Taysha Gene Therapies, Inc.

Greetings and welcome to the Tayshia Gene Therapy's first quarter 2024 earnings call. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press 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, Hayley Collins. Thank you. You may begin.

Thank you. Good afternoon and welcome to Tayshia's first quarter 2024 financial results and corporate update conference call. Earlier today, Tayshia issued a press release announcing financial results for the first quarter ended March 31st, 2024. 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, Tayshia's CEO, Sukumar Nagandran, President and Head of R&D, and Cameron 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 TASHA 102, including the reproducibility and durability of any favorable results initially seen in our first and second patient's dose 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. 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 TASHA'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 the actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and regulatory interactions for our product candidates, our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties, and the requirements of substantial funding to conduct our research and development activities. For a list and description of the risks and uncertainties that we face, please see the reports 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 31st, 2024, that we filed today. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, May 14th, 2024. TASHA 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.

Thank you, Haley, 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. Sukundagendran, President and Head of R&D of TASHA, will provide an update on our lead TASHA 102 program and clinical evaluation for the treatment of Rett syndrome. Cameron Alam, our chief financial officer, will follow up with a financial update. 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 TASHA 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 and 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 TASHA-102. We believe this progress reinforces the therapeutic potential of TASHA-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 TASHA 102 program with the goal of generating critical longer-term clinical data across broad range of ages and stages of patients with Rett syndrome in multiple geographies that will guide the next phase of our studies. 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, 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 ME-CP2 expression results in a mixture of cells that are either deficient in ME-CP2 protein or express ME-CP2 protein normally, which makes Rett syndrome challenging to treat with traditional small molecule and gene therapy approaches. We believe our TASHA-102 gene therapy candidate, equipped with the novel MI-102 RNA-responsive autoregulatory element, or MIRAIR technology, has the potential to appropriately address this challenge by mediating ME-CP2 expression in the central nervous system on a cell-by-cell basis to overcome the risks associated with both under- and overexpression of ME-CP2 protein. We are evaluating TASHA-102 in two ongoing Phase I-II 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 TASHA-102 in females aged 12 years and older with Rett syndrome. We are currently enrolling patients in Part A, the dose escalation portion of the trial, which is evaluating two dose levels of TASHA-102 sequentially. Two patients have been dosed to date in cohort one with the low dose of TASHA-102 of 5.7 e to the 14 total vector genomes, and dosing in cohort one is now considered complete. Following review of the clinical data from the first three patients treated with TASHA-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 final key elements of the Part B aspect of our trial, the dose expansion portion. including hierarchy of efficacy endpoints, study duration, and the maximum tolerated dose or maximum administered dose. Therefore, advancing to cohort two, evaluating the high dose of TASHA-102 of 1E to the 15 total vector genomes earlier than planned accelerates our ability to inform our clinical development and regulatory strategy for part B. 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 2024. 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 four Rett syndrome, and different genetic mutations and severity of disease. Recall, when we initiated and revealed 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. Therefore, it was very exciting last November to announce the encouraging initial impact of TASHA-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. As of the six-month assessment, patient one showed sustained improvement across key efficacy measures at decreased steroid levels, with new improvements observed in the red Syndrome Behavioral Questionnaire, or RSVQ. 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, or RMBA, as of the 12-week assessment, and significantly reduced seizures as of the 19-week assessment following treatment. The longer-term clinical observations reported by the principal investigator showed that both patients had sustained and 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. 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. Sukhu will discuss these observations in more detail. The longer-term safety profile is also encouraging. Data from the first two adult patients showed that TASHA-102 was well tolerated with no treatment emerging serious adverse events as of week 35 assessment for patient 1 and as of the 19-week assessment for patient 2. 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 TASHA-102, supports the durability and transformational potential of TASHA-102 across multiple genotypes of Rett syndrome and further validates our construct. We are also focused on evaluating the therapeutic potential of TASHA-102 in the pediatric population, where we hope to see a similar safety profile and a consistent pattern of response across clinical domains in the pediatric patients with different genotypes treated with the low dose of TASHA-102. Our ongoing Reveal Phase 1-2 pediatric trial is evaluating the safety and preliminary efficacy of TASHA-102 and female patients with Rett syndrome age five to eight years old. We are currently enrolling pediatric patients in part A of the trial, which will evaluate two dose levels of TASHA-102 sequentially. We have dosed the second pediatric patient in cohort one, 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. Patients typically approach stage 3 disease, known as the pseudo-stationary 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 and spoken language, gait abnormalities, and stereotypic hand movements, which results in the loss of independence and in most cases leads to lifelong caregiver dependence. 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. 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 Rett syndrome. Recently, we were pleased to receive Regenerative Medicines 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 with a low dose of TASHA-102. A regenerative medicine therapy is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious condition, 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 in Rett syndrome and the therapeutic potential of patient 102 to bring meaningful change to patients and families with Rett syndrome. We will work closely with the FDA and other regulatory agencies as we continue to advance our TASHA 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 studies. 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 Sukhu to provide a more in-depth discussion of TASHA-102. Sukhu?