Q1 2024 Taysha Gene Therapies Inc Earnings Call

Operator: [music].

Operator: Greetings and welcome to Taysha Gene Therapy's first quarter 2024 earnings call. At this time, all participants are in a listen-only mode.

Greetings and welcome to the Taser gene therapies first quarter 'twenty 'twenty four earnings call.

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

Operator: A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please raise a star and then zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Hayleigh Collins.

Speaker Change: A brief question and answer session will follow the formal presentation.

Operator: If anyone should require operator assistance during the conference. Please press Star then zero on your telephone keypad.

Operator: As a reminder, this conference is being recorded.

Operator: It is now my pleasure to introduce your host Hailey Collins. Thank you you may begin.

Hayleigh Collins: Thank you. You may begin. Thank you. Good afternoon, and welcome to Taysha's first quarter 2024 Financial Results and Corporate Update conference call. Earlier today, Taysha issued a press release announcing financial results for the first quarter ended March 31st, 2024.

Hayleigh Collins: Thank you good afternoon, and welcome to <unk> first quarter 2024 financial results and corporate update conference call.

Hayleigh Collins: Earlier today <unk> issued a press release announcing financial results for the first quarter ended March 31st 2020 for a copy of this press release is available on the company's website and through our SEC filings.

Hayleigh Collins: A copy of this press release is available on the company's website and through our SEC filings. Joining me on today's call are Sean Nolan, Taysha's CEO, 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 Taysha 102, including the reproducibility and durability of any favorable results initially seen in our first and second patients dosed in the REVEAL trial to positively impact quality of life and the course of disease in the patients we seek to treat, our research, development, and regulatory plans for our product candidates, including the timelines for our clinical trials and reporting results therefrom, and our current cash resources supporting our planned operating expenses and capital requirements into 2026.

Hayleigh Collins: Joining me on today's call are Sean Nolan Tisha CEO, you can learn again drain president and head of R&D and Kamran Alam Chief Financial Officer, We will hold a question and answer session. Following our prepared remarks.

Hayleigh Collins: These statements may include the expected timing and results of clinical trials for 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 actual results to differ materially from those stated or implied in such forward-looking statements.

Speaker Change: Please note that on today's call, we will be making forward looking statements, including statements relating to the therapeutic and commercial potential of peso 102, including the reproducibility and durability of any favorable results initially seen in our first and second patients dose in the reveal trial positively impact quality of life in force of disease and the patients we seek to treat.

Speaker Change: Our research development and regulatory plans for our product candidates, including the timelines for our clinical trial and reporting results therefrom and our current cash resources supporting our planned operating expenses and capital requirements into 2026.

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.

This call May also contain forward looking statements relating to teach us growth forecasted cash runway in future operating results discovery and development of product candidates.

Speaker Change: [noise] alliances intellectual property as well as matters that are not historical facts or information.

Speaker Change: Various risks may cause.

Company Representative: The results to differ materially from those stated or implied in such forward looking statements. These risks include uncertainties related to the timing and results of clinical trials and regulatory interactions for our product candidates our dependence upon strategic alliances and other third party relationships our ability to obtain patent protection for our discoveries.

Hayleigh Collins: These risks include uncertainties related to the timing and results of clinical trials and regulatory interactions for our product candidates, our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties, and the requirements of substantial funding to conduct our research and development activities. For a list and description of the risks and uncertainties that we face, please see the reports that we have filed with the Security and Exchange Commission, including in our annual report on Form 10-K for the full year ended December 31, 2023 and our quarterly report on Form 10-Q for the quarter ended March 31, 2024, which we filed today.

Speaker Change: Limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activities.

Lyft: For Lyft and description of the risks and uncertainties that we face. Please see the reports that we filed with the security and Exchange Commission, including in our annual report on Form 10-K for the full year ended December 31, 2023, and our quarterly report on Form 10-Q for the quarter ended March 31, 2024 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, May 14, 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 said, I would now like to turn the call over to our CEO, Sean Nolan.

Lyft: Call contains time sensitive information that is accurate only as of the date of this live broadcast may 14th 2024.

Lyft: <unk> 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 John Nolan.

Sean Nolan: Thank you, Hayleigh, and welcome everyone to our first quarter 2024 financial results and corporate update conference call. Today, I will begin with a brief update on our recent activities. Then, Dr. Sukumar Nagendran, President and Head of R&D of Taysha, will provide an update on our LEAD Taysha 102 program and clinical evaluation for the treatment of Rett Syndrome. Kamran Alam, our Chief Financial Officer, will follow up with a financial update.

Haley: Thank you Haley and welcome.

Sean Nolan: I will provide closing remarks and open the call up for questions. We are pleased with the recent progress that we've made to advance Taysha 102, our lead gene therapy program and clinical evaluation for the treatment of Rett syndrome. This includes reporting encouraging longer-term data for the first two adult patients dosed in the low dose cohort, enrolling the first patient in the high-dose cohort of our REVEAL Phase 1-2 Adolescent and Adult Trial earlier than planned, dosing the second patient in our REVEAL Phase 1-2 Pediatric Trial, and receiving Regenerative Medicine Advanced Therapy designation from the FDA for Taysha 102.

Sean Nolan: Every one of our first quarter 2024 financial results and corporate update conference call today, I will begin with a brief update on our recent activities.

Sean Nolan: We believe this progress reinforces the therapeutic potential of Taysha 102 across a broad population of patients with Rett syndrome and supports the continued clinical evaluation of our gene therapy program. We believe that we are well-positioned for continued execution across our key upcoming value-creating milestones for our Taysha 102 program with the goal of generating critical, longer-term clinical data across a broad range of ages and stages of patients with Rett syndrome in multiple geographies that will guide the next phase of our study.

Speaker Change: Then Dr. Susan again, DRAM, President and head of R&D, Acacia who will provide an update on our lead case, you're one or two programs in clinical evaluation for the treatment of Ret syndrome.

Speaker Change: Kamran Alam, our Chief Financial Officer will follow up with the financial update I will provide closing remarks and open the call up for questions.

Kamran Alam: We are pleased with the recent progress that we've made to advance tissue 102, our lead gene therapy program in clinical evaluation for the treatment of Ret syndrome.

Kamran Alam: This includes reporting encouraging longer term data for the first two adult patients dosed in the low dose cohort.

Kamran Alam: And enrolling the first patient in the high dose cohort of our reveal phase one two adolescent and adult trial earlier than planned.

Speaker Change: The second patient and our reveal phase once your pediatric trial and received regenerative.

Speaker Change: Medicine advanced therapy designation.

Speaker Change: From the FDA for tissue went up to <unk>.

Speaker Change: We believe this progress reinforces the therapeutic potential of <unk>, one or two across a broad population of patients with <unk> syndrome and supports the continued clinical evaluation of our gene therapy program.

Speaker Change: We believe that we are well positioned for continued execution across our key upcoming value, creating milestones for our tissue 102 program with the goal of generating critical longer term clinical data across a broad range of ages and stages of patients with ret syndrome, and multiple geographies that will guide the next day.

Speaker Change: Days of our studies.

Sean Nolan: The unmet need and burden of care for Rett Syndrome is high. As a rare neurodevelopmental disorder caused by mutations of the MECP2 gene, Rett syndrome afflicts an estimated 15,000 to 20,000 patients in the United States, the European Union, and the United Kingdom. Currently, there are no approved disease-modifying therapies that treat the genetic root cause of the disease, and there is a significant unmet medical need. The random X inactivation and subsequent mosaic pattern of MECP2 expression results in a mixture of cells that are either deficient in MECP2 protein or express MECP2 protein normally, which makes Rett syndrome challenging to treat with traditional small molecule and gene therapy approaches.

Speaker Change: The unmet need and burden of care.

Speaker Change: For Ret syndrome is high.

Sean Nolan: We believe our Taysha 102 gene therapy candidate, equipped with the novel MI, RNA Responsive Autoregulatory Element, or MIRARE technology, has the potential to appropriately address this challenge by mediating MECP2 expression in the central nervous system on a cell-by-cell basis to overcome the risks associated with both under- and overexpression of MECP2 protein.

unknown: That's a rare neurodevelopmental disorder caused by mutations of the <unk> Ret syndrome Afflicts, an estimated 15 to 20000 patients.

Speaker Change: The United States European Union, and the United Kingdom.

Speaker Change: Currently there are no approved disease modifying therapies that she the genetic root causes of disease and there is a significant unmet medical need.

Mahdi Goudarzi: The random acts and activation and subsequent mosaic pattern of M. ECP two expression results and a mixture of cells that are either deficient in <unk> protein or express <unk> protein normally which makes ret syndrome challenging to treat with traditional small molecule and gene therapy approaches.

We: We believe our tissue one or two gene therapy candidate equipped with the novel M. I.

Mahdi Goudarzi: <unk> responsive auto regulatory element or am I rare technology has the potential to appropriately address this challenge by midyear using <unk> two expression in the central nervous system on a cell by cell basis to overcome the risks associated with both under and over expression of MHC future approach.

Sean Nolan: We are evaluating Taysha-102 in two ongoing Phase 1-2 reveal trials, an adolescent and adult trial taking place in Canada and the U.S., and a pediatric trial taking place in the U.S. with clearance in the U.K. As a reminder, our REVEAL Phase 1-2 Adolescent and Adult Trial is a first-in-human study assessing the safety and preliminary efficacy of Ta We are currently enrolling patients in Part A, the dose escalation portion of the trial, which is evaluating two dose levels of Taysha 102 sequentially. Two patients have been dosed to date in Cohort 1 with a low dose of Taysha 102 of 5.7 e to the 14 total vector genomes.

Speaker Change: We are evaluating tissue, one or two in two ongoing phase <unk> reveal trials in adolescent and adult trial, taking place in Canada and the U S.

Speaker Change: And a pediatric trial, taking place in the U S with clearance in the U K.

Sean Nolan: And dosing in Cohort 1 is now considered complete. Following review of the clinical data from the first three patients treated with Taysha-102 across the adolescent and adult trial and the pediatric trial, the Independent Data Monitoring Committee, or IDMC, approved our request to proceed to an early dose escalation in the adolescent and adult trial. Data from Part A of the trial will be assessed by regulatory agencies and the IDMC to provide guidance to determine the final key elements of the Part B aspect of our trial.

Tissue: As a reminder, our reveal phase one two adolescent and adult trial is the first in human study assessing the safety and preliminary efficacy of tissue 102 females, aged 12 years and older with Ret syndrome.

Speaker Change: 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.

Speaker Change: Two patients have been dosed to date in cohort one was the low dose of tissue, one or two of five seven and eight of the 14 total vector genomes and dosing in cohort one is now considered complete.

Speaker Change: Following review of the clinical data from our first three patients treated with tissue, one or two across the adolescent and adult trial and the pediatric trial.

Speaker Change: The independent data monitoring committee or <unk> approved our request to proceed to an early dose escalation in the adolescent and adult trial.

IBM seats: Data from part a of the trial will be assessed by regulatory agencies and the IBM seats provide guidance to determine final key elements of the part b.

IBM seats: Part B aspect of our trial.

Sean Nolan: The Dose Expansion, including the Hierarchy of Efficacy Endpoints, Study Duration, and the Maximum Tolerable Dose or Maximum Administered Dose. Therefore, advancing to Cohort 2, evaluating the high dose of Taysha-102 of 1 e to the 15 total vector genomes earlier than planned accelerates our ability to inform our clinical development and regulatory strategy for Part B.

IBM seats: The dose expansion portion, including hierarchy of efficacy endpoints study duration and the maximum tolerated dose or maximum administered dose.

IBM: Therefore, advancing two cohort two evaluating the high dose of <unk>, one or two of one either the <unk> told them of vector genomes earlier than planned accelerates our ability to inform our clinical development and regulatory strategy for part B.

Sean Nolan: We're pleased to share the first patient in a high dose cohort has been enrolled in the study, and dosing is scheduled to take place here in the second quarter of 2020. Earlier this year, we announced encouraging longer-term data for the first two adult patients treated in the low-dose cohort with late motor deterioration, stage 4 Rett syndrome, and different genetic mutations and severity of disease. Recall, when we initiated REVEAL, our focus was primarily on safety, with little expectation of efficacy for the adult population among key opinion leaders in the Rett syndrome community due to the advanced stage of the disease.

Speaker Change: We're pleased to share the first patient in in the high dose cohort has been enrolled in the study and dosing is scheduled to take place here in the second quarter of 2024.

Speaker Change: Earlier this year, we announced encouraging longer term data for the first two adult patients treated in the low dose cohort with late motor deterioration stage for ret syndrome, and different genetic mutations and severity of disease.

Speaker Change: Recall, when we initiated and reveal our focus was primarily on safety with little expectation of efficacy for the adult population among key opinion leaders in the Ret syndrome community due to the advanced stage of the disease.

Sean Nolan: Therefore, it was very exciting last November to announce the encouraging initial impact of Taysha-102 appeared to have across multiple clinical domains in the first two adult patients as early as four weeks following treatment, despite the trial participants having very different genetic mutations and disease severity. We presented longer-term follow-up data in the first quarter of this year, including a six-month follow-up assessment for the first adult patient, showing a continued durable response with sustained and new improvements in the absence or reduction of steroid levels.

Speaker Change: Therefore, it was very excited last November to announce the encouraging initial impact of tissue, one or two appeared to have across multiple clinical domains. In the first two adult patients as early as four weeks following treatment. Despite the trial participants, having very different genetic mutations and disease severity.

Speaker Change: We presented longer term follow up data in the first quarter of this year, including a six month follow up assessment for the first adult patient showing a continued durable response with sustained a new improvements and the absence of reduction of steroid levels.

Sean Nolan: As of the six-month assessment, Patient 1 showed sustained improvement across key efficacy measures at decreased steroid levels, with new improvements observed in the Rett Syndrome Behavioral Questionnaire, or RSBQ. Additionally, the second adult patient demonstrated sustained improvements across key efficacy measures with new improvements observed in certain measures, including the revised motor behavior assessment for RMBA as of the 12-week assessment and significantly reduced seizures as of the 19-week assessment following treatment. Moreover, the longer-term clinical observations reported by the principal investigator showed that both patients had sustained new improvements across multiple clinical domains impacting activities of daily living, including motor skills, socialization, and communication, autonomic function, and seizures, compared to earlier post-treatment assessments.

Speaker Change: As of the six month assessment patient one showed sustained improvement across key efforts key efficacy measures at decrease steroid levels with new improvements observed in the ret syndrome, Behavioural questionnaire or RSV Q.

Speaker Change: Additionally, the second adult patient demonstrated sustained improvements across key efficacy measures with new improvements observed in certain measures, including the revised motor behavior assessment for our MBA as of the 12 week assessment and significantly reduce seizures as of the 19 week assessment following.

Speaker Change: Uh huh.

Unknown Executive: Moreover, the longer term clinical observations reported by the principal investigator showed that both patients had sustained the new improvements across multiple clinical domains impacting activities of daily living including motor skills, socialization and communication autonomic function and seizures compared to earlier.

Sue: Your post treatment assessments importantly, these continued improvements were reported at week 35, following completion of the steroid taper for the first patient and at week 19 decrease steroid levels for the second patient Sue will discuss these observations in more detail.

Sean Nolan: Importantly, 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. Suku will discuss these observations in more detail.

Sean Nolan: The longer-term safety profile is also encouraged. Data from the first two adult patients showed that Taysha 102 was well tolerated with no treatment-emergent serious adverse events at week 35 for patient one and at 19 weeks for patient two. We believe the safety profile and continued improvement across multiple clinical domains, even at reduced steroid levels in both adult patients with advanced stage 4 Rett syndrome treated with the low dose of Taysha 102, supports the durability and transformational potential of Taysha 102 across multiple genotypes of Rett syndrome and further validates our concept.

Sue: The longer term safety profile is also encouraging data from the first two adult patients showed the Taishan 102 was well tolerated with no treatment emergent serious adverse events as the week 35 assessment for patient one and as the 19 week assessment for patients too.

Sue Smith: We believe the safety profile and continued improvement across multiple clinical domains, even at reduced steroid levels in both the adult patients in both adult patients with advanced stage for Ret syndrome treated with the low dose of tissue went on to supports the durability and transformational potential of tissue, one or two across multiple gene.

Speaker Change: The types of Ret syndrome, and further validates our construct.

Sean Nolan: We are also focused on evaluating the therapeutic potential of Taysha-102 in the pediatric population, where we hope to see a similar safety profile and a consistent pattern of response across clinical domains in pediatric patients with different genotypes treated with the low dose of Taysha-102. Our ongoing REVEAL Phase 1-2 Pediatric Trial is evaluating the safety and preliminary efficacy of Taysha 102 in female patients with Rett Syndrome aged 5 to 8 years old.

Unknown Executive: We are also focused on evaluating the therapeutic potential of <unk> 102 in the pediatric population, where we hope to see similar a similar safety profile and a consistent pattern of response across clinical domains in the pediatric patients with different genotypes treated with the logos of tissue or one or two.

Speaker Change: Our ongoing review of Phase one two pediatric trial is evaluating the safety and preliminary efficacy of <unk> 102 in female patients with Ret syndrome age five to eight years old.

Sean Nolan: We are currently enrolling pediatric patients in Part A of the trial, which will evaluate two dose levels of Taysha 102 sequentially. We have dosed the second pediatric patient in Cohort 1, the low-dose cohort, of 5.7 e to the 14 total vector genomes following the IDMC's review of the initial six-week data from the first pediatric patient dose. While this trial captures a younger patient population with an earlier stage of disease compared to our adolescent and adult trial, it is important to understand that most patients with stage 3 Rett syndrome have already developed the hallmark symptoms of the disease and therefore present with many advanced disease manifestations.

Speaker Change: We are currently enrolling pediatric patients in part a of the trial, which will evaluate two dose levels of patient 102 sequentially.

Unknown Executive: We have dosed the second pediatric patient in cohort one the low dose cohort of 5.7, either the 14th total vector genomes. Following the <unk> review of the initial six week data from the first pediatric patient dose.

Speaker Change: While this trial captures a younger patient population with an earlier stage of disease compared to our adult adolescent and adult trial. It is important to understand that most patients with stage three ret syndrome have already developed the hallmark symptoms of the disease, and therefore present with many advanced disease manifestations.

Sean Nolan: Patients typically approach stage three of the disease, known as the pseudostationary symptom stage, after a period of deterioration and rapid regression of learned skills, particularly relating to language and hand movement. The regression period is also characterized by partial or complete loss of acquired purposeful hand skills in spoken language, gait abnormalities, and stereotypic hand movements, which results in the loss of independence and, in most cases, leads to lifelong caregiver dependence.

Unknown Executive: Patients typically approach stage III disease, known as the studios stationary symptom stage after a period of deterioration and rapid regression of learn skills, particularly relating to language and hand movement there.

Speaker Change: The regression period is also characterized by a partial or complete loss of acquired purpose purposeful hand skills and spoken language gate abnormalities and stereotypic can movements, which results in the loss of independence and in most cases leads the lifelong caregiver dependents.

Sean Nolan: Many patients in this age group also suffer from seizures that can significantly impact their quality of life. Similar to the adult population, the heterogeneity among pediatric patients is high due to the broad spectrum of genetic backgrounds that result in variable phenotypic symptoms and severity in Rett syndrome. Part A of the pediatric trial is intended to include patients across a broad spectrum of genetic backgrounds, which will help us generate a robust data set to inform our development plan for the next phase of the study.

Unknown Executive: Many patients in this age group also suffered from seizures that can significantly impact their quality of life.

Speaker Change: Similar to the adult population the heterogeneity among pediatric patients is high due to the broad spectrum of genetic backgrounds that result in variable phenotypic symptoms and severity in ret syndrome.

Speaker Change: Part a of the pediatric trial is intended to include patients across a broad spectrum of genetic backgrounds, which will help us generate a robust data set to inform our development plan for the next phase of the study.

Sean Nolan: We hope to see a consistent pattern of response across key clinical domains in pediatric patients with different genotypes treated in the low-dose cohort, which we believe will bring us closer to our goal of bringing a potentially transformative treatment to all patients with Rett syndrome. Recently, we were pleased to receive Regenerative Medicine's Advanced Therapy, or RMAT, designation from the FDA following review of available safety and efficacy data from the first two adult patients and the first pediatric patient dose of Taysha 102. A regenerative medicine therapy is eligible for RMAP designation if it is intended to treat, modify, reverse, or cure a serious condition.

Speaker Change: We hope to see a consistent pattern of response across key clinical domains in the pediatric patients with different genotypes treated in the low dose cohort, which we believe will bring us closer to our goal of bringing a potentially transformative treatment to all patients with ret syndrome.

Speaker Change: Recently, we were pleased to receive regenerative medicine advanced therapy, or our mat designation from the FDA. Following review of available safety and efficacy data from the first two adult patients and the first pediatric patient dose with a low dose official 102.

Speaker Change: Our regenerative medicine therapies eligible for arm that designation if it is intended to treat modify reverse or cure a serious condition and preliminary clinical evidence indicates that therapy has the potential to address unmet needs for such a condition.

Sean Nolan: And preliminary clinical evidence indicates the therapy has the potential to address unmet needs for such a condition. Sponsored companies receiving RMAT designation can benefit from increased interactions with FDA involving senior managers to help expedite drug development. We believe receiving RMAT designation is important recognition from the FDA that reinforces the high unmet need for Rett syndrome and the therapeutic potential of Taysha 102 to bring meaningful change to patients and families with Rett syndrome.

Sponsored companies: Sponsored companies receiving armet designation can benefit from increased interactions with FDA involving senior managers to help expedite drug development. We believe receiving our math designation is important recognition from the FDA that reinforces the high unmet need and ret syndrome, and the therapeutic potential.

Sponsored companies: Essential location, one or two to bring meaningful change to patients and families with <unk> syndrome.

Sean Nolan: We will work closely with the FDA and other regulatory agencies as we continue to advance our Taysha 102 program. We look forward to the year ahead as we remain focused on further expanding into pediatric patients, executing trials in multiple geographies, evaluating the high dose across age groups, and generating critical longer-term clinical data across a broad population of patients with Rett syndrome that will guide the next phase of our study.

We: We will work closely with the FDA and other regulatory agencies as we continue to advance our takes you one or two program.

We: We look forward to the year ahead as we remain focused on further expanding into pediatric patients.

Speaker Change: Executing trials in multiple geographies evaluating the high dose across age groups and generating critical longer term clinical data across a broad population of patients with ret syndrome that will guide the next phase of our studies.

Sean Nolan: We expect to provide an update on clinical data from the completed low-dose cohort of our REVEAL Adolescent and Adult Trial and initial available data from the low-dose cohort of our REVEAL Pediatric Trial in mid-2024. Additionally, we expect to report initial available data from the high-dose cohort for both of our REVEAL trials in the second half of 2024. I will now turn the call over to Suku to provide a more in-depth discussion of Taysha 102. Okay, Suku?

We: We expect to provide an update on clinical data from the completed low dose cohort of our reveal adolescent and adult trial.

Speaker Change: An initial available data from the low dose cohort of our reveal pediatric trial in mid 'twenty 'twenty four.

Speaker Change: Additionally, we expect to report initial available data from the high dose cohort for both of our reveal trials in the second half of 2024.

Speaker Change: I will now turn the call over to Sue to Brian to provide a more in depth discussion of tissue 102 sucrose.

Sukumar Nagendran: Thank you, Sean, and good afternoon, everyone. I'm pleased to provide an update on our Taysha 102 Gene Therapy Program in clinical evaluation for the treatment of breast cancer. Rett syndrome is a rare neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene, which encodes the MECP2 protein, an essential regulator of neuronal and synaptic function in the brain. The disorder is characterized by loss of communication and hand function, slowing and or regression of development, motor and respiratory impairment, seizures, intellectual disabilities, and shortened life expectancy. Let's think about progression. It is divided into four key stages, beginning with early onset developmental stagnation at 6 to 18 months of age, followed by rapid regression, plateauing, and late water deterioration.

Sue Smith: Thank you Sean and good afternoon, everyone I'm pleased to provide an update on our peso onto a gene therapy program in clinical evaluation for the treatment of Ret syndrome.

Speaker Change: Let's syndrome is a rare neurodevelopmental disorder caused by mutations in the X link, Mississippi, two gene, which encodes the Mississippi to a protein and a central regulator of neurons and dielectric function in the brand.

Speaker Change: The disorder is characterized by lots of communication and hand function Boeing and our regression of development water and respiratory impairment these their intellectual disabilities and stocking life expectancy.

Sue Smith: That pendulum progression.

Unknown Executive: Is divided into four key stages, beginning with early onset developmental stagnation at six to 18 months always followed by rapid regression towing.

Speaker Change: Towing and late quarter deterioration.

Sukumar Nagendran: As a reminder... Taysha 102 is a self-complementary intrathecally-delivered AAV9 gene transfer therapy designed as a one-time treatment. Because of the risks associated with both, under an over-expression of MHCP2, we have combined high-throughput microRNA profiling, and Expressions, to create a MyRare.

Unknown Executive: As a reminder.

Tom: Thanks, Tom I know too is a self complementary in particularly delivered.

Tom: Nine gene cell therapy designed as a one time treatment.

Tom: Because of the risk.

Tom: With book.

Tom: And then all I expect to have at least 52, we have combined HIFU.

Tom: High throughput Microtomy profiling.

Speaker Change: <unk> expression.

dad: And my dad.

Sukumar Nagendran: Our novel mRNA target panel designed to, Mediate MSCP2 expression in the central nervous system on a cell-by-cell basis controls the therapeutic levels of MSCP2. With miRAR, endogenous miRNA are activated in the presence of MeCP2 protein and are thought to base pair with targets in the viral genome encoded microRNA to ultimately decrease protein expression levels through RNA interferon. 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.

my dad: So now I'll end my.

Speaker Change: Target panel designed to meet.

Speaker Change: Immediate in Mississippi to expression in the central nervous system on a cell by cell basis.

Speaker Change: Controllers the therapeutic levels.

Speaker Change: <unk>.

Speaker Change: But they're minor.

Speaker Change: In our semi R&D are activated in the presence of Mississippi to protein and I'll talk to best out of it.

Speaker Change: <unk> not seen the violence Zinno encoded my cot and air to ultimate the decrease protein expression.

Unknown Executive: Through RNA interference.

Unknown Executive: That said, we will not do is expected to provide the necessary function of the Mississippi.

Speaker Change: Two protein in cells lacking.

Speaker Change: While protecting against toxic or expressing Mississippi two in healthy cells.

Sukumar Nagendran: Clinical and preclinical data continue to support the ability of Taysha 102 to produce and maintain safe transgene expression levels in the central nervous system. As Sean mentioned, we observed a similar pattern of response across multiple clinical domains, impacting activities of daily living in both adult patients treated in the low-dose cohort of our Reveal Phase I, II adolescent and adult studies. These patients have very different genetic mutations and associated disease severity. The first patient is a 20-year-old female with a large deletion within her ME3P2 gene that manifests in a more severe disease phenotype and was completely non-ambulatory at baseline.

Mahdi Goudarzi: Clinical and preclinical data continue to support the ability of peso on our tool to produce and maintain their <unk> gene expression there both in the central nervous system.

Mahdi Goudarzi: As Sean mentioned, we observed a similar pattern of restaurants across multiple clinical demand impacting at the activities of daily living in both adult patients treated in the low dose cohort of our reveal faithful one two adolescent and adult trial.

Speaker Change: These patients.

Speaker Change: A very different genetic mutations and associated disease severity.

Speaker Change: Pension is a 20 year old female.

Pension: With the large deletion.

Pension: Capital gene that manifest in a more severe disease phenotype, and what's completely non ambulatory at baseline while the.

Sukumar Nagendran: While the second patient is a 21-year-old female with a mysense mutation in her MECP2 gene that manifests as a mild phenotype and could walk with prompting at baseline, further protocol. Prophylactic immunosuppression therapy began prior to Taysha's one or two administrations. The steroid paper was initiated at week 17 and completed by week 33 for the first patient. At the 35th week post-treatment assessment, the principal investigator observed that the initial improvements across multiple clinical domains had been maintained following completion of the steroid paper, and new improvements were observed compared to earlier post-treatment assessments.

Pension: The second patient is a 21 year old female with them.

Speaker Change: My sense, we'll take.

My sense: Capital gene that manifest as a milder phenotype and could work with prompting a baffling.

Speaker Change: Okay.

Speaker Change: Further protocol.

Speaker Change: Prophylactic Immunosuppressant therapy begin.

Speaker Change: They sell a lot to administration.

Tampa: Tampa was initiated at <unk> 17, and completed by week, So it's easy for the patient.

Tampa: And at the Pentagon or the <unk> post treatment assessment.

Unknown Executive: Kibali investigators observed that.

Unknown Executive: Initial improvement across multiple clinical domain had.

Unknown Executive: <unk> had been maintained following completion of Tampa and new improvement of subs.

Unknown Executive: Impaired earlier post treatment assessment.

Unknown Executive: [laughter].

Sukumar Nagendran: Specifically, 35 weeks following treatment, the first patient showed sustained improvement in motor function, including restored leg movement and the ability to sit unassisted for the first time in over a decade. And his hand function, 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. Progressive loss of hand function is a hallmark characteristic of Rett syndrome.

Unknown Executive: Typically 35 weeks following treatment.

Speaker Change: Patients showed sustained improvement in motor function, including restore like movement and the ability to sit unassisted for the plus sign in over a decade, and his hand function, including the gains ability to grasp objects within non dominant hand and transfer them to a dominant hand.

Speaker Change: For the first time.

Speaker Change: Its infancy.

Speaker Change: Stronger stabler, how can function is a hallmark characteristic of ret syndrome.

Sukumar Nagendran: And the key area of concern for caregivers given its limits, communication, daily activities, and independence. We believe we sustain improvements in hand function, which are not typically observed. In the National History of AIDS Syndrome, support the therapeutic potential of Taysha 102 to bring meaningful change to patients and caregivers. Sustained improvements in autonomic function were also observed in the first patient, including improved breathing patterns, circulation, and sleep quality, while they gained the ability to sleep through the night for the first time in 20 years, resulting in the patient being more alert and interactive during the day.

Speaker Change: And a key area of concern for caregivers given its limit communication daily activities and independence.

Speaker Change: We believe the sustained improvement in hand function.

Speaker Change: Which are not typically observed.

Speaker Change: In the natural history of Ret syndrome support the therapeutic potential of peso on our tool to bring meaningful tends to patients and caregivers.

Speaker Change: Sustained improvement in autonomic function, while also observed in the fourth patient, including improved breathing pattern to lessen and heap quantity.

Speaker Change: While the games ability to sleep through the night for the first time in 20 years.

Alec: Nothing in the patient being more Alec interactive during the day.

Sukumar Nagendran: A week 35 post-treatment, the principal investigator observed new improvements in the first patient in socialization and communication, including increased vocalization and the enhanced ability to use an eye-driven communication device. Difficulty in communication, including loss of speech, is also a prominent symptom of Brett syndrome and a key area of concern for caregivers as it directly interferes with the patient's ability to communicate their needs and express their interests.

Unknown Executive: Week 35 post treatment the principal investigator of the new improvements in the.

Unknown Executive: Patient and socialization and communication, including increased localization and the inherent stability.

Speaker Change: Isn't either one communication device.

Speaker Change: Difficultly in communication in clean speech is also permanent tunnel syndrome.

vakhegula: And a key area of concern vakhegula as it directly interferes with the pace and the ability to communicate their need that extra net interest.

Sukumar Nagendran: Based on caregiver input, we believe the ability to communicate could give patients a sense of control and greater independence. The first patient seizure was overall well controlled with a stable seizure event through week 35 at lower levels of anti-seizure medication. Related to baseline, and the patient now no longer experiences unprovoked seizures. Now let's turn to the second patient, the second adult patient, at the 19-week post-treatment assessment while the patient was on decreased steroid levels.

Caregiver: Caregiver input, we believe the ability to communicate could give patients defense of control and greater independence.

Caregiver: The first patient seizure, but overall well control with Diablo themed event through week 35 at lower levels of anti seizure medication.

Caregiver: To baseline in the past and now no longer experience unprovoked seizure.

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

Speaker Change: Of the 19 week post treatment assessment.

Speaker Change #100: While the patients wasn't decrease the right levels.

Sukumar Nagendran: The patient showed sustained improvement in motor skills with improvement in handwriting techniques for the first time, regression at age 3, and in socialization and communication with increased interest in social communication and activities, including increased response to spoken words and icons. The patient also showed improvements in autonomic function with sustained improvements in breathing presence, and circulation. The principal investigator also observed new improvements in the second patient's seizure frequency at week 19, with a significant reduction in seizures and a 25 percent lower level of anti-seizure medicine relative to base. The patient's pre-treatment seizure frequency was approximately 2 to 4 seizures per week, and the patient has been seizure free for 17 weeks as of the 19-week post-treatment assessment.

Speaker Change: Sure sustained improvement in motor skills.

Speaker Change #102: Improvement enhanced theoretically for the first time.

Speaker Change #101: Insignificant at H C.

Speaker Change #103: And then socialization and communication with increased interest in social communication and activities, including increased advanced a spokesman wasn't icon.

Speaker Change #106: The patient also.

Speaker Change: So our improvement.

Speaker Change #107: Let me pumpkin sustained improvement in building patents in circulation.

Speaker Change #107: Investigators also observed new improvements in the second patient.

Speaker Change #110: At week 19, with a significant reduction in season and a 25%.

Investigators: Lower level of anti seizure medicine relative to being flat.

Speaker Change #110: Ah patients pretreatment piece of silicon.

Speaker Change #104: There's approximately 2% to 40 here for a week.

Speaker Change #115: And the patient has been seizure free.

Speaker Change #105: While 17 weeks is up the 19 weak cost headwind.

Sukumar Nagendran: Additionally, both patients demonstrated continued improvement across consistent, Clinical and Caregiver Reported Efficacy Measures based on the six-month assessment and decreased steroid levels for the first patient and 12-week assessment for the second patient. This includes sustained improvement in Clinical Global Impression Improvement or CGII, and Tehran Global Impression Improvement or PGII.

Speaker Change #118: Additionally, both patients demonstrated continued improvement.

Speaker Change #105: Consistent.

Speaker Change #105: P.

Speaker Change #120: Clinical and calculate it put it if it doesn't make sense.

Speaker Change #109: Based on a six month assessment and decrease the right level for the first patients and 12 week assessment.

Speaker Change #105: Patient.

Speaker Change #105: This includes sustained improvement in.

Patient: Clinical global impression of improvement are C. G I.

Speaker Change #108: They are in global impression of improvement of Pgi I E.

Speaker Change #108: Your bank.

Sukumar Nagendran: Motor Behavior Assessment or RMBA, Rett Syndrome Behavior Questionnaire or RFBQ, and in seizure dialogue. The first patient also demonstrated a sustained improvement in CGIS and the Red Syndrome Hand Function Scale at six months post-treatment relative to earlier post-treatment assessment. These similar assessments across key efficacy measures observed in both adult patients reinforce the clinical observation from their principal investigators. Overall, we are highly encouraged by the consistent and early responses that were sustained through long-term follow-up assessment and the new improvements that developed in the two adult patients with different disease severity. We believe this improvement You should not reduce your steroid levels.

RMB: Modern behavior assessment of RMB.

RMB: <unk> syndrome behaviour questionnaire on August <unk>.

Speaker Change #117: And in <unk>.

Speaker Change #123: The first patient also demonstrated a sustained improvement.

Speaker Change #117: In CGI.

Speaker Change #119: And the Ret syndrome hand function scale.

Paul: At six months post treatment relative to earlier, Paul for 15 months.

Speaker Change #116: These similar assessments across key efficacy measures observed at book adult patients reinforces the critical observations.

Unknown Executive: From their principal investigator.

Speaker Change #137: Overall, we are highly encouraged by the consistent and early responses there.

Unknown Executive: They include long term follow up assessment and the new improvements now developing the two adult patients with different disease severity.

Unknown Executive: We believe these improvements.

Unknown Executive: But at reduced.

Unknown Executive: Liberals.

principal investigator: Completed.

Sukumar Nagendran: Completed, with a well-tolerated thirsty profile, supports the durability and transformative potential of Taysha-102 across multiple genotypes for X syndrome. With the LODOS cohort complete, In the adolescent and adult trial, we are currently focused on collecting data with the high dose to further explore the clinical impact of Taysha 1 or 2. We have enrolled the first patient in the high-dose cohort, and dosing is scheduled to take place in the second quarter of 2024. Now, let's turn to the first.

principal investigator: With a well tolerated safety profile.

Florida Timna: Supports the durability and transformative potential of phase, one or two across multiple genotypes, Florida Timna.

Florida Timna: With the low dose cohort complete.

Florida Timna: Yeah, the elephant in the adult trial. We are currently focused on collecting data with the hydro to further explore the clinical impact of dish out one or two.

Florida Timna: We enrolled the first patient in the high dose cohort and dosing schedule to take that.

Speaker Change #138: Second quarter of consultant and plentiful.

Speaker Change #138: Now, let's turn to the first.

Sukumar Nagendran: The pediatric trial, titled Reveal Phase 1-2 Pediatric Trials, similar to the Reveal Phase 1-2 Adolescent and Adult Trials, was designed primarily as a safety study. Efficacy data being collected across a variety of measures is hypothesis-generating and will inform our thinking relative to Part B of the trial. Therefore, Part A of the trial is intended to include patients with diverse genetic backgrounds to evaluate the clinical impact of Taysha 1 or 2 across a broad range of pediatric patients.

Speaker Change #135: The pediatric trial.

Speaker Change #127: Its title real fast one two pediatric trial similar to the reveal phase one two adolescent and adult trial.

Speaker Change #145: Whilst the defense, primarily as a safety study.

Speaker Change #127: The efficacy data being collected across.

Speaker Change #139: A variety of measures this hypothesis generating.

Speaker Change #125: And will inform our thinking.

Speaker Change #126: Part B of the trial, therefore part a of the trial is intended to include patients.

Speaker Change #126: With diverse backgrounds.

Speaker Change #148: We evaluate the clinical impact of <unk> across a broad range of pediatric patients.

Sukumar Nagendran: As Sean mentioned, similar to the adult population, the heterogeneity amongst pediatric patients is high due to the broad spectrum of genetic backgrounds that resulted in different phenotypic symptoms and 17 patients with Rett syndrome. Phenotypic variation commonly occurs between individuals with the same MHCP2 mutation and is attributed to different in the random X chromosome inactivation that results in a miniature mixture of cells with different levels of MECP2 protein expression.

Sean Nolan: As Sean mentioned the minutes of the adult population.

Speaker Change #136: The heterogeneity amongst pediatric patients with high <unk>.

Speaker Change #134: The broad spectrum of identity backlogs.

Speaker Change #128: Differentiation, if you take symptoms and.

Sean: In 17 patients with <unk> syndrome.

Speaker Change #149: I think the aviation, commonly all kinds of the games and this is just the same it must be accretive location.

Speaker Change #129: And is attributed to defend.

Speaker Change #143: And the random X chromosomes and activation.

Speaker Change #142: In a miniature mixed cell cell the different levels of the Mississippi to protein expression.

Sukumar Nagendran: Because of this, the baseline status and overall disease severity of the patient will continue to be of importance to consider when interpreting the data, regardless of the age or stage of disease. Our hope is that pediatric patients with different genotypes who are treated with the low dose of Taysha 102 will show consistent safety profiles and recapitulate the meaningful improvement across clinical domains that we have observed in the adult patients. We have discussed the first two pediatric patients in cohort one, evaluating the low dose of Taysha 1 or 2.

Speaker Change #140: Because of this the baseline.

Speaker Change #141: And overall disease severity of the patients.

Speaker Change #130: To be up important to consider when interpreting the data regardless of age or stage of disease.

Speaker Change #130: Our hope is that the pediatric patients had different genotypes, well treated with a low dose of <unk>, one or two.

Speaker Change #132: So consistent safety profile and recapture cleared the meaningful improvement across critical demand that we have observed in the adult patients.

Speaker Change #131: We have discussed the first two pediatric.

Speaker Change #133: We have dosed the first two pediatric patients in cohort one evaluating the low dose of two.

Sukumar Nagendran: We expect to report the initial available Taysha efficacy data from Hot One in mid-2024. We remain focused on completing. Dosing in Part A of Both Revealed Trials and Anticipates Significant Data Collection in 2024. Our efforts to expand our clinical trials remain underway, and we are currently focused on additional site activation in the U.S. for a Revealed Adolescent and Adult Trial, with the goal of expanding the ongoing trial in Canada into the U.S. in our Revealed Pediatric Trial, as we have focused on site activation in I will now turn the call over to Kamran to discuss our financial results.

Speaker Change #133: We expect to report initial available thereafter, if the data from.

Speaker Change #150: The hot one in mid 2024.

Speaker Change #150: We remain focused on completing.

Speaker Change #133: Dosing and party of both of the real trials and anticipate significant data collection in 2024.

Speaker Change #133: Our efforts to expand our clinical trials remain underway and focus on that issue of site activation in the U S.

Speaker Change #144: But our real adolescent and adult club.

Speaker Change #147: With the goal of expanding.

Speaker Change #147: The ongoing trial in Canada into the U S.

Speaker Change #152: And now with pediatric trial, and we are focused on site activation in the U K with a goal of expanding our ongoing pediatric trial.

Speaker Change #152: In the U S.

Speaker Change #152: Into the U K as well.

Kamran Alam: Thank you, Suku. Research and development expenses were $20.7 million for the three months ended March 31, 2024, compared to $12.5 million for the three months ended March 31, 2023. The $8.2 million increase was primarily driven by an increase in good manufacturing practice or GMP batch activities during the three months ended March 31, 2024, which is representative of the intended commercial manufacturing process for Taysha 102. Additionally, clinical trial expenses increased primarily due to ongoing activities in the REVEAL adolescent, adult, and pediatric trial.

Speaker Change #151: I will now turn the call over to Cameron to.

Cameron: To discuss our financial results Kamran.

Sue: Thank you Sue.

Kamran Alam: Research and development expenses were $27 million for the three months ended March 31, 2024, compared to $12 $5 million for the three months ending March 31 2023.

Kamran Alam: The $8 2 million dollar increase was primarily driven by an increase in good manufacturing practice or GMP batch activities. During the three months ended March 31, 2024, which is representative of the Intel.

Sue: Ended commercial manufacturing process for <unk> 102.

Sue: Additionally, clinical trial expenses increased primarily due to ongoing activity and the reveal adolescent and adult and pediatric trial.

Kamran Alam: General and administrative expenses were $7.1 million for the three-month-ended March 31, 2024, compared to $8.8 million for the three-month-ended March 31, 2023. The decrease of $1.7 million was due to reduced general and administrative compensation as a result of lower headcount and a reduction in consulting and professional fees.

Sue: General and administrative expenses were $7 $1 million for the three months ended March 31, 2024, compared to $8 $8 million for the three months ended March 31 2023 the.

Sue: A decrease of $1 $7 million was due to reduced general and administrative compensation as a result of lower head count and a reduction in consulting and professional fees.

Sean Nolan: The net loss for the three-month ended March 31, 2024 was $24.1 million, or $0.10 per share, as compared to a net loss of $17.6 million, or $0.28 per share, for the three-month ended March 31, 2023. As of March 31, 2024, Taysha had $124 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. Sean

Sue: Net loss for the three months ended March 31, 2024 was $24 $1 million or 10 cents per share as compared to a net loss of $17 $6 million or 28 cents per share for the three months ended March 31 2023.

Sue: As of March 31, 2024 pace, you had $124 million in cash and cash equivalents.

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

Speaker Change #154: I will now turn the call back over to Sean for his closing remarks, Sean.

Sean Nolan: Thank you, Kamran. Throughout the first quarter of 2024, we have made important progress on the clinical development of Taysha-102 to sustain the new improvements in both adult patients with advanced stage 4 Rett syndrome. We are very encouraged. And we look forward to moving to the high dose and further evaluating patient 102 across a broad population of ages and stages of patients with Rett syndrome. We are focused on completing dose escalation for both of our reveal trials and collecting data to inform the next phase of our studies.

Sean: Thank you Cameron throughout the first quarter of 2024, we have made important progress on the clinical development of <unk> sustained a new improvements in both adult patients with advanced stage for Ret syndrome are very encouraging and we look forward to moving to the high dose and further evaluating patient went on to.

Sue: <unk> across a broad population of ages and stages of patients with Ret syndrome.

Sue: We are focused on completing dose escalation for for both of our reveal trials and collecting data to inform the next phase of our studies. We will continue to look for similar patterns of improvement across adults adolescents and pediatric patient populations in the year ahead, we have many clinical milestones expected.

Sean Nolan: We will continue to look for similar patterns of improvement across adult, adolescent, and pediatric patient populations. In the year ahead, we have many clinical milestones expected, and we look forward to providing additional updates, including reporting initial clinical data from our REVEAL pediatric trial and providing an update on the completed low-dose cohort from our REVEAL adolescent and adult trial in mid-2024. With that, I will now ask the operator to begin our Q and A session. Operator?

Sue: And we look forward to providing additional updates including reporting initial clinical data from our reveal pediatric trial and providing an update on the completed low dose cohort from our reveal adolescent and adult trial in mid 2024.

Sue: With that I will now ask the operator to begin our Q&A session operator.

Operator: Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press the star and then 1 on your telephone keypad. A confirmation tone will indicate your line is in the question... You may press star and then 2 if you would like to remove a question from the... Participants using Speakeasy equipment. It may be necessary to pick up your handset before pressing the start button.

Speaker Change #159: Thank you.

Speaker Change #155: We will now be conducting a question and answer session.

Speaker Change #161: If you would like to ask a question. Please press Star then one on your telephone keypad.

Speaker Change #157: Information tone will indicate your line is in the question queue you may have.

Speaker Change #156: Sorry, and then two if you would like to remove your question from the queue.

Speaker Change #156: For participants using speaker equipment, it might be necessary to pick up your handset before pressing the star keys.

Operator: It is requested that you ask one question and one follow-up question. The first question we have is from Kristen Kluska of Cantor Fitzgerald. Please go ahead. Hi everyone, congrats on the RMAT designation!

Speaker Change #165: Is your question that you ask one question and one follow up question.

Speaker Change #164: The first question, we have is from Christian <unk> of Cantor Fitzgerald.

Speaker Change #158: Fitzgerald. Please go ahead.

Speaker Change #162: Hi, everyone. Congrats on the RMR does it.

Kristen Kluska: So, you've been very transparent providing all the data you've collected to the street, but we continue to get a lot of questions about expectations for the younger population. So how should we be thinking about ways to measure some anecdotes since this population isn't as advanced? I know it's heterogeneous, with different genetic backgrounds, but for younger patients, are there any domains in particular that stand out? Thank you. Thanks for the question, Kristen.

Speaker Change #167: So you've been very transparent providing all the data you collect it.

Speaker Change #166: But we continue to get a lot of questions about expectations for the younger.

Speaker Change #160: So how should we be thinking about ways to measure it.

Speaker Change #163: This population is and as far as I know.

Speaker Change #163: Heterogeneity different genetic background, but for younger patients are there any demand in particular that stand out. Thank you.

Kristen Kluska: I'll take a stab at that and ask Sukum to further comment on it. But I think what's important is, again, that we recognize the fact that the pediatric patient population that we're studying, ages five to eight, has very advanced disease. And they generally have all the hallmark symptoms that people who are adults have. They may not have had it for very long, but again, they may have had it for six or seven years or something along those lines.

Kristen: Thanks for the question Kristen I'll take a stab at that and and asks included two further opine on it but I think what's important is again that that we recognize the fact that the pediatric patient population that we're studying agents five.

Kristen: Has very advanced disease, and they have generally all the hallmark.

Speaker Change #163: Symptoms that people who are adults have they may not have had a very long, but again. They may have had it for six or seven years or something along those lines. So it's a very entrenched disease and the severity has to be different based on the the genotype. So from our perspective, what would be I think a.

Sean Nolan: So it's a very entrenched disease, and the severities can be different based on the genotypes. So from our perspective, what would be, I think, a dramatic response at the low dose would be a consistent response to what we're seeing in the adults, meaning that there's clinical impact occurring across multiple domains, and that it's occurring very rapidly, you know, post treatment. And I think that that would further reinforce our belief that we're, you know, potentially dealing with transformational therapy here.

Speaker Change #163: <unk>.

Speaker Change #163: <unk> response in the low dose would be a consistent response to what we're seeing in the adults, meaning that there is clinical impact occurring across multiple domains and then it's occurring very rapidly you know.

Speaker Change #163: Post treatment.

Speaker Change #169: And I think that that would further reinforce our belief that were.

Speaker Change #169: Potentially dealing with the transformational therapy here and I think with pediatric patients that stands to reason that it could be that over the course of time.

Sean Nolan: And I think with pediatric patients, it stands to reason that, over the course of time, they could have, ultimately, a better outcome than, let's say, an adult. But just remember, it takes time for people to make such dramatic improvements. I mean, if you put it in terms that probably most on the call can appreciate it.

Speaker Change #169: They they have a ultimately a better outcome than let's say an adult.

Speaker Change #170: But just remember it takes time for people to to make such dramatic improvements I mean, if you put it in the terms of probably most on the call can appreciate it if you have children.

Sean Nolan: If you have children, you know, the first words may be coming at, you know, eight to ten to twelve months post-birth. So it takes time to develop. And so if you've had the disease and you haven't been able to speak, as an example, for multiple years, to expect that there's going to be a transformational occurrence happening in the first three months isn't reasonable.

Speaker Change #170: The first words, maybe coming at eight to 10 to 12 months post birth.

Speaker Change #170: So it takes time to develop mentally gets it and so if you have had the disease and you haven't been able to speak as an example for multiple years to expect that theres going to be.

Speaker Change #170: Transformational occurrence happening in the first three months I don't think as is reasonable, but I think if you see consistently that gross motor functions, improving fine motor functions, improving the hansard are becoming more.

Sean Nolan: But I think if you see consistently that gross motor function is improving, fine motor function is improving, the hands are becoming more... You know, efficient in what they can do, socialization and the attempt at communication improve, seizure improvement. Those are the things that I think are going to tell us if we've got, you know, an effect happening from a clinical perspective. And again, keeping in mind that we're at a low dose. Let me pause there and ask Suku, is there anything you would add to that for perspective on Kristen?

Speaker Change #170: You know efficient in what they can do the socialization and the attempt to communication improves seizure improvement those are the things that I think are going to tell us if you've got you know.

Speaker Change #170: Affect happening from a clinical perspective, and again keeping in mind that we're at the low dose.

Speaker Change #174: Let me pause there and ask <unk> is there anything you would add to that for for perspective Christine.

Sukumar Nagendran: So, Sean, you, I think, laid it out very clearly. And what I would also just, I mean, remind Kristen and the audience is that given that we are treating the root cause of the disease with our Gene Replacement Therapy. The duration of the disease, whether it's a younger patient or an older patient. The severity of the genotype and the actual severity, presentation that this patient had that I think will also drive, at times, the consistent efficacy that we've shown so far in adult patients.

Christine: So Shawn I mean, you have I think laid out laid it out very clearly.

Christine: I would also just.

Speaker Change #175: I mean remind crystal in the audience.

Speaker Change #172: Is that given that we are treating the root cause of the disease.

Speaker Change #171: It does in replacement therapy.

Speaker Change #171: The duration.

Speaker Change #171: Of the disease.

Speaker Change #170: Since our older patients.

Speaker Change #181: The severity of the genotype and the extra the ability of the clinical presentation. This complex syndromic.

Speaker Change #170: Presentation that these patients have that I think will also drive.

Speaker Change #170: The consistent.

Speaker Change #170: Efficacy that we've shown so finally adult patients so what I'm, saying is I think.

Sukumar Nagendran: So what I'm saying is, I think this gene therapy will treat patients across the age ranges fairly effectively, but we have to see as we recruit patients into the pediatric trial and gather that data to confirm this as well. Thank you so much.

Speaker Change #170: This is gene therapy, I think will create the patient across the age ranges fairly carefully, but we have to see as they recruit the patients since the pediatric trial and gather the data to confirm this as well.

Kristen Kluska: That was very helpful. And then for my follow-up, regarding the RMAT designation, I understand you can't share any data from the third patient yet, but can you please comment to us on the length or the amount of data that the FDA had from this patient when they gave you that designation? Thanks so much again.

Speaker Change #179: Thank you so much that was very helpful. And then for my follow up to the arm that designation I. Appreciate you can't share any data from patient the therapy, yet, but can you comment to us the land or the amount of data that the FDA had from this patient when they gave you that designation. Thanks so much.

Speaker Change #170: Again.

Sean Nolan: Yeah, thank you, Kristen. Suku, do you want to take that question? Yeah, sure. Absolutely, Sean. So, when we filed for the ARMAT designation, Kristen, we filed with data from two adult patients who were dosed in Canada and one pediatric patient who was dosed in the U.S. And the FDA reviewed the data set and found that our product has what they consider a significant clinical impact to qualify to receive the RMAC designation, and then, as you know, once you get the RMAC designation.

Kristen: Yes, Thank you Kristen.

Speaker Change #177: So could you want do you want to take that question, yes, sure absolutely Sean so.

Speaker Change #170: When we file well.

Speaker Change #180: Well the automotive ignition system with.

Speaker Change #178: We filed with the data from the two adult patients.

Speaker Change #170: Who are both in Canada, and one pediatric patient was dosed in the U S.

Speaker Change #170: And the FDA has reviewed that dataset.

FDA: And found that.

FDA: Our product has.

FDA: But they would consider significant clinical impact.

FDA: To qualify to receive the automatic designation and then as you know once we get the automatic designation.

Sean Nolan: The FDA obviously then commits a lot more time to working with the sponsor on its product and program because there is a commitment now that this disease that we are trying to address has significant unmet medical needs and justifies very close collaboration between the sponsor and the FDA. So overall, we are very excited that we received it, and it's a good thing for patients. Thank you. The next question we have is from Salveen Richter of Goldman Sachs. Please go ahead. Good afternoon, thanks for taking my questions.

FDA: The FDA, obviously, then commit a lot more time in working with our sponsor on its product and program because guys commitment now that this disease that we are trying to address a significant.

FDA: Significant unmet medical need and justified.

FDA: Very close collaboration between the sponsor and the FDA. So overall, we are very excited that you received it and it's a good thing for patients.

Speaker Change #183: Thank you. The next question we have is from Celgene Mr of Goldman Sachs. Please go ahead.

Salveen Jaswal Richter: With regard to the mid-year update from the low-dose cohort, can you just frame this for us in the context of what we've seen so far, where you've had, you know, new benefits and or basically maintained the benefit thus far? And then, secondly, with regard to RMAT, help us understand how you're thinking about the regulatory process from here on in. Thank you.

Speaker Change #186: Good afternoon, Thanks for taking my questions.

Speaker Change #185: With regard to the mid year update from the lung cancer cohort can you just frame this for us in the context of what we've seen so far where you've had.

Speaker Change #184: New benefits and are basically maintain the benefit thus far and then secondly, with regard to our mat.

Speaker Change #182: Help us understand how you're thinking about the regulatory process from here on this board.

Speaker Change #182: Thank you.

Speaker Change #187: Sure. Thanks Avi.

Sean Nolan: So in terms of what to expect, we're gonna give an update mid-year on the two adult patients that we've dosed. So we'll work to share the most recent clinical observations and evaluations that have been done. And again, this time both patients would be off of steroids, as an example.

Speaker Change #189: So in terms of what to expect.

Speaker Change #187: So we're going to give an update mid year.

Speaker Change #182: On the two adult patients that we've dosed so well.

Speaker Change #182: We'll work to share the most recent.

Avi: Clinical observations and evaluations that have been done.

Speaker Change #182: And again this this should at this time, both both patients would be off of steroids. As an example, so you know.

Sean Nolan: So we'll make sure we highlight the end points that we've shared to date, the clinical observations that we've shared to date, and try to give a very fulsome update on how they are tracking over the course of time. And with the pediatrics, think of it in the same terms relative to the end points. It's possible we could show some additional data that wasn't collected in the adult study as part of this mid-year update as well.

Speaker Change #182: We'll make sure we highlight the endpoints that we've shared to date the clinical observations that we've shared today and try to give a very fulsome update on and how they are.

Speaker Change #182: Tracking over the course of time and with the Pediatrics think of it in the same terms relative to the endpoints.

Speaker Change #182: It's possible we could show some additional data that wasn't collected in the adult study.

Speaker Change #182: As part of this.

Speaker Change #182: You know mid year update as well and we will provide the most recent available information we have for both of these patients and so what we wanted to do is is really give all of you.

Sean Nolan: And we'll provide the most recent available information we have for both of these patients. And so what we wanna do is really give all of you. A good landscape shot over the course of time in adults, what have we seen?

Speaker Change #182: A good Lance landscape shot over the course of time in adults what if we see.

Sean Nolan: And, you know, again today, what we've been able to outline is that there's been consistent effect across multiple clinical domains. So, the gross and fine motor function, the socialization and communication aspects, seizures, hand function, you know, all of that, we seem to have movement going in the right direction for both patients, regardless of their genotype. We want to provide that same type of overview for the first two pediatric patients. And, you know, in our view, a win at the low dose would be seeing a consistent type effect across these domains for the pediatric patient.

Speaker Change #182: And again today, but we've been able to outline that there has been consistent effect across multiple clinical domains. So the gross and fine motor function, the socialization and communication aspects seizures hand function.

Speaker Change #182: All of that we seem to have movement going in the right direction for both patients regardless of the genotype. We wanted to provide that same type of an overview for the first two pediatric patients and in our view a winning at the low dose would be seen consistent type effect across these domains.

Speaker Change #182: For the pediatric patients.

Sean Nolan: As it relates to RMAT, you know, we're excited about this for a number of reasons. First of all, what's fantastic is that you get very ready access to the FDA, including folks at a senior level. So, you know, what's the benefit of that?

Speaker Change #182: As it relates to two arm at.

Speaker Change #182: We're excited about this for a number of reasons first of all what's fantastic is that.

Speaker Change #182: You you get very ready access to.

Speaker Change #182: Two the F D a.

Sean Nolan: You know, you can be very much more collaborative just because you've got the opportunities to talk through things such as what we're seeing and what we think we might want to do with endpoints and trial design and get their feedback early on. And that obviously can help dramatically in terms of reducing the amount of time and increasing the probability of success in a potentially registrational trial. So, you know, we are very thankful to the agency for granting us that particular designation. You know, what you do is, within about 60 days, you have your initial meeting with them.

Speaker Change #182: Including folks at a senior level.

Speaker Change #182: So what's the what's the good of that you can be very much more collaborative just because you've got the opportunities to talk through things such as what we're seeing and what we think we might want to do with endpoints and trial design and get their feedback early on and.

Speaker Change #182: That obviously can help dramatically in terms of reducing the amount of time and increasing the probability of success.

Speaker Change #182: The potentially registrational trial, so we're very thankful to the agency for granting that particular designation to us.

Speaker Change #182: You know what what you do is within about 60 days is your is your initial meeting with them.

Sukumar Nagendran: You know, so again, as we're generating, you know, this data, it'll be very early on; we'll be able to have nice pulse checks with the FDA relative to our thinking and their thinking. And, you know, we think we're pretty aligned going into it, but this will further enhance that. So, I think that the communication aspect and who you're able to talk to are probably the most critical aspects of garnering the RMAT designation. But let me ask Suku, you know, if there's additional considerations that I didn't outline that you think are important. And Sean, I mean... based on what you've already discussed with Salveen.

Speaker Change #182: So again.

Speaker Change #182: We are generating this data.

Speaker Change #182: Very very early on we'll be able to.

Speaker Change #182: <unk> pulse checks with the FDA relative to our thinking in their thinking.

Speaker Change #182: We think we're pretty aligned going into it but this will further enhance things. So I think that the communication aspect and who you are able to talk to are probably you know the.

Speaker Change #182: The most critical aspects of garnering the RMS segment.

Speaker Change #197: As a nation, but let me ask <unk>, if theres additional considerations that I didn't outlined that you think are important.

Speaker Change #193: Well I mean.

Speaker Change #190: Based on what you've already discussed the Calvin.

Sean Nolan: And as I said earlier, the RMAT obviously gives you much closer contact with senior officials within the FDA CBER, and it also... actually allows the company, the sponsor, to understand what they are thinking when it comes to the initial data for our product and the program and what else could be done to accelerate the program if necessary. So essentially, I mean, it's a process designation that the FDA has created that allows the sponsor to truly accelerate a program that we think is going to make a significant difference in this patient population, especially when there is a significant unmet medical need.

Speaker Change #190: And as I said earlier.

Calvin: And that obviously gives you a much closer contact with senior officials.

Speaker Change #192: Within the F D S Iba and it also acts.

Speaker Change #195: I Love the company the sponsor to understand as far as the FDA, what theyre thinking when it comes to the initial data all of our product on the program.

Speaker Change #195: And what else can be done.

Speaker Change #195: The programming.

Speaker Change #192: So essentially I mean, it's a.

Speaker Change #192: It's the process designation that the FDA has created that allows the sponsor to truly accelerate our program that we think is going to make a significant difference in this patient population, especially when there's a significant unmet medical need so.

Sean Nolan: So, as I said, you know, my teams will work very closely with the FDA when it comes to the clinical and CMC meetings and so forth to move this program forward in an appropriate but rapid manner. Yeah, the only other thing I would add is that, you know, we highlighted it in our remarks, but the other thing I think that's important about RMAT is that it's granted based on the preliminary clinical data that you're sharing.

Speaker Change #192: Said Oh my teams can work very closely with.

Speaker Change #192: The FDA when it comes to the clinical and CMC meetings and so forth.

Speaker Change #192: To move this program forward and inappropriate but rapid manner.

Speaker Change #194: Yes, the only other thing I would add is that we highlighted in our remarks, but the other thing I think that's important about our Madison, It's granted based on the preliminary clinical data that you're you're sharing and so we shared the two adult patients worth of data and I think Kristina asked the question about the.

Sean Nolan: And so, you know, we share the two adult patients' worth of data. And I think Kristen asked the question about the pediatric patient. I believe it was four-week data from a pediatric patient. So, you know, it's also an indicator that, you know, a very objective third party is sensing that there could be, you know, a potential benefit to the patient population that's suffering from the disease. So, again, we're pleased we have it and look forward to the first interaction under RMAT with the agency.

Speaker Change #194: The pediatric patient I believe it was the it was four week data from the pediatric population. So it's also an indicator of that.

Speaker Change #194: Hum.

Speaker Change #199: A very objective third party.

Speaker Change #199: Essentially that there could be.

Speaker Change #194: A potential benefit to the patient population that is suffering from the disease. So again, we're pleased we have it and look forward to the the first interaction under our met with the agency.

Speaker Change #196: Next question please.

Speaker Change #192: Yeah.

Operator: Next question, please. The next question we have is from Whitney Ijem of Kanakor, Genoa T. Please go ahead. Hey guys.

Speaker Change #201: The next question, we have is from Whitney Jim of Canaccord Genuity. Please go ahead.

Whitney Ijem: I'll add my congratulations on RMAP. And I guess my question is around Acelas. Can you remind us how they are being kept in the loop on the data? Is there sort of like a regular quarterly data sharing session, or what does that communication look like? Sure, Whitney.

Whitney Ijem: Hey, guys I'll add my congrats on that and I guess, Mike. My question is around this Dallas can you can you remind us how they are being or to what extent they are being kept in the loop on the data is there sort of like a regular quarterly data sharing session or what is that communication look like.

Sean Nolan: I mean, there's a formal, you know, structure around quarterly updates to the Estella's team. But I would also just remind everybody that, you know, we do have Richard Wilson, you know, as an observer on our board. So, he's obviously in real time, anything we're updating the board on, he's very aware of that.

Speaker Change #197: Sure I mean, there's there's formal.

Speaker Change #197: Structure around quarterly updates to the Astellas scheme, but I would also just remind everybody that we.

Speaker Change #197: We do have.

Speaker Change #197: Richard Wilson as an observer on our board. So he he obviously is.

Speaker Change #197: In real time anything we're updating the board on he's.

Speaker Change #197: He is very aware of that I can say that if we are having regulatory interactions.

Whitney Ijem: I can say that if we're having regulatory interactions, you know, members of the Estella's team are participating in that. So, you know, I would say there's very clear transparency with Estella about the data that's being generated and key strategic aspects of the program and communications with regulatory authorities that are being shared. Hopefully, that helps you out. Yeah, very helpful.

Speaker Change #197: Members from from the Astellas humor participating in that so.

Speaker Change #197: I would say, there's very clear transparency with with Astellas about the data that's being generated and key strategic aspects of the program and communications with regulatory.

Speaker Change #197: <unk>.

Speaker Change #197: That are being sure.

Speaker Change #197: Hopefully that helps you out.

Speaker Change #197: Got it very helpful. Thank you.

Speaker Change #197: Sure.

Chris Raymond: Thank you. The next question we have is from Chris Raymond of Piper Sandler. Please go ahead. Chris, your line is live, and you can ask a question.

Speaker Change #202: The next question, we have is from Chris Raymond of Piper Sandler. Please go ahead.

Chris Raymond: Chris Your line is now have you may ask a question.

Operator: We seem to have no response from that line. The next question we have is from Joon Lee of Jewish Securities. Please go ahead.

Chris Raymond: It seems we have no response from that one. The next question. We have is from Joon Lee of <unk> Securities. Please go ahead.

Joon So Lee: Congratulations on the data and the progress, and thanks for taking our questions. You're scheduled to present data on June 19th at a RETS conference. Is that when we can expect initial pediatric data at the low dose? And do you have any plans to host a webcast around the event for the investigation?

Speaker Change #204: Hey, congrats on the data and the progress and thanks for taking our question.

Joon So Lee: Canceled to protect data on June 19th conference is that when we can expect initial pediatric data and the low dose and do you have any clause to host a webcast around events to the investors. Thank you.

Sean Nolan: Yeah, that would be the We have a platform where we'd like to give the update on the pediatric data and the update on the adult cohort one. And, you know, we haven't we haven't decided the specifics around further investor communication, but there will be some. Thank you. Thank you. The next question we have is from Maureen Raycroft of Jefferies. Please go ahead.

Joon So Lee: Yeah.

Speaker Change #206: It would be the.

Speaker Change #207: The platform, where we'd like to give the update on the pediatric data and the update on the.

Speaker Change #207: The adult cohort one.

Speaker Change #208: And we Havent, we havent decided the specifics around further investor communication, but there will be some.

Speaker Change #209: Yes, okay.

Speaker Change #210: Looking forward. Thank you.

Speaker Change #210: Thank you.

Speaker Change #210: The next question we have is from Maury Raycroft of Jefferies. Please go ahead.

Unknown Executive: Hi, congrats on the progress and thanks for taking my questions. Just a clarification question, initially, are you saying which month you dose the second pediatric patient, or can you say how much total follow-up you'll have in the midyear update for the pediatric patients? I don't believe we gave specific dosing dates for the second pediatric patient, but what I would think about is that, you know, We would have four to eight weeks of data, most likely, for that second patient.

Unknown Executive: Hi, Congrats on the progress and thanks for taking my questions.

Unknown Executive: Just a clarification question initially or are you, saying, which month you dose the second pediatric patient or can you say how much total follow up you'll have been that the mid year update for pediatric patients.

Speaker Change #211: I don't believe we gave specific dosing date for the for the second pediatric patients but.

Speaker Change #212: What I would think about is that you know.

Speaker Change #213: We would have four to eight weeks of data most likely for that second patient.

Sean Nolan: Got it. And also clarifying for the pediatric data, are there specific measures or any unique efficacy measures that you're going to show for the pediatric population, like the MSEL-A measure in the mid-year update? You know, we're still working through the presentation. I mean, so I can tell you the things that you've seen on the adults. We'll do our best to share that information. I would say that we're still working through the presentation, but there could be some measures that are shown that we haven't seen to date because they're not part of the adult study.

Speaker Change #213: Got it and.

Speaker Change #214: And also clarifying for the pediatric data are there specific measures or any unique efficacy measures are they going to show for the pediatrics like that M. S E L. A measure.

Speaker Change #214: And the mid year update.

Speaker Change #215: We're still working through the presentation. So I can tell you the things that you're seeing on the adults will do our best to share that information.

Speaker Change #215: I would say that there were still working through the presentation, but there could be some.

Speaker Change #215: Some measures that are shown that we havent to date because they are not part of the adult study. So I'd just say stay tuned on that.

Sean Nolan: So I'd just say, you know, stay tuned on that. Again, simply because we're working through it all and collecting data at this point, but stay tuned for more on that. Okay, okay, thanks for taking my questions. I'll hop back in the queue.

Speaker Change #215: <unk>.

Speaker Change #215: Again simply because we're working through it all and collecting the data at this point, but.

Speaker Change #215: Stay tuned for more on that morning.

Speaker Change #216: Okay. Okay. Thanks for taking my questions I'll hop back in queue.

Speaker Change #216: Sure.

Unknown Executive: Sure. The next question we have is from Chris Raymond of Piper Handler. Please go ahead. Sorry about the technical issues earlier.

Speaker Change #216: The next question, we have is from Chris Raymond of Piper Sandler. Please go ahead.

Speaker Change #217: Sorry about the technical issues earlier.

Chris Raymond: Just, if this got asked already, I apologize; I got disconnected. We've heard some market chatter around the relative advantages of, you know, a competitor program which uses ICP.

Speaker Change #218: And if this got asked already I apologize I got disconnected, but.

Chris Raymond: We've heard some some market chatter around the relative advantages of interests equal administration versus.

Speaker Change #219: You know a competitive program, which uses ICD.

Sean Nolan: And we've heard some folks maybe positing that there might be a disadvantage for one. I guess I'm kind of curious about this because you guys have seen, you know, pretty clear early improvement in autonomic function, some communication improvement, even seizures. You know, so maybe, just in broad strokes, remind us of the data that you have that shows the vector gets into the brain and has broad distribution. Yeah, you know, I'll ask Sukumar to take this question.

Speaker Change #220: And we've heard some folks may be positive that there there might be a disadvantage for one or two in terms of impacting brain function.

Speaker Change #221: I guess I'm kind of curious about this because you guys have seen you know pretty clear early improvement in autonomic functions communication proven even seizures.

Speaker Change #222: So that maybe just in broad strokes remind us of the data that you have this shows the vector gets into the brain and has broad distribution and then I have a follow up.

Sukumar Nagendran: I would just say that the, you know, what I would point to, and then Sukumar can fill in any gaps or take it down a different path. But I think the most important thing is that you're, you are, it's a combination of biodistribution and likely total MECP2 production. There's some threshold you have to get over before you really start to see the impact on the disease. And, you know, when you point to all of the preclinical work that's been done, right?

Speaker Change #223: Yeah, I'll I'll ask <unk> to take this question I would just say that the.

Speaker Change #223: What I would point to in that suite.

Speaker Change #224: Phil filling any gaps or take it down a different path, but I think the most important thing is that you're you're it's a combination bio distribution and likely total MVC to produce there is some threshold you have to get over to where you're right you really start to see the impact.

Phil: On the disease and you know when you point to all of the preclinical work that's been done right. I mean, I think I think other gene therapies here have done one clinical trial and our one preclinical trial in pizza Pizza mice in ICB, we've done that and I think the results are.

Sukumar Nagendran: I mean, I think other gene therapies here have done, you know, one clinical trial or one, you know, preclinical trial in P0, P2 mice in ICD. You know, we've done that, and I think the results are very striking for Taysha 102 at a lesser dose given intrathecally. And importantly, we also did work in different ages of mice, right? You know, P7, P14, P28, looking, you know, you're trying to, those should be harder mice to affect the phenotype.

Phil: <unk> are very striking.

Speaker Change #226: For <unk>, one or two.

Speaker Change #226: The lesser dose given interests equally.

Speaker Change #227: And importantly, we also did work in different ages of Mikes right P 714 P 28 looking.

Speaker Change #227: Trying to both should be harder mice to affect the phenotype.

Sean Nolan: And, you know, again, we saw very good outcomes there as well with the intrathecal route. But most importantly, I think it's looking at the clinical data, right? And one of the reasons we've reported like we have thus far is that we wanted to share with everybody the different clinical domains that are being affected. Right, so if you're looking at gross and fine motor function, you're looking at speech and socialization, you know, seizure impact, hand coordination, those are all different areas of the brain. Right, so there has to be distribution and level enough to have the impact that we're seeing.

Speaker Change #228: And again, we saw very good.

Speaker Change #229: Pumps, there as well with the issue with FICO route.

Speaker Change #229: But most importantly.

Speaker Change #230: I think it's looking at the clinical data right and one of the reasons. We've reported like we have thus far is we wanted to share with everybody. The different clinical domains that are being affected right. So you are looking at gross and fine motor function Youre looking at speech and socialization.

Speaker Change #230: Seizure impact hand coordination those are all different.

Speaker Change #230: Areas of the brain.

Speaker Change #230: So there has to be distribution in level enough to have the impact that we're that we're seeing.

Sean Nolan: And again, I point to the RMAT designation and the threshold to get it for demonstrating some preliminary clinical efficacy in a disease with very high unmet need. So, you know, I understand the academic discussion of one route versus another, but I think that the preponderance of the evidence would indicate, whether it's preclinical or, more importantly, clinical data that 102 has a significant effect on the disease, and we're seeing that in real time. But, Sukumar, you may have more to add. Please go ahead.

Speaker Change #231: And again I point to the RMS designation and the threshold to get at is demonstrating some preliminary clinical efficacy in a disease with very high unmet need.

Speaker Change #231: You know I understand the academic discussion of of one route versus another but I think that the preponderance of the evidence would indicate whether its preclinical or more important clinical data that went on to has a significant effect on.

Super: On the disease, and we're seeing that in real time, but Super you may have more more to add please go ahead.

Sukumar Nagendran: Well, Sean, I think you gave him quite a good explanation. The only other thing I would add is that Brett syndrome is thought to be not just a neurodevelopmental disorder but also a result of the rapidity with which both adult patients responded to our gene therapy given by lumbar puncture.

Super: So Sean I think you gave him quite a good explanation the only other thing I would add.

Speaker Change #233: Is that.

Speaker Change #234: Brett syndrome is thought to be not just in neuro developmental disorder.

Super: It's a neural network maintenance disorder, and the reason I pointed this out.

Super: Is.

Super: The rapidity with which both adult patients responded to a gene therapy, given the lumbar puncture, so, especially when it comes to subtle dysfunction.

Sukumar Nagendran: So especially when it comes to autonomic dysfunction, these are getting corrected 10 days post-dosing with our gene therapy. So this raises another question that I guess with gene therapy, regardless of product, you may never need perfect biodistribution. It's really trying to understand the pathophysiology of the disease. So, my point is, when MECP2 gets in or is in the nucleus of every neuron or astrocyte, it activates, it appears. Thousands of genes. Some of these genes are silent, so transcription is prevented while other genes are actually activated.

Speaker Change #235: Uh huh.

Speaker Change #236: Getting corrected 10 days post dosing without gene therapy. So so this latest another question that.

Speaker Change #236: With the I guess with gene therapy, regardless of product you may never need perfect by distribution, it's really trying to understand the pathophysiology of the disease, So that I point to.

Speaker Change #237: M. A C P to get thinner is in the nucleus.

Speaker Change #238: Every neuron extra site.

Speaker Change #238: Give it it up here.

Speaker Change #238: Dozens of genes.

Speaker Change #238: Some of these genes silenced.

Speaker Change #238: Transcription is prevented while other genes actually activated so I guess, what I'm getting at is just think of this all cost struck conductor like picture.

Sean Nolan: So I guess what I'm getting at is just think of this orchestra conductor picture, where MECP-2 is the sick orchestra conductor, and once you wake him up and restore him, the entire orchestra starts playing, and then your brain function starts getting restored, and that's kind of what we're seeing with the adult patients that we've dosed up. And just to follow up, I think when you guys gave your last update, you know, there was some discussion around the... The fact that you were tapering steroids... and, you know, the impact of steroid tapering on the RSVQ improvement in patient one. Any progress here maybe or an update on teasing that out?

Speaker Change #239: Mississippi too sick, Lucas, our conductor and wants to wake them up and they saw him.

Speaker Change #239: Cause if that's playing and then yeah brain function starts getting restored and that's kind of what you're seeing with the adult patients that we've dosed up to now.

Speaker Change #240: Thanks, maybe just a follow up.

Speaker Change #241: When you guys gave your last update you know there was some discussion around the presence.

Speaker Change #240: Hum.

Speaker Change #242: The fact that you were tapering steroids.

Speaker Change #243: And you know the impact of of steroid tapering on the RSP Q improvement in patient one.

Speaker Change #243: Any progress here, maybe or update on teasing that out as you continue dosing.

Speaker Change #244: Dosing patients.

Sukumar Nagendran: Well, I would say, Sukum, feel free to jump in here. But, but, you know, that end of one patient is interesting. We'll have to see if we see the same thing as more time elapses with other patients. But initially, there was a thesis that the benefit that we were seeing efficacy-wise was because of the steroids. And, you know, what we've demonstrated is that, number one, we tried to highlight to everybody that no one uses steroids to treat, [inaudible] And, I think patient one is showing that, you know, she had reduced anxiety and irritability as a result of going off the steroids.

Speaker Change #245: Well I would say <unk> feel free to jump in here, but but you know that that N of one patient I think is interesting we'll have to see as more time elapses with other patients if we see the same thing but.

Speaker Change #245: Initially there was a there was a thesis that the benefit that we were seeing efficacy wise just because of the steroids.

Speaker Change #245: And.

Speaker Change #246: What we've demonstrated is that number one we tried to highlight to everybody that no one uses steroids to treat.

Speaker Change #246: This disease not number one.

Speaker Change #246: And I think we've just missed that but we wanted to show that after the steroids were gone there was no loss or dimunition of effect.

Speaker Change #246: But the flip side to it is I think that we may see that Theres a case to be made that steroids are asked actually masking some of the benefits of the therapy.

Speaker Change #247: And I think patient one is showing that she had reduced.

Anxiety and irritability as.

Speaker Change #247: As a result of going off the steroids and I can tell you you know when you look at the patients that have been treated to date. The steroids are hard I mean, they're on it for a long period of time at a very high dose.

Sukumar Nagendran: And I can tell you, you know, when you look at the patients that have been treated to date, the steroids are hard on them. I mean, they're on them for a long period of time at a very high dose. And, you know, if you think about it, a lot of these girls have very bad GERD or reflux. Well, the steroids make that worse. And then

Speaker Change #247: <unk>.

Speaker Change #248: Do you think about it.

Speaker Change #248: A lot of these girls have very bad GERD or reflux will the steroids make that worse and then.

Sean Nolan: Steroids can make you irritable, right? And it can be negative in terms of your ability to sleep, which then it's like a cycle, right? So I actually, like, believe that as the steroids are backed down and eventually are removed, there may be, you know, positive outcomes that we see that are being masked, particularly when you think about an RSVQ where the caregiver's having to provide an update on things, and they're probably tired and irritable, too, because they've been dealing with a child that doesn't feel well.

Speaker Change #249: Steroids can make irritable alright, and it can be negative in terms of your ability to sleep.

Speaker Change #249: Which then it's like a cycle right. So I actually like I believe that that is the steroids are back down and eventually are removed there may be.

Speaker Change #249: Positive.

Speaker Change #249: Outcomes that we see that we're being mass, particularly when you think about an RSV Q, where the where the caregivers give us having to provide an update on things and they are probably tired of near double two because they've been dealing with a child that doesn't feel well so.

Sean Nolan: So, you know, that's the distinction that we were trying to make. We'll have to see as more patients, you know, come off steroids if that's totally accurate, but that seems to be the case. And it's certainly, you know, I think patient number one would help support that. But Suku, is there anything else you'd add to that one?

Speaker Change #249: That's the distinction that we're trying to make will have to see as more patients come off steroids.

Speaker Change #249: It's totally accurate, but let's see.

Seems to be the case and that certainly I think patient one would help support that thesis.

Speaker Change #250: But sucre is there anything else you'd add to that one.

Sukumar Nagendran: Not much else, Sean, as you pointed out, I think steroids and other immunosuppressants, What we are learning is the shorthand side of the use of them, the more effective they're going to be. The next question we have is from Gil Blum of Needham & Co. Please go ahead.

Speaker Change #251: Not much else on I mean, as you pointed out.

Speaker Change #251: I think steroids and other immuno suppressant.

Speaker Change #251: But we are adding as the short end either.

Speaker Change #252: Use of them the more effective it's going to be.

Speaker Change #252: Yes.

Speaker Change #253: Thanks, guys.

Speaker Change #254: The next question, we have is from Copeland of Needham <unk> co. Please go ahead.

Gil Blum: Hi everyone, and thanks for taking our questions. And again, congrats on the progress. So maybe I'm harping a bit here, but

Speaker Change #255: Hi, everyone and thanks for taking my questions and again congrats on the progress.

Speaker Change #256: So maybe I'm being a bit here, but.

Sean Nolan: Just to help me understand, what do you guys mean by a similar pattern of activity? I mean, there are multi-domain indications, right? Some of these patients are very heterogeneous. Just to help me understand that, and I do have a follow-up. Yeah, sure. I mean, I would say very simplistically, you know, if you think about the endpoints, like CGI, CGI, RSVQ, and what those measure, yeah, we're going to give updates on those types of scales. But it's also thinking about the domains, you know, like the gross and fine motor function and function, you know, speech and socialization.

Speaker Change #257: Just to help me understand what you guys mean by similar pattern of activity mean does their multi domain indications right.

Speaker Change #257: Some of these patients are very heterogeneous just to help me understand that.

Speaker Change #257: Follow up.

Speaker Change #258: Yes, sure I mean, I would say very Simplistically, if you think about the endpoints like CGI CGI S.

Speaker Change #259: RSV Q and then but those measure yeah, we were gonna give updates on those types of scales, but it's but it's also thinking about the domains like the you have the gross and fine motor function.

Speaker Change #259: And function.

Speaker Change #260: Speech and socialization.

Sean Nolan: The seizure aspect of things. So, you know, we've always tried to paint a snapshot of the fact that the disease just hits so many different areas in each patient. And each patient can have, you know, more or less severity in one area versus another. I mean, it's very, you know, heterogeneous, as you know. And so we're just trying to say that it's the same thing for the pediatric patients. They're going to present in a similar fashion in terms of multiple domains being affected.

Speaker Change #260: The seizure aspect of things. So we've always tried to paint a snapshot of.

Speaker Change #261: The fact that the disease just get so many different.

Speaker Change #261: Areas for each patient and each patient can have you know.

Speaker Change #261: More or less severity.

Speaker Change #261: In one area versus another I mean, it's very a hetero genius as you know and so we're just we're just trying to say that it's the same thing for the pediatric patients are going to present in a similar fashion in terms of multiple domains being affected.

Sean Nolan: They've had the disease for, you know, for this group at least five, six years. And to us, it's important to show that we're affecting the disease across these domains similar to what we're seeing in the adults at a low dose. But Suku, again, if there's something there you want to highlight further, please do. Sean, I mean, I don't really have too much to add other than to remind everyone.

Speaker Change #261: Had the disease for you know for this group at least five years six years.

Speaker Change #261: And.

Speaker Change #261: To us it's important to show that were affecting the disease across these domains similar to what we're seeing in the adults at the low dose.

Speaker Change #262: But again, if there is something there you want to highlight further please do.

Speaker Change #262: Hum.

Tom: Tom I mean.

Tom: I don't really have too much to add other than reman.

Tom: Remind everyone.

Sukumar Nagendran: This is a very complex syndromic disease where multiple aspects of, I guess, human biology are made abnormal. And I think, as Gil pointed out, and as we know, the phenotypic presentation does vary quite a lot. So when it comes to the impact of a therapeutic intervention, I mean look, our hope, my hope is that we want to do gene replacement therapy in particular.

This is a very complex syndromic diseases.

Tom: Multiple aspects of Hum.

Tom: I guess the human biology.

Speaker Change #263: <unk> abnormal and I think as Gil pointed out and as you know.

Speaker Change #264: The phenotypic presentation does vary quite a lot.

So when it comes to the.

Speaker Change #264: The impact of a therapeutic intervention.

Speaker Change #265: I mean look I hope my hope is that well.

Speaker Change #266: Want to do the gene replacement building particular approach.

Gil Blum: You are able to restore function regardless of the syndromic presentation. So as you accumulate more data, then hopefully, that proves our point, you know. All right, it's very helpful. Now, is there any reason to believe that potential improvements in pediatrics will be larger than what we've seen in adults, but maybe not in kind of the learned functions that you guys discussed before? How about autonomic functions? I mean, they are younger.

Speaker Change #266: You are able to restore function regardless.

Speaker Change #266: After syndromic presentation, so as we accumulate more data than hopefully that proves that point.

Speaker Change #266: Alright.

Speaker Change #266: Helpful.

Speaker Change #267: Is there any reason to believe that potential improvements in pediatrics will be larger than what was seen in adults, but maybe not and kind of the learning functions that you guys discussed before.

Speaker Change #268: How 'bout autonomic functions I mean, they are younger patients.

Speaker Change #267: Okay.

Sukumar Nagendran: Sukumar, you want to take that question? Yeah, so was that Gil, Sean? Yeah, Gil was asking, you know, might autonomic function have a faster improvement or greater improvement in a pediatric patient versus an adult? That is a tough question. I mean, I would assume at this point in time that it's probably safer to say even that in the two adult patients, we were rapidly correcting autonomic dysfunction within 10 days. If you are able to do those kind of autonomic corrections in the pediatric population also within 10 days, I think that will be remarkable. Outcome for this therapeutic intervention. Now the caveat, as you say Gil, is whether you can do it in half the time.

Speaker Change #271: <unk> you want to take that question.

Speaker Change #272: Yes, so what that gives us so.

Speaker Change #272: Gil was asking Mike autonomic function.

Speaker Change #269: Have a have a faster improvement or greater improvement.

Speaker Change #270: In a pediatric patient versus an adult.

Speaker Change #270: Uh huh.

Speaker Change #270: Oh.

Speaker Change #273: That is a tough question I mean I.

I would assume at this point in time.

Probably fair to say.

Speaker Change #274: Even that.

Speaker Change #275: Two adult patients rapidly correcting autonomic dysfunction within 10 days, okay able to do both.

Speaker Change #276: Those kind of economic correction in the pediatric population all of a sudden within 10 days I think that'll be a remarkable.

Speaker Change #275: Outcome.

Speaker Change #275: The pubic intervention now the caveat there Gil is can you do it in half the time.

Sukumar Nagendran: Honestly, I don't know. We have to dose the patients and see what happens, but at the same time, when it comes to autonomic dysfunction, at least the features we are aware of in Rett syndrome, the rapidity of response, like say you get it addressed in two days versus eight or ten days. I don't think, in the bigger picture, clinically, we make that much of a difference, you know? I hope that helps, Joe. The next question we have is from Yanan Zhu of Wells Fargo; please go ahead. Great

Speaker Change #277: Honestly I don't know we have to dose the patients and see what happens but at the same time.

Speaker Change #277: When it comes to autonomic dysfunction.

Speaker Change #277: The features that all add up in Ret syndrome.

Speaker Change #278: PTT a restaurant, let's say you get hit.

Speaker Change #278: This included eight or 10 days I don't think in the bigger picture clinically we admit that.

Joe: Hope that helps Joe.

Speaker Change #278: Yeah.

Speaker Change #279: The next question we have is from <unk> <unk> of Wells Fargo. Please go ahead.

Yanan Zhu: Thanks for taking our questions. Since you mentioned heterogeneity, greater heterogeneity even in younger patients, I was wondering, for the two patients you've treated so far at baseline, what are the severity levels like? I.e., could there be a very mild phenotype and therefore incurring the caveat of the potential to see less of an effect? And then there is a follow-up. Can you take that one, Sukum, please?

Speaker Change #280: Great. Thanks for taking our questions.

Speaker Change #281: You mentioned the heterogeneity.

Speaker Change #282: Greater heterogeneity, even in younger patients I was wondering for the two patients he treated so far at baseline.

Speaker Change #283: The severity level at Lake.

Speaker Change #284: He could there be.

Speaker Change #285: Very mild.

Speaker Change #285: Phenotype.

Speaker Change #286: And therefore incurring as a caveat.

Speaker Change #286: So to.

Speaker Change #287: To see less of an effect.

Speaker Change #288: Okay, and then I have a follow up thanks.

Speaker Change #289: Can you take that one please.

Sukumar Nagendran: Yes, Sean, so I just want to make sure I heard the question correctly. At the beginning, I think I heard you say that the pediatric population tends to be a lot more heterogeneous. I assume compared to the adult population in that scenario, is that what you said? Right, I'm just saying that in your prepared remarks, you highlighted variability of disease for the pediatric patient population. Yeah.

Speaker Change #290: Yes, so I just want to make sure I heard the question though.

Speaker Change #291: I think I heard you say.

Speaker Change #292: But the pediatric population tends to be a lot more heterogeneous.

Speaker Change #293: I assume compared to the adult population with.

Speaker Change #294: Is that what you said.

Speaker Change #295: Right I'm, just say I thought I heard it.

Speaker Change #296: In our prepared remarks, you highlighted variability of the disease for the pediatric patient population.

Yanan Zhu: So, I was wondering, in that context, for the two patients you have dosed so far, what are the baseline disease severity levels? Are they, you know, reasonably high so that it's reasonable to expect to see some benefit if there could be any? Or could there be, for example, one of the patients may have a very mild disease and therefore be difficult to demonstrate benefit? So, I think the heterogeneity...

Speaker Change #295: Population.

Speaker Change #297: I was wondering in that context.

Speaker Change #298: For the two patients you have dosed so far.

Speaker Change #299: Is there and what are the baseline disease severity levels are they.

Speaker Change #300: Reasonably high for that it's reasonable to expect to see some benefit if there could be any or could there be.

Speaker Change #301: For example, one of patient may have a very mild disease, and therefore difficult to demonstrate benefit.

Speaker Change #302: So I.

Speaker Change #303: I think the heterogeneity.

Sukumar Nagendran: So my understanding is across the board. When it comes to that syndrome, regardless of age, I mean, so, but having said that. I think if you take patient by patient with Rett syndrome, regardless of age, and look at the complexities of the syndromic presentation, at the present time, what we would anticipate is a consistent response clinically, given that the gene therapy has shown a rapid response and more sustained response in the two adult patients where one never expected a response, right? So pediatric patients, obviously, we haven't disclosed the baseline characteristics. I need the data yet.

Speaker Change #303: But my understanding is across the board.

Speaker Change #304: When it comes to that syndrome, regardless of age so.

Speaker Change #305: Having said that.

Speaker Change #305: I think if you take a patient by patient with Ret syndrome.

Speaker Change #306: God bless of AIDS and because of the complexities of the Syndromic presentation.

Speaker Change #306: At the present time.

Speaker Change #307: But we would anticipate is a consistent response clinically.

Speaker Change #308: Given that the gene therapy has shown rapid response and more sustained responses to adult patients who have one never expect a spot right.

Pediatric patients obviously, we haven't disclosed.

Sukumar Nagendran: So all I can say is stay tuned, and my hope is when you go to the higher dose, the effect that we have should be consistent across the board. The only other thing I think to again address is the autonomic dysfunction seen in a young pediatric patient. Well, I guess the concept is if your network is young.

Speaker Change #309: Baseline characteristics and you have the data yet so all I can say is stay tuned and my hope is that you'll go to the higher dose.

Speaker Change #309: The fact that we have.

Speaker Change #310: Regardless of the clinical features of the syndrome should.

Speaker Change #311: It should be consistent across the board.

Speaker Change #311: The other thing I think to again.

It addresses the autonomic dysfunction.

Speaker Change #312: <unk> young pediatric patient.

Speaker Change #313: I guess the concept is if your network is yellow.

Sukumar Nagendran: The odds are you should respond even quicker. I mean, obviously, I don't think anyone has done gene therapy to assess that yet. And hopefully, as we gather more data in the pediatric population, we can help answer that question. Yeah, the only other thing I would, I would, I would say to Yanan is that, you know, per the protocol, basically, you're going to see similar severities in that the CGI-S range is between four to six. Okay, so it's very similar to the adult trial in severity. Got it. That's super helpful.

Speaker Change #314: The value for this one even quicker.

Speaker Change #315: So obviously I don't think anyone has done.

Speaker Change #316: Gene therapy to assess that.

Speaker Change #317: And hopefully as you gather more data in the pediatric population, we can help answer that question.

Speaker Change #318: Yeah. The only other thing I would I would I would say to that is that further protocol basically.

Speaker Change #319: Youre going to see similar severities and that the CGI S.

Speaker Change #320: The range is between four to six.

Speaker Change #320: Okay. So it's very similar to the the adult trial in severe.

Yanan Zhu: And then maybe the follow-up is about the next patient. Or perhaps, if I can, I may ask patient number two, Has the IDMC safety evaluation been done yet, or is that still pending? And for the third patient, I was wondering if you still plan to dose that patient with the low dose, or could you do something similar to what you did for the adult cohort and reassign that patient to a higher dose based on the data you have accumulated?

Speaker Change #321: Got it that's Super helpful. And then maybe a follow up here just about the next patient.

Speaker Change #322: And perhaps if I may ask for patient number two.

Speaker Change #323: Has the IBM seas safety evaluation been down yet or is that still upcoming.

Speaker Change #324: And for the third patient.

Speaker Change #324: I was wondering is the plan still to build that patients with a low dose or could you do something similar to what you did for the adult cohort and reassigned that patient.

Speaker Change #324: Too high a higher dose based on.

Speaker Change #325: The data you have.

Speaker Change #326: Accumulated thank you.

Sean Nolan: Thank you. Yeah, that's a good question, Jan. And so basically, the IDMC has not yet met for patients who are coming in the next couple weeks. And, you know, I think the answer to your question about whether you would go to the high dose after only two patients is going to depend on a combination of things. It will certainly start with safety and any observed efficacy. And also, again, we haven't talked to the IDMC, so, like, don't read into what I'm saying. I'm just giving you an example.

Speaker Change #327: Yes, that's a good question John and so basically the <unk> has not yet met.

Speaker Change #328: For patients who is coming in in the next the next.

Speaker Change #329: Couple of weeks.

Speaker Change #330: And I.

Speaker Change #330: I think the answer to your question on would you go to the high dose after only two patients I think it is going to depend on a combination of things. It will certainly start with the safety and any observed efficacy.

Speaker Change #331: Two to evaluate.

Speaker Change #332: And also again, we haven't talked to the Ibs C. So like Don.

Speaker Change #333: Read into what I'm, saying I'm, just giving an example.

Sean Nolan: They could say, well, it's pediatrics, and, you know, we would like to see, you know, a third patient's dose just simply because they're pediatric. So, you know, I think your logic makes a lot of sense. We'll just have to see how things play out, and it'll start with the data presentations at ID&G. Okay. Thank you for taking all the questions.

Speaker Change #334: Could say well, it's pediatrics and we would like to see.

Speaker Change #334: A third patient dose just simply because the pediatrics so.

Speaker Change #335: I think your logic makes a lot of sense, we'll just have to see how things play out and it will start with the data presentation for the I didn't see.

Speaker Change #336: Understood. Thank you for taking all the questions.

Speaker Change #337: Sure. Thank you.

Speaker Change #337: Yes.

Yanan Zhu: Sure, thank you. The next question we have is from Jack Allen of Baird; please go ahead. All right, thanks for taking the questions and congratulations on all the progress. Just one quick one from me, and similar to the question of mine as the last couple of questions that were asked here. But I know it was asked about the phenotypes of these patients, the pediatric patients that we're going to get data from in the next couple of weeks here. But how about the genotypes?

Speaker Change #338: The next question we have is from Jack <unk> of Baird. Please go ahead.

Speaker Change #339: Alright, thanks for taking the questions and congratulations on the progress just one quick one from me similar question of mine is at the last couple of questions that were asked it here but.

Speaker Change #341: As of the phenotype of these patients pediatric patients that we can get data from in the next couple of weeks here how about the genotype. So anything you can say as it relates to.

Jack Kilgannon Allen: Anything you can say as it relates to what kind of genotypes these two patients have? Yeah, we haven't disclosed that, but Sukumar, you want to comment on that? So I just want to make sure Sean, I got the question. So this is in the two pediatric patients, right? Right. Like seeing a significant deletion, are we seeing, you know, missense mutations, you know?

Speaker Change #340: What kind of genotype three patients.

Speaker Change #342: Yes, we haven't disclosed that but but secret you want them you want to comment on that.

Speaker Change #343: So I just Wanna picture Sun I got the question. So this is the two pediatric patients right.

Speaker Change #343: Right.

Jimmy that we like.

Speaker Change #344: Seeing a significant deletion or are we seeing Mrs sensor mutations.

Speaker Change #344: Yeah.

Speaker Change #344: So [laughter].

Sean Nolan: So, um... So Sean, I mean, can I, I guess we haven't disclosed the genotypes at this point in time. So I assume without going into too much detail, what I can tell you is one patient is, which, as I recall, is very mild, and the other patient is more towards the serious side. And now keep in mind that they do evaluate C.G.I.S. and so forth to see how sick the patients are. And so, that also gives you a feel for what one would anticipate as a response to the therapy. But there's a caveat, though.

Speaker Change #344: So some of them in the kind.

Speaker Change #345: Can I I guess, we haven't disclosed when the genotype at this point in time, so I assume without going into too much detail, but.

Speaker Change #346: I can tell you is one person is.

Speaker Change #347: I had a club every mile.

Speaker Change #348: Our miles and the other percentage.

Speaker Change #349: More towards the severe side.

Speaker Change #350: Now keep in mind that.

Speaker Change #351: They do evaluate C D.

Speaker Change #351: And so forth.

Speaker Change #352: Healthy patient, though.

Speaker Change #353: And so that also gives you a feel.

Speaker Change #353: What one would anticipate.

Speaker Change #353: As a response to the therapy, but there is a caveat.

Sukumar Nagendran: What we're observing is even if someone, as a patient with retinitis, has a milder phenotype due to a mysense mutation, some of their symptomology actually gets treated remarkably well. And the reason I say that is, if you think of a second adult patient who was dosed in Canada, this was a patient who had multiple seizures and two anti-phileptics and, if I recall, had four seizures a week.

Speaker Change #354: What we are observing.

Speaker Change #354: If someone is a patient with the rest of them has a milder phenotype.

Speaker Change #354: My sense of mutation.

Speaker Change #355: My mother, Symptomology, a city gets treated remarkably well.

Speaker Change #356: Yeah that is if you think of.

Speaker Change #356: The current adult patient was dosed in Canada.

Speaker Change #356: Because a person to have multiple seizures.

Speaker Change #356: And.

Speaker Change #357: Well, it's not two anti epileptics.

Speaker Change #358: And for the club for seizures, a week noted special it appears to be seizure free.

Sukumar Nagendran: Now this patient appears to be seizure-free, and the anti-seizure medicine doses have been decreased by 25%. So, I guess I hope that draws a parallel because sometimes these patients have 10 different clinical features. The question on the table then becomes, which of these can you hopefully address, control, or eliminate such that the patient gets much stronger and can have a productive life?

Speaker Change #359: The seizure medicine doses have been decreased by 25%.

Speaker Change #359: So I guess I hope that draws a parallel.

Speaker Change #360: Because sometimes these patients have 10 different clinical feature.

Speaker Change #361: Question on the table, then becomes which are these can you hopefully address control or eliminate that said the patient gets much stronger.

Speaker Change #362: Have a productive life.

Speaker Change #361: Yeah.

Jack Kilgannon Allen: Got it. Great. That's great, Kyler.

Speaker Change #363: Got it great that's great color. Thanks, so much and looking forward to the data.

Jack: Thanks Jack.

Sukumar Nagendran: Thanks so much. I'm looking forward to the data. Thanks, Jack. The last question we have is from Silvan Tuerkcan of Citizens JNP. Please go ahead. Thank you for taking my question and congratulations on the RMAT designation. I also just have a question on the pediatric patients, given that they may be more heterogeneous. Is there anything on the safety side that would be important to consider here?

Silvan Tuerkcan: The last question, we have is from Silvan <unk> of citizens JMP. Please go ahead.

Silvan Tuerkcan: Yeah. Thank you for taking my question and congrats on the our Mac designation.

Silvan Tuerkcan: Do they have comorbidities? In that vein, please. Thank you. Sure. I would just clarify, and Suku, correct me if I'm wrong, the pediatric patient isn't any more heterogeneous than the adult. That's correct. It's the same distribution, to my knowledge, Sean. Right. And Suku, any comment on Yanan's, "Inaudible" So Yanan, you're

Speaker Change #366: I also have a question on the pediatric patients.

Speaker Change #367: Even that baby more heterogeneous is there anything on the safety side that that will be important to come today here to the Apple Comorbidities.

Speaker Change #367: Anything.

Speaker Change #368: In that vein. Please thank you.

Speaker Change #370: Sure I would just clarify too secret correct me, if I'm wrong, the pediatric patient isn't any more heterogeneous than the adult.

Speaker Change #369: That's correct.

Speaker Change #371: To my knowledge John.

Speaker Change #372: Right and so any.

Speaker Change #372: Any comment on that.

Speaker Change #372: Question.

Speaker Change #373: So I don't know.

Sean Nolan: In the question, I mean, do you mind repeating it? Yeah, sure. I was just wondering, in pediatrics in general, if there's anything on the safety profile side that, you know, we may have to be aware of, you know, this, the smaller livers, they, you know, anything with toxicities, but also maybe comorbidities that smaller patients have that adolescents don't. No, no, that's a good question because we did discuss that in great detail, you know, before we launched this program and given that the infrastructure of Doha, about 15 to 20% does get into systemic circulation.

Speaker Change #374: No question I mean, do you mind repeating your building.

Speaker Change #374: Building.

Speaker Change #375: Yes sure.

Speaker Change #376: Just wondering in pediatrics in general if if there's anything on the safety profile side that we may have to be a way of goodness, they're smaller livers.

Speaker Change #376: Anything, but patisserie east, but also maybe comorbidities that smaller patients have.

Speaker Change #378: Since gone out thank you.

Speaker Change #377: That's a good question because we.

Speaker Change #377: We did discuss that in greater detail before we launched this program and.

Speaker Change #379: In particular a dog.

Speaker Change #379: 15% to 20% it does get into systemic circulation.

Sean Nolan: And you know, as you know, AB9 is trophic to the liver. That's where it goes. But elevation of liver enzymes with an intrathecal dosage is pretty low compared to systemic doses, highly unusual. Any change in blood count, also highly unusual.

Speaker Change #381: And as you know AAV 19th drop it to the liver, that's where it goes but elevation in liver enzymes within particular dosage is pretty low compared to systemic doses highly unusual.

Speaker Change #382: Hey, Tien tsin blood count highly unusual.

Sukumar Nagendran: Compliment Activation, and you know the thrombotic events that have been seen with DMT are highly unusual if ever with interstitial therapy purely because we are giving such a low dose. Thank you very much. Thank you. The antibodies and T-cells being made to the transgene are highly unusual. So I guess my point is, from a gene therapy standpoint... I guess there's also ganglion changes. But again, it's not common. So my point is, if you do the risk-benefit analysis.

Speaker Change #382: Complement activation.

Speaker Change #383: And Tom Bartlett events that have been seen at DMT highly unusual if ever.

Speaker Change #384: The hotel is purely because we're giving such a low dose.

Speaker Change #385: Let me think.

Speaker Change #385: Antibodies and T cells being made.

Speaker Change #386: Francine highly unusual so I guess my point is from a gene therapy standpoint.

Speaker Change #387: I guess, there's also the ganglia in Tianjin, but again its not comment so my point is.

Speaker Change #387: The risk benefit analysis.

Sukumar Nagendran: For the Rett Syndrome program, the benefit, I think far outweighs the risk. And so, we haven't had any concerns up until now. Great. Thanks. Thanks for the call. Thanks so much. We have reached the end of the question and answer session, and I would like to turn the floor back over to Sean Nolan for closing. Just thank everybody for your time this evening, and we look forward to providing further updates here in the coming weeks on both the Cohort 1 adults, as well as the available data for the two pediatric patients.

But so that's been a program that benefits I think far outweighs the risk.

Speaker Change #387: And so and we haven't had any concern about.

Speaker Change #388: Great. Thanks, Thanks for the color.

Yeah.

Susan: Thanks, Susan.

Sukumar Nagendran: Thank you all. Have a good night. This concludes today's conference. Thank you for joining us. You may now disconnect your line. [inaudible] ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?

Susan: We have reached the end of the question and answer session and I would like to turn the floor back over to Sean Nolan for closing comments.

Sean Nolan: Oh, just thank everybody for your time this evening and we look forward to providing further updates here in the next coming weeks on both the cohort one adults as well as the available data for the two pediatric patients. Thank you all have a good night.

Susan: Yes.

Speaker Change #390: This concludes today's conference.

Speaker Change #391: For joining US you may now disconnect your lines.

Speaker Change #391: [music].

Okay.

Speaker Change #391: [music].