Q4 2023 Taysha Gene Therapies Inc Earnings Call

March 19, 2024

Speaker Change: [music].

Operator: Greetings and welcome to Taysha Gene Therapies' 4th quarter and Full Year 2023 Earnings Call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star 0 on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce Hayleigh Collins, Director, Head of Corporate Communications and Investor Relations. Thank you, you may begin.

Operator: Greetings and welcome to Taysha Gene Therapies' 4th Quarter and Full Year 2023 Earnings Call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star 0 on your telephone keypad. As a reminder, this conference is being recorded.

Greetings and welcome to Taser gene therapies fourth quarter and full year 2023 earnings call.

At this time all participants are in a listen only mode.

A question and answer session will follow the formal presentation.

If anyone should require operator assistance during the conference. Please press star zero on your telephone keypad.

Operator: As a reminder, this conference is being recorded. It is now my pleasure to introduce Hayleigh Collins, Director, Head of Corporate Communications and Investor Relations. Thank you, you may begin. Good afternoon, and welcome to Taysha's full year 2023 Financial Results and Corporate Update conference call. Earlier today, Taysha issued a press release announcing financial results for the full year ended December 31st, 2023. A copy of this press release is available on the company's website and through its SEC filings.

As a reminder, this conference is being recorded. It is now my pleasure to introduce Hayleigh Collins, Director, Head of Corporate Communications and Investor Relations. Thank you, you may begin.

As a reminder, this conference is being recorded.

It is now my pleasure to introduce Haley Collins director head of corporate Communications and Investor Relations. Thank you you may begin.

Operator: It is now my pleasure to introduce Hayleigh Collins, Director, Head of Corporate Communications and Investor Relations. Thank you, you may begin.

Hayleigh Collins: Thank you. Good afternoon and welcome to Taysha's Full Year 2023 Financial Results and Corporate Update Conference Call. Earlier today, Taysha issued a press release announcing financial results for the full year ended December 31, 2023. A copy of this press release is available on the company's website and through our SEC filings.

Hayleigh Collins: Thank you good afternoon, and welcome to <unk> full year 2023 financial results and corporate update conference call earlier today <unk> issued a press release announcing financial results for the full year ended December 31 2023.

Hayleigh Collins: A copy of this press release is available on the company's website and through our SEC filings.

Hayleigh Collins: Joining me on today's call are Sean Nolan, Taysha's CEO; Sukumar Nagendran, President and Head of R&D and Kamran Alam, Chief Financial Officer. We will hold a question and answer session following our prepared remarks. Please note that on today's call, we will be making forward-looking statements, including statements relating to the therapeutic and commercial potential of TSHA-102; including the reproducibility and durability of any favorable safety results initially seen in our first and second 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; our research, development and regulatory plans for our product candidates, including timing for clinical trials and reporting results therefrom; and our current cash resources supporting our planned operating expenses and capital requirements into 2026.

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

Speaker Change: Turning me on today's call are Sean Nolan Asia, CEO, Sue can learn a gantry president and head of R&D and Kamran Alam Chief Financial Officer, We will hold a question and answer session. Following our prepared remarks. Please note that on today's call, we will be making forward looking statements, including statements relating to the therapeutic and commercial potential.

Please note that on today's call, we will be making forward-looking statements, including statements relating to the therapeutic and commercial potential of TSHA-102; including the reproducibility and durability of any favorable safety results initially seen in our first and second 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; our research, development and regulatory plans for our product candidates, including timing for clinical trials and reporting results therefrom; and our current cash resources supporting our planned operating expenses and capital requirements into 2026.

Speaker Change: It takes you one or two including the reproducibility and durability of any favorable safety results. Initially seen in our first and second patients dose in the reveal trial to positively impact quality of life and alter the course of disease and the patients we seek to treat our research development and regulatory plans for our product candidates, including timing for our clinical trials and reporting.

Speaker Change: Her both their problem and our current cash resources supporting our planned operating expenses and capital requirements into 2026. These.

Hayleigh Collins: 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 of regulatory actions for our product candidates, our dependence on 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 that we filed today.

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.

Speaker Change: 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.

Speaker Change: This call May also contain forward looking statements relating to patient growth forecasted cash runway in 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 <unk> actual results to differ materially from those stated or implied.

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 of regulatory actions for our product candidates, our dependence on 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 that we filed today.

Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements.

Speaker Change: Such forward looking statements. These risks include uncertainties related to the timing and results of clinical trials up some regulatory actions for our product candidates are dependent on 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.

These risks include uncertainties related to the timing and results of clinical trials of regulatory actions for our product candidates, our dependence on 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 that we filed today.

Speaker Change: 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 that we filed today this call.

Hayleigh Collins: This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, March 19th, 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.

This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, March 19, 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.

This call contains time sensitive information that is accurate only as of the date of this live broadcast March 19 2024.

Speaker Change: 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.

Speaker Change: That I would now like to turn the call over to our CEO Sean Nolan.

Sean Nolan: Thank you, Hayleigh and welcome everyone to our 2023 Full Year Financial Results and Corporate Update Conference Call. Today, I will begin with a brief update on our corporate and clinical activities. Then, Dr. Suku Nagendran, President and Head of R&D of Taysha, will provide an update on our lead TSHA-102 program and clinical evaluation for the treatment of Rett syndrome. Kamran Alam, our Chief Financial Officer, will follow up with a financial update. I will provide closing remarks and open the call up for questions.

Sean P. Nolan: Thank you Haley and welcome everyone.

Sean P. Nolan: 123, full year financial results and corporate update conference call.

Sean P. Nolan: Today, I will begin with a brief update on our corporate and clinical activities than doctors Sukru Mcandrew, President and head of R&D of tissue, who will provide an update on our lead T shirt 102 program in clinical evaluation for the treatment of Ret syndrome.

Sean P. Nolan: Chairman, along our Chief Financial Officer will follow up with a financial update.

Speaker Change: I will provide closing remarks and open the call up for questions.

Sean P. Nolan: In 2023, we made tremendous progress on the development of TSHA-102, our lead gene therapy program and clinical evaluation for the treatment of Rett syndrome, which is a rare neurodevelopmental disorder with significant unmet medical need. This included generating initial clinical data in adult patients and expanding the trial into the adolescent population, obtaining regulatory clearance to initiate the clinical evaluation of TSHA-102 in two additional geographies and dosing the first patient in our pediatric trial. Importantly, we believe these accomplishments enable us to focus our efforts this year on generating critical, long-term clinical data in a broad range of ages and stages of Rett syndrome patients across multiple geographies. We now have two ongoing first-in-human trials evaluating the safety and preliminary efficacy of TSHA-102 -- the REVEAL Phase 1/2 adolescent and adult trial in Canada and the US and the REVEAL Phase 1/2 pediatric trial in the United States, with clearance in the UK. Today, we are excited to report longer-term clinical data from our first two adult patients treated with the low dose of TSHA-102 in our adolescent and adult trials.

In 2023, we made tremendous progress on the development of TSHA-102, our lead gene therapy program and clinical evaluation for the treatment of Rett syndrome, which is a rare neurodevelopmental disorder with significant unmet medical need. This included generating initial clinical data in adult patients and expanding the trial into the adolescent population, obtaining regulatory clearance to initiate the clinical evaluation of TSHA-102 in two additional geographies and dosing the first patient in our Pediatric Trial.

Sukumar Nagendran: In 2023, we made tremendous progress on the development of <unk> 102, our lead gene therapy program in clinical evaluation for the treatment of Ret syndrome, which is a rare neurodevelopmental disorder with significant unmet medical need.

Sukumar Nagendran: This included generating initial clinical data in adult patients and expanding the trial into the adolescent population obtaining regulatory clearance to initiate the clinical evaluation of <unk> 102, and two additional geographies and dosing the first patient in our pediatric trial.

Importantly, we believe these accomplishments enable us to focus our efforts this year on generating critical, long-term clinical data in a broad range of ages and stages of Rett syndrome patients across multiple geographies. We now have two ongoing first-in-human trials evaluating the safety and preliminary efficacy of TSHA-102 -- the REVEAL Phase 1/2 Adolescent and Adult Trial in Canada and the US and the REVEAL Phase 1/2 Pediatric Trial in the United States, with clearance in the UK. Today, we are excited to report longer-term clinical data from our first two adult patients treated with the low dose of TSHA-102 in our Adolescent and Adult Trials.

Sukumar Nagendran: Importantly, we believe use accomplishments enable us to focus our efforts this year on generating critical long term clinical data and a broad range of ages and stages of ret syndrome patients across multiple geographies.

Sukumar Nagendran: We now have two ongoing first in human trials evaluating the safety and preliminary efficacy of tissue 102.

Sukumar Nagendran: The reveal phase one two adolescent and adult trial in Canada and the U S.

Sukumar Nagendran: The reveal phase one two pediatric trial in the United States with clearance in the U K.

Sukumar Nagendran: Today, we are excited to report longer term clinical data from our first two adult patients treated with the low dose of tissue 102 mineral adolescent and adult trial.

Sean P. Nolan: As a reminder, our ongoing review of the Phase 1/2 Adolescent and Adult trial is a first-in-human, randomized dose escalation and dose expansion trial evaluating 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 two dose levels of TSHA-102 sequentially. Two patients have been dosed to date in cohort one, evaluating the low dose of TSHA-102 of 5.7x1014 and dosing in cohort one is now considered complete. Today, we're pleased to provide an update on the encouraging follow-up data from the first two adult patients treated in the low-dose cohort. Recall, when we initiated the REVEAL trial, there were low expectations of efficacy for the Stage 4 adult population among KOLs in the Rett Syndrome community due to the advanced and relentless progression of disease. The focus was placed primarily on safety.

As a reminder, our ongoing review of the Phase 1/2 Adolescent and Adult Trial is a first-in-human, randomized dose escalation and dose expansion trial evaluating 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 two dose levels of TSHA-102 sequentially. Two patients have been dosed to date in cohort one, evaluating the low dose of TSHA-102 of 5.7x1014 and dosing in cohort one is now considered complete.

Sukumar Nagendran: As a reminder, our ongoing review of phase one two adolescent and adult trial is a first in human open label.

Sukumar Nagendran: Randomized dose escalation and dose expansion trial evaluating the safety and preliminary efficacy of tissue 102, and females, aged 12 years and older with stage for Ret syndrome.

Sukumar Nagendran: We are currently enrolling patients in part a the dose escalation portion of the trial, which is evaluating two dose levels of tissue, one or two sequentially.

Sukumar Nagendran: Two patients have been dosed to date in cohort one evaluating the low dose limitation 102 of $5 seven that you did the 2014 and dosing in cohort one is now considered complete.

Today, we're pleased to provide an update on the encouraging follow-up data from the first two adult patients treated in the low-dose cohort. Recall, when we initiated the REVEAL trial, there were low expectations of efficacy for the Stage 4 adult population among KOLs in the Rett Syndrome community due to the advanced and relentless progression of disease. The focus was placed primarily on safety. Therefore, it was very exciting when we announced the encouraging initial impact that TSHA-102 appeared to have across multiple clinical domains in the first two adult patients treated as early as four weeks, following the treatment that we reported in November 2023. The data presented today for Patient 1 is from her six-month post-treatment assessment with clinical observations from week 35 post-treatment. Importantly, we continue to see a durable response and we are seeing sustained improvement in the absence or reduction of steroid levels.

Sukumar Nagendran: Today, we're pleased to provide an update on the encouraging follow up data from the first two adult patients treated in the low dose cohort.

Sukumar Nagendran: Recall, when we initiated the reveal trial there were low expectations of efficacy for the stage for adult population among kols in the Ret syndrome community due to the advanced and relentless progression of disease.

Sukumar Nagendran: The focus was placed primarily on safety.

Sean P. Nolan: Therefore, it was very exciting when we announced the encouraging initial impact that Taysha 102 appeared to have across multiple clinical domains and the first two adult patients treated as early as four weeks following the treatment that we reported in November 2023. The data presented today for patient one is from her six-month post-treatment. Six-month post-treatment assessment with clinical observations from week 35 post-treatment. Importantly, we continue to see a durable response, and we are seeing sustained improvement in the absence or reduction of steroid levels.

Sukumar Nagendran: Therefore, it was very exciting when we announced the encouraging initial impact the tissue went out two appeared to have across multiple clinical domains and the first two adult patients treated as early as four weeks following the treatment that we reported in November 2023.

Therefore, it was very exciting when we announced the encouraging initial impact that TSHA-102 appeared to have across multiple clinical domains in the first two adult patients treated as early as four weeks, following the treatment that we reported in November 2023. The data presented today for Patient 1 is from her six-month post-treatment assessment with clinical observations from week 35 post-treatment. Importantly, we continue to see a durable response and we are seeing sustained improvement in the absence or reduction of steroid levels.

Sukumar Nagendran: The data presented today for patient one is from her six month post treatment six.

Sukumar Nagendran: Six month post treatment assessment with clinical observations from week 35 post treatment <unk>.

Sukumar Nagendran: Importantly, we continue to see a durable response and we are seeing sustained improvement in the absence of reduction of steroid levels.

Sean P. Nolan: We have received many questions since initially announcing Patient 1 data about the possible impact of steroids on the disease itself. We are not surprised but, nonetheless, pleased to highlight today that patient improvements were maintained or further improved in the absence of steroids. As of the six-month assessment, Patient 1 showed sustained improvement across key efficacy measures at decreased steroid levels with new improvement observed in the Rett Syndrome Behaviour Questionnaire, or RSBQ. Additionally, the second adult patient also sustained improvements across key efficacy measures, with new improvement observed in certain measures, including the Revised Motor-Behavior Assessment, or R-MBA, and significantly reduced seizures at 12 weeks post-treatment. The longer-term clinical observations reported by the principal investigator show that both patients had sustained and new improvements across multiple clinical domains, including autonomic function, social communication, motor skills and seizures -- compared to earlier post-treatment assessments.

We have received many questions since initially announcing Patient 1 data about the possible impact of steroids on the disease itself. We are not surprised but, nonetheless, pleased to highlight today that patient improvements were maintained or further improved in the absence of steroids. As of the 6-month assessment, Patient 1 showed sustained improvement across key efficacy measures at decreased steroid levels with new improvement observed in the Rett Syndrome Behaviour Questionnaire, or RSBQ.

Sukumar Nagendran: We have received many questions since initiating.

Since initially announcing patient one data about the possible impact of steroids in the disease itself.

We are not surprised but nonetheless pleased to highlight today that patient improvements were maintained or further improved and the absence of steroids.

Sukumar Nagendran: As with the six month assessment patient one has showed sustained improvement across key efficacy measures a decrease steroids at levels with new improvement observed in the ret syndrome, Behavioural questionnaire or RSP Q.

Sukumar Nagendran: Additionally, the second adult patient also sustained improvements across key efficacy measures with new improvement observed in certain measures, including the revised motor behavior assessment or R. M B, a and significantly reduce seizures at 12 weeks post treatment.

Additionally, the second adult patient also sustained improvements across key efficacy measures, with new improvement observed in certain measures, including the Revised Motor-Behavior Assessment, or R-MBA, and significantly reduced seizures at 12 weeks post-treatment. The longer-term clinical observations reported by the principal investigator show that both patients had sustained and new improvements across multiple clinical domains, including autonomic function, social communication, motor skills and seizures -- compared to earlier post-treatment assessments.

Sukumar Nagendran: The longer term clinical observations reported by the principal investigator showed that both patients had sustained and new improvements across multiple clinical domains, including autonomic function, social communication motor skills and seizures compared to earlier post treatment assessments.

Sukumar Nagendran: Accordingly.

Sean P. Nolan: These continued improvements were reported at week 35 following completion of the steroid taper for the first patient and at week 19 at decreased steroid levels for the second patient. As a reminder, these two patients have quite different genetic mutations. The first patient's MECP2 mutation manifests in a more severe disease phenotype than the second patient's mutation. For example, patient one was completely non-ambulatory at baseline, whereas patient two could walk with prompting. Despite the different clinical baseline characteristics, both patients showed improvements across multiple clinical domains as early as four weeks following treatment. And importantly, both patients showed sustained and new improvements across those clinical domains at the longer-term assessments. In addition to the positive safety data, we are encouraged by the longer-term safety profile observed.

These continued improvements were reported at week 35 following completion of the steroid taper for the first patient and at week 19 at decreased steroid levels for the second patient. As a reminder, these two patients have quite different genetic mutations. The first patient's MECP2 mutation manifests in a more severe disease phenotype than the second patient's mutation. For example, patient one was completely non-ambulatory at baseline, whereas patient two could walk with prompting.

Sukumar Nagendran: These continued improvements were reported.

35, following completion of the steroid taper for the first patient and at week 19, a decrease steroid levels for the second patient.

Sukumar Nagendran: As a reminder, these two patients have quite different genetic mutations the first patients M. A C. P. Two mutation manifests in a more severe disease phenotype than the second patients mutation for.

Sean P. Nolan: For example, patient one was completely non-ambulatory at baseline, whereas patient two could walk with prompt... Despite the different clinical baseline characteristics, both patients showed improvements across multiple clinical domains as early as four weeks following treatment. And importantly, both patients showed sustained and new improvements across those clinical domains at the longer-term assessment. In addition to the positive safety data, we are encouraged by the longer-term safety profile observed.

Sukumar Nagendran: For example, patient one was completely non ambulatory at baseline, whereas patients who could work with prompting despite.

Despite the different clinical baseline characteristics, both patients showed improvements across multiple clinical domains as early as four weeks following treatment. And importantly, both patients showed sustained and new improvements across those clinical domains at the longer-term assessments. In addition to the positive safety data, we are encouraged by the longer-term safety profile observed. Data from the first two adult patients showed that TSHA-102 was well-tolerated with no treatment-emergent serious adverse events as of the 35-week assessment for Patient 1 and as of the 19-week assessment for Patient 2. We believe the safety profile and these continued improvements across multiple clinical domains, even at reduced steroid levels in both adult patients with advanced Stage 4 Rett syndrome, support the durability and transformative potential of TSHA-102 across multiple genotypes of Rett syndrome and further validate our construct. Suku will discuss the clinical observations and efficacy data in more detail shortly. Now, let's turn to our pediatric trial.

Sukumar Nagendran: Despite the different clinical baseline characteristics, both patients showed improvements across multiple clinical domains as early as four weeks following treatment and.

Sukumar Nagendran: And importantly, both patients showed sustained a new improvements across those clinical domains at the longer term assessments.

Sukumar Nagendran: In addition to the positive safety data, we are encouraged by the longer term safety profile observed.

Sean P. Nolan: Data from the first two adult patients showed that Taysha 102 was well-tolerated with no treatment-related serious adverse events at the 35-week assessment for patient one and at the 19-week assessment for patient two. We believe the safety profile and these continued improvements across multiple clinical domains, even at reduced steroid levels, in both adult patients with advanced stage 4 Rett syndrome support the durability and transformative potential of Taysha 102 across multiple genotypes of Rett syndrome and further validate our construct. Sukumar will discuss the clinical observations and efficacy data in more detail shortly. Now, let's turn to our pediatric trial.

Sukumar Nagendran: Data from the first two adult patients showed the tissue 102 was well tolerated with no treatment emergent serious adverse events as well as the 35 week assessment for patient one and there's the 19 week assessment for patients too.

Sukumar Nagendran: We believe the safety profile and these continued improvements across multiple clinical domains, even at reduced steroid levels in both adult patients with advanced stage for Ret syndrome support the durability and transformative potential of tissue, one or two across multiple gino types of ret syndrome and further VAT.

We believe the safety profile and these continued improvements across multiple clinical domains, even at reduced steroid levels in both adult patients with advanced Stage 4 Rett syndrome, support the durability and transformative potential of TSHA-102 across multiple genotypes of Rett syndrome and further validate our construct. Suku will discuss the clinical observations and efficacy data in more detail shortly. Now, let's turn to our pediatric trial.

believe the safety profile and these continued improvements across multiple clinical domains, even at reduced steroid levels in both adult patients with advanced Stage 4 Rett syndrome, support the durability and transformative potential of TSHA-102 across multiple genotypes of Rett syndrome and further validate our construct. Suku will discuss the clinical observations and efficacy data in more detail shortly. Now, let's turn to our pediatric trial.

Sukumar Nagendran: Elevated our construct.

Sukumar Nagendran: Sue will discuss the clinical observations and efficacy data in more detail shortly.

Sue Gantry: Now, let's turn to turn to our pediatric trial are ongoing reveal phase one two pediatric trial is a first in human open label randomized dose escalation and dose expansion trial evaluating the safety and preliminary efficacy of tissue 102, and females age five to eight years old with stage III Ratzinger.

Sean P. Nolan: Our ongoing REVEAL Phase 1/2 Pediatric Trial is a first-in-human, open-label, randomized dose escalation and dose expansion trial evaluating the safety and preliminary efficacy of TSHA-102 in females aged 5 to 8 years old with Stage 3 Rett syndrome. We are currently enrolling patients in Part A, the dose escalation portion of the trial, which is evaluating two dose levels of TSHA-102 sequentially. We've dosed the first pediatric patient in cohort one, evaluating the low dose of TSHA-102 of 5.7x1014 here in the US.

Sue Gantry: We are currently enrolling patients in part a the dose escalation portion of the trial, which is evaluating two dose levels of tissue 102 sequentially.

Sue Gantry: We've dosed the first pediatric patient in cohort one evaluating the low dose of tissue 102, a $5 seven and eight of the 14 here in the U S.

Sean P. Nolan: The Independent Data Monitoring Committee, or IDMC, recently convened to review these longer-term clinical data from the first two adult patients and the initial six-week data from the first pediatric patient treated with the low dose of TSHA-102. Following review, the IDMC approved our request to proceed to dose escalation in the adolescent and adult trial, which enables us to initiate dosing with a high dose of TSHA-102 earlier than planned. This is a critical step in our development plan, as advancing to the high dose accelerates our ability to further inform our clinical development and regulatory strategy for Part B of the study by at least a quarter. With cohort one now completed in our Adolescent and Adult Trial, we plan to dose the first patient in cohort two, evaluating the high dose of TSHA-102 of 1x 1015 in the 2nd quarter of 2024. Initial data from cohort two of the Adolescent and Adult Trial is expected in the second half of 2024. The IDMC also approved dosing of the second pediatric patient in cohort one in the REVEAL Phase 1/2 Pediatric trial. The patient has been identified and dosing is scheduled to take place this quarter. We plan to complete enrollment in the low and high dose cohorts of the Pediatric Trial this year with initial available data from the low dose cohort, expected in mid-2024, as we disclosed previously in early January.

The Independent Data Monitoring Committee, or IDMC, recently convened to review these longer-term clinical data from the first two adult patients and the initial six-week data from the first pediatric patient treated with the low dose of TSHA-102. Following review, the IDMC approved our request to proceed to dose escalation in the adolescent and adult trial, which enables us to initiate dosing with a high dose of TSHA-102 earlier than planned. This is a critical step in our development plan, as advancing to the high dose accelerates our ability to further inform our clinical development and regulatory strategy for Part B of the study by at least a quarter.

Sue Gantry: The independent data monitoring committee or I D. M. C. Recently convened to review these longer term clinical data from the first two adult patients and the initial six week data from the first pediatric patient treated with the low dose of tissue 102.

Sue Gantry: Following review the I D. M. C approved our request to proceed to dose escalation in the adolescent and adult trial, which enables us to initiate dosing with the high dose of tissue 102 earlier than planned.

Sue Gantry: This is a critical step in our development plan is advancing to the high dose accelerates our ability to further inform our clinical development and regulatory strategy for part B of the study by at least a quarter.

Sue Gantry: With cohort one now completed in our adolescent and adult trial, we plan to dose the first patient in cohort to.

With cohort one now completed in our Adolescent and Adult Trial, we plan to dose the first patient in cohort two, evaluating the high dose of TSHA-102 of 1x 1015 in the 2nd quarter of 2024. Initial data from cohort two of the Adolescent and Adult Trial is expected in the second half of 2024. The IDMC also approved dosing of the second pediatric patient in cohort one in the REVEAL Phase 1/2 Pediatric trial. The patient has been identified and dosing is scheduled to take place this quarter. We plan to complete enrollment in the low and high dose cohorts of the Pediatric Trial this year with initial available data from the low dose cohort, expected in mid-2024, as we disclosed previously in early January.

Sue Gantry: We value with either high dose of Tisha, one or two of wanting to the 15 in the second quarter of 'twenty 'twenty four.

Sue Gantry: Initial data from cohort two of the adolescent and adult trial is expected in the second half of 2024.

Sean P. Nolan: The IDMC also approved dosing of the second pediatric patient in Cohort 1 in the Reveal Phase 1-2 Pediatric trial. The patient has been identified, and dosing is scheduled to take place this quarter. We plan to complete enrollment in the low- and high-dose cohorts of the pediatric trial this year, with initial available data from the low-dose cohort expected in mid-2024, as we disclosed previously in early January.

Sue Gantry: The <unk> also approved dosing of the second pediatric patient in cohort, one and the reveal phase one two pediatric trial.

Sue Gantry: The patient has been identified and dosing is scheduled to take place this quarter.

Sue Gantry: Plan to complete enrollment in the low and high dose cohorts of the pediatric trial. This year with initial available data from the low dose cohort expected in mid 2024 as we disclosed previously in early January. Additionally, initial data from the high dose cohort of pediatric trials expected in the second half of 2020.

Sean P. Nolan: Additionally, initial data from the high dose cohort of Pediatric Trials are expected in the second half of 2024. Overall, we're focused on completing dosing in Part A of both studies this year. Importantly, data from Part A will be assessed by regulatory agencies and the IDMC to provide guidance to determining final key elements of Part B, the dose expansion portion of the study -- including the hierarchy of efficacy endpoints, study design and the maximum tolerated dose or maximum administered dose.

Four.

Sue Gantry: Overall, we're focused on completing dosing and part a of both studies. This year importantly data from part a will be assessed by regulatory agencies and the I D. M. C to provide guidance to determining final key elements of part B. The dose expansion portion of the study, including the hierarchy of.

Sue Gantry: If we could see endpoints study design and the maximum tolerated dose or maximum administered dose.

Sean P. Nolan: Another key focus in 2023 was broadening the clinical evaluation of TSHA-102 across geographies. In our REVEAL Adolescent and Adult Trial, we recently announced the expansion of the ongoing trial in Canada into the US, following our submission of the protocol to the US Food and Drug Administration, or FDA. We're now focused on site initiation activities in the US for the Adolescent and Adult Trial, in addition to our ongoing US site initiation activities in our Pediatric Trial. In our REVEAL Pediatric Trial, we announced earlier this year that the UK Medicines and Healthcare Products Regulatory Agency, or MHRA, authorized the clinical trial application for TSHA-102 in pediatric patients with Rett syndrome, enabling expansion of our ongoing pediatric trial in the US into the UK and we're currently focused on site initiation activities. Additionally, we are pleased to share that TSHA-102 received Innovative Licensing and Access Pathway Designation, or ILAP, from the MHRA, which is a program that's designed to accelerate the review path of novel treatments. We believe this further reinforces the high, unmet medical need for patients with Rett syndrome. As a reminder, TSHA-102 has already received Fast Track designation and Orphan Drug and Rare Pediatric Disease designations from the FDA and has been granted Orphan Drug designation from the European Commission for the treatment of Rett syndrome. Lastly, we are pleased to share that we have strengthened our clinical and regulatory leadership with the promotion of Dr. Meredith Schultz to Chief Medical Officer and Rumana Haque-Ahmed to Chief Regulatory Officer. Dr. Schultz and Ms. Haque-Ahmed will continue to report to Suku.

Another key focus in 2023 was broadening the clinical evaluation of TSHA-102 across geographies. In our REVEAL Adolescent and Adult Trial, we recently announced the expansion of the ongoing trial in Canada into the US, following our submission of the protocol to the US Food and Drug Administration, or FDA. We're now focused on site initiation activities in the US for the Adolescent and Adult Trial, in addition to our ongoing US site initiation activities in our Pediatric Trial.

Sue Gantry: Another key focus in 2023 was broadening the clinical evaluation of tissue 102 across geographies.

Sue Gantry: Our reveal adolescent and adult trial, we recently announced the expansion of the ongoing trial in Canada into the U S. Following our submission of the protocol to the U S food and drug administration or F. D. A.

Sue Gantry: <unk> now focused on site initiation activities in the U S for the adolescent and adult trial. In addition to our ongoing U S site initiation activities and our pediatric trial.

Sean P. Nolan: In our reveal pediatric trial, we announced earlier this year that the UK Medicines and Healthcare Products Regulatory Agency, or MHRA, authorized the clinical trial application for Taysha 102 in pediatric patients with Rett syndrome, enabling expansion of our ongoing pediatric trial in the U.S. into the U.K., and we're currently focused on site initiation activities. Additionally, we are pleased to share that Taysha 102 received Innovative Licensing and Access Pathway Designation, or ILAP, from the MHRA, which is a program that's designed to accelerate the review path of novel treatments. We believe this further reinforces the high unmet medical need for patients with Rett syndrome. As a reminder, Taysha 102 has already received fast-track designation and orphan drug and rare pediatric disease designations from the FDA and has been granted orphan drug designation from the European Commission for the treatment of rheumatoid arthritis. Lastly, we are pleased to share that we have strengthened our clinical and regulatory leadership with the promotion of Dr. Meredith Schultz, the Chief Medical Officer, and Rumana Ahmed, to Chief Regulatory Officer. Dr. Schultz and Ms. Haqqamed will continue to report to Sukumar.

Sue Gantry: And our reveal pediatric trial, we announced earlier this year that the UK medicines and healthcare products regulatory agency or M. H R. E authorized a clinical trial application for tissue 102 in pediatric patients with ret syndrome, enabling expansion of our ongoing pediatric trial.

In our REVEAL Pediatric Trial, we announced earlier this year that the UK Medicines and Healthcare Products Regulatory Agency, or MHRA, authorized the clinical trial application for TSHA-102 in pediatric patients with Rett syndrome, enabling expansion of our ongoing pediatric trial in the US into the UK and we're currently focused on site initiation activities. Additionally, we are pleased to share that TSHA-102 received Innovative Licensing and Access Pathway Designation, or ILAP, from the MHRA, which is a program that's designed to accelerate the review path of novel treatments. We believe this further reinforces the high, unmet medical need for patients with Rett syndrome. As a reminder, TSHA-102 has already received Fast Track designation and Orphan Drug and Rare Pediatric Disease designations from the FDA and has been granted Orphan Drug designation from the European Commission for the treatment of Rett syndrome. Lastly, we are pleased to share that we have strengthened our clinical and regulatory leadership with the promotion of Dr. Meredith Schultz to Chief Medical Officer and Rumana Haque-Ahmed to Chief Regulatory Officer. Dr. Schultz and Ms. Haque-Ahmed will continue to report to Suku.

Sue Gantry: In the U S into the U K.

Sue Gantry: And we're currently focused on site initiation site initiation activities. Additionally.

Sue Gantry: Additionally, we are pleased to share that tissue 102 received innovative licensing and access pathway designation or I lap from the M. H R E, which is a program that's designed to accelerate the review path of novel treatments. We believe this further reinforces the high unmet medical need for.

We believe this further reinforces the high, unmet medical need for patients with Rett syndrome. As a reminder, TSHA-102 has already received Fast Track designation and Orphan Drug and Rare Pediatric Disease designations from the FDA and has been granted Orphan Drug designation from the European Commission for the treatment of Rett syndrome. Lastly, we are pleased to share that we have strengthened our clinical and regulatory leadership with the promotion of Dr. Meredith Schultz to Chief Medical Officer and Rumana Haque-Ahmed to Chief Regulatory Officer. Dr. Schultz and Ms. Haque-Ahmed will continue to report to Suku.

Sue Gantry: With Ret syndrome as.

Sue Gantry: As a reminder, Tisha 102 has already received fast track designation and orphan drug and rare pediatric disease designations from the FDA and has been granted orphan drug designation.

Sue Gantry: Some of the European Commission for the treatment of Ret syndrome.

Sue Gantry: Lastly, we are pleased to share that we have strengthened our clinical and regulatory leadership with the promotion of Dr. Meredith Schultz, the Chief Medical Officer and Romana.

Sue Gantry: Ahmed two chief regulatory Officer Doctor Shoals Mishap, I'm, Ed will continue to report to Sue good.

Sean P. Nolan: Dr. Schultz is a board-certified licensed pediatric neurologist who is experienced in treating patients with Rett syndrome. Dr. Schultz brings more than 17 years of clinical experience and has led numerous gene therapy clinical trials for rare diseases in her career. As Chief Medical Officer, Dr. Schultz will lead the company's clinical development, clinical operations, medical affairs and safety activities. Rumana Haque-Ahmed brings nearly 30 years of experience in global regulatory strategy and product development in multiple therapeutic areas. She has been instrumental in the development and execution of our regulatory strategies for TSHA-102, including obtaining IND and CTA clearances across three countries. And she's led the regulatory interactions across Taysha's gene therapy portfolio. She will continue to lead the company's Regulatory Affairs Department and regulatory interactions.

Dr. Schultz is a board-certified licensed pediatric neurologist who is experienced in treating patients with Rett syndrome. Dr. Schultz brings more than 17 years of clinical experience and has led numerous gene therapy clinical trials for rare diseases in her career. As Chief Medical Officer, Dr. Schultz will lead the company's clinical development, clinical operations, medical affairs and safety activities.

Sue Gantry: Doctor Shoals is a board certified licensed pediatric neurologists, who has experience in treating patients with ret syndrome.

Sue Gantry: Dr. Shultz brings more than 17 years of clinical experience and has led numerous gene therapy clinical trials for rare diseases and her career.

Dr. Schulz: As Chief Medical Officer, Dr. Schulz will lead the company's clinical development clinical operations Medical affairs and safety activities.

Sean P. Nolan: Ramana Hakkamed brings nearly 30 years of experience in global regulatory strategy and product development in multiple therapeutic areas. She has been instrumental in the development and execution of our regulatory strategies for Taysha 102, including obtaining IND and CTA clearances across three countries. And she's led the regulatory interactions across Taysha's gene therapy portfolio. She will continue to lead the company's Regulatory Affairs Department and regulatory interactions.

Rumana Haque-Ahmed brings nearly 30 years of experience in global regulatory strategy and product development in multiple therapeutic areas. She has been instrumental in the development and execution of our regulatory strategies for TSHA-102, including obtaining IND and CTA clearances across three countries. And she's led the regulatory interactions across Taysha's gene therapy portfolio. She will continue to lead the company's Regulatory Affairs Department and regulatory interactions.

Dr. Schulz: Romano HOKA med brings nearly 30 years of experience in global regulatory strategy and product development in multiple therapeutic areas. She has been instrumental in the development and execution of our regulatory strategies for tissue 102, including obtaining I N D and C T a clearances across three countries.

Dr. Schulz: And she's led the regulatory interactions across patients gene therapy portfolio, you will continue to lead the company's regulatory affairs department and regulatory interactions.

Sukumar Nagendran: Dr. Schultz and Ms. Haque-Ahmed have been instrumental to the clinical development of our TSHA-102 program and we look forward to continuing to partner with them in their new leadership positions. With a significant focus on execution in the year ahead, we believe our team is well-positioned to continue to accelerate the development of TSHA-102. As you can see, we have made exciting progress across our TSHA-102 program over the past year. The sustained and new improvements in both adult patients with advanced Stage 4 syndrome, coupled with the initial six-week clinical data from the first pediatric patient that was reviewed by the IDMC, support the therapeutic potential of TSHA-102 for a broad population of patients with Rett syndrome. Looking ahead, we are focused on generating clinical data across a broad range of ages and stages of patients with Rett syndrome in multiple geographies, with multiple value inflection catalysts anticipated in 2024. We look forward to further evaluating the therapeutic potential of TSHA-102 for patients and families living with Rett syndrome. I will now turn the call over to Suku to provide more in-depth discussion on our clinical program in Rett syndrome. Suku?

Dr. Schultz and Ms. Haque-Ahmed have been instrumental to the clinical development of our TSHA-102 program and we look forward to continuing to partner with them in their new leadership positions. With a significant focus on execution in the year ahead, we believe our team is well-positioned to continue to accelerate the development of TSHA-102. As you can see, we have made exciting progress across our TSHA-102 program over the past year. The sustained and new improvements in both adult patients with advanced Stage 4 syndrome, coupled with the initial six-week clinical data from the first pediatric patient that was reviewed by the IDMC, support the therapeutic potential of TSHA-102 for a broad population of patients with Rett syndrome. Looking ahead, we are focused on generating clinical data across a broad range of ages and stages of patients with Rett syndrome in multiple geographies, with multiple value inflection catalysts anticipated in 2024. We look forward to further evaluating the therapeutic potential of TSHA-102 for patients and families living with Rett syndrome.

Dr. Schulz: Schultz Masako Med <unk>.

Dr. Schulz: Have been instrumental to the clinical development of our tissue 102 program and we look forward to continuing to partner with them in their new leadership positions with a significant focus on execution in the year ahead. We believe our team is well positioned to continue to accelerate the development of Tisha 102.

Dr. Schulz: As you can see we have made exciting progress across our tissue 102 program over the past year the sustained a new improvements in both adult patients with advanced stage for syndrome, coupled with the initial six week clinical data from the first pediatric patient that was reviewed by the I D. M. C support the therapeutic potential of tissue went out.

The sustained and new improvements in both adult patients with advanced Stage 4 syndrome, coupled with the initial six-week clinical data from the first pediatric patient that was reviewed by the IDMC, support the therapeutic potential of TSHA-102 for a broad population of patients with Rett syndrome. Looking ahead, we are focused on generating clinical data across a broad range of ages and stages of patients with Rett syndrome in multiple geographies, with multiple value inflection catalysts anticipated in 2024. We look forward to further evaluating the therapeutic potential of TSHA-102 for patients and families living with Rett syndrome.

Dr. Schulz: Two for a broad population of patients with Ret syndrome. Looking ahead, we are focused on generating clinical data across a broad range of ages and stages of patients with ret syndrome in multiple geographies with multiple value inflection catalysts anticipated in 2024.

Dr. Schulz: We look forward to further evaluating the therapeutic potential of tissue 102 for patients and families living with Ret syndrome.

I will now turn the call over to Suku to provide more in-depth discussion on our clinical program in Rett syndrome. Suku?

Dr. Schulz: I'll turn the call over to Sue to provide more in depth discussion on our clinical program and Ret syndrome Sukru. Thank you, Sean and good afternoon, everyone. I'm pleased to provide an update on that day, so why not to a gene therapy program in clinical evaluation for the treatment of <unk> syndrome.

Suku?

Sukumar Nagendran: Thank you, Sean and good afternoon, everyone. I'm pleased to provide an update on our TSHA-102 gene therapy program in clinical evaluation for the treatment of Rett syndrome. Rett syndrome is a rare, neurodevelopmental disorder 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. This disorder is characterized by loss of communication and hand function, slowing and regression of development, more time respiratory impairment, seizures, intellectual disabilities and shortened life expectancy. Rett syndrome progression is divided into four key stages, beginning with early onset stagnation at 6 to 18 months of age, followed by rapid regression, plateau and late motor deterioration. The X-chromosomal inactivation and silencing of MECP2 expression that occurs randomly with Rett syndrome results in a mixture of cells that are either deficient in or express MECP2 normally.

Sukumar Nagendran: Thank you, Sean and good afternoon, everyone.

I'm pleased to provide an update on our TSHA-102 gene therapy program in clinical evaluation for the treatment of Rett syndrome. Rett syndrome is a rare, neurodevelopmental disorder 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. This disorder is characterized by loss of communication and hand function, slowing and regression of development, motor and respiratory impairment, seizures, intellectual disabilities and shortened life expectancy.

Sue Gantry: <unk> syndrome is a rare neurodevelopmental disorder caused by mutations in the excellent M. A C. P. Two gene encoding metals CPG binding protein Tau in Mississippi to protein, which is essential for regulating neuronal dysfunction in the brain.

Sue Gantry: Disorder characterized by loss of communication and hand function slowing and regression of development more than respiratory impairment seizures intellectual disabilities, and shorten life expectancy.

Rett syndrome progression is divided into four key stages, beginning with early onset stagnation at 6 to 18 months of age, followed by rapid regression, plateau and late motor deterioration. The X-chromosomal inactivation and silencing of MECP2 expression that occurs randomly with Rett syndrome, results in a mixture of cells that are either deficient in or express MECP2 normally. This heterogeneity in MECP2 expression is what makes Rett syndrome challenging with traditional small molecule and simple gene therapy approaches. But we believe our construct equipped with the novel miRNA-Responsive Auto-Regulatory Element, or miRARE, can appropriately address this challenge and provide therapeutic benefit. As a reminder, TSHA-102 is a self-complementary, intrathecally-delivered AAV9 gene transfer therapy designed as a one-time treatment. Because of the risk associated with both under and overexpression of MECP2, we have combined high throughput microRNA profiling and genome mining to create miRARE, a novel mRNA target panel designed to mediate MECP2 expression in the central nervous system on a cell-by-cell basis. With miRARE, endogenous microRNA which activated in the presence of MECP2, are thought to base pair with targets in the viral genome encoded miRNA and ultimately decrease protein expression levels through RNA interference.

Sue Gantry: <unk> syndrome progression is divided into four key stages, beginning with early onset stagnation at six to 18 months of age followed by rapid regression battle in late motor deterioration.

Sue Gantry: The X chromosome and activation and silencing <unk> two expression that occurs randomly with <unk> syndrome, resulting a mixed set of cells that hide the depths shouldn't in well express MHC, if we do normally.

Sukumar Nagendran: This heterogeneity in MECP2 expression is what makes Rett syndrome challenging with traditional small molecule and simple gene therapy approaches. But we believe our construct equipped with the novel miRNA responsive autoregulatory element, or miRAR, can appropriately address this challenge and provide therapeutic benefit. As a reminder, TSHA-102 is a self-complementary intrathecally-delivered AV9 gene transfer therapy designed as a one-time treatment. Because of the risk associated with both under and over expression of MECP2, we have combined high throughput microRNA profiling and genome mining to create MIReA, a novel mRNA target panel designed to mediate MECP2 expression in the central nervous system on With miRAR, endogenous microRNAs, which are activated in the presence of MECP2, are thought to base pair with targets in the viral genome encoded mRNA and ultimately decrease protein expression levels through RNA interference.

Sue Gantry: This heterogeneity in Mississippi to expression is walk mixed ret syndrome challenging with traditional small molecule <unk> simple gene therapy approaches, but we believe our construct equipped with the Navajo and my out any other sponsors regulatory element and morale.

But we believe our construct equipped with the novel miRNA-Responsive Auto-Regulatory Element, or miRARE, can appropriately address this challenge and provide therapeutic benefit. As a reminder, TSHA-102 is a self-complementary, intrathecally-delivered AAV9 gene transfer therapy designed as a one-time treatment. Because of the risk associated with both under and overexpression of MECP2, we have combined high throughput microRNA profiling and genome mining to create miRARE, a novel mRNA target panel designed to mediate MECP2 expression in the central nervous system on a cell-by-cell basis. With miRARE, endogenous microRNA which activated in the presence of MECP2, are thought to base pair with targets in the viral genome encoded miRNA and ultimately decrease protein expression levels through RNA interference.

But we believe our construct equipped with the novel miRNA-Responsive Auto-Regulatory Element, or miRARE, can appropriately address this challenge and provide therapeutic benefit. As a reminder, TSHA-102 is a self-complementary, intrathecally-delivered AAV9 gene transfer therapy designed as a one-time treatment. Because of the risk associated with both under and overexpression of MECP2, we have combined high throughput microRNA profiling and genome mining to create miRARE, a novel miRNA target panel designed to mediate MECP2 expression in the central nervous system on a cell-by-cell basis.

Sue Gantry: Appropriately address this challenge and provide therapeutic benefit.

Sue Gantry: As a reminder, teach out one or two is a self complementary traditionally delivered AAV nine gene transfer therapy designed as a one time treatment.

Sue Gantry: Because of the risk associated with book and then all that especially on Mississippi do we have combined high throughput.

Sue Gantry: Micro RNA profiling and genome mining to create them either at Nava.

Sue Gantry: And then Todd panel designed to mediate any C. P to expression in the central nervous system on a cell by cell basis.

With miRARE, endogenous microRNA which activated in the presence of MECP2, are thought to base pair with targets in the viral genome encoded miRNA and ultimately decrease protein expression levels through RNA interference. Thus, TSHA-102 is expected to provide the necessary function of the MECP2 protein in cells lacking MECP2 while protecting against toxic overexpression of MECP2 in healthy cells. By increasing MECP2 levels in MECP2-deficient cells and maintaining healthy levels of MECP2 output in normal cells, TSHA-102 has demonstrated the ability to produce and maintain safe transgene expression in the CNS in pre-clinical models. As Sean mentioned, TSHA-102 is currently being investigated in the ongoing REVEAL Phase 1/2 Adolescent and Adult Trial. The trial, which was designed primarily as a safety study, is also measuring pre-specified efficacy measures. All efficacy data being collected in this Phase 1, Phase 2 trial is hypothesis-generating. As we continue to generate long-term data across more patients and cohorts this year, these data across measures will further inform our thinking relative to optimal primary endpoint selection for registrational study purposes.

Sue Gantry: With that my rare endogenous micro RNA, which activated in the presence of NBC Bedew I'll talk a baseband with deposits and the viral genome and quota and Melanie and ultimately decrease protein expression levels through RNA interference.

Sukumar Nagendran: Thus Taysha-102 is expected to provide the necessary function of the MECP2 protein in cells lacking MECP2 while protecting against toxic overexpression of MECP2 in healthy cells. By increasing MECP2 levels in MECP2 deficient cells and maintaining healthy levels of MECP2 output in normal cells, Taysha-102 has demonstrated the ability to produce and maintain safe transgene expression in the CNS in preclinical models. As Sean mentioned, Taysha 102 is currently being investigated in the ongoing REVEAL Phase I-II Adolescent and Adult Trial. The trial, which was designed primarily as a safety study, is also measuring pre-specified efficacy measures. All efficacy data being collected in this phase one, phase two trial is hypothesis-generating. As we continue to generate long-term data across more patients and cohorts this year, these data across measures will further inform our thinking relative to optimal primary and point selection for registrational study purposes.

Sue Gantry: <unk> two is expected to provide the necessary functions of the MCP to protein in cells lacking in Mississippi to while protecting against toxic overexpression of <unk> in healthy cells.

Sue Gantry: The increase in <unk>, Mississippi, two levels and in Mississippi to division sales and maintaining healthy levels of MCP to output in normal cells. They shall not demonstrated the ability to produce and maintain safe transgene expression in the CNS in preclinical models.

As Sean mentioned, TSHA-102 is currently being investigated in the ongoing REVEAL Phase 1/2 Adolescent and Adult Trial. The trial, which was designed primarily as a safety study, is also measuring pre-specified efficacy measures. All efficacy data being collected in this Phase 1, Phase 2 trial is hypothesis-generating. As we continue to generate long-term data across more patients and cohorts this year, these data across measures will further inform our thinking relative to optimal primary endpoint selection for registrational study purposes.

Sue Gantry: As Sean mentioned dish out one or two is currently being investigated in the ongoing reveal phase one two adolescent and adult trial. The trial, which was designed primarily as a safety study is also Michigan pre specified efficacy measures.

Sue Gantry: All of that because the data being collected in this phase one phase two trial this hypothesis generating.

Sue Gantry: As we continue to generate long term data across all patients in cohorts this year.

Sue Gantry: This data cost measures will further inform our thinking relative to optimize the primary endpoint selection for a registrational study purposes.

Sukumar Nagendran: Today, we are pleased to share long-term data from the two adult patients treated with TSHA-102. I will be discussing data from two different time points for each patient. Efficacy assessments were captured at month 6 for Patient 1 and week 12 for Patient 2. Safety data and clinical observations from the principal investigator were captured at week 35 for Patient 1, following completion of a steroid taper and week 19 for Patient 2 at decreased steroid levels compared to earlier post-treatment assessments. All these data have been reviewed by the Independent Data Monitoring Committee.

Sue Gantry: Today, we are pleased to share the long term data from the two adult patients treated with one or two I will be discussing data from two different time points for each patient.

Sue Gantry: Does he assessments were captured at month six location to one and week 12 locations too.

Sue Gantry: Safety data and clinical observations from the principal the principal investigator well captured at week 35 locations. One following completion of a city like Tampa and weak 19th location to a decreased steroid levels compared to earlier post treatment assessment.

Sue Gantry: All of these data have been reviewed by the independent data monitoring Committee.

Sukumar Nagendran: We will begin with an overview of the baseline status of the two patients prior to treatment with TSHA-102. As a reminder, the two adult patients who have been treated with the low dose of TSHA-102, differ in the severity of their disease. Both patients have been diagnosed with Stage 4 Rett syndrome, the late motor deterioration stage, which is the most advanced stage of the disease. However, the patients possess different genetic backgrounds and mutation types in the MECP2 gene, which manifests in dramatically different phenotypes and clinical severity. Studies have confirmed that MECP2 mutation types can be a reliable predictor of Rett syndrome disease severity, with more severe mutations correlating to greater motor dysfunction, loss of ambulation and higher prevalence of scoliosis. Patient 1, a 20-year-old female, has a large deletion with her MECP2 gene that manifests as a highly severe phenotype.

We will begin with an overview of the baseline status of the two patients prior to treatment with TSHA-102. As a reminder, the two adult patients who have been treated with the low dose of TSHA-102, differ in the severity of their disease. Both patients have been diagnosed with Stage 4 Rett syndrome, the late motor deterioration stage, which is the most advanced stage of the disease. However, the patients possess different genetic backgrounds and mutation types in the MECP2 gene, which manifests in dramatically different phenotypes and clinical severity.

We will begin with an overview of the baseline status of the two patients prior to treatment with <unk> 102.

Sue Gantry: Minder, the two adult patients who have been treated with a low dose of <unk>, one or two before in the severity of their disease, what patients have been diagnosed with stage four red syndrome, the lift motor deterioration stage, which is the most advanced stage of the disease. However, the patients possess different.

Sue Gantry: <unk> backgrounds, and mutation types, Indiana, and Mississippi to gene, which manifest in dramatically different phenotypes and clinical separately.

Sue Gantry: These have confirmed that it meets the ability of mutation types can be reliable can be reliable predictable syndrome disease stability with more severe mutations correlating to greater motor dysfunction loss of ambulation and higher prevailing subsequent doses.

Studies have confirmed that MECP2 mutation types can be a reliable predictor of Rett syndrome disease severity, with more severe mutations correlating to greater motor dysfunction, loss of ambulation and higher prevalence of scoliosis. Patient 1, a 20-year-old female, has a large deletion with her MECP2 gene that manifests as a highly severe phenotype. This patient's severity is evident by her clinical presentation at baseline. Prior to treatment, she was in a constant state of hypertonia, with complete loss of ambulation and was wheelchair-bound. She had lost the ability to sit or stand by eight years of age, as documented in the patient's medical history. She also became non-verbal at this time. Additionally, the patient had limited body movement, requiring 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. She experienced frequent apnea and hyperventilation episodes and had a history of seizures. The patient's level of severity is reflected in our baseline scores across efficacy measures, including Clinical Global Impression Severity, or CGIS, which is a 7-point scale anchored to signs and symptoms of Rett syndrome that rates the severity of the patient's illness relative to the clinician's experience with participants who have the same diagnosis. At baseline, the patient's CGIS score was 6, indicating severely ill. In contrast, the second patient, a 21-year-old female, has a missense mutation in her MECP2 gene that manifests in a milder phenotype. The patient presented with a milder form of disease, which is reflected in her clinical presentation at baseline. Prior to treatment, she had only partial loss of ambulation and could walk with prompting but she experienced progressive kyphosis and bradykinesia that developed in her late teens, impacting her gait and balance, as documented in the patient's medical history. Hand stereotypies appeared at 3 years of age following regression and she mostly held her hands firmly together. She also became non-verbal at this time. Her ability to reach and grasp objects was weak. Additionally, the patient experienced frequent hyperventilation episodes and had a history of frequent seizures. A level of severity is reflected in the baseline scores across efficacy measures. Her baseline CGIS score was 4, indicating moderately ill.

Question, one a 20 year old female has a large deletion with Mississippi, two gene that manifest as a highly severe phenotype. This patient seven it is evidenced by his clinical presentation at this time.

Sue Gantry: The treatment she loves it.

Sue Gantry: Constant state of Hypotonia and complete loss of Ambulation and most wheelchair bound she had lost the ability to sit or stand by a T O somebody age as documented in the patient's medical history. She also became nonverbal at this time.

Sukumar Nagendran: This patient's severity is evident by her clinical presentation at base. Prior to treatment, she was in a constant state of hypertonia with complete loss of angulation and was wheelchair-bound. She had lost the ability to sit or stand by eight years of age, as documented in the patient's medical history. She also became nonverbal at this time. Additionally, the patient had limited body movement, requiring 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.

She had lost the ability to sit or stand by 8 years of age, as documented in the patient's medical history. She also became non-verbal at this time. Additionally, the patient had limited body movement, requiring 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. She experienced frequent apnea and hyperventilation episodes and had a history of seizures. The patient's level of severity is reflected in her baseline scores across efficacy measures, including Clinical Global Impression Severity, or CGIS, which is a 7-point scale anchored to signs and symptoms of Rett syndrome that rates the severity of the patient's illness relative to the clinician's experience with participants who have the same diagnosis. At baseline, the patient's CGIS score was 6, indicating severely ill. In contrast, the second patient, a 21-year-old female, has a missense mutation in her MECP2 gene that manifests in a milder phenotype. The patient presented with a milder form of disease, which is reflected in her clinical presentation at baseline. Prior to treatment, she had only partial loss of ambulation and could walk with prompting but she experienced progressive kyphosis and bradykinesia that developed in her late teens, impacting her gait and balance, as documented in the patient's medical history. Hand stereotypies appeared at 3 years of age following regression and she mostly held her hands firmly together. She also became non-verbal at this time. Her ability to reach and grasp objects was weak. Additionally, the patient experienced frequent hyperventilation episodes and had a history of frequent seizures. A level of severity is reflected in the baseline scores across efficacy measures. Her baseline CGIS score was 4, indicating moderately ill.

Sue Gantry: And then the patient had limited body movement, requiring constant back support.

Sue Gantry: Last final gross motor function early in childhood she.

She had very little hand function with essentially no function of non dominant.

Sue Gantry: She experienced frequent apnea and hyperventilation episodes and had a history of seizures.

Sue Gantry: Okay.

Sue Gantry: The patients level of severity is reflected in our baseline scores across the efficacy measures, including clinical global impression of severity of CGI S, which is a seven point scale and cut the signs and symptoms of <unk> syndrome that read the severity of the patients relative to the clinicians experience with participants.

Sukumar Nagendran: She experienced frequent apnea and hyperventilation episodes and had a history of seizures. The patient's level of severity was reflected in a baseline score across efficacy measures, including clinical global impression severity, or CGIS, which is a seven-point scale anchored to signs and symptoms of Brett syndrome that rates the severity of the patient's illness relative to the clinician's experience with participants who have the same diagnosis. At baseline, the patient's EGS score was 6, indicating that she was severely ill. In contrast, the second patient, a 21-year-old female, has a mysense mutation in her MECP2 gene that manifests in a milder phenotype. A patient presented with a milder form of disease, which was reflected in her clinical presentation at baseline. Prior to treatment, she had only partial loss of emulation and could walk with prompting, but she experienced progressive kyphosis and bradykinesia that developed in her late teens, impacting her gait and balance, as documented in the patient's medical history. Hand stereotypes appeared at three years of age following regression, and she mostly held her hands firmly together. She also became nonverbal at this time. Her ability to reach and grasp objects was weak.

The patient's level of severity is reflected in her baseline scores across efficacy measures, including Clinical Global Impression Severity, or CGIS, which is a 7-point scale anchored to signs and symptoms of Rett syndrome that rates the severity of the patient's illness relative to the clinician's experience with participants who have the same diagnosis. At baseline, the patient's CGIS score was 6, indicating severely ill. In contrast, the second patient, a 21-year-old female, has a missense mutation in her MECP2 gene that manifests in a milder phenotype. The patient presented with a milder form of disease, which is reflected in her clinical presentation at baseline. Prior to treatment, she had only partial loss of ambulation and could walk with prompting but she experienced progressive kyphosis and bradykinesia that developed in her late teens, impacting her gait and balance, as documented in the patient's medical history. Hand stereotypies appeared at 3 years of age following regression and she mostly held her hands firmly together. She also became non-verbal at this time. Her ability to reach and grasp objects was weak. Additionally, the patient experienced frequent hyperventilation episodes and had a history of frequent seizures. A level of severity is reflected in the baseline scores across efficacy measures. Her baseline CGIS score was 4, indicating moderately ill.

The patient's level of severity is reflected in her baseline scores 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 the 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.

Sue Gantry: We will have the same diagnosis at baseline patients suggest call was fix indicating severely ill.

Sue Gantry: In contrast, the set.

Sue Gantry: On page 21 year old female has a license mutation in her in Mississippi to gene Manny.

Sue Gantry: Manifesting a milder phenotype.

Sue Gantry: The patient presented with a milder form of disease, which is reflected in the clinical presentation at baseline prior to treatment. She had only a partial loss of ambulation and could work with prompting but she experienced progressive kyphosis as bradykinesia theyre developing her late teens impacting her gait and balance.

In contrast, the second patient, a 21-year-old female, has a missense mutation in her MECP2 gene that manifests in a milder phenotype. The patient presented with a milder form of disease, which is reflected in her clinical presentation at baseline. Prior to treatment, she had only partial loss of ambulation and could walk with prompting but she experienced progressive kyphosis and bradykinesia that developed in her late teens, impacting her gait and balance, as documented in the patient's medical history. Hand stereotypies appeared at 3 years of age following regression and she mostly held her hands firmly together. She also became non-verbal at this time. Her ability to reach and grasp objects was weak. Additionally, the patient experienced frequent hyperventilation episodes and had a history of frequent seizures. A level of severity is reflected in the baseline scores across efficacy measures. Her baseline CGIS score was 4, indicating moderately ill.

Sue Gantry: As documented in the patient's medical history.

Sue Gantry: And still you have to piece appeared at three years of age following regression and she mostly held our hands firmly together.

Sue Gantry: She also became run bubble at this time I.

Sue Gantry: <unk> ability to reach and grasp objects once a week and it's usually the patient experienced frequent hyperventilation episodes and had a history of frequent seizure.

Hand stereotypies appeared at 3 years of age following regression and she mostly held her hands firmly together. She also became non-verbal at this time. Her ability to reach and grasp objects was weak. Additionally, the patient experienced frequent hyperventilation episodes and had a history of frequent seizures. A level of severity is reflected in the baseline scores across efficacy measures. Her baseline CGI-S score was 4, indicating moderately ill.

Sue Gantry: Our level of severity in the baseline scores across efficacy measures.

Sukumar Nagendran: Additionally, the patient experienced frequent hyperventilation episodes and had a history of frequent seizures. A level of severity, a baseline score across efficacy measures, is reflected in the baseline scores across efficacy measures. For example, her baseline CGI score was 4, indicating moderately.

Sue Gantry: It's affecting their baseline scores across efficacy measures.

Sue Gantry: Baseline CGI S school by school, indicating moderately deal.

Sue Gantry: The key takeaway is that they allow phenotypic differences between the two stage four patients which are correlated to their genetic status.

Sue Gantry: We saw a consistent pattern of improvement across key clinical domains and efficacy measures as early as four weeks post treatment with a low dose a patient one more tool in both adult patients. Despite the differences in the identity et cetera, So Saturday actually.

Sukumar Nagendran: The key takeaway is that there are phenotypic differences between the two Stage 4 patients, which are correlated to their genetic status. We saw consistent pattern of improvement across key clinical domains and efficacy measures as early as four weeks post-treatment with the low dose of TSHA-102 in both adult patients, despite the differences in their genetic status or severity. As Sean mentioned, we are pleased to share long-term data showing that both patients are having a durable response. Specifically, both patients sustained improvements and demonstrated new improvements compared to the initial post-treatment assessment, based on efficacy assessments and observations from the principal investigators. Based on clinical observations from the principal investigator, both patients showed sustained and new improvements across multiple clinical domains impacting activities of daily living, including autonomic function, seizure, socialization, and communication, and motor skills following treatment with a low dose of Taysha 102. Let's begin with an overview of the long-term clinical observations for patient one. Per the protocol, prophylactic immunosuppressant therapy began prior to Taysha 102 administration.

The key takeaway is that there are phenotypic differences between the two Stage 4 patients, which are correlated to their genetic status. We saw consistent pattern of improvement across key clinical domains and efficacy measures as early as four weeks post-treatment with the low dose of TSHA-102 in both adult patients, despite the differences in their genetic status or severity. As Sean mentioned, we are pleased to share long-term data showing that both patients are having a durable response.

Sue Gantry: Sean mentioned, we are pleased to share long term data showing that both patients are having a durable response, specifically both patient sustained improvement and demonstrated new improvements compared to the initial post treatment assessment.

Sue Gantry: Based on the efficacy assessments and observations from the principal investigator.

Sue Gantry: Based on clinical observations from the principal investigator both patients showed sustained a new improvements across multiple clinical domains impacting activities of daily living including economic function.

Specifically, both patients sustained improvements and demonstrated new improvements compared to the initial post-treatment assessment, based on efficacy assessments and observations from the principal investigator. Based on clinical observations from the principal investigator, both patients showed sustained and new improvements across multiple clinical domains, impacting activities of daily living including autonomic function, seizure, socialization and communication and motor skills following treatment with a low dose of TSHA-102. Let's begin with an overview of the long-term clinical observations for patient one. Per the protocol, prophylactic immunosuppressant therapy began prior to Taysha 102 administration.

Sue Gantry: Seizures, socialization and communication and motor skills following treatment with a low dose of <unk>, one or two.

Speaker Change: Let's begin with an overview.

Speaker Change: The long term clinical observations locations one.

Speaker Change: Further protocol prophylactic Immunosuppressant therapy begin I'll began prior to <unk> I wonder if the administration.

Speaker Change: First patient steroid taper was initiated at <unk> 17, and completed at week 30 Threep.

Let's begin with an overview of the long-term clinical observations for Patient 1. Per the protocol, prophylactic immunosuppressant therapy began prior to TSHA-102 administration. The first patient's steroid taper was initiated at week 17 and completed at week 33. At 35-week post-treatment assessment, the principal investigator observed that the patient's improvements across multiple clinical domains had been maintained following completion of the steroid taper, as well as the new improvements that were observed compared to earlier post-treatment assessments. Specifically, 35 weeks following treatment, the first patient demonstrated sustained improvements from initial 4 and 6-week assessments in multiple clinical domains after the completion of the steroid care by including motor improvement. At the patient's initial 6-week assessment, she had gained the ability to sit unassisted for the first time in over a decade and had restored movements in her legs. At week 35, following the completion of the patient's steroid taper, these improvements of sitting unassisted and restored movement in her legs had been maintained, as documented by video evidence.

Speaker Change: 35 week course treatment assessment, the principal investigators observed that the patients improvements across multiple clinical domains had been maintained following completion of the steroid taper as well as the new improvements that Bob Zev compared to earlier post treatment assessment.

Sukumar Nagendran: The first patient's steroid taper was initiated at week 17 and completed at week 33. At a 35-week post-treatment assessment, the principal investigator observed that the patient's improvements across multiple clinical domains had been maintained following completion of the steroid taper, as well as new improvements that were observed compared to earlier post-treatment assessments. Specifically, 35 weeks following treatment, the first patient demonstrated sustained improvements from initial four- and six-week assessments in multiple clinical domains after the completion of the steroid care, including motor improvement. At her initial six-week assessment, she had gained the ability to sit unassisted for the first time in over a decade and had restored movements in her legs. At week 35, following the completion of the patient's steroid taper, these improvements of sitting unassisted and restored movement in her legs had been maintained, as documented by video evidence.

Speaker Change: Specifically 35 weeks following treatment the first patient demonstrated sustained improvements probably initial four and six week assessments in multiple clinical domains. After the completion of the steroid taper, including motor improvement.

Speaker Change: The patient's initial six week assessment. She had gained the ability to sit unassisted for the first time in over a decade.

Specifically, 35 weeks following treatment, the first patient demonstrated sustained improvements from initial 4 and 6-week assessments in multiple clinical domains after the completion of the steroid care by including motor improvement. At the patient's initial 6-week assessment, she had gained the ability to sit unassisted for the first time in over a decade and had restored movements in her legs. At week 35, following the completion of the patient's steroid taper, these improvements of sitting unassisted and restored movement in her legs had been maintained, as documented by video evidence.

Speaker Change: Restored movements in their legs.

Speaker Change: Weaker refining following the completion of the patients steroid taper. These improvements are sitting unassisted and restored movement and Alex had been maintained as documented by video evidence.

Speaker Change: Further our patient sustained improvement in hand function at week 35, including again, the ability to grasp objects with a non dominant tan and transfer them to a dominant and 10 for the first time since infancy as documented by video evidence at least 35. She also showed a sustained improvement in her ability.

Speaker Change: To grasp with abdominal pain.

Speaker Change: Additionally, the patient demonstrated the ability to open a hand, the associates of fingers scratch her nose and touch screen following treatment.

Sukumar Nagendran: Further, the patient sustained improvement in hand function at week 35, including the gained ability to grasp objects with a non-dominant hand and transfer them to a dominant hand for the first time since infancy, as documented by video evidence. At week 35, she also showed a sustained improvement in her ability to grasp with her dominant hand. Additionally, the patient demonstrated the ability to open her hand, dissociate her fingers, scratch her nose and touch a screen following treatment. Progressive loss of hand function is a hallmark characteristic of Rett syndrome and a key concern for caregivers that impacts a patient's ability to communicate and impedes daily activities but, ultimately, limits independence.

Further, the patient sustained improvement in hand function at week 35, including the gained ability to grasp objects with a non-dominant hand and transfer them to a dominant hand for the first time since infancy, as documented by video evidence. At week 35, she also showed a sustained improvement in her ability to grasp with her dominant hand. Additionally, the patient demonstrated the ability to open her hand, dissociate her fingers, scratch her nose and touch a screen following treatment.

Speaker Change: Progressive loss of hand function is a hallmark characteristic of ret syndrome, and a key concern for caregivers.

Speaker Change: In fact, the patients ability to communicate and impedes daily activities.

Speaker Change: Domestic limits independence. These.

Speaker Change: This sustained improvement in hand function certified weeks following treatment, which are not observed in the natural history of Ret syndrome are very encouraging and support the potential of peso on her two to bring meaningful therapeutic benefit to patients and caregivers.

Speaker Change: The patient also demonstrated sustained improvements in economic function at week 35, with improved breathing patterns reduced billing dispute matters, including less petroleum spills.

Progressive loss of hand function is a hallmark characteristic of Rett syndrome and a key concern for caregivers that impacts a patient's ability to communicate and impedes daily activities but, ultimately, limits independence. These sustained improvements in hand function, 35 weeks following treatment -- which are not 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 patient also demonstrated sustained improvements in autonomic function at week 35 with improved breathing patterns, reduced breathing dysrhythmias, including less breath-holding spells and infrequent hyperventilation compared to before treatment. As a result, she experienced a sustained improvement in sleep quality and duration through week 35. Caregivers reported that following treatment, the patient slept through the night for the first time in 20 years. Therefore, she is much more alert during the day.

Speaker Change: Frequent hyperventilation compared to before treatment as a result, she experienced a sustained improvement in sleep quality and duration through week 35.

Sukumar Nagendran: These sustained improvements in hand function, 35 weeks following treatment, which are not observed in the natural history of Brett syndrome, are very encouraging and support the potential of Taysha 102 to bring meaningful therapeutic benefit to patients and caregivers. The patient also demonstrated sustained improvements in autonomic function at week 35 with improved breathing patterns, reduced breathing dysrhythmias, including less breath-holding spells and infrequent hyperventilation compared to before treatment. As a result, she experienced a sustained improvement in sleep quality and duration through week 35. Caregivers reported that following treatment, the patient slept through the night for the first time in 20 years. Therefore, she is much more alert during the day.

Speaker Change: Fabulous report or that following treatment.

Speaker Change: Patients sleep through the night for the first time in 20 years. Therefore, she is much more alert during the day.

Speaker Change: Additionally club perfusion of the extremities is a characteristic signing patients with ret syndrome that is talked to result from this autonomic, meaning it's controlled by the autonomic nervous system. Therefore, it's encouraging that the patient also showed a sustained improvement in circulation at week 35 post treatment with the patients' hands.

The patient also demonstrated sustained improvements in autonomic function at week 35 with improved breathing patterns, reduced breathing dysrhythmias, including less breath-holding spells and infrequent hyperventilation compared to before treatment. As a result, she experienced a sustained improvement in sleep quality and duration through week 35. Caregivers reported that following treatment, the patient sleeps through the night for the first time in 20 years. Therefore, she is much more alert during the day.

And feed restored to normal temperature and color that's before treatment of hands and feet, we used to call them blue based on the principal investigators clinical observations.

Speaker Change: At week 35 post treatment the principal investigators observed new improvements and socialization and communication since the patients initial six week assessment as.

Sukumar Nagendran: Additionally, poor perfusion of the extremities is a characteristic sign in patients with Rett syndrome that is thought to result from dysautonomia, meaning it's controlled by the autonomic nervous system. Therefore, it's encouraging that the patient also showed a sustained improvement in circulation at week 35 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. At week 35 post-treatment, the principal investigator observed new improvements in socialization and communication since the patient's initial 6-week assessment. As of the week 35 assessment, the patient was more alert and socially interactive, with increased communication of her needs using vocalization. Caregivers reported that she showed an enhanced ability to use an eye-driven communication device, which caregivers said she hadn't expressed interest in before treatment.

Additionally, poor perfusion of the extremities is a characteristic sign in patients with Rett syndrome that is thought to result from dysautonomia, meaning it's controlled by the autonomic nervous system. Therefore, it's encouraging that the patient also showed a sustained improvement in circulation at week 35 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.

Speaker Change: As up to week 35 assessment of patient was more I look and socially interactive with increased communication of our needs using localization.

Speaker Change: <unk> reported that she showed an enhanced ability.

Speaker Change: To use an idea one communication device, which gave US said she hadn't expressed interest in before treatment.

Speaker Change: Typically following treatment the patient was able to use the device much life should leave with gander ability to activate functions on the screen of the device.

At week 35 post-treatment, the principal investigator observed new improvements in socialization and communication since the patient's initial 6-week assessment. As of the week 35 assessment, the patient was more alert and socially interactive, with increased communication of her needs using vocalization. Caregivers reported that she showed an enhanced ability to use an eye-driven communication device, which caregivers said she hadn't expressed interest in before treatment. Specifically, following treatment, the patient was able to use the device much more efficiently with this gained ability to activate functions on the screen of the device.

Speaker Change: Difficult in communication, including loss of speech is one of the most prominent symptoms of <unk> syndrome, and is an area of key area of concern for caregivers directly interfere with the patient's ability to communicate their needs and express their interests.

These new improvements observed at week 35 post treatment are highly encouraging as alternative augmentative communication speech output technologies.

Speaker Change: My I guess.

Speaker Change: Can be leveraged by patients and families.

Speaker Change: <unk> syndrome, as a supplement to a replacement for an extra speeds.

Sukumar Nagendran: Specifically, following treatment, the patient was able to use the device much more efficiently with this gained ability to activate functions on the screen of the device. Difficulty in communication, including loss of speech, is one of the most prominent symptoms of Rett syndrome and is a key area of concern for caregivers as it directly interferes with the patient's ability to communicate their needs and express their interests. These new improvements observed at week 35 post-treatment are highly encouraging as alternative and augmentative communication speech output technologies activated by eye gaze can be leveraged by patients and families with Rett syndrome as a supplement to or replacement for natural speech. We believe that the ability to communicate could give patients a sense of control and greater independence.

Specifically, following treatment, the patient was able to use the device much more efficiently with this gained ability to activate functions on the screen of the device.

Speaker Change: We believe that the ability to communicate could give patients a sense of control and greater independence.

Difficulty in communication, including loss of speech, is one of the most prominent symptoms of Rett syndrome and is a key area of concern for caregivers as it directly interferes with the patient's ability to communicate their needs and express their interests. These new improvements observed at week 35 post-treatment are highly encouraging as alternative and augmentative communication speech output technologies activated by eye gaze can be leveraged by patients and families with Rett syndrome as a supplement to or replacement for natural speech. We believe that the ability to communicate could give patients a sense of control and greater independence. The principal investigator also observed that the patient's seizures have overall been well-controlled through week 35 following treatment at lower levels of anti-seizure medicines relative to baseline and that the patient no longer experiences unprovoked seizures. These observations are supported by data from the seizure diaries.

Speaker Change: Principal investigators also observed that the patient seizures.

Speaker Change: Overall, it's been well control.

Speaker Change: Following treatment had lower levels of Antiseizure medicines relative to baseline and that the patient no longer experiences unprovoked seizures.

Speaker Change: These observations are supported by data from the seizure diaries.

Speaker Change: Now, let's turn to the second adult patient.

Speaker Change: The 19 week post treatment assessment, the principal investigators observed that the patient improvement across multiple clinical demand had been maintained while the patient was on decreased steroid levels as well as new improvements that's all observed compared to our initial four and six week assessment.

We believe that the ability to communicate could give patients a sense of control and greater independence. The principal investigator also observed that the patient's seizures have overall been well-controlled through week 35 following treatment at lower levels of anti-seizure medicines relative to baseline and that the patient no longer experiences unprovoked seizures. These observations are supported by data from the seizure diaries.

Sukumar Nagendran: The principal investigator also observed that the patient's seizures have overall been well-controlled through week 35 following treatment at lower levels of anti-seizure medicines relative to baseline and that the patient no longer experiences unprovoked seizures. These observations are supported by data from the seizure diaries. Now, let's turn to the second adult patient. At the 19-week post-treatment assessment, the principal investigator observed that the patient's improvement across multiple clinical domains had been maintained while the patient was on decreased steroid levels, as well as new improvements that were observed compared to the initial 4 and 6-week assessments. Specifically, she sustained improvements in motor skills with a reduction in hand stereotypies -- which are repetitive, purposeless hand movements and the diagnostic hallmark of Rett syndrome. Before treatment, the patient mostly held her hands firmly together.

The principal investigator also observed that the patient's seizures have overall been well-controlled through week 35 following treatment at lower levels of anti-seizure medicines relative to baseline and that the patient no longer experiences unprovoked seizures. These observations are supported by data from the seizure diaries. Now, let's turn to the second adult patient. At the 19-week post-treatment assessment, the principal investigator observed that the patient's improvement across multiple clinical domains had been maintained while the patient was on decreased steroid levels, as well as new improvements that were observed compared to the initial 4 and 6-week assessments.

Speaker Change: Specific Alicia sustained improvements in motor skills.

Speaker Change: Enhanced easier to peers, which are repetitive purposeless and movements.

Speaker Change: And the diagnostic Hallmark Opex syndrome.

Speaker Change: For treatment of patients, mostly held our hands firmly.

Now, let's turn to the second adult patient. At the 19-week post-treatment assessment, the principal investigator observed that the patient's improvement across multiple clinical domains had been maintained while the patient was on decreased steroid levels, as well as new improvements that were observed compared to the initial 4 and 6-week assessments. Specifically, she sustained improvements in motor skills with a reduction in hand stereotypies -- which are repetitive, purposeless hand movements and the diagnostic hallmark of Rett syndrome.

Speaker Change: Together.

Speaker Change: So you have to piece had improved for the first time since regression at age three.

Speaker Change: The initial four six week assessment.

Speaker Change: Based on the principal investigators observations and supported by video evidence suppression displayed less forceful handling and that trends were more often open and relapsed through week 19.

Specifically, she sustained improvements in motor skills with a reduction in hand stereotypies -- which are repetitive, purposeless hand movements and the diagnostic hallmark of Rett syndrome. Before treatment, the patient mostly held her hands firmly together. Her hand stereotypies had improved for the first time since regression at age 3, at the initial 4, 6-week assessment. Based on the principal investigator's observations and supported by video evidence, the patient displayed less forceful handling and the hands were more often open and relaxed through week 19. The sustained improvement in hand stereotypies at week 19 post-treatment is encouraging and it provides new opportunities for fine motor skill learning.

Specifically, she sustained improvements in motor skills with a reduction in hand stereotypies -- which are repetitive, purposeless hand movements and the diagnostic hallmark of Rett syndrome.

Speaker Change: Sustained improvement enhanced easier to piece at week 19 post treatment.

Speaker Change: Currency and it provides new opportunities for fine motor skills learning.

Speaker Change: Ah patient also sustained improvements and socialization and communication through week 19, there's an increased interest in social communication and activities.

Before treatment, the patient mostly held her hands firmly together. Her hand stereotypies had improved for the first time since regression at age 3, at the initial 4, 6-week assessment. Based on the principal investigator's observations and supported by video evidence, the patient displayed less forceful handling and the hands were more often open and relaxed through week 19. The sustained improvement in hand stereotypies at week 19 post-treatment is encouraging and it provides new opportunities for fine motor skill learning.

Sukumar Nagendran: Her hand stereotypes had improved for the first time since regression at age three, at the initial four, six-week assessment. Based on the principal investigator's observations and supported by video evidence, the patient displayed less forceful handling, and the hands were more often open and relaxed through week 19. The sustained improvement in hand stereotypies at week 19 post-treatment is encouraging, and it provides new opportunities for fine motor skill learning.

Speaker Change: Including increased response to spoken word that eye contact she also sustained improvements in autonomic function at week 19.

Speaker Change: With improvements in breathing district news, including Hyperventilation and reduced ethnic spells. The patient also showed sustained improvement in circulation at week 19 post treatment with the patients hands and feet restoring normal temperature and color, whereas before treatment the patients' hands and feet for usually call them blue.

Sukumar Nagendran: The patient also sustained improvements in socialization and communication through week 19, with an increased interest in social communication and activities, including increased response to spoken words and eye contact. She also sustained improvements in autonomic function at week 19, with improvements in breathing dysrhythmias, including hyperventilation and reduced apneic spells. The patient also showed sustained improvements in circulation at week 19 post-treatment, with the patient's hands and feet restoring normal temperature and color; whereas before treatment, the patient's hands and feet were usually cold and blue, based on the principal investigator's observation.

Speaker Change: Based on the basic well invest a good observation.

Speaker Change: Notably the second patient demonstrated a pronounced improvement in seizure frequency at <unk>.

Speaker Change: <unk> 19 post treatment the significant reduction in seizures at low levels of anti seizure medicine relative to baseline. These.

Speaker Change: These observations are supported by data from the seizure diaries, which I will discuss in more detail later.

Speaker Change: Both patients also demonstrated sustained and new improvements across key efficacy measures following treatment with one or two which reinforces this clinical observations from the principal investigator.

Speaker Change: Let's begin with an update on the efficacy data we reported at the six month post treatment assessment from the patient so.

Sukumar Nagendran: Notably, the second patient demonstrated a pronounced improvement in seizure frequency at week 19 post-treatment, a significant reduction in seizures at lower levels of anti-seizure medicine relative to baseline. These observations are supported by data from the seizure diaries, which I will discuss in more detail later. Both patients also demonstrated sustained and new improvements across key efficacy measures following treatment with TSHA-102, which reinforces these clinical observations from the principal investigator. I will begin with an update on the efficacy data reported at the six-month post-treatment assessment from the first patient. The first patient sustained improvements across key efficacy measures at decreased steroid levels and showed improvements at six months post-treatment. Specifically, she showed sustained improvement from the initial four-week assessment in Clinical Global Impression Improvement, or CGI, Clinical Global Impression Severity, or CGI-S, and Torrential Global Impression Improvement, or PGII. The Syndrome Hand Function Scale, or RSHFS, the Revised Motor Behavior Assessment, or RMBA, and CSADAS.

Notably, the second patient demonstrated a pronounced improvement in seizure frequency at week 19 post-treatment, a significant reduction in seizures at lower levels of anti-seizure medicine relative to baseline. These observations are supported by data from the seizure diaries, which I will discuss in more detail later. Both patients also demonstrated sustained and new improvements across key efficacy measures following treatment with TSHA-102, which reinforces these clinical observations from the principal investigator.

Speaker Change: The first patient sustained improvement across key efficiency efficacy measure that decreased ceroid levels and showed improvement at six months post treatment specifically she has sustained improvement from the initial four week assessment and the clinical global impression improve little CGI I critical.

Speaker Change: Global impression Saturday D O C J S.

Speaker Change: Parenteral global impression of improvement of Pgi I, the ret syndrome hand function scale, all honest fast.

Speaker Change: Device motor behavior assessment.

Speaker Change: R M B and CS.

Speaker Change: C. G. I I is a clinician reported seven point assessment of overall improvement following treatment that could direct syndrome.

Let's begin with an update on the efficacy data reported at the 6-month post-treatment assessment from the first patient. The first patient sustained improvements across key efficacy measures at decreased steroid levels and showed improvements at 6 months post-treatment. Specifically, she has sustained improvement from the initial 4-week assessment in Clinical Global Impression Improvement, or CGI-I; Clinical Global Impression Severity, or CGI-S, Parental Global Impression Improvement, or PGI-I, the Rett Syndrome Hand Function Scale or RSHFS, the Revised Motor-Behavior Assessment or R-MBA and seizure diaries.

Speaker Change: Council key aspects of the disease to determine global in scope.

Speaker Change: 10 schools to indicating much improved loss reported that the six month assessment, which is consistent with the score imported at the full week assessment.

Speaker Change: Additionally, the patient demonstrated a sustained one point improvement from the baseline score six indicating severely ill close call it five indicating markedly.

Speaker Change: And CGI S at month, six which is consistent.

Speaker Change: The skull.

Speaker Change: Weak for Pgi I is a caregiver reported assessment of overall improvement following treatment that uses a seven point scale of sustained score two indicating much improved was reported at month six.

Sukumar Nagendran: CGI-I is a clinician-reported 7-point assessment of overall improvement following treatment, adapted to Rett syndrome that accounts for key aspects of the disease to determine a global change score. A sustained score of 2, indicating much improvement, was reported at the 6-month assessment which is consistent with the score reported at the 4-week assessment. Additionally, the patient demonstrated a sustained 1-point improvement from the baseline score of 6 indicating severely ill to a score of 5 indicating markedly ill in CGI-S at month six, which is consistent with the score at week 4. PGI-I is a caregiver-reported assessment of overall improvement following treatment that uses a 7-point scale. A sustained score of 2, indicating much improved, was reported at month 6. The RSHFS is a clinician-reported assessment of hand function in patients with Rett syndrome, which is evaluated by an experienced, independent physical therapist with expertise in the hand function of Rett patients, who codes the demonstrated hand function in each video at one of four levels, assessing the best score for large objects ranging from no active grasping of any object to independent. The highest score that can be achieved for this assessment is 4.

CGI-I is a clinician-reported 7-point assessment of overall improvement following treatment, adapted to Rett syndrome that accounts for key aspects of the disease to determine global change score. A sustained score of 2, indicating much improve, was reported at the 6-month assessment which is consistent with the score reported at the 4-week assessment. Additionally, the patient demonstrated a sustained 1-point improvement from the baseline score of 6, indicating severely ill to a score of 5, indicating markedly ill, in CGI-S at month 6 -- which is consistent with the score at week 4.

The RSA, so fast as a clinician reported assessment of and function in patients with Ret syndrome, which is evaluated by an experienced independent physical therapists with expertise in the hand function of renovations with Gordon, but demonstrate a hand function in each video.

Speaker Change: 104 levels assessing the best score for large objects ranging from no active gossiping of any object to independent grasping the highest score that can be achieved for this assessment is a for.

PGI-I is a caregiver-reported assessment of overall improvement following treatment that uses a 7-point scale. A sustained score of 2, indicating much improved, was reported at month 6. The RSHFS is a clinician-reported assessment of hand function in patients with Rett syndrome, which is evaluated by an experienced, independent physical therapist with expertise in the hand function of Rett patients, who codes then the demonstrated hand function in each video at one of four levels, assessing the best score for large objects ranging from no active grasping of any object to independent grasping. The highest score that can be achieved for this assessment is a 4.

Speaker Change: The first patient demonstrated a sustained improvement in Rs X F. S. At six months following treatment. Although there are no changes from the baseline score three indicating the ability to hold an object for at least two seconds in her dominant hand, she was able to increase the number of objects held from one or two.

Speaker Change: Additionally, she has gained some basic gossiping ability in our non dominant Anne and sustained this improvement at six months post treatment.

Speaker Change: At baseline she could not hold any objects in a non dominant pan and at six months of school of cool was demonstrated indicating the ability to hold an object, but these two seconds when sister to grass.

Sukumar Nagendran: The first patient demonstrated a sustained improvement in RSHFS at 6 months following treatment. Although, there are no changes from the baseline score of 3, indicating the ability to hold an object for at least two seconds in her dominant hand; she was able to increase the number of objects held from one to two. Additionally, she has gained some basic grasping ability in a non-dominant hand and sustained this improvement at 6 months post-treatment. At baseline, she could not hold any objects in her non-dominant hand and at 6 months, a score of 2 was demonstrated, indicating the ability to hold an object for at least two seconds when assisted to grasp. Again, it is very important to note that hand function improvements are rarely observed in the natural history of Rett syndrome. The R-MBA, which is a 24-question clinician-reported scale measuring disease behaviors of Rett syndrome, saw the total score improvement of 1 point from the baseline score of 43 to a score of 42 at month 6.

The first patient demonstrated a sustained improvement in RSHFS at 6 months following treatment. Although, there are no changes from the baseline score of 3, indicating the ability to hold an object for at least two seconds in her dominant hand; she was able to increase the number of objects held from one to two. Additionally, she has gained some basic grasping ability in a non-dominant hand and sustained this improvement at 6 months post-treatment. At baseline, she could not hold any objects in her non-dominant hand and at 6 months, a score of 2 was demonstrated, indicating the ability to hold an object for at least two seconds when assisted to grasp.

Speaker Change: Again, it is very important to note that hand function improvements are really observe in the natural history of Ret syndrome.

Speaker Change: The RMB, which is the 24 question clinician reported scale measuring disease behaviors of Ret syndrome.

Speaker Change: So the total score improvement of one point from the baseline score of 43 to a score of 42 at month six.

Speaker Change: <unk> observed in motor dysfunction in respiratory behaviors.

Speaker Change: Seizure diaries showed that the patient had stable seizure events at lower level of anti seizure medications relative to baseline to week 35 post treatment.

Sukumar Nagendran: And at 6 months, a score of 2 was demonstrated, indicating the ability to hold an object for at least two seconds when assisted to grasp. Again, it is very important to note that hand function improvements are rarely observed in the natural history of Rett syndrome. The RMBA, which is a 24-question clinician-reported scale measuring disease behaviors of Rett syndrome, saw the total score improvement of 1 point from the baseline score of 43 to a score of 42 at month 6.

Speaker Change: Based on caregiver reported medical history.

Speaker Change: For trade when the patient had two to four seizures per year as we stratify the patient seizures are confined to periods, where her anti seizure medication levels.

Again, it is very important to note that hand function improvements are rarely observed in the natural history of Rett syndrome. The R-MBA, which is a 24-question clinician-reported scale measuring disease behaviors of Rett syndrome, saw the total score improvement of 1 point from the baseline score of 43 to a score of 42 at month 6. Improvements were observed in motor dysfunction and respiratory behavior. Seizure diaries showed that the patient had stable seizure events at lower level of anti-seizure medication, relative to baseline through week 35 post-treatment based on caregiver-reported medical history. Before treatment, the patient had 2 to 4 seizures per year. As of week 35, the patient's seizures were confined to periods where her anti-seizure medication levels declined to below 50 micromoles per liter, whereas before treatment with TSHA-102, she required levels of 100 micromoles per liter or greater to control the seizures. Importantly, the first patient also showed new improvement in a 6-month assessment of the Rett Syndrome Behavior Questionnaire, RSBQ. The RSBQ, which is a 45-item caregiver-administered questionnaire that assesses Rett syndrome characteristics, The patient demonstrated a 30-point total score improvement from the baseline score of 52 to a score of 22 at month 6. The score was driven by improvements in hand behavior, breathing problems, general mood, repetitive face movements, nighttime behaviors, fear and anxiety, body rocking and facial expressions.

Speaker Change: Declined to below 50, micro most veleta, whereas before tradesman with tissue I wont go too she required levels of hunger and micro amongst the liter of greater control of our thesis.

Importantly, the first patient also shorten your improvement in a six month assessment in <unk> syndrome behaviour questionnaire RSV Q.

Sukumar Nagendran: Improvements were observed in motor dysfunction and respiratory behavior. Seizure diaries showed that the patient had stable seizure events at lower levels of anti-seizure medication relative to baseline through week 35 post-treatment. Based on caregiver-reported medical history, before treatment, the patient had 2 to 4 seizures per year. As of week 35, the patient's seizures were confined to periods where her anti-seizure medication levels declined to below 50 micromoles per liter, whereas before treatment with Taysha-102, she required levels of 100 micromoles per liter or greater to control her seizures. Importantly, the first patient also showed new improvement in a six-month assessment of the Rett Syndrome Behavior Questionnaire, RSBQ. The RSBQ, which is a 45-item caregiver-administered questionnaire that assesses Rett Syndrome characteristics,

Speaker Change: <unk>, which is a 45 item caregiver administered questionnaire that.

Speaker Change: Assessors read syndrome characteristics.

Speaker Change: Patients demonstrated a 30 point total score improvement from the baseline score 52 gross Gulf grades two at month six.

Speaker Change: <unk> was driven by improvements in hand behavior.

Speaker Change: Breathing problems.

Before treatment, the patient had 2 to 4 seizures per year. As of week 35, the patient's seizures were confined to periods where her anti-seizure medication levels declined to below 50 micromoles per liter, whereas before treatment with TSHA-102, she required levels of 100 micromoles per liter or greater to control the seizures. Importantly, the first patient also showed new improvement in a 6-month assessment of the Rett Syndrome Behavior Questionnaire, RSBQ. The RSBQ, which is a 45-item caregiver-administered questionnaire that assesses Rett syndrome characteristics, The patient demonstrated a 30-point total score improvement from the baseline score of 52 to a score of 22 at month 6. The score was driven by improvements in hand behavior, breathing problems, general mood, repetitive face movements, nighttime behaviors, fear and anxiety, body rocking and facial expressions.

Speaker Change: General mood rapidly pay a small months nighttime behavior fear and anxiety body drafting and facial expressions.

Speaker Change: Now, let us discuss the efficacy data reported at the week 12 post treatment assessment from the second Division.

Speaker Change: Recall that the second patient had a CGI S severity score, indicating moderately ill wasn't the baseline C. J S call six indicating severe.

Importantly, the first patient also showed new improvement in a 6-month assessment of the Rett Syndrome Behavior Questionnaire, RSBQ. The RSBQ, which is a 45-item caregiver-administered questionnaire that assesses Rett syndrome characteristics, The patient demonstrated a 30-point total score improvement from the baseline score of 52 to a score of 22 at month 6. The score was driven by improvements in hand behavior, breathing problems, general mood, repetitive face movements, nighttime behaviors, fear and anxiety, body rocking and facial expressions.

Speaker Change: Okay shouldn't one at week 12 post treatment the second patient demonstrated sustained and new improvements across key efficacy measures from the initial four week assessment.

Sukumar Nagendran: The patient demonstrated a 30-point total score improvement from the baseline score of 52 to a score of 22 at month 6. The score was driven by improvements in hand behavior, breathing problems, general Mood, Repetitive Face Movements, Night Time Behaviors, Fear and Anxiety, Body Rocking, and Facial Expressions.

Speaker Change: Our sustained score three indicating minimally improved was reported at week 12, and both CGI I and Pgi I am which is consistent with the skull that put it at the four week assessment for patients too.

Speaker Change: Ah patients showed a two point improvement in the <unk> total score from the baseline score of 37 to a school 35 at week 12.

Speaker Change: Improvements are absorbing breathing body rocking facial expression general ward and repetition faithfulness.

Sukumar Nagendran: Now, let us discuss the efficacy data reported at the week 12 post-treatment assessment from the second phase. Recall that the second patient had a CGI-S severity score of 4, indicating moderately ill; versus a baseline CGI-S score of 6, indicating severely ill, for Patient 1. At week 12 post-treatment, the second patient demonstrated sustained and new improvements across key efficacy measures from the initial 4-week assessment. A sustained score of 3, indicating minimally improved, was reported at week 12 in both CGI-I and PGI-I, which is consistent with the score reported at the 4-week assessment for Patient 2. The patient showed a 2-point improvement in the RSBQ total score, from the baseline score of 37 to a score of 35 at week 12. Improvements were observed in breathing, body rocking, facial expression, general mood and repetitive face movements.

Now, let us discuss the efficacy data reported at the week 12 post-treatment assessment from the second patient. Recall that the second patient had a CGI-S severity score of 4, indicating moderately ill; versus a baseline CGI-S score of 6, indicating severely ill, for Patient 1. At week 12 post-treatment, the second patient demonstrated sustained and new improvements across key efficacy measures from the initial 4-week assessment. A sustained score of 3, indicating minimally improved, was reported at week 12 in both CGI-I and PGI-I, which is consistent with the score reported at the 4-week assessment for Patient 2.

Speaker Change: Fortunately the second patient also demonstrated new improvements at the 12 week assessment in RMB.

Speaker Change: She demonstrated a 17 point improvement in the RMB a total score from the baseline score $38 21 at week 12, which was driven by improvements in social skills respiratory behavior include.

Speaker Change: Including less frequent hyperventilation and breath, holding seizures trunk of rocking stereotypic hand movements and our mounting an aberrant behavior.

Speaker Change: The patient also showed new improvements at week 19 in seizures.

Speaker Change: Seizure diaries showed a significant reduction in seizure events at 25% lower levels of anti seizure medicine relative to baseline to week 19 was treatment based on caregiver reported medical history.

The patient showed a 2-point improvement in the RSBQ total score, from the baseline score of 37 to a score of 35 at week 12. Improvements are observed in breathing, body rocking, facial expression, general mood and repetitive face movements. Importantly, the second patient also demonstrated new improvements at the 12-week assessment in R-MBA. She demonstrated a 17-point improvement in the R-MBA total score, from the baseline score of 38 to a score of 21 at week 12, which was driven by improvements in social skills, respiratory behavior -- including less frequent hyperventilation and breath holding, seizures, truncal rocking, stereotypic hand movements and hand mouthing and aberrant behavior. The patient also showed new improvements at week 19 in seizures. The seizure diary showed a significant reduction in seizure events at 25% lower levels of anti-seizure medicines relative to baseline, through week 19 post-treatment based on caregiver-reported medical history. Relative to the baseline seizure frequency of 2 to 4 seizures per week, there has been a significant reduction in seizures post-treatment with TSHA-102. Since treatment with TSHA-102, Patient 2 had a single seizure event with 17 weeks reported seizure-free, as of week 19 post-treatment. There were no changes reported in CGI-S or RSHFS at week 12.

Speaker Change: Relative to the baseline seizure frequency of two to four seizures per week, there's been a significant reduction in seizures post treatment with dish out one or two since treatments with taishan, one or two patients who had a single C. J O N with 17 weeks reported seizure free.

Sukumar Nagendran: Importantly, the second patient also demonstrated new improvements at the 12-week assessment in RMBA. She demonstrated a 17-point improvement in the RMBA total score from the baseline score of 38 to a score of 21 at week 12, which was driven by improvements in social skills, respiratory behavior, including less frequent hyperventilation and breath holding, seizures, truncal rocking, stereotypic hand movements, and our mouthing and aberrant behavior. The patient also showed new improvements at week 19. The seizure diary showed a significant reduction in seizure events at 25% lower levels of anti-seizure medicines relative to baseline through week 19 post-treatment based on caregiver-reported medical history. Relative to the baseline seizure frequency of 2 to 4 seizures per week, there has been a significant reduction in seizures post-treatment with Taysha 102. Since treatment with Taysha 102, patient 2 had a single seizure event with 17 weeks reported seizure-free as of week 19 post-treatment... There were no changes reported in CGI-S or RS-HFS at week 12.

Speaker Change: Reached 19 Boston.

Speaker Change: Uh huh.

Speaker Change: There were no changes reported in CGI S. All RSA test fast at week 12, although at week 12, the principal investigator reported a sustained improvement in the patients, hence teaser TPS, which are not measured in honest hff's.

She demonstrated a 17-point improvement in the R-MBA total score, from the baseline score of 38 to a score of 21 at week 12, which was driven by improvements in social skills, respiratory behavior -- including less frequent hyperventilation and breath holding, seizures, truncal rocking, stereotypic hand movements and hand mouthing and aberrant behavior. The patient also showed new improvements at week 19 in seizures. The seizure diary showed a significant reduction in seizure events at 25% lower levels of anti-seizure medicines relative to baseline, through week 19 post-treatment based on caregiver-reported medical history. Relative to the baseline seizure frequency of 2 to 4 seizures per week, there has been a significant reduction in seizures post-treatment with TSHA-102. Since treatment with TSHA-102, Patient 2 had a single seizure event with 17 weeks reported seizure-free, as of week 19 post-treatment. There were no changes reported in CGI-S or RSHFS at week 12.

Speaker Change: The first time since regression at age sleep depression displayed less forceful hadn't any and more fun and relaxed hands.

Speaker Change: More data details on this available data can be found in our press release issued today and our Form 10-K for the year ending December 31, 2023 filed with the SEC.

Speaker Change: Overall were highly encouraged by the safety profile and the durable responses reported in these long term data in both of those patients treated with a low dose of stage one or two the critical takeaway is that following treatment with one or two that were early improvements observed across multiple clinical domains and the tool steel.

Relative to the baseline seizure frequency of 2 to 4 seizures per week, there has been a significant reduction in seizures post-treatment with TSHA-102. Since treatment with TSHA-102, Patient 2 had a single seizure event with 17 weeks reported seizure-free, as of week 19 post-treatment. There were no changes reported in CGI-S or RSHFS at week 12. However, at week 12, the principal investigator reported a sustained improvement in the patient's hand stereotypies, which are not measured in RSHFS. For the first time since regression at age 3, the patient displayed less forceful hand-wringing and more open and relaxed hand. More details on this available data can be found in our press release issued today and our Form 10-K for the year ending December 31st, 2023, filed with the SEC. Overall, we are highly encouraged by the safety profile and the durable response reported in these long-term data in both adult patients treated with the low dose of TSHA-102. The critical takeaway is that following treatment with TSHA-102, there were early improvements observed across multiple clinical domains in the two Stage 4 adult patients with different genetic mutation, severity and phenotypic expression.

Age for adult patients with different genetic mutation severity and phenotypic expression and importantly, both patient showed sustained new improvements across those clinical domains that we've identified post treatment for patient one and reached 19 post treatment for patient two we believe the safety profile.

Speaker Change: And continued improvements observed even at reduced steroid levels, both adult patients with advanced stage Forex syndrome support the durability and transformative potential of <unk>, one or two across multiple genotypes of ret syndrome.

Sukumar Nagendran: However, at week 12, the principal investigator reported a sustained improvement in the patient's hand stereotypies, which are not measured in RS-HFS. For the first time since regression at age 3, the patient displayed less forceful grip, More details on this available data can be found in our press release issued today and in our Form 10-K for the year ending December 31, 2023, filed with the SEC. Overall, we are highly encouraged by the safety profile and the durable response reported in these long-term data in both adult patients treated with the low dose of Taysha 102. The critical takeaway is that following treatment with Taysha 102, there were early improvements observed across multiple clinical domains in the two stage four adult patients with different genetic mutations, severity, and phenotypic expression.

For the first time since regression at age 3, the patient displayed less forceful hand-wringing and more open and relaxed hand. More details on this available data can be found in our press release issued today and our Form 10-K for the year ending December 31st, 2023, filed with the SEC. Overall, we are highly encouraged by the safety profile and the durable response reported in these long-term data in both adult patients treated with the low dose of TSHA-102. The critical takeaway is that following treatment with TSHA-102, there were early improvements observed across multiple clinical domains in the two Stage 4 adult patients with different genetic mutation, severity and phenotypic expression.

Speaker Change: With the low dose cohort completed the adolescent and adult trial will focus on collecting data with the Idose shawano tool to further explore the clinical impact of dish or one or two in patients with stage four ret syndrome.

Based on the <unk> review of the clinical data from both adult and the initial.

Speaker Change: Clinical data from the first pediatric patients treated with a low dose of tissue or new to the <unk> approved our request to proceed earlier dose escalation in the adolescent and adult trial. The <unk> also approved dosing in the second pediatric patient in cohort one the low dose cohort now reveal phase one two pediatric trial.

The critical takeaway is that following treatment with TSHA-102, there were early improvements observed across multiple clinical domains in the two Stage 4 adult patients with different genetic mutation, severity and phenotypic expression. And importantly, both patients showed sustained and new improvements across those clinical domains at week 35 post-treatment for Patient 1 and week 19 post-treatment for Patient 2. We believe the safety profile and continued improvements observed, even at reduced steroid levels, in both adult patients with advanced Stage 4 Rett syndrome, support the durability and transformative potential of TSHA-102 across multiple genotypes of Rett syndrome. With the low dose cohort complete, the Adolescent and Adult Trial will focus on collecting data with the high dose TSHA-102 to further explore the clinical impact of TSHA-102 in patients with Stage 4 Rett syndrome. Based on the IDMC's review of the clinical data from both adults and the initial, clinical data from the first pediatric patient treated with the low dose of TSHA-102,

Reveal trials have two part trial design.

Speaker Change: This escalation from partner will be assessed by the regulatory agencies and <unk> to provide guidance on key find out early months upon b or the dose expansion portion of the study, including hierarchy of efficacy endpoints study duration and the maximum tolerated dose or maximum administered dose.

Sukumar Nagendran: And importantly, both patients showed sustained and new improvements across those clinical domains at week 35 post-treatment for patient one and week 19 post-treatment for patient two. We believe the safety profile and continued improvements observed even at reduced steroid levels in both adult patients with advanced stage four Rett syndrome support the durability and transformative potential of Taysha 102 across multiple genotypes of Rett syndrome. With the low-dose cohort complete, the adolescent and adult trial will focus on collecting data with the high-dose Taysha 102 to further explore the clinical impact of Taysha 102 in patients with stage 4 Rett syndrome. Based on the IDMC's review of the clinical data from both adults and the initial, clinical data from the first pediatric patient treated with the low dose of Taysha 102.

Speaker Change: Therefore, advancing to cohort two in the adolescent and adult trial will expedite our ability to inform other clinical development and regulatory plan for part B After studies.

Speaker Change: This year, we are focusing on completing dosing and partly of both trials, we anticipate significant data collection in 2024 with many clinical catalysts expected in the year ahead.

With the low dose cohort complete, the Adolescent and Adult Trial will focus on collecting data with the high dose TSHA-102 to further explore the clinical impact of TSHA-102 in patients with Stage 4 Rett syndrome. Based on the IDMC's review of the clinical data from both adults and the initial, clinical data from the first pediatric patient treated with the low dose of TSHA-102, the IDMC approved our request to proceed to an earlier dose escalation in the Adolescent and Adult trial. The IDMC also approved dosing in the second pediatric patient in cohort one, the low dose cohort, in our REVEAL Phase 1/2 Pediatric Trial. Both REVEAL trials have a two-part trial design. Dose escalation from Part A will be assessed by the regulatory agencies and the IDMC to provide guidance on key elements of Part B -- or the dose expansion portion of the study -- including hierarchy of efficacy endpoints, study duration and the maximum tolerated dose or maximum administered dose.

Speaker Change: As we discussed in early January we expect to report initial safety and efficacy data from cohort one evaluating the low dose a patient on one or two in the pediatric trial mid 2024. We also expect to report initial data from cohort two evaluating the hydro silk rational one or two in the second half of 2024.

Speaker Change: In both the adolescent and adult and pediatric trial.

Speaker Change: As Sean noted earlier, our efforts to expand our clinical trials remain underway and we are currently focused on additional site activation in the U S or adolescent and adult trial with the goal of expanding our analysis and adult trial in Canada into the U S.

Sukumar Nagendran: The IDMC approved our request to proceed to an earlier dose escalation in the adolescent and adult trial. The IDMC also approved dosing in the second pediatric patient in cohort one, the low dose cohort, in a revealed phase one, two pediatric trial. Both revealed trials have a two-part trial design. Dose escalation from Part A will be assessed by regulatory agencies and the IDMC to provide guidance on key elements of Part B, or the dose expansion portion of the study, including the hierarchy of efficacy endpoints, study duration, and the maximum tolerated dose or maximum administered dose.

Speaker Change: So focus on site activation in the U K for a pediatric trial with the goal of expanding our ongoing pediatric trial in the U S into the U K.

Both REVEAL trials have a two-part trial design. Dose escalation from Part A will be assessed by the regulatory agencies and the IDMC to provide guidance on key elements of Part B -- or the dose expansion portion of the study -- including hierarchy of efficacy endpoints, study duration and the maximum tolerated dose or maximum administered dose. Therefore, advancing to cohort two in the Adolescent and Adult Trial will expedite our ability to inform our clinical development and regulatory plan for Part B of the studies. This year, we are focusing on completing dosing in Part A of both trials. We anticipate significant data collection in 2024, with many clinical catalysts expected in the year ahead. As we discussed in early January, we expect to report initial safety and efficacy data from Cohort 1, evaluating the low dose of Tracia-102 in the pediatric trial, in mid-2024. We also expect to report initial data from Cohort 2, evaluating the high dose of Tracia-102 in the second half of 2024 in both the adolescent and adult trials and the pediatric trials. As Sean noted earlier, our efforts to expand our clinical trials remain underway, and we are currently focused on additional site activation in the U.S. for our adolescent and adult trial with the goal of expanding our adolescent and There is a significant unmet medical need for Rett syndrome caused by a pathogenic, likely pathogenic MHCPT mutation afflicting between 15,000 to 20,000 patients in the U.S., EU, and UK, and a high burden of care associated with it. We are pleased that Taysha 102 recently received ILAB designation from the U.K. MHRA.

Speaker Change: As a reminder, there are no approved disease modifying therapies currently available that create that route the genetic root cause of ret syndrome, there's a significant unmet medical need that slipped syndrome caused by a pathogenic or likely pathogenic <unk> mutation afflicting between 15000 to 20000 patients in the U S.

Speaker Change: You in UK and a high burden of care associated we are pleased that they shall not too recently received <unk> designation from the U K image capture one or two has also received fast track designation and orphan drug designation and rare pediatric disease designation from the FDA and has been granted orphan drug designation.

Sukumar Nagendran: Therefore, advancing to Cohort 2 in the Adolescent and Adult Trial will expedite our ability to inform our clinical development and regulatory plan for Part B of the study. This year, we are focusing on completing dosing in Part A of both trials. We anticipate significant data collection in 2024, with many clinical catalysts expected in the year ahead. As we discussed in early January, we expect to report initial safety and efficacy data from Cohort 1, evaluating the low dose of Tracia-102 in the pediatric trial, in mid-2024. We also expect to report initial data from Cohort 2, evaluating the high dose of Tracia-102 in the second half of 2024 in both the adolescent and adult trials and the pediatric trials. As Sean noted earlier, our efforts to expand our clinical trials remain underway, and we are currently focused on additional site activation in the U.S. for our adolescent and adult trial with the goal of expanding our adolescent and There is a significant unmet medical need for Rett syndrome caused by a pathogenic, likely pathogenic MHCPT mutation afflicting between 15,000 to 20,000 patients in the U.S., EU, and UK, and a high burden of care associated with it. We are pleased that Taysha 102 recently received ILAB designation from the U.K. MHRA.

Speaker Change: From the European Commission for the treatment of <unk> syndrome.

This year, we are focusing on completing dosing in Part A of both trials. We anticipate significant data collection in 2024, with many clinical catalysts expected in the year ahead. As we discussed in early January, we expect to report initial safety and efficacy data from cohort one, evaluating the low dose of TSHA-102 in the Pediatric Trial, in mid-2024. We also expect to report initial data from cohort two, evaluating the high dose of TSHA-102, in the second half of 2024 in both the Adolescent and Adult Trials and the Pediatric Trial. As Sean noted earlier, our efforts to expand our clinical trials remain underway and we are currently focused on additional site activation in the US for our Adolescent and Adult Trial, with the goal of expanding our Adolescent and Adult Trial in Canada, into the US. We're also focused on site activation in the UK for our Pediatric Trial, with the goal of expanding our ongoing Pediatric Trial in the US, into the UK. As a reminder, there are no approved disease-modifying therapies currently available that treat the root -- the genetic root cause of Rett syndrome. There is significant unmet medical need for Rett syndrome caused by a pathogenic -- likely pathogenic -- MECP2 mutation, afflicting between 15,000 to 20,000 patients in the US, EU and UK and a high burden of care associated with it. We are pleased that TSHA-102 recently received ILAP designation from the UK MHRA.

Speaker Change: Overall, we are highly encouraged by the safety profile in long term efficacy reported as opposed to adult patients as well as <unk> approval for both the second pediatric patients. Following review of the initial six week clinical data from the first pediatric patient dose limitation of one or two.

Speaker Change: This year, we are focused on collecting data across multiple aegis of patients the low and high dose of peso on roku to further inform our clinical and regulatory strategy for the next phase of the study.

Speaker Change: We look forward to sharing additional progress this year.

Speaker Change: I will now turn the call over to Cameron to discuss our financial results camera.

As Sean noted earlier, our efforts to expand our clinical trials remain underway and we are currently focused on additional site activation in the US for our Adolescent and Adult Trial, with the goal of expanding our Adolescent and Adult Trial in Canada, into the US. We're also focused on site activation in the UK for our Pediatric Trial, with the goal of expanding our ongoing Pediatric Trial in the US, into the UK. As a reminder, there are no approved disease-modifying therapies currently available that treat the root -- the genetic root cause of Rett syndrome. There is significant unmet medical need for Rett syndrome caused by a pathogenic -- likely pathogenic -- MECP2 mutation, afflicting between 15,000 to 20,000 patients in the US, EU and UK and a high burden of care associated with it. We are pleased that TSHA-102 recently received ILAP designation from the UK MHRA.

Cameron: Thank you Sue and good afternoon.

Cameron: Revenue for the full year ended December 31, 2023 was $15 $5 million compared to $2 $5 million for the full year ended December 31, 2022 as revenue was derived entirely from our option agreement with Astellas gene therapy. The increase in revenue was primarily a result of Ret syndrome research.

Cameron: Development activities performed in 2023.

Cameron: Research and development expenses were $56 8 million for the full year ended December 31, 2023, compared to $91 $2 million for the full year ended December 31 2022.

There is significant unmet medical need for Rett syndrome caused by a pathogenic -- likely pathogenic -- MECP2 mutation, afflicting between 15,000 to 20,000 patients in the US, EU and UK and a high burden of care associated with it. We are pleased that TSHA-102 recently received ILAP designation from the UK MHRA. TSHA-102 has also received Fast Track designation, an Orphan Drug designation and Rare Pediatric designation from the FDA and has been granted Orphan Drug designation from the European Commission for the treatment of Rett syndrome. Overall, we're highly encouraged by the safety profile and long-term efficacy reported in the first two adult patients, as well as IDMC's approval to dose the second pediatric patient following review of the initial six-week clinical data from the first pediatric patient dosed with Taysha 102. This year, we are focused on collecting data across multiple ages of patients with a low and high dose of Taysha 102 to further inform our clinical and regulatory strategy for the next phase of the study. We look forward to sharing additional progress this year. I will now turn the call over to Kamran to discuss our financial results. Kamran

Cameron: The decrease was due to reduced research and development head count lower research and development manufacturing expenses and a reduction in third party research and development consulting fees, mainly related to preclinical studies and IND, enabling toxicology study.

Sukumar Nagendran: Taysha 102 has also received Fast-Track designation, an often-drug designation, and rare pediatric designation from the FDA, and has been granted rare pediatric designation from the European Commission for the treatment of Rett syndrome. Overall, we're highly encouraged by the safety profile and long-term efficacy reported in the first two adult patients, as well as IDMC's approval to dose the second pediatric patient following review of the initial six-week clinical data from the first pediatric patient dosed with Taysha 102. This year, we are focused on collecting data across multiple ages of patients with a low and high dose of Taysha 102 to further inform our clinical and regulatory strategy for the next phase of the study. We look forward to sharing additional progress this year. I will now turn the call over to Kamran to discuss our financial results. Kamran

Cameron: General and administrative expenses were $30 million for the full year ended December 31, 2023, compared to $37 $4 million for the full year ended December 31 2022.

Cameron: The decrease was primarily attributed to a reduction in compensation expenses as a result of lower head count and reduced corporate insurance and consulting expenses.

Overall, we're highly encouraged by the safety profile and long-term efficacy reported in the first two adult patients, as well as IDMC's approval to dose the second pediatric patient following review of the initial 6-week clinical data from the first pediatric patient dosed with TSHA-102. This year, we are focused on collecting data across multiple ages of patients with a low and high dose of TSHA-102, to further inform our clinical and regulatory strategy for the next phase of the study. We look forward to sharing additional progress this year. I will now turn the call over to Kamran to discuss our financial results. Kamran?

Cameron: Net loss for the full year ended December 31, 2023 was $111 6 million or <unk> 96 per share as compared to a net loss of $166 million or $3 78 per share for the full year ended December 31 2022.

Cameron: The net loss includes a nonrecurring noncash expenses $34 5 million relates to the change in fair value from the pre funded warrants as a result of the August 2023 private placement financing.

Cameron: As of December 31, 2023, Asia had $143 $9 million in cash and cash equivalent.

Cameron: The company continues to expect that its current cash resources will support planned operating expenses and capital requirements into 2026.

I will now turn the call over to Kamran to discuss our financial results. Kamran?

Cameron: I will now turn the call back over to Sean for his closing remarks.

Kamran Alam: Thank you, Suku and good afternoon. Revenue for the full year ended December 31, 2023 was $15.5 million compared to $2.5 million for the full year ended December 31, 2022. As revenue was derived entirely from our option agreement with Estella's Gene Therapy, the increase in revenue is primarily a result of Rett Syndrome research and development activities performed in 2023. Research and development expenses were $56.8 million for the full year ended December 31, 2023, compared to $91.2 million for the full year ended December 31, 2022. The decrease was due to reduced research and development headcount, lower research and development manufacturing expenses, and a reduction in third-party research and development consulting fees mainly related to preclinical studies and IND-enabling toxicology. General and administrative expenses were $30 million for the full year ended Dec. 31, 2023 compared to $37.4 million for the full year ended Dec. 31, 2022.

Kamran Alam: Thank you, Suku and good afternoon.

Sean P. Nolan: Thank you Cameron.

Revenue for the full year ended December 31, 2023 was $15.5 million compared to $2.5 million for the full year ended December 31, 2022, as revenue was derived entirely from our option agreement with Astellas Gene Therapy. The increase in revenue is primarily a result of Rett syndrome research and development activities performed in 2023. Research and development expenses were $56.8 million for the full year ended December 31, 2023, compared to $91.2 million for the full year ended December 31, 2022. The decrease was due to reduced research and development headcount, lower research and development manufacturing expenses and a reduction in third-party research and development consulting fees, mainly related to pre-clinical studies and IND-enabling toxicology study. General and administrative expenses were $30 million for the full year ended December 31, 2023 compared to $37.4 million for the full year ended December 31, 2022. The decrease was primarily attributed to a reduction in compensation expenses, as a result of lower headcount and reduced corporate insurance and consulting expenses. Net loss for the full year ended December 31, 2023 was $111.6 million or $0.96 per share, as compared to a net loss of $166 million or $3.78 per share for the full year ended December 31, 2022. The net loss includes a non-recurring and non-cash expense of $34.5 million related to a change in fair value from the pre-funded warrants as a result of the August 2023 private placement financing. As of December 31, 2023, Taysha had $143.9 million in cash and cash equivalents.

Sean P. Nolan: As you heard today, we've made significant progress in the clinical development of our tissue 102 program. We are highly encouraged by the safety profile and durable response reported that reduce steroid levels and the longer term data from both patients and the low dose of a reveal adolescent and adult trial.

Sean P. Nolan: These continued improvements in both adult patients with advanced stage for Ret syndrome, coupled with the <unk> approval the dose the second pediatric patients. Following review of the initial clinical data from the first pediatric patient dose rotation 102 reinforced the transformative potential of Taishan 102 across the board.

Sean P. Nolan: <unk> Ah patients with Ret syndrome building on the momentum from 2023, we believe 'twenty 'twenty four is poised to be transformational year for the company.

The decrease was due to reduced research and development headcount, lower research and development manufacturing expenses and a reduction in third-party research and development consulting fees, mainly related to pre-clinical studies and IND-enabling toxicology study. General and administrative expenses were $30 million for the full year ended December 31, 2023 compared to $37.4 million for the full year ended December 31, 2022. The decrease was primarily attributed to a reduction in compensation expenses, as a result of lower headcount and reduced corporate insurance and consulting expenses. Net loss for the full year ended December 31, 2023 was $111.6 million or $0.96 per share, as compared to a net loss of $166 million or $3.78 per share for the full year ended December 31, 2022. The net loss includes a non-recurring and non-cash expense of $34.5 million related to a change in fair value from the pre-funded warrants as a result of the August 2023 private placement financing. As of December 31, 2023, Taysha had $143.9 million in cash and cash equivalents.

Sean P. Nolan: This year, we're focused on data generation across broad range of ages and stages of patients with ret syndrome in multiple geographies with the goal of completing dosing and partly a bold trials with the low and high dose of tissue 102 to inform the next phase of the studies with.

Sean P. Nolan: With many clinical catalysts expected in the year ahead, we look forward to providing additional updates on our progress with that I will now ask the operator to begin our Q&A session operator.

Sean P. Nolan: Okay.

Speaker Change: Thank you, ladies and gentlemen at this time well be conducting a question and answer session.

Kamran Alam: The decrease was primarily attributed to a reduction in compensation expenses as a result of lower headcount and reduced corporate insurance and consulting. The net loss for the full year ended December 31, 2023 was $111.6 million, or $0.96 per share, as compared to a net loss of $166 million, or $3.78 per share, for the full year ended December 31, 2022. The net loss includes a non-recurring and non-cash expensive $34.5 million related to a change in fair value from the pre-funded warrants as a result of the August 2023 private placement financing. As of December 31, 2023, Taysha had $143.9 million in cash and cash equivalents.

Speaker Change: Good question, you May press Star one on your telephone keypad.

Speaker Change: Information tone will indicate your line is in the question queue you.

Speaker Change: You May press star two if you'd like to remove your question from the queue.

Net loss for the full year ended December 31, 2023 was $111.6 million or $0.96 per share, as compared to a net loss of $166 million or $3.78 per share for the full year ended December 31, 2022. The net loss includes a non-recurring and non-cash expense of $34.5 million related to a change in fair value from the pre-funded warrants as a result of the August 2023 private placement financing. As of December 31, 2023, Taysha had $143.9 million in cash and cash equivalents. The company continues to expect that its current cash resources will support planned operating expenses and capital requirements into 2026. I will now turn the call back over to Sean for his closing remarks. Thank you, Kamran. As you heard today, we've made significant progress in the clinical development of our Taysha 102 program. We are highly encouraged by the safety profile and durable response reported that reduced steroid levels and the longer-term data from both patients in the low dose of our REVEAL adolescent and adult trial. These continued improvements in both adult patients with advanced stage 4 Rett syndrome, coupled with the IDMC's approval to dose the second pediatric patient, following review of the initial clinical data from the first pediatric patient dose of Taysha 102, reinforced the Building on the momentum from 2023, we believe 2024 is poised to be a transformational year for the company.

Speaker Change: For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star key and the interest of time, please limit yourself to one question and one follow up.

Speaker Change: Our first question comes from the line of Whitney <unk> with.

Whitney: Canaccord. Please proceed with your question.

Whitney: Hey, guys. Thanks for thanks for all the updates I guess to limit myself to one just can you help set expectations into the pediatric data mid year and in particular, our understanding of stage three and I think <unk> talked about this a little bit before but is that the disease is kind of stable more gabe on potentially some improvements.

Whitney: In terms of the natural history, so how should we be thinking about and kind of what you could show at the initial update versus maybe over the longer term in the pediatric update.

Sean P. Nolan: The company continues to expect that its current cash resources will support planned operating expenses and capital requirements into 2026. I will now turn the call back over to Sean for his closing remarks. Thank you, Kamran. As you heard today, we've made significant progress in the clinical development of our Taysha 102 program. We are highly encouraged by the safety profile and durable response reported that reduced steroid levels and the longer-term data from both patients in the low dose of our REVEAL adolescent and adult trial. These continued improvements in both adult patients with advanced stage 4 Rett syndrome, coupled with the IDMC's approval to dose the second pediatric patient, following review of the initial clinical data from the first pediatric patient dose of Taysha 102, reinforced the Building on the momentum from 2023, we believe 2024 is poised to be a transformational year for the company.

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

Whitney: As you sit here thanks.

Speaker Change: Thanks, Courtney I guess I would say that number one keep in mind that the pediatric patients.

Thank you, Kamran. As you heard today, we've made significant progress in the clinical development of our Taysha 102 program. We are highly encouraged by the safety profile and durable response reported that reduced steroid levels and the longer-term data from both patients in the low dose of our REVEAL adolescent and adult trial. These continued improvements in both adult patients with advanced stage 4 Rett syndrome, coupled with the IDMC's approval to dose the second pediatric patient, following review of the initial clinical data from the first pediatric patient dose of Taysha 102, reinforced the Building on the momentum from 2023, we believe 2024 is poised to be a transformational year for the company.

Sean Nolan: Thank you, Kamran.

As you heard today, we've made significant progress in the clinical development of our TSHA-102 program. We are highly encouraged by the safety profile and durable response reported that reduced steroid levels and the longer-term data from both patients in the low dose of our REVEAL Adolescent and Adult Trial. These continued improvements in both adult patients with advanced Stage 4 Rett syndrome, coupled with the IDMC's approval to dose the second pediatric patient following review of the initial clinical data from the first pediatric patient dose with TSHA-102, reinforced the transformative potential of TSHA-102 across a broad population of patients with Rett syndrome. Building on the momentum from 2023, we believe 2024 is poised to be a transformational year for the company. This year, we're focused on data generation across a broad range of ages and stages of patients with Rett syndrome in multiple geographies, with the goal of completing dosing in Part A of both trials, with the low and high doses of TSHA-102 to inform the next phase of the studies. With many clinical catalysts expected in the year ahead, we look forward to providing additional updates on our progress. With that, I will now ask the operator to begin our Q&A session. Operator?

Speaker Change: We'll likely be in a severity range of C. G I S.

Speaker Change: Queen four and six which is which is similar to what's happening in the adolescent and adult trial and I think if you talk to the Kols out there you'd get very consistent feedback that that's that's the most appropriate severity range to study in a first in human trial.

Speaker Change: Pork for a gene therapy with this particular disease. So I think where do you get to answer. Your question you know you're going to see.

Speaker Change: A bit of a spectrum of patients right. You you know someone who's a four is going to be different than someone who's a six we've seen that with our first two adult patients here.

Building on the momentum from 2023, we believe 2024 is poised to be a transformational year for the company. This year, we're focused on data generation across a broad range of ages and stages of patients with Rett syndrome in multiple geographies, with the goal of completing dosing in Part A of both trials, with the low and high doses of TSHA-102 to inform the next phase of the studies. With many clinical catalysts expected in the year ahead, we look forward to providing additional updates on our progress.

Speaker Change: You know the time to impact.

It's a new population.

Speaker Change: You would you'd like to think that you should see a relatively similar time to effect and hopefully you know initial magnitude of effect is relatively similar.

Sean P. Nolan: This year, we're focused on data generation across a broad range of ages and stages of patients with Rett syndrome in multiple geographies with the goal of completing dosing in Part A of both trials with the low and high doses of Taysha 102 to inform the next phase of the study. With many clinical catalysts expected in the year ahead, we look forward to providing additional updates on our progress. With that, I will now ask the operator to begin our Q&A session. Operator?

Speaker Change: Depending upon the severity of the disease. It is also possible that it could take longer to see change in someone that's less severe versus more severe. So if you think about on a mid year readout I would say that we dosed our first patient at the.

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

Operator: Next time, we'll be back with a new episode of The Daily Watch. Hey guys, thanks for watching. I guess to limit myself to one, can you help set expectations for the pediatric data mid year? And in particular, our understanding of stage three, and I think you guys have talked about this a little bit before, but the disease is kind of stable, more variable, and potentially some improvements in terms of the natural history. So how should we be thinking about what you could show at the initial update versus maybe over the longer term in the pediatric updates as we go through the year? Thanks, Whitney.

Operator: Thank you. Ladies and gentlemen, at this time, we will be conducting a question and answer session. If you'd like to ask a question, you may press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star key. In the interest of time, please limit yourself to one question and one follow up. Our first question comes from the line of Whitney Ijem from Canaccord. Please proceed with your question.

Speaker Change: End of 2023.

Speaker Change: You know so we'd likely have between four to six months of data at that particular time, you know we've guided to dosing the second patient this quarter.

Our first question comes from the line of Whitney Ijem from Canaccord. Please proceed with your question.

Hey, guys. Thanks for all the updates. I guess to limit myself to one, can you help set expectations into the pediatric data mid-year? And in particular, our understanding of Stage 3 -- and I think you guys have talked about this a little bit before but is that the disease is kind of stable, more variable and potentially, some improvements in terms of the natural history. So, how should we be thinking about what you could show at the initial update versus maybe over the longer term in the pediatric updates as we go through the year? Thanks. Thanks, Whitney.

Whitney Ijem: Hey, guys. Thanks for all the updates. I guess to limit myself to one, can you help set expectations into the pediatric data mid-year? And in particular, our understanding of Stage 3 -- and I think you guys have talked about this a little bit before -- but is that the disease is kind of stable, more variable and potentially, some improvements in terms of the natural history. So, how should we be thinking about what you could show at the initial update versus maybe over the longer term in the pediatric updates as we go through the year? Thanks.

Oh, so you're probably talking.

Speaker Change: Yeah.

Speaker Change: Two to three months of data for that patient.

Speaker Change: We have early data for the third patient depending upon the timing of that.

Speaker Change: That particular dosing so hopefully that gives you a little bit of a flavor of what to expect.

Speaker Change: Thanks.

Speaker Change: Thank you.

Thanks, Whitney. I guess I would say that, number one, keep in mind that the pediatric patients will likely be in a severity range of CGI-S of between 4 and 6 -- which is similar to what's happening in the Adolescent and Adult Trial. And I think if you talk to the KOLs out there, you'd get very consistent feedback that that's the most appropriate severity range to study in a first-in-human trial for a gene therapy with this particular disease. So I think, Whitney, to answer your question, you're going to see a bit of a spectrum of patients -- someone who's a 4 is going to be different than someone who's a 6. We've seen that with our first two adult patients here, that the time to impact -- it's a new population, you would like to think that you should see a relatively similar time to effect and hopefully, initial magnitude of effect is relatively similar. depending upon the severity of the disease. It's also possible that it could take longer to see change in someone that's less severe versus more severe. So, if you think about a mid-year readout, I would say that we dosed our first patient at the end of 2023 so, we'd likely have between four to six months of data at that particular time. We've got into dosing the second patient this quarter so, you're probably talking between two to three months of data for that patient. And, potentially, early data for the third patient, depending upon the timing of that particular dosing. So hopefully, that gives you a little flavor of what to expect. That does, thanks. Thank you. Salven, Hey guys.

Sean Nolan: Thanks, Whitney. I guess I would say that, number one, keep in mind that the pediatric patients will likely be in a severity range of CGI-S of between 4 and 6 -- which is similar to what's happening in the Adolescent and Adult Trial. And I think if you talk to the KOLs out there, you'd get very consistent feedback that that's the most appropriate severity range to study in a first-in-human trial for a gene therapy with this particular disease. So I think, Whitney, to answer your question, you're going to see a bit of a spectrum of patients -- someone who's a 4 is going to be different than someone who's a 6.

Whitney Glad Ijem: I guess I would say that, number one, keep in mind that the pediatric patients will likely be in a severity range of CGIS between four and six, which is similar to what's happening in the adolescent and adult trial. And I think if you talk to the KOLs out there, you'd get very consistent feedback that that's the most appropriate severity range to study in a first-in-human trial for a gene therapy with this particular disease. So I think, Whitney, to answer your question, you know, you're going to see... A bit of a spectrum of patients right you know someone who's a four is going to be different than someone who's a six we've seen that with our first two adult patients here you know that the time to impact you know it's a new population, You would like to think that you should see a relatively similar time to effect and hopefully you know initial magnitude of effect is relatively similar.

Speaker Change: Our next question comes from the line of solving Richter with Goldman Sachs. Please proceed with your question.

Salveen Jaswal Richter: Hey, guys good evening.

Salveen Jaswal Richter: Thank you for taking my question and congrats on the data on that.

Let's quickly what is your hypothesis around what is driving the RSP EQM per patient one at week 25, noting that scar was relatively flat from weeks Boy. That's filed and then how should we think about expectations.

Speaker Change: Particular score map truck on the far right. Thank you.

Speaker Change: I can go first and Susan can jump in but I would say with patient number one the changes that you saw on RSP Q were primarily driven by anxiety going down general mood, improving and hand function improvement those those will the doses of three.

We've seen that with our first two adult patients here, that the time to impact -- it's a new population, you would like to think that you should see a relatively similar time to effect and hopefully, initial magnitude of effect is relatively similar, depending upon the severity of the disease. It's also possible that it could take longer to see change in someone that's less severe versus more severe. So, if you think about a mid-year readout, I would say that we dosed our first patient at the end of 2023 so, we'd likely have between four to six months of data at that particular time. We've got into dosing the second patient this quarter so, you're probably talking between two to three months of data for that patient. And, potentially, early data for the third patient, depending upon the timing of that particular dosing. So hopefully, that gives you a little flavor of what to expect.

We've seen that with our first two adult patients here, that the time to impact -- it's a new population, you would like to think that you should see a relatively similar time to effect and hopefully, initial magnitude of effect is relatively similar, depending upon the severity of the disease. It's also possible that it could take longer to see change in someone that's less severe versus more severe. So, if you think about a mid-year readout, I would say that we dosed our first patient at the end of 2023 so, we'd likely have between four to six months of data at that particular time. We've guided to dosing the second patient this quarter so, you're probably talking between two to three months of data for that patient. And, potentially, early data for the third patient, depending upon the timing of that particular dosing. So hopefully, that gives you a little flavor of what to expect.

Whitney Glad Ijem: Depending upon the severity of the disease, it's also possible that it could take longer to see, you know, change in someone that's less severe versus, you know, more severe. So, if you think about a mid-year readout, I would say that, you know, we dosed our first patient at the end of 2023, so we'd likely have between, you know, four to six months of data at that particular time. You know, we've got into dosing the second patient this quarter, you know, so you're probably talking, you know, you know, between. [inaudible] Thank you. Salven, Hey guys.

Main drivers in the in the latest decrease in that particular scale.

So, if you think about a mid-year readout, I would say that we dosed our first patient at the end of 2023 so, we'd likely have between four to six months of data at that particular time. We've guided to dosing the second patient this quarter so, you're probably talking between two to three months of data for that patient. And, potentially, early data for the third patient, depending upon the timing of that particular dosing. So hopefully, that gives you a little flavor of what to expect.

Susan: You know I would just say one potential as offices right now on some of the mood aspects.

Is that you know these patients are on very high levels of steroids for a long period of time and you know we'll have to see how other patients do as well, but but one you know potential is that reducing the steroids you know that.

We've guided to dosing the second patient this quarter so, you're probably talking between two to three months of data for that patient. And, potentially, early data for the third patient, depending upon the timing of that particular dosing. So hopefully, that gives you a little flavor of what to expect.

Susan: The level of irritability, the impact on sleep, just the overall mood could be improving as a result of that.

That does, thanks. Thank you. Salven, Hey guys.

Whitney Ijem: That does, thanks.

Thank you. Salven, Hey guys.

Sean Nolan: Thank you.

Operator: Our next question comes from the line of Salveen Richter with Goldman Sachs. Please proceed with your question.

Elizabeth Webster: Hey, guys. Good evening. This is Elizabeth, on for Salveen. Thank you for taking our question and congrats on the data. Mechanistically, what is your hypothesis around what is driving the RSBQ improvement for Patient 1 at week 25, noting that that score was relatively flat from week 4 to 12? And then, how should we think about expectations for this particular score metric on the forward? Thank you.

Susan: Put another way it's possible that the steroids, you know somewhat masked benefits.

Susan: Until they are either reduced significantly or further redrawn. So we're quite encouraged by what we've seen in that aspect of things and hopefully that gives you a bit of perspective on how we're thinking of it at this juncture.

Speaker Change: Got it thank you.

Speaker Change: Thank you.

Our next question comes from the line of Christian Costco with Cantor Fitzgerald. Please proceed with your question.

Elizabeth Daniels Webster: I can go first and Suku can jump in. But I would say, with patient number one, the changes that you saw in RSBQ were primarily driven by anxiety going down, general mood improving and hand function improvement. Those are the three main drivers in the latest decrease in that particular scale. I would just say, one potential hypothesis right now on some of the mood aspects is that -- these patients are on very high levels of steroids for a long period of time. And we'll have to see how other patients do as well but one potential is that you're reducing the steroids, the level of irritability, the impact on sleep, just the overall mood could be improving as a result of that. Put another way, it's possible that the steroids somewhat mask benefits until they're either reduced significantly or further withdrawn. So, we're quite encouraged by what we've seen in that aspect of things and hopefully, that gives you a bit of perspective on how we're thinking of it. And we'll [inaudible] at this juncture. Got it, thank you.

I can go first and Suku can jump in. But I would say, with patient number one, the changes that you saw in RSBQ were primarily driven by anxiety going down, general mood improving and hand function improvement. Those are the three main drivers in the latest decrease in that particular scale. I would just say, one potential hypothesis right now on some of the mood aspects is that -- these patients are on very high levels of steroids for a long period of time. And we'll have to see how other patients do as well but one potential is that you're reducing the steroids, the level of irritability, the impact on sleep, just the overall mood could be improving as a result of that. Put another way, it's possible that the steroids somewhat mask benefits until they're either reduced significantly or further withdrawn. So, we're quite encouraged by what we've seen in that aspect of things and hopefully, that gives you a bit of perspective on how we're thinking of it. And we'll [inaudible] at this juncture.

Sean Nolan: I can go first and Suku can jump in. But I would say, with patient number one, the changes that you saw in RSBQ were primarily driven by anxiety going down, general mood improving and hand function improvement. Those are the three main drivers in the latest decrease in that particular scale. I would just say, one potential hypothesis right now on some of the mood aspects is that -- these patients are on very high levels of steroids for a long period of time.

Christian Costco: Hi, everyone. Thanks for taking my question and congrats on the data update I wanted to ask about the leap anecdote for patient.

Christian Costco: So we understand that sleep issues are very common.

But they can predict pretty.

Sean P. Nolan: You know, I would just say one potential hypothesis right now on some of the mood aspects is that, you know, these patients are on very high levels of steroids for a long period of time. And, you know, we'll have to see how other patients do as well, but one potential benefit is that you're reducing the steroids. You know, the level of irritability, the impact on sleep, just the overall mood could be improving as a result of that. Put another way, it's possible that the steroids somewhat mask benefits until they're, you know, either reduced significantly or further withdrawn. So, you know, we're quite encouraged by what we've seen in that aspect of things, and hopefully, that gives you a bit of perspective on how we're thinking of it. And we'll see you at this juncture. I got it.

Christian Costco: Currently depending on the type of information.

Christian Costco: So can you speak more to the background expected for the patient based on their mutation and essentially what difficulties they were having.

Christian Costco: So was there any.

And we'll have to see how other patients do as well but one potential is that you're reducing the steroids, the level of irritability, the impact on sleep, just the overall mood could be improving as a result of that. Put another way, it's possible that the steroids somewhat mask benefits until they're either reduced significantly or further withdrawn. So, we're quite encouraged by what we've seen in that aspect of things and hopefully, that gives you a bit of perspective on how we're thinking of it. And we'll [inaudible] at this juncture.

Christian Costco: Our lapping or other notable attack and essentially what you believe is happening that you were able to see the drastic changes there. Thank you.

Speaker Change: Yes. So that's an important question because as you pointed out many patients with ret syndrome do have significant sleep abnormalities and sometimes they also correlated with the respiratory abnormalities that can coexist and in this patient of one <unk>.

As observed by the Paradise was that this patient never ever seem to have a reasonable nights sleep and always had a very disruptive night sleep, which included restless leg features night terrors et cetera and.

Elizabeth Webster: Got it, thank you.

Unknown Caller: Thank you. Thank you. Hi everyone.

Thank you. Thank you.

Sean Nolan: Thank you.

Operator: Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald. Please proceed with your question.

Hi, everyone. Thanks for taking my question and congrats on these data updates. I wanted to ask about the sleep anecdote you shared for Patient 1. So, we understand that sleep issues are very common in Rett syndrome patients but they can present pretty differently depending on the type of mutation. So, can you speak more to the background expected for this patient based on their mutation and, essentially, what difficulties they were having sleeping through the night? Was there any sleep screaming or laughing or other notable effects? And, essentially, what you believe is happening that you were able to see the drastic change there. Thank you. Yes, so that's an important question because, as you pointed out, many patients with Rett syndrome do have significant sleep abnormalities, and sometimes they're also correlated with respiratory abnormalities that can coexist.

Kristen Kluska: Hi, everyone. Thanks for taking my question and congrats on these data updates. I wanted to ask about the sleep anecdote you shared for Patient 1. So, we understand that sleep issues are very common in Rett syndrome patients but they can present pretty differently depending on the type of mutation.

Speaker Change: Post gene therapy.

Unknown Caller: Thanks for taking my question, and congrats on these data updates. I wanted to ask about the sleep anecdote you shared for patient one. So we understand that sleep issues are very common in Rett syndrome patients, but they can present pretty differently depending on the type of mutation.

Speaker Change: The feedback from the cardio, especially the father was that this patient was now sleeping through the night and that's the first time he was getting a good night's sleep. So obviously the gene therapy itself I think well.

Speaker Change: Speculating, what we think is restarting in Mississippi to function in the sleep centers and probably helping with many features of sleep.

So, can you speak more to the background expected for this patient based on their mutation and, essentially, what difficulties they were having sleeping through the night? Was there any sleep screaming or laughing or other notable effects? And, essentially, what you believe is happening that you were able to see the drastic change there. Thank you.

Sukumar Nagendran: So can you speak more to the background expected for this patient based on their mutation and, you know, essentially what difficulties they were having sleeping through the night? So was there any sleep screaming or laughing or other notable effects? And essentially, what you believe is happening is that you were able to see the drastic change there. Thank you. Yes, so that's an important question because, as you pointed out, many patients with Rett syndrome do have significant sleep abnormalities, and sometimes they're also correlated with respiratory abnormalities that can coexist.

Speaker Change: That resulted in this patient being restored to almost a normal state. Your second question I think was on seizures, so patient Guan.

You start to have about neutral for the year.

Yes. So, that's an important question because, as you pointed out, many patients with Rett syndrome do have significant sleep abnormalities and sometimes they're also correlated with the respiratory abnormalities that can coexist. And in this Patient 1, what was observed by the parents was that this patient never, ever seemed to have a reasonable night's sleep and always had a very disruptive night's sleep -- which included restless leg features, night terrors, et cetera. And post-gene therapy, the feedback from the carer -- especially the father -- was that this patient was now sleeping through the night and that's the first time he had been getting a good night's sleep. So obviously, the gene therapy itself, I think -- we're speculating but we think is restoring MECP2 function in the sleep center and probably helping with many features of sleep that resulted in this patient being restored to almost a normal state. Your second question, I think, was on seizures. So, Patient 1, is thought to have about two to four seizures a year. I'm sorry, did you have another --

Sukumar Nagendran: Yes. So, that's an important question because, as you pointed out, many patients with Rett syndrome do have significant sleep abnormalities and sometimes they're also correlated with the respiratory abnormalities that can coexist. And in this Patient 1, what was observed by the parents was that this patient never, ever seemed to have a reasonable night's sleep and always had a very disruptive night's sleep -- which included restless leg features, night terrors, et cetera.

Speaker Change: I'm sorry, what did you have.

Speaker Change: Okay sorry.

Speaker Change: Just on.

Speaker Change: The difference is about sleep disturbance is relative to the mutations that they experience.

Unknown Caller: And in this patient one, what was observed by the parents was that this patient never ever seemed to have a reasonable night's sleep and always had a very disruptive night's sleep, which included restless leg features, night terrors, et cetera. And post-gene therapy, the feedback from the carrier, especially the father, was that this patient was now sleeping through the night, and that was the first time he had been getting a good So obviously, the gene therapy itself, I think we're speculating, but we think it is restoring MECP to function in the sleep centers and probably helping with many features of sleep that resulted in this patient being restored to almost a normal state. Your second question, I think, was about seizures. So patient one is thought to have about two to four seizures a year. I'm sorry, did you have another?

Speaker Change: Yeah.

Speaker Change: So this patient had a large deletion, which resulted in a severe phenotype.

Speaker Change: To my knowledge I don't take.

Speaker Change: The severity of the genotype is necessarily correlated with the severity of the sleep abnormalities that correlation doesn't seem to be clear so, but this fashion anyway patient one head.

And post-gene therapy, the feedback from the carer -- especially the father -- was that this patient was now sleeping through the night and that's the first time he had been getting a good night's sleep. So obviously, the gene therapy itself, I think -- we're speculating but we think is restoring MECP2 function in the sleep center and probably helping with many features of sleep that resulted in this patient being restored to almost a normal state. Your second question, I think, was on seizures. So, Patient 1, is thought to have about two to four seizures a year. I'm sorry, did you have another --

Severe sleep abnormalities and if your question also is that what is the actual pathophysiology behind it I don't think anybody fully understands that but all I can tell you is the clinical observation is that the gene therapy appears to have.

Speaker Change: Restored normal sleep patterns does that help.

Speaker Change: Yes. Thank you so much.

Speaker Change: Thank you.

Speaker Change: Our next question comes from the line of Gil Blum with Needham and company. Please proceed with your question.

Your second question, I think, was on seizures. So, Patient 1, is thought to have about two to four seizures a year. I'm sorry, did you have another --

Afternoon.

Gil Joseph Blum: Let me also add my congratulations to progress.

Gil Joseph Blum: So just one from US can you maybe put into context, the burden experienced by.

Sukumar Nagendran: Yeah, sorry. Sorry, no, the question was just on the differences about sleep disturbances relative to the mutations that they experience -- that they have. Yeah. So this perspiration had a large deletion, which resulted in a severe phenotype, but to my knowledge, I don't think the severity of the genotype is necessarily correlated with the severity of the sleep abnormality.

Kristen Kluska: Yeah, sorry. Sorry, no, the question was just on the differences about sleep disturbances relative to the mutations that they experience -- that they have.

Adult patients from being on steroids on a daily basis.

Gil Joseph Blum: Are there ever taper during the standard of care for adult patients during the natural course of the disease. Thank you.

Sukumar Nagendran: Yeah. So, this first patient had a large deletion, which resulted in a severe phenotype. But to my knowledge, I don't think the severity of the genotype is necessarily correlated with the severity of the sleep abnormality. That correlation doesn't seem to be clear. So -- but this patient and Patient 1 had severe sleep abnormalities. And if your question also is that what is the actual pathophysiology behind it, I don't think anybody fully understands that. But all I can tell you is that clinical observation is that the gene therapy appears to have restored normal sleep patterns. Does that help? Yes, thank you so much. Appreciate it. Thank you. Our next question comes from the line of Gil Blum with Needham and, Next question. Question: Do you think that the US military has a better chance of winning the war than the United States?

Gil Joseph Blum: Yeah.

Speaker Change: Yeah. So thats another good question so.

<unk> suppression of immuno modulation in general is not used to treat patients in a disease modifying fast fashion.

Sukumar Nagendran: That correlation doesn't seem to be clear. So, but this patient, anyway, patient one had severe sleep abnormalities. And if your question also is about what the actual pathophysiology behind it is, I don't think anybody fully understands that.

Speaker Change: It has been tried in the past using drugs like sirolimus or prednisolone of hydrocortisone to treat <unk> syndrome, but it hasn't had any positive impact on disease duration severity or outcome.

Sukumar Nagendran: But all I can tell you is that the clinical observation is that the gene therapy appears to have restored normal sleep patterns. Does that help? Yes, thank you so much. Thank you. Our next question comes from the line of Gil Blum with Needham and, Next question. Question: Do you think that the US military has a better chance of winning the war than the United States?

Speaker Change: What you are seeing in our trial, though is because it's a gene therapy trial Suraj and Sirolimus are being used as immuno modulator reagents to allowed us to get over that initial period, where there might be some theoretical risk of the treatment itself.

Sukumar Nagendran: Yes, thank you so much. Appreciate it. Thank you. Our next question comes from the line of Gil Blum with Needham and, Next question. Question: Do you think that the US military has a better chance of winning the war than the United States?

Kristen Kluska: Yes, thank you so much. Appreciate it.

Sukumar Nagendran: Thank you. Our next question comes from the line of Gil Blum with Needham and, Next question. Question: Do you think that the US military has a better chance of winning the war than the United States?

Sean Nolan: Thank you.

Our next question comes from the line of Gil Blum with Needham and Company. Please proceed with your question. Next question. Question: Do you think that the US military has a better chance of winning the war than the United States?

Operator: Our next question comes from the line of Gil Blum with Needham and Company. Please proceed with your question.

Speaker Change: Our next question comes from the line of June Lee with <unk>. Please proceed with your question.

Gil Blum: Good afternoon. Let me also add my congratulations to the progress. So, just one from us. Can you maybe put into context the burden experienced by adult Rett patients from being on steroids on a daily basis and are steroids ever tapered during the standard of care for adult patients during the natural course of the disease? Thank you.

Speaker Change: Hi, Good afternoon. This is Matthew on for June and congrats on the quarter and thanks for taking our questions.

Operator: Answer: No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. Good afternoon. I'll also add my own, Progress. So, just one from us: can you maybe put into context the burden experienced by, edited by Mark McIntosh 2020 University of Georgia College of Agricultural and Environmental Sciences UGA Extension Office of Communications and Creative Services Office of Communications and Creative Services Office of Communications and Creative Services, Are steroids ever tapered during the standards of care for adult patients during the natural course of the disease? Yeah,

Matthew: We have a couple if I may.

Matthew: First.

Matthew: Could you please elaborate on the safety and efficacy of using a fixed dose for patients.

Sukumar Nagendran: Good afternoon. I'll also add my own, Progress. So, just one from us: can you maybe put into context the burden experienced by, edited by Mark McIntosh 2020 University of Georgia College of Agricultural and Environmental Sciences UGA Extension Office of Communications and Creative Services Office of Communications and Creative Services Office of Communications and Creative Services, Are steroids ever tapered during the standards of care for adult patients during the natural course of the disease? Yeah, so that's another good question. So, immunosuppression or immunomodulation in general is not used to treat Rett patients in a disease-modifying fashion. It has been tried in the past using drugs like sirolimus or prednisolone or hydrocortisone to treat Rett syndrome, but it hasn't had any positive impact on disease duration, severity, or outcome.

Good afternoon. I'll also add my own, Progress. So, just one from us: can you maybe put into context the burden experienced by, edited by Mark McIntosh 2020 University of Georgia College of Agricultural and Environmental Sciences UGA Extension Office of Communications and Creative Services Office of Communications and Creative Services Office of Communications and Creative Services, Are steroids ever tapered during the standards of care for adult patients during the natural course of the disease? Yeah,

Matthew: As young as three years old to adults and if you expect to achieve a comparable exposure level in the CNS of these patients.

Speaker Change: The answer to that I can start would be that the.

Speaker Change: The overall CNS fluid volume between a three year old than an adult actually is very there's very little difference which is why.

Sukumar Nagendran: So, that's another good question. Immunosuppression or immunomodulation, in general, is not used to treat Rett patients in a disease-modifying fashion. It has been tried in the past using drugs like SIROLIMUS or PREDNISOLONE or HYDROCORTISONE to treat Rett syndrome but it hasn't had any positive impact on disease duration, severity or outcome. What we are seeing in our trial, though, is because it's a gene therapy trial -- steroids and SIROLIMUS are being used as immunomodulatory agents to allow us to get over that initial period where there might be some theoretical risk of the treatment itself.

Speaker Change: We're comfortable the IDM sees comfortable the regulators have all been comfortable based on the preclinical data using that fixed dose.

Speaker Change: And the same across patient populations essentially.

Speaker Change: Thank you and the other.

Speaker Change: Other question is that how do you envision a registered a registrational trial.

Operator: So, what we are seeing in our trial, though, is because it's a gene therapy trial, steroids and sirolimus are being used as immunomodulatory agents to allow us to get over that initial period where there might be some theoretical risk of the treatment itself. Our next question comes from the line of Joon Lee with Truist. Please proceed with your question.

So, what we are seeing in our trial, though, is because it's a gene therapy trial, steroids and sirolimus are being used as immunomodulatory agents to allow us to get over that initial period where there might be some theoretical risk of the treatment itself.

Speaker Change: Looked like if data supports and if you think M. D. R. I as a measure could be considered given the nature of the disease requiring multiple domain improvement.

Speaker Change: Balances.

Speaker Change: You know I would say a couple of things as it relates to clinical trial design I think the headline is we feel like there is multiple pathways that we can go down in multiple end points that are there for consideration, which is a good place to be at this particular juncture.

Operator: Our next question comes from the line of Joon Lee with Truist. Please proceed with your question.

Mehdi Goudarzi: Hi, good afternoon. This is Mehdi, on for Joon and congrats on the quarter. And thanks for taking our questions. We have a couple, if I may. First, could you please elaborate on the safety and efficacy of using a fixed dose for patients as young as three years old to adults and if you expect to achieve a comparable exposure level in the CNS of these patients?

Mahdi Goudarzi: First, could you please elaborate on the safety and efficacy of using a fixed dose for patients as young as three years old to adults, and if you expect to achieve a comparable exposure level in the CNS of these patients? The answer to that, I can start by saying that the overall CNS fluid volume between a three-year-old and an adult actually is very, there's very little difference, which is why, you know, we're comfortable, the IDMC is comfortable, the regulators have all been comfortable based on the preclinical data using that fixed dose in the same way across patient populations essentially.

First, could you please elaborate on the safety and efficacy of using a fixed dose for patients as young as three years old to adults, and if you expect to achieve a comparable exposure level in the CNS of these patients?

Speaker Change: We've always been very steadfast in our view that we were going to use part a to get to a better informed view and that we would have a discussion with the FDA prior to starting part B of the study if we wanted to refine endpoints and refined our trial design.

Sean Nolan: The answer to that -- I can start -- would be that the overall CNS fluid volume between a three-year old and an adult, actually is very, there's very little difference. Which is why we're comfortable, the IDMC is comfortable, the regulators have all been comfortable based on the pre-clinical data using that fixed dose in the same -- across patient populations, essentially.

That was one of the reasons, we put out press release out a few weeks ago, when we announced that the IV M. C had allowed us to go to the higher dose earlier, because we think that stop.

Speaker Change: Hopefully provide more clarity to us relative to endpoints and potentially trial design as well. So we can't say anything declarative what right now about what exactly we're going to do I would say, where we continued to be very.

Sean P. Nolan: Thank you. And the other question is that, how do you envision a registrational trial would look like if data supports and if you think MDRI as a measure could be considered given the nature of the disease requiring multiple domain improvement analysis? You know, I would say a couple of things.

Mehdi Goudarzi: Thank you. And the other question is that, how do you envision a registrational trial would look like if data supports and if you think MDRI as a measure could be considered given the nature of the disease requiring multiple domain improvement analysis?

Speaker Change: Encouraged of the pathway that we're on to be further informed in the coming quarters that can help us with the F. D E and I think in terms of the endpoints again, we know that there's a pathway there with CGI I and RSP Q and there may be additional.

You know, I would say a couple of things. As it relates to clinical trial design, I think the headline is, we feel like there's multiple pathways that we can go down and multiple endpoints that are there for consideration -- which is a good place to be at this particular juncture. We've always been very steadfast in our view that we were going to use Part A to get to a better informed view and that we would have a discussion with the FDA, prior to starting Part B of the study if we wanted to refine endpoints and refine our trial design. So, that was one of the reasons we put a press release out a few weeks ago when we announced that the IDMC had allowed us to go to the higher dose earlier because we think that step will, hopefully, provide more clarity to us relative to endpoints and ,potentially, trial design as well. So, you know, we can't say anything declarative right now about what exactly we're going to do.

Sean Nolan: You know, I would say a couple of things. As it relates to clinical trial design, I think the headline is, we feel like there's multiple pathways that we can go down and multiple endpoints that are there for consideration -- which is a good place to be at this particular juncture. We've always been very steadfast in our view that we were going to use Part A to get to a better informed view and that we would have a discussion with the FDA, prior to starting Part B of the study if we wanted to refine endpoints and refine our trial design.

Sean P. Nolan: As it relates to clinical trial design, I think the headline is that we feel like there are multiple pathways that we can go down and multiple endpoints that are there for consideration, which is a good place to be at this particular juncture. We've always been very steadfast in our view that we were going to use Part A to get to a better informed view and that we would have a discussion with the FDA prior to starting Part B of the study if we wanted to refine endpoints and refine our trial design. So that was one of the reasons we put out our press release a few weeks ago when we announced that the IDMC had allowed us to go to the higher dose earlier because we think that step will hopefully provide more clarity to us relative to endpoints and potentially trial design as well. So, you know, we can't say anything declarative right now about what exactly we're going to do.

Speaker Change: End points for consideration, but again, we think we'll be better informed on as we continue to step through dosing patients, particularly at the high dose.

Speaker Change: Hopefully that makes thank you.

Speaker Change: Yeah, Jack for picking up restaurants.

Speaker Change: Our next question comes from the line of Yaron.

Yaron: With Wells Fargo. Please proceed with your question.

That was one of the reasons we put a press release out a few weeks ago when we announced that the IDMC had allowed us to go to the higher dose earlier because we think that step will, hopefully, provide more clarity to us relative to endpoints and ,potentially, trial design as well. So, you know, we can't say anything declarative right now about what exactly we're going to do. I would say, we continue to be very encouraged of the pathway that we're on to be further informed in the coming quarters that can help us with the FDA. And I think in terms of the endpoints, again, we know that there's a pathway there with CGI-I and RSBQ and there may be additional endpoints for consideration that, again, we think we'll be better informed on as we continue to step through dosing patients, particularly at the high dose. Hopefully, that makes sense.

Yaron: Oh, great. Thank you for taking our questions and.

Yaron: Congrats on the progress.

Yaron: I was wondering hum.

Yaron: First patient seeing a pediatric trial and you're calling through the six week safety monitoring Committee evaluation.

So, you know, we can't say anything declarative right now about what exactly we're going to do. I would say we continue to be very encouraged by the pathway that we're on to be further informed in the coming quarters that can help us with the FDA. And I think in terms of, you know, the endpoints, again, we know that there's a pathway there with CGI and RSVQ, and there may be additional endpoints for consideration that, again, we think will be better informed on as we continue to step through dosing patients, particularly at the high dose. Hopefully, that makes sense.

Yaron: Wondering if there any color from that patient in terms of Ah <unk>.

Sean P. Nolan: I would say we continue to be very encouraged by the pathway that we're on to be further informed in the coming quarters that can help us with the FDA. And I think in terms of, you know, the endpoints, again, we know that there's a pathway there with CGI and RSVQ, and there may be additional endpoints for consideration that, again, we think will be better informed on as we continue to step through dosing patients, particularly at the high dose. Hopefully, that makes sense.

I would say, we continue to be very encouraged of the pathway that we're on to be further informed in the coming quarters that can help us with the FDA. And I think in terms of the endpoints, again, we know that there's a pathway there with CGI-I and RSBQ and there may be additional endpoints for consideration that, again, we think we'll be better informed on as we continue to step through dosing patients, particularly at the high dose. Hopefully, that makes sense.

Yaron: Improvement that could be consistent with what youre seeing in the adult trial or in general potential for such improvement.

Yaron: In the pediatric population.

Speaker Change: Really appreciate the question I, just would I'd go back to and we dosed the first patient in the pediatric patient at the very end of.

Speaker Change: Of December and about a week later, we put out a press release, saying that we wanted to begin to.

Yanan Zhu: Thank you. Yeah, thanks for taking our questions. Our next question comes from a line from Yanan Zhu with Wells Fargo.

Mehdi Goudarzi: Thank you. Yeah, thanks for taking our questions.

Speaker Change: Disclose data on a cohort basis and that we felt that was the most appropriate thing to do versus growing patient by patient and so you know all I can tell you at this point in time is that the idea M. C saw the initial pediatric data as well as the data that we just reported on the two.

Operator: Our next question comes from the line of Yanan Zhu with Wells Fargo. Please proceed with your question.

Sean P. Nolan: Oh, great. Thank you for taking our questions. Congratulations on the progress. So, I was wondering, since the first patient in a pediatric trial has gone through the six-week safety monitoring committee evaluation, is there any color from that patient in terms of improvement that could be consistent with what you are seeing in the adult trial? Or, in general, the potential for such improvement in the pediatric population? Thank you. I really appreciate the question.

Yanan Zhu: Oh, great. Thank you for taking our questions. Congrats on the progress. So, I was wondering, since the first patient seen in a pediatric trial has gone through the 6-week safety monitoring committee evaluation, is there any color from that patient in terms of improvement that could be consistent with what you are seeing in the adult trial? Or, in general, potential for such improvement in a pediatric population? Thanks.

Speaker Change: Adults and that was in their calculus as they decided that we could go to the high dose in the adolescent and adult study and we can proceed the dosing the second adolescent patient so beyond that we'd really prefer not to comment and then proceed.

Really appreciate the question. I just would, I'd go back to -- we dosed the first patient, the pediatric patient, at the very end of December and about a week later, we put out a press release saying that we wanted to begin to disclose data on a cohort basis and that we felt that was the most appropriate thing to do versus going patient by patient. And so, you know, all I can tell you at this point in time is that the IDMC saw the initial pediatric data, as well as the data that we just reported on the two adults, and that was in their calculus as they decided that we could go to the high dose in the adolescent and adult study and we could proceed to dosing the second adolescent patient. So, beyond that, we'd really prefer not to comment and proceed with our path forward to disposing that data in a more wholesome manner at mid-year. Understood. Thank you for the answer.

Sean Nolan: Really appreciate the question. I just would, I'd go back to -- we dosed the first patient, the pediatric patient, at the very end of December and about a week later, we put out a press release saying that we wanted to begin to disclose data on a cohort basis and that we felt that was the most appropriate thing to do versus going patient by patient.

Yanan Zhu: I just would, I'd go back to, we dosed the first patient, the pediatric patient, at the very end of December, and about a week later, we put out a press release saying that we wanted to begin to disclose data on a cohort basis and that we felt that was the most appropriate thing to do versus going patient by patient. And so, you know, all I can tell you at this point in time is that the IDMC saw the initial pediatric data as well as the data that we just reported on the two adults, and that was in their calculus as they decided that we could go to the high dose in the adolescent and adult studies, and we could proceed to dosing the second adolescent patient. So beyond that, we'd really prefer not to comment and proceed with our path forward to disposing of that data in a more wholesome manner at mid-year. understood. Thank you for the answer.

Speaker Change: Forward to disclosing that data in a more wholesome manner at mid year.

Speaker Change: Understood. Thank you for the answer if I may a quick.

And so, all I can tell you at this point in time, is that the IDMC saw the initial pediatric data, as well as the data that we just reported on the two adults. And that was in their calculus, as they decided that we could go to the high dose in the Adolescent and Adult study and we could proceed to dosing the second adolescent patient. So, beyond that, we'd really prefer not to comment and proceed with our path forward to disclosing that data in a more wholesome manner at mid-year.

Speaker Change: A quick follow up question on the patient one and two in the adult.

Speaker Change: That dataset.

Speaker Change: We can see clearly a patient why has continued improvement or new improvement in RFP queue patient to have new improvement E. R. M B a.

Speaker Change: But interestingly the yeah.

Speaker Change: The other endpoint for those patients seems to be pretty flat.

Understood. Thank you for the answer. If I may do a quick follow-up question on the Patient 1 and Patient 2 in the adult dataset. We can see clearly, Patient 1 has continued improvement or new improvement in RSBQ, Patient 2 has new improvement in R-MBA but, interestingly, the other end point for those patients seems to be pretty flat. So, how do you think about that and is there a potential for the other endpoint to also improve in the future? Thank you. If you're referring to CGI-I, you know, I would say that -- is that what you're talking about? Sorry Sorry CGII, I fully appreciate that.

Yanan Zhu: Understood. Thank you for the answer. If I may do a quick follow-up question on the Patient 1 and Patient 2 in the adult dataset. We can see clearly, Patient 1 has continued improvement or new improvement in RSBQ, Patient 2 has new improvement in R-MBA but, interestingly, the other end point for those patients seems to be pretty flat. So, how do you think about that and is there a potential for the other endpoint to also improve in the future? Thank you.

Sean P. Nolan: If I may do a quick follow-up question on patient one and patient two in the adult data set, we can clearly see that patient one has continued improvement or new improvement in RSV-2, patient two has new improvement in RMDA, but interestingly, the other end point for those patients seems to be pretty flat. So how do you think about that, and is there a potential for the other endpoint to also improve in the future? Thank you. And if you're referring to CGII, you know, I would say that, is that what you're talking about? Sorry Sorry CGII, I fully appreciate that.

Speaker Change: So how do you think about that and is there a potential for the other endpoint to also improve in the future. Thank you.

Speaker Change: If you're referring to like CGI.

Speaker Change: Hi.

Speaker Change: You know I would say that.

Speaker Change: Is that what youre talking about Oh, sorry, sorry C. J I fully appreciate that even maintenance of the prior numbers according to our hour okay.

If you're referring to CGI-I, you know, I would say that -- is that what you're talking about? Sorry Sorry CGII, I fully appreciate that.

Sean Nolan: If you're referring to CGI-I, you know, I would say that -- is that what you're talking about?

Sorry. Sorry, CGI-I. I fully appreciate that. Even maintenance of the prior numbers, according to our check with the doctors -- that's a very, very encouraging sign to have those minimally improved ratings maintained in a follow-up and also to have the much improved for the other patient maintained. Those are great achievements. I'm talking about RSBQ and R-MBA, where both patients had one score improve and the other score relatively flat. Yeah, so that's what I'm talking about. I gotcha. So patient number one, first of all, the RMBA is administered by the clinician in the hospital, the RSVQ is provided by the caregivers in the home setting, and they ask different questions. Okay, so it's a little difficult to put apples and oranges together, but I would say this. We actually asked the primary investigator this same question, and what she said was... The patient number one has become very aware of what's going on in her surroundings. If I showed you the video from pre-treatment, she was very, very, almost in a catatonic state in a wheelchair, really not interacting. Now she's much more aware. She's trying to communicate and vocalize.

Yanan Zhu: Sorry. Sorry, CGI-I. I fully appreciate that. Even maintenance of the prior numbers, according to our check with the doctors -- that's a very, very encouraging sign to have those minimally improved ratings maintained in a follow-up and also to have the much improved for the other patient maintained. Those are great achievements. I'm talking about RSBQ and R-MBA, where both patients had one score improve and the other score relatively flat. Yeah, so that's what I'm talking about.

Speaker Change: With a doctor that that's a very very encouraging sign to to have no minimum money improved ratings are maintained in a.

Sean P. Nolan: Even maintenance of the prior numbers, according to our check with the doctors, that's a very, very encouraging sign to have those minimally improved ratings maintained in a follow-up, and also to have the much improved ratings for the other patient maintained. Those are great achievements. I'm talking about RSVQ and RMBA, where both patients had one score improve, and the other score was relatively flat. Yeah, so that's what I'm talking about. I gotcha. So patient number one, first of all, the RMBA is administered by the clinician in the hospital, the RSVQ is provided by the caregivers in the home setting, and they ask different questions. Okay, so it's a little difficult to put apples and oranges together, but I would say this. We actually asked the primary investigator this same question, and what she said was... The patient number one has become very aware of what's going on in her surroundings. If I showed you the video from pre-treatment, she was very, very, almost in a catatonic state in a wheelchair, really not interacting. Now she's much more aware. She's trying to communicate and vocalize.

Speaker Change: Following.

Speaker Change: Follow up and also to have that much.

Speaker Change: Much improved for the paint the other patient maintained those are great achievements and talking about RSP Q and R. M B, a where both patient had one score.

Speaker Change: Improve and the other score a relatively a flat yeah.

Speaker Change: Yeah, that's what I'm talking about.

Speaker Change: I gotcha. So in patient number one so first of all the RMB is administered by the clinician and the hospital. The RSP Q is provided by the caregivers in the home setting and they ask different questions. Okay. So so it's a little difficult to put at.

I gotcha. So, in patient number one -- first of all, the R-MBA is administered by the clinician in the hospital; the RSBQ is provided by the caregivers in the home setting and they ask different questions, okay? So, it's a little difficult to put apples to oranges but I would say this -- we actually asked the primary investigator this same question and what she said was, patient number one has gotten very aware of what's going on in her surroundings. If I showed you the video from pre-treatment, she was very, very -- almost in a catatonic state in a wheelchair, really not interacting. Now, she's much more aware. She's trying to communicate and vocalize. And basically, what the PI told us is, she does not like going through the testing at the hospital. She gets irritated and she doesn't want to cooperate. And at this point, she has the strength to not cooperate. So, that has been driving some of the -- it's driving the score that you're saying. She's essentially not necessarily cooperating with some aspects of the testing; where in the home setting, she's getting very much a comfortable situation and the parents are seeing it. The other thing I would say, is that some of the improvement that I mentioned earlier in the RSBQ that Patient 1 had was in the anxiety, the general mood aspect of things. That is not captured in the R-MBA.

Sean Nolan: I gotcha. So, in patient number one -- first of all, the R-MBA is administered by the clinician in the hospital; the RSBQ is provided by the caregivers in the home setting and they ask different questions, okay? So, it's a little difficult to put apples to oranges but I would say this -- we actually asked the primary investigator this same question and what she said was, patient number one has gotten very aware of what's going on in her surroundings. If I showed you the video from pre-treatment, she was very, very -- almost in a catatonic state in a wheelchair, really not interacting.

Apples to oranges, but I would I would say this we we actually asked the primary investigator the.

Speaker Change: The same question and and what she said was.

Speaker Change: The patient number one.

Speaker Change: Has has gotten very aware of what's going on in her surroundings.

Speaker Change: If I showed you the video from pre treatment. She was very very almost like in a catatonic state in a wheelchair really not interacting now she is much more aware she's she's trying to communicate and vocalized and basically.

Now, she's much more aware. She's trying to communicate and vocalize. And basically, what the PI told us is, she does not like going through the testing at the hospital. She gets irritated and she doesn't want to cooperate. And at this point, she has the strength to not cooperate. So, that has been driving some of the -- it's driving the score that you're saying. She's essentially not necessarily cooperating with some aspects of the testing; where in the home setting, she's getting very much a comfortable situation and the parents are seeing it. The other thing I would say, is that some of the improvement that I mentioned earlier in the RSBQ that Patient 1 had was in the anxiety, the general mood aspect of things. That is not captured in the R-MBA.

Sean P. Nolan: And basically, what the PI told us is that she does not like going through the testing at the hospital. She gets irritated, and she doesn't want to cooperate. And at this point, she has the strength to not cooperate. So that has been driving some of the... It's driving the score that you're saying.

Speaker Change: With the P. I told us as she does not like.

Speaker Change: Going through the testing at the hospital she gets irritated.

Speaker Change: And she doesn't want to cooperate and and at this point. She has the strength to not cooperate. So that is that has been driving some of the.

Speaker Change: It's driving the score that you're saying she she is essentially not necessarily cooperating with some aspects of the disease of the testing.

Sean P. Nolan: She's essentially not necessarily cooperating with some aspects of the disease and of the testing, where in the home setting, you know, she's getting a very comfortable situation, and her parents are seeing it. The other thing I would say is that some of the improvement that I mentioned earlier in the RSVQ that patient one had was in the anxiety, the general mood aspect of things. That is not captured in the RMBA.

Speaker Change: We're in the in the home setting you know she's getting very much okay.

Speaker Change: Comfortable situation and.

The other thing I would say, is that some of the improvement that I mentioned earlier in the RSBQ that Patient 1 had was in the anxiety, the general mood aspect of things. That is not captured in the R-MBA. So, that's one aspect there. On Patient 2, her R-MBA improved significantly and it was driven, essentially, by her socialization, her interest in communicating with people and also her seizures. Those were big drivers. In the RSBQ -- neither of those is addressed, neither one of those is quantified. And in the RSBQ, again, she had an elevation in anxiety and some of the nighttime behaviors which, again, if you think about what I said about Patient 1 and steroids, that could also be the case. She has had a bit of an issue with tolerating the steroids. So hopefully, again, that gives you some perspective on those two things. And Suku have something to add as well. And also, for Patient 2, I would highlight the seizures were decreased by 95% post-gene therapy treatment. So this patient had, I think, 8 to 16 seizures a month. And other than one seizure, day 13 post-treatment, the patient has had none. No new seizures. And also, the use of combination anti-epileptic meds has dropped by 25%.

Speaker Change: She's the parents are seeing is the other thing I would say is that some of the improvement that I mentioned earlier on the RSP Q. The patient one had was in the anxiety. The general mood aspect of things that is not captured in the R. M B yet.

Sean P. Nolan: So that's, you know, that's one aspect there of patient two. You know, her RMBA improved significantly, and it was driven essentially by her socialization, her interest in communicating with people, and also her seizures. You know, those were big drivers.

Speaker Change: So that's.

Speaker Change: That's one aspect there on patient too.

Speaker Change: Per our MBA improves significantly and it was driven essentially by her socialization her interest and communicating with people and also her seizures. So those were big drivers.

Those were big drivers. In the RSBQ -- neither of those is addressed, neither one of those is quantified. And in the RSBQ, again, she had an elevation in anxiety and some of the nighttime behaviors which, again, if you think about what I said about Patient 1 and steroids, that could also be the case. She has had a bit of an issue with tolerating the steroids. So hopefully, again, that gives you some perspective on those two things. And Suku have something to add as well.

Sukumar Nagendran: In the RSVQ, neither of those is addressed, nor is either of those quantified. And in the RSVQ, again, she had an elevation in anxiety and some of the nighttime behaviors, which again, if you think about what I said about patient one and steroids, that could also be the case. She has had a bit of an issue with tolerating the steroids. So hopefully, again, that gives you some perspective on those two things, and Suku had something to add as well. And also, for patient two, I would highlight that the seizures were decreased by 95% post-gene therapy treatment. So this patient had, I think, eight to 16 seizures a month. And other than one seizure, on day 13 post-treatment, the patient has had none, no new seizures. And also, the use of combination anti-epileptic meds has dropped by 25%.

Speaker Change: In the RSP Q. Neither of those is is addressed neither one of those is quantified.

Speaker Change: And in the RSP queue again, she had an elevation in anxiety and and some of the nighttime behaviors, which again, if you think about what I said about patient wanted to steroids that that could also be the case. She she has had a bit of an issue with tolerating the steroids. So hopefully again that gives.

Speaker Change: Just some perspective on those two things and Sukru had something that as well and also for patients two I would highlight the seizures decreased by 95% post gene therapy treatment. So this patient had I think 8%.

Sukumar Nagendran: Yeah. And also, for Patient 2, I would highlight the seizures were decreased by 95% post-gene therapy treatment. So this patient had, I think, 8 to 16 seizures a month. And other than one seizure, day 13 post-treatment, the patient has had none. No new seizures. And also, the use of combination anti-epileptic meds has dropped by 25%. That is a big deal from a clinical standpoint and for the parents and caregivers and from an activities of daily living standpoint. The second thing you should notice in Patient 2, some of the hand function and stereotypic movements have decreased -- which also makes it promising that this patient may eventually get independent functionality of the hands. And there is something else that goes on in about 40% of these patients with Rett syndrome, which is the upper and lower extremities have abnormal circulation, which means the hands and feet get quite cold and at times, painful. And you would note in Patient 2 and Patient 1, that result post-gene therapy treatment. So, other than R-MBA and RSBQ -- which, obviously, we focus on for different reasons -- these major clinical observations, I think, could be life-changing in this patient population. Our next. In the line of Jack Allen, Robert W. Baird.

Speaker Change: <unk> made to 16 seizures, a month and other than one seizure data didn't post treatment. The patient has had none no new seizures and also the use of our combination anti epileptic med sub dropped by 25% that is a big deal from a clinical standpoint, and for the parents and caregivers and some in activities of daily.

Sukumar Nagendran: That is a big deal from a clinical standpoint and for the parents and caregivers and from an activities of daily living standpoint. The second thing you should notice in patient two is that some of the hand function and stereotypic movements have decreased, which also makes it promising that this patient may eventually get independent functionality of the hands. And there is something else that goes on in about 40% of these patients with Rett syndrome, which is that the upper and lower extremities have abnormal circulation, which means the hands and feet get quite cold and at times painful.

Speaker Change: Living standpoint, the second thing you should notice and patients too.

Speaker Change: Some of the hand function and Sidoti pick movements have decrease which also makes it a promising that discretion may eventually get independent functionality of the hands.

And there is something else that goes on in about 40% of these patients with Rett syndrome, which is the upper and lower extremities have abnormal circulation, which means the hands and feet get quite cold and at times, painful. And you would note in Patient 2 and Patient 1, that result post-gene therapy treatment. So, other than R-MBA and RSBQ -- which, obviously, we focus on for different reasons -- these major clinical observations, I think, could be life-changing in this patient population.

Speaker Change: And there is something else that goes on in about 40% of these patients with ret syndrome, which is the upper and lower extremities.

Speaker Change: Enormous escalation, which means the hands than we'd get quite cool and at times painful and you would note in patient two and patient one that.

Sukumar Nagendran: And you would note in patient two and patient one, that result post-gene therapy treatment. So other than RMB and RSVQ, which obviously we focus on for different reasons, these major clinical observations could be life-changing in this patient population. Our next. In the line of Jack Allen, Robert W. Baird.

That result post gene therapy treatment, so other than our RMB in RSV, <unk>, which obviously, we focus on for different reasons. These major clinical observations I think could be life changing in this patient population.

Operator: Our next question comes from the line of Jack Allen, Robert W. Baird. Please proceed with your question.

Speaker Change: Our next question comes from the line of Jack Allen Robert W. Baird. Please proceed with your question.

Jack Allen: Alright, thanks for taking the question and congratulations on the progress. I'm looking to zoom out a little bit and take attention to the Astellas collaboration that you have. It seems like you're really developing data quite quickly, especially with the pediatric low dose data expected in the middle of this year and the potential initial high dose data later this year. Can you remind us of the structure of the Astellas deal and how it relates to the Rett program and what measures are in place to ensure you get a fair deal? I believe the option was fairly open-ended when that deal was struck.

Speaker Change: Alright, thanks for taking the question and congratulations on the progress.

Speaker Change: I'm looking to zoom out a little bit and.

Speaker Change: Take attention to the Astellas collaboration that you have it seems like you're really developing data quite quickly, especially with the pediatric low dose data expected in the middle of this year and then potential initial high dose data later this year can.

Speaker Change: Can you remind us of the structure of this Dallas deal and how it relates to the rap program and what measures are in place to ensure you get a fair deal I believe the option was fairly open ended when that deal was struck.

Speaker Change: Yeah, I mean, essentially what astellas has as a as a REIT.

Kamran Alam: Yeah. I mean, essentially, what Astellas has is a right to negotiate an option with us, an exclusive right that they have. There's no pre-determined terms, to your particular point. The option period gets triggered after a number of -- about a handful of pediatric patients have, call it, six months of data or so. So, there's no time crunch at this particular point in time where Astellas has to come in and either request an opt-in or not, that's likely a 2025 topic. The other point that I want to really stress, is that Astellas certainly has line of sight to things but it doesn't -- the agreement itself doesn't preclude another party, who might be interested in the program or in the company, from making an unsolicited offer. That's fine. We would just have to notify Astellas of that and they would have the ability to counter, if you will, but there's no blocking right in it. Hopefully, Jack, that gives you some perspective on that. Or did you have a follow-up?

Speaker Change: To negotiate an option with us an exclusive right that they have theres no pre determined terms to cheer particular point.

Speaker Change: The option period gets gets triggered after a number of about a handful of pediatric patients.

Speaker Change: Call it six months of data or so so there is no time crunch at this particular point in time.

Speaker Change: You know, we're astellas has to come in and either request an opt in or not.

That's likely.

Speaker Change: A 2025 topic the other point that I want I want to really you know.

Kamran Alam: The other point that I want to really stress, is that Astellas certainly has line of sight to things but it doesn't -- the agreement itself doesn't preclude another party, who might be interested in the program or in the company, from making an unsolicited offer. That's fine. We would just have to notify Astellas of that and they would have the ability to counter, if you will, but there's no blocking right in it. Hopefully, Jack, that gives you some perspective on that. Or did you have a follow-up?

Speaker Change: Stress is that you know.

Speaker Change: Astellas certainly has line of sight to things, but it doesn't the agreement itself doesn't preclude.

Speaker Change: Another party, who might be interested in the program or in the company from making an unsolicited offer that that's fine.

Sean P. Nolan: That's fine. We would just have to notify Estella of that, and they would have the ability to counter, if you will, but there's no blocking right in it. Hopefully, Jack, that gives you some perspective on that. Or did you have a follow-up question? Yes, that's great, Keller. I actually do have a brief follow-up question about enrollment. How are you thinking about enrollment in these studies and any interpatient staggers? I know your competitor has recently announced that they're expanding a lower dose cohort, and they're allowed to dose in concurrence. At what point do you think you could get to concurrent dosing and what's the current stagger? The current stagger is 42 days and an IDMC meeting before you can proceed to the next patient. I think that, you know, it's a bit of a... more of an art than a science, and I think it's when you have enough data that you can make a request to remove the stagger.

That's fine. We would just have to notify Estella of that, and they would have the ability to counter, if you will, but there's no blocking right in it. Hopefully, Jack, that gives you some perspective on that. Or did you have a follow-up question?

We would just have to notify astellas of that and then they would have the ability to.

Speaker Change: To counter it if you will but theres no theres no blocking right at it.

Speaker Change: Yeah, Jack that gives you some perspective on that or did you have a follow up.

Jack Allen: Yep, that's great color. I actually do have a brief follow-up question about enrollment. How are you thinking about enrollment in these studies and any interpatient staggers? I know your competitor has recently announced that they're extending a lower dose cohort and they're allowed to dose in concurrence. At what point do you think you could get to concurrent dosing and what's the current stagger between patients right now? The current stagger is 42 days and an IDMC meeting before you can proceed to the next patient. I think that, you know, it's a bit of a... more of an art than a science, and I think it's when you have enough data that you can make a request to remove the stagger.

Yes, that's great color I actually do have a brief follow up around enrollment.

Speaker Change: How are you thinking about enrollment in these studies and any inter patient staggers I know your competitor has recently announced that they are expanding at a lower dose cohort and they're allowed to dose.

Speaker Change: Concurrent.

Speaker Change: At what point do you think you could get to concurrent dosing and what's the current stagger between patients right now.

Kamran Alam: The current stagger's 42 days and an IDMC meeting before you can proceed to the next patient. I think that it's a bit of an art than a science and I think it's when you have enough data that you can make a request to remove the stagger. I think, for us, a good -- we took the three patients' worth of data and so we think, based on this data, we've demonstrated safety, preliminary efficacy and based on the pre-clinical data, there's a rationale to go to a higher dose and we're able to do that. So, instead of dosing three low dose patients in the adult study, we were able to do two patients and then move to the high dose -- which we think is going to be more informative to the overall program and, potentially, better for patients. So, if you apply that logic, there would be a point in time where we would be comfortable, potentially going to the IDMC and talking about removing the stagger and that's something we have to do when we feel that we've got data that we feel sufficient to support that request in a credible manner.

Speaker Change: The current staggers 42 days.

And then our DMC meeting before you can proceed to the next patient.

Speaker Change: Think that you know, it's a bit of a.

Speaker Change: Of an art than a science I think it's when you have enough data that you can make a request to remove the stagger you know I think for us.

Sean P. Nolan: You know, I think for us, a good example of that is, you know, we took three patients' worth of data and said, we think, based on this data, we've demonstrated safety, preliminary efficacy, and based on the preclinical data, there's a rationale to go to a higher dose, and we're able to do that. So instead of dosing three low-dose patients in the adult study, we were able to do two patients and then move to the higher dose, which we think is going to be more informative for the overall program and potentially better for patients. So, if you apply that logic, you know, there would be a point in time where we would be comfortable potentially going to the IDMC and talking about removing this dagger. And that's just something we'll have to do when we feel that, you know, we've got data that we feel is sufficient to support that request in a credible manner.

Speaker Change: It does.

Speaker Change: No. We took the three patients worth of data in and said we think based on this data you know we've demonstrated the safety preliminary efficacy and based on the preclinical data that there is a rationale to go to a higher dose and we were able to do that so instead of dosing three low dose.

Kamran Alam: So, instead of dosing three low dose patients in the adult study, we were able to do two patients and then move to the high dose -- which we think is going to be more informative to the overall program and, potentially, better for patients. So, if you apply that logic, there would be a point in time where we would be comfortable, potentially going to the IDMC and talking about removing the stagger and that's something we have to do when we feel that we've got data that we feel sufficient to support that request in a credible manner.

Speaker Change: Patients in the adult study, we were able to do two patients and then move to the higher dose, which we think is going to be more informative to the overall program and potentially better for patients.

Speaker Change: So if you apply that logic.

Speaker Change: There would be a point in time, where we would be comfortable potentially going to the IBM Z and talking about removing the stagger.

Speaker Change: And that's just something we'll have to do when we feel that we.

Speaker Change: We've got data that we feel is sufficient to support that requested a credible manner.

Jack Kilgannon Allen: So, Got it. Great. Thanks so much for the call and congratulations again on the progress. Thanks, Jack.

So, if you apply that logic, there would be a point in time where we would be comfortable, potentially going to the IDMC and talking about removing the stagger and that's something we have to do when we feel that we've got data that we feel sufficient to support that request in a credible manner.

Got it. Great. Thanks so much for the color and congratulations again on the progress. Thanks, Jack.

Jack Allen: Got it. Great, thanks so much for the color and congratulations again on the progress.

Speaker Change: Got it great. Thanks, so much for the color and congratulations again on the progress.

Speaker Change: Thanks Jay.

Speaker Change: Yeah.

Kamran Alam: Thanks, Jack.

We have time for one last question. Our last question comes from the line of Silvan.

Unknown Caller: We have time for one last question. Last, Yeah, thank you. Congratulations on the great update and thank you for taking my question. I just have a question about your dose, roughly going ahead, you can double the dose faster than you expected. Can you just talk about what that means in terms of the, you know, in terms of the efficacy results that you're hoping for? Do you think there could be a greater increase, or what is your hope for the higher dose? I'll start and ask Suku to comment as well, but first of all, when you look at the preclinical data, there is a dose response. So you would expect there to be a greater response moving to the higher dose. But you know, what's driving that?

Operator: We have time for one last question. Our last question comes from the line of Silvan Tuerkcan with Citizens JMP, Please proceed with your question.

Yeah, thank you. Congrats on the great update and thank you for taking my question. I just have a question about your dose -- roughly going ahead, you can double the dose faster than you expected. Can you just talk about what that means in terms of the efficacy results that you're hoping for? Do you think there could be a greater increase or what is your hope for the higher dose here? I'll start and ask Suku to opine as well but, first of all, when you look at the preclinical data, there is a dose response. So you would expect there to be a greater response moving to the higher dose. But you know, what's driving that?

Silvan Tuerkcan: Yeah, thank you. Congrats on the great update and thank you for taking my question. I just have a question about your dose -- roughly going ahead, you can double the dose faster than you expected. Can you just talk about what that means in terms of the efficacy results that you're hoping for? Do you think there could be a greater increase or what is your hope for the higher dose here?

Silvan: With citizens JMP. Please proceed with your question.

Silvan: Yeah. Thank you congrats on the great update and thank you for taking my question.

Silvan: I have a question about your dose roughly going ahead. Your you can double the dose faster than you expected can you just talk about what that means and in the you know in terms of the efficacy results that you're hoping for did you think there could be a greater increase or what is your hope for higher dose here.

I'll start and ask Suku to opine as well but, first of all, when you look at the preclinical data, there is a dose response. So, you would expect there to be a greater response moving to the higher dose. What's driving that? You anticipate that by giving roughly 75%, 80% more dose, that you'd be transducing more cells, you'd be generating more MECP2 in the cells that need more MECP2 and that overall, you should have a more significant clinical effect than what was seen in the low dose. Thank you. Yeah, if I may have a quick... That is all the time we have. Goodbye. I'd like to hand it back to management for closing remarks. Okay, I just want to thank everyone for taking the time and appreciate you listening to the story and the work you're to continue to progress in 2024 and generate additional data and, hopefully, more value-creating milestones for the investors and care for the patients. So, thank you, and have a good night.

Sean Nolan: I'll start and ask Suku to opine as well but, first of all, when you look at the preclinical data, there is a dose response. So, you would expect there to be a greater response moving to the higher dose. What's driving that? You anticipate that by giving roughly 75%, 80% more dose, that you'd be transducing more cells, you'd be generating more MECP2 in the cells that need more MECP2 and that overall, you should have a more significant clinical effect than what was seen in the low dose.

Silvan: Well I'll start and ask Sue could opine as well, but first of all when you look at the preclinical data. There is a dose response. So you you would expect there to be a greater response moving to the higher dose whats driving that you.

You would anticipate that by giving roughly 75, 80% more dose, you'd be transducing more cells, you'd be generating more MECP2 in the cells that need more MECP2, and that overall, you should have, you know, a more significant clinical effect than what was seen at the low dose. Thank you. Yeah, if I may have a quick... That is all the time we have. Goodbye. I'd like to hand it back to management for closing remarks. Okay, I just want to thank everyone for taking the time and appreciate you listening to the story and the work you're to continue to progress in 2024 and generate additional data and, hopefully, more value-creating milestones for the investors and care for the patients. So, thank you, and have a good night.

Sue Gantry: We anticipate that by giving roughly 70, 580% more dose that you'd be trans dusing more cells you'd be generating more M. A C. P too in the cells that need more <unk>.

Speaker Change: And that overall you should have you know.

More significant clinical effect than what was seen in in the low dose.

Thank you. Yeah, if I may have a quick -- That is all the time we have. Goodbye. I'd like to hand it back to management for closing remarks. Okay, I just want to thank everyone for taking the time and appreciate you listening to the story and the work you're to continue to progress in 2024 and generate additional data and, hopefully, more value-creating milestones for the investors and care for the patients. So, thank you, and have a good night.

Silvan Tuerkcan: Thank you. Yeah, if I may have a quick --

That is all the time we have. Yeah, you can -- Goodbye. I'd like to hand it back to management for closing remarks. Okay, I just want to thank everyone for taking the time and appreciate you listening to the story and the work you're to continue to progress in 2024 and generate additional data and, hopefully, more value-creating milestones for the investors and care for the patients. So, thank you, and have a good night.

Operator: That is all the time we have.

Speaker Change: Thank you.

Speaker Change: Yeah, if I'm right that quick.

Yeah, you can -- Goodbye. I'd like to hand it back to management for closing remarks. Okay, I just want to thank everyone for taking the time and appreciate you listening to the story and the work you're to continue to progress in 2024 and generate additional data and, hopefully, more value-creating milestones for the investors and care for the patients. So, thank you, and have a good night.

Sean Nolan: Yeah, you can --

Speaker Change: Okay.

I'd like to hand it back to management for closing remarks. Okay, I just want to thank everyone for taking the time and appreciate you listening to the story and the work you're to continue to progress in 2024 and generate additional data and, hopefully, more value-creating milestones for the investors and care for the patients. So, thank you, and have a good night.

Operator: I'd like to hand it back to management for closing remarks.

Speaker Change: That is all the time that you can ask questions.

Sean Nolan: Okay, I just want to thank everyone for taking the time and appreciate you listening to the story and we're eager to continue to progress in 2024 and generate additional data and, hopefully, more value-creating milestones for the investors and care for the patients. So, thank you and have a good night. Ladies

I'd like to hand, it back to management for closing remarks.

Speaker Change: Okay I just want to thank everyone for taking the time and.

Speaker Change: I appreciate you listening to the story and we're.

Continuing to progress in 2024, and generate additional data and hopefully more value, creating milestones for the investors and care for the patients. So thank you and have a good night.

Operator: Ladies and gentlemen, this does conclude today's teleconference. Thank you for your participation. You may disconnect your lines at this time and have a wonderful day.

Speaker Change: Ladies and gentlemen, this does conclude today's teleconference. Thank you for your participation you may disconnect. Your lines at this time and have a wonderful day.

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