clinical severity. Patient one who was dosed with TSHA-102 at age 20 has a large deletion within her MECP2 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 anchored to signs and symptoms of Rett syndrome that rates the severity of patient's illness relative to the clinician's experience with participants who have the same diagnosis. At baseline the patient's CGI-S score was 6 indicating severely ill. Prior to treatment, the first adult patient was in a constant state of hypertonia with complete loss of ambulation and was wheelchair-bound. She had lost her ability to sit or stand by age eight years old as documented in the patient's medical history. Additionally, the patient had limited body movement, required 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 non-dominant hand.
By age six she also became nonverbal. Around this time she experienced frequent apnea and hyperventilation episodes and had a history of seizures with 2-4 seizures per year at baseline. In contrast, the second patient was dosed with TSHA-102 at 21 years old, has a missense mutation in a 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, but she had impaired gait and balance that 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 nonverbal around the same time.
Additionally, the patient experienced frequent hyperventilation episodes and had a history of frequent seizures, 2-4 seizures per week at baseline. While the disease separately differed between the two 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 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 eight as documented in her medical history. Further, the patient was very socially withdrawn and minimally interactive pre treatment. We will now show video evidence of these observations from her baseline assessment.
Please, can I play with him a bit longer? What do you think, Pepper? And what is your name, young man? I'm Kai. Well, Caillou, you go off and play and I'll have a glass of that delicious looking lemonade. Let's go, Pepper.
[Foreign language]
In the baseline video, the 20-year-old patient was seated in an upright position on the hospital bed with the full support of the backrest. 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.
There she is.
I'm just gonna put this up.
Stresses me out.
I can't.
[Foreign language]
Yeah.
We're so proud of you.
Yes.
You're. Look at you.
Without the brace and anything.
Yeah.
She doesn't have the brace. She don't feel it that much.
I didn't try the brace. Yeah. Good job. No.
Sketches.
Oh, there you go.
Yeah.
Not happy.
Yeah.
I'm Dr. Mayor. Mayor.
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 a 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 they appeared to be awakened 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.
They're watching Crusty.[Foreign language] You're doing good sweetie.
We believe the 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 protocol. Patient 1 began prophylactic immunosuppressant therapy 7 days prior to TSHA-102 administration. A steroid taper was completed by week 36 and a 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, scratch 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 ideas driven communication device at week 25 which she hadn't expressed interest in 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 patient's 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.
Therefore, it's 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 to normal temperature and color, whereas before treatment the hands and feet were usually cold and blue based on the principal investigator's clinical observations. The principal investigator also reported that the first patient's seizures were overall well controlled 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 2-4 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 a 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 which are repetitive, purposeless hand movements and a diagnostic hallmark of Rett syndrome. Before treatment, the patient mostly held her hands firmly together and hand stereotypies had improved for the first time since regression at age 3 at the initial 4- and 6-week assessment. The sustained improvement in hand stereotypies is encouraging and may provide new opportunities for fine motor skill learning. 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 antiseizure medication relative to the baseline seizure frequency of 2-4 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 developed 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 age 2 for the second patient. 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.
Patient 1 showed sustained improvements in Clinical Global Impression – Severity (CGI-S) and Clinical Global Impression – Improvement (CGI-I) compared to baseline. She also demonstrated new improvements in Parental Global Impression – Improvement (PGI-I). The Rett syndrome Behavior Questionnaire (RSBQ) 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 (RSHFS) week 52 assessment has not been completed yet. The patient developed improvement at the late assessment at week 25 compared to baseline.
Patient 2 showed sustained improvement in CGI-I 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, trunk or rocking, and stereotypic hand movements. Patient 2 did not show a change in CGIs at 25 weeks post treatment compared to baseline and there was a slight increase in RSBQ total score reported at week 25. The critical takeaway is that collectively early improvements shown in the two 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 the steroid taper in both adult patients with advanced Stage 4 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 1/2 pediatric trial is evaluating the safety and preliminary efficacy of TSHA-102 in female patients with Stage 3 Rett syndrome age five to eight years old. Enrollment criteria require patients should be post regression and to have entered a stage of stabilization, meaning there have not been any identified loss of skills in the last six months.
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, evaluated the low dose of TSHA-102 of 5.7 E14 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 and initial clinical improvement across multiple domains.
In the first two 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 of 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 deemed 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 with early evidence of developmental gains.
Importantly, both pediatric patients with different genotypes treated with a low dose of TSHA-102 showed a similar safety profile improvements across consistent clinical domains to those that we observe in the 2 adult patients treated with the low dose. Importantly, we believe this supports the broad treatment potential of TSHA-102. Similar to adult patients, the pediatric patients have different genetic backgrounds and associated disease severity. Patient 1, a 6-year-old female, has the deletion within MECP2 gene that manifests as a moderate phenotype at baseline. The patient's CGI-S score was 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 limited hand function and lost the ability to use eating utensils at 1.5 years of age and loss of interest by age 2. She has been mostly nonverbal since the age of 1 and the ability to use her eye gaze driven communication device and speak 3 words inconsistently baseline. She experienced withholding spells and had a 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 mild 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 apraxic gait at 1.5 years of age, impacting her gait and balance.
Additionally, the patient had impaired hand function since the age of one 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 one and could use her eye gaze driven communication device at baseline. Additionally, the patient experienced frequent hyperventilation episodes and had a history of seizures with approximately 2-4 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 the differences in genetic 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 her pincer grip. 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.
About 3 seconds. Okay, put it in her left hand.
Four.
In the baseline video, the patient held an object for around 1 second showing evidence of a very limited hand function ability pre-treatment which limited the 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 pre-treatment. We will now show a snapshot of the video evidence of this improvement.
Good holding it. I see you holding it. Good holding. Oh, you going to bring it to your mouth? Is that what you do with the spoon? You can bring it to your mouth. Oh, such a big girl. You are still hanging on to it. You're still hanging on to it, honey.
Good job.
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 week 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.
Pin into your hand. Okay. Let's grab on to that and hang on to it. Can you move that around?
Can you give it to Mom? Can I have that pen?
You're saying hi.
Yeah. You are very distracted by looking at me. That's who you want to look at, huh?
Can I have that pen?
Where's the pen? Give the pen to Mom.
Can I have this?
No.
You're gonna hang on to it.
You are. For quite a long time, actually.
Can I have it?
Okay.
But that's not.
See, I am just stubborn. Oh, can you get a?
Come on.
No, just kidding.
You're gonna keep that pen. That is the longest I've ever seen you hold anything. Yeah, and you would. You're going up and down without throwing it on the floor.
You hit my thigh. I didn't lose it.
Yeah. Is she preferring the right hand at this point?
It's always been her daughter.
Yeah. There was one day when she was doing more with the left.
Yeah. Yeah.
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 a pincer grip by age 2. We believe the patient's improvements in 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.
Which one?
Oh, thank you. What about this one? Which one goes here? Yeah.
In the baseline video, the second pediatric patient displayed frequent hyperventilation followed by a breath-holding spell for the patient's medical history. These breathing abnormalities appeared at age four. At week eight post-treatment, the patient showed improvement in breathing patterns for the first time since age four. During the R-MBA assessment, we will show video evidence supporting this improvement.
Food here. Let's do two of them. All right. Which one do you want? Almost thinking about using those hands, but. I think she's kind of looking at the food. Yeah, mostly. Okay.
You want the yogurt?
Do you want the yogurt?
Yeah, I think so.
Do you have to finish some of this?
Yeah.
Okay, let's have this one, because this one you can have. Okay.
As seen in the video, at eight 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 four patients treated with low dose TSHA-102 experience 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 truncus 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 oral 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 vagal nerves in the central nervous system, which are involved with the coordination and movements involved in chewing and swallowing and involuntary functions under the control of the autonomic nervous system. Importantly, this indicates that 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 the use of new words and the gained ability to string multiple words together and identify object functions for the first time.
The patient also gained new skills in visual reception and receptive language including the ability to identify an object from memory, follow two unrelated commands and identify the function of objects and action words which she was unable to do pre-treatment. 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 three months. Now let's turn to the second pediatric patient as of week 8 post-treatment, the PI, a principal investigator, reported improvements across multiple clinical domains and early evidence of developmental gains including 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 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 which she was unable to do at baseline. The principal investigator also reported improvements 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 was one of the most severe aspects of the disease impacting the patient and her caregiver's quality of life prior to treatment. Pre treatment, the patient had approximately 2-4 seizures per day since the age of 3 with a medical history of hospitalization for seizure control.
Two weeks post-TSHA- 102 , the test patient demonstrated a reduction in seizure frequency with several days reported as seizure-free. The patient experienced an 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 done although her seizures resolved prior to discharge. A new anti-seizure 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 develop 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 of Early Learning at week 12 post treatment. We will go more in depth on the Mullen Scales of Early Learning shortly. At week 12 there was slight increase in RSBQ total score for the first pediatric patient compared to day 7.
The second pediatric patient demonstrated an 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 at 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 two pediatric patients treated with the low dose of TSHA-102 across multiple efficacy measures further reinforces 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 of Early Learning is a standardized cognitive developmental assessment adapted for use in patients with Rett syndrome. The MSEL.
MSEL-A functionally evaluate skills compared to developmental milestones across four 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 a trained psychologist or a psychometrician and the scores are reviewed by a certified central rater. The assessment evaluates where patients with Rett syndrome fall on a developmental curve compared to a standard developmental milestone for each domain assess the patient's developmental age e quivalence 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 MSEL-A.