Taysha Gene Therapies, Inc.

Greetings and welcome to Tayshia Jean Therapy's fourth quarter and full year 2023 earnings call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce Haley Collins, Director, Head of Corporate Communications and Investor Relations. Thank you. You may begin.

Thank you. Good afternoon and welcome to Tayshia's full year 2023 financial results and corporate update conference call. Earlier today, Tayshia issued a press release announcing financial results for the full year ended December 31st, 2023. A copy of this press release is available on the company's website and through our SEC filings. Joining me on today's call are Sean Nolan, Taysha'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 Taysha-102, including the reproducibility and durability of any favorable safety results initially seen in our first and second patients dosed in the reveal trial to positively impact quality of life and alter the course of disease in the patients we seek to treat, our research, development, and regulatory plans for our product candidates, including timing for 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 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 TASHA's actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and regulatory actions for our product candidates, our dependence on strategic alliances and other third-party relationships, our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties, and the requirements of substantial funding to conduct our research and development activities. For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the Securities and Exchange Commission, including in our annual report on Form 10-K for the full year ended December 31st, 2023 that we filed today. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, March 19th, 2024. TASHA undertakes no obligation to revise or update any forwarding statements to reflect events or circumstances after the date of this conference call. except as may be required by applicable securities laws. With that, I would now like to turn the call over to our CEO, Sean Nolan.

Thank you, Haley, and welcome, everyone, to our 2023 Full-Year Financial Results and Corporate Update Conference Call. Today, I will begin with a brief update on our corporate and clinical activities. Then, Dr. Sukundagandran, President and Head of R&D of Tayshia, will provide an update on our lead Tayshia 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. In 2023, we made tremendous progress on the development of TASHA 102, our lead gene therapy program and clinical evaluation for the treatment of Rett syndrome, which is a rare neurodevelopmental disorder with significant unmet medical need. This included generating initial clinical data in adult patients and expanding the trial into the adolescent population, obtaining regulatory clearance to initiate the clinical evaluation of TASHA-102 and two additional geographies, and dosing the first patient in our pediatric trial. Importantly, we believe these accomplishments enable us to focus our efforts this year on generating critical long-term clinical data in a broad range of ages and stages of Rett syndrome patients across multiple geographies. We now have two ongoing first in human trials evaluating the safety and preliminary efficacy of TASHA-102. The REVEAL Phase 1-2 adolescent and adult trial in Canada and the U.S. and the REVEAL Phase 1-2 pediatric trial in the United States with clearance in the U.K. Today we are excited to report longer-term clinical data from our first two adult patients treated with the low dose of TASHA-102 in our adolescent and adult trial. As a reminder, our ongoing review of phase 1-2 adolescent and adult trial is a first in human, open-label, randomized dose escalation and dose expansion trial evaluating the safety and preliminary efficacy of TASHA-102 in females aged 12 years and older with stage 4 Rett syndrome. We are currently enrolling patients in Part A, the dose escalation portion of the trial, which is evaluating two dose levels of Tayshia-102 sequentially. Two patients have been dosed to date in Cohort 1, evaluating the low dose of Tayshia-102 of 5.7e-14, and dosing in Cohort 1 is now considered complete. We're pleased to provide an update on the encouraging follow-up data from the first two adult patients treated in the low-dose cohort. Recall, when we initiated the REVEAL trial, there were low expectations of efficacy for the stage 4 adult population among KOLs in the Rett syndrome community due to the advanced and relentless progression of disease. The focus was placed primarily on safety. Therefore, it was very exciting when we announced the encouraging initial impact that TASHA-102 appeared to have across multiple clinical domains in the first two adult patients treated as early as four weeks following the treatment that we reported in November 2023. The data presented today for patient one is from her six-month post-treatment assessment with clinical observations from week 35 post-treatment. Importantly, we continue to see a durable response and we are seeing sustained improvement in the absence or reduction of steroid levels. We have received many questions since initiating, since initially announcing Patient 1 data about the possible impact of steroids on the disease itself. We are not surprised but nonetheless pleased to highlight today that patient improvements were maintained or further improved in the absence of steroids. As of the six-month assessment, patient one has showed sustained improvement across key efficacy measures at decreased steroid levels with new improvement observed in the Rett Syndrome Behavioral Questionnaire, or RSVQ. Additionally, the second adult patient also sustained improvements across key efficacy measures with new improvement observed in certain measures including the Revised Motor Behavior Assessment, or RMBA, and significantly reduced seizures at 12 weeks post-treatment. The longer-term clinical observations reported by the principal investigator showed that both patients had sustained and new improvements across multiple clinical domains, including autonomic function, social communication, motor skills, and seizures, compared to earlier post-treatment assessments. 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. As a reminder, these two patients have quite different genetic mutations. The first patient's MECP2 mutation manifests in a more severe disease phenotype than the second patient's mutations. For example, patient one was completely non-ambulatory at baseline, whereas patient two could walk with prompting. Despite the different clinical baseline characteristics, both patients showed improvements across multiple clinical domains as early as four weeks following treatment. And importantly, both patients showed sustained and new improvements across those clinical domains at the longer-term assessments. In addition to the positive safety data, we are encouraged by the longer-term safety profile observed. Data from the first two adult patients showed that TASHA-102 was well-tolerated with no treatment emergence, serious adverse events as of the 35-week assessment for patient one and as of the 19-week assessment for patient two. We believe the safety profile and these continued improvements across multiple clinical domains, even at reduced steroid levels in both adult patients with advanced stage four Rett syndrome support the durability and transformative potential of TASHA-102 across multiple genotypes of Rett syndrome, and further validate our construct. Sukku will discuss the clinical observations and efficacy data in more detail shortly. Now let's turn to our pediatric trial. Our ongoing reveal phase 1-2 pediatric trial is a first in human, open-label, randomized, dose escalation and dose expansion trial evaluating the safety and preliminary efficacy of TASHA-102 in females aged five to eight years old with stage three 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. We've dosed the first pediatric patient in cohort one, evaluating the low dose of TASHA-102 of 5.7e-14 here in the U.S. The Independent Data Monitoring Committee, or IDMC, recently convened to review these longer-term clinical data from the first two adult patients and the initial six-week data from the first pediatric patient treated with the low dose of TASHA-102. Following review, the IDMC approved our request to proceed to dose escalation in the adolescent and adult trial. which enables us to initiate dosing with the high dose of TASHA-102 earlier than planned. This is a critical step in our development plan as advancing to the high dose accelerates our ability to further inform our clinical development and regulatory strategy for Part B of the study by at least a quarter. With cohort one now completed in our adolescent and adult trial, we plan to dose the first patient in cohort two, evaluating the high dose of TASIA-102 of 1E-15 in the second quarter of 2024. Initial data from cohort 2 of the adolescent and adult trial is expected in the second half of 2024. The IDMC also approved dosing of the second pediatric patient in cohort 1 in the Reveal Phase 1-2 pediatric trial. The patient has been identified and dosing is scheduled to take place this quarter. We plan to complete enrollment in the low- and high-dose cohorts of the pediatric trial this year, with initial available data from the low-dose cohort expected in mid-2024, as we discussed previously in early January. Additionally, initial data from the high-dose cohort of pediatric trials expected in the second half of 2024. Overall, we're focused on completing dosing in Part A of both studies this year, Importantly, data from Part A will be assessed by regulatory agencies and the IDMC to provide guidance to determining final key elements of Part B, the dose expansion portion of the study, including the hierarchy of efficacy endpoints, study design, and the maximum tolerated dose or maximum administered dose. Another key focus in 2023 was broadening the clinical evaluation of TASHA-102 across geographies. In our REVEAL adolescent and adult trial, we recently announced the expansion of the ongoing trial in Canada into the U.S. following our submission of the protocol to the U.S. Food and Drug Administration, or FDA. We're now focused on site initiation activities in the U.S. for the adolescent and adult trial in addition to our ongoing U.S. site initiation activities in our pediatric trial. In our REVEAL pediatric trial, we announced earlier this year that the UK Medicines and Healthcare Products Regulatory Agency, or MHRA, authorized the clinical trial application for TASHA-102 in pediatric patients with Rett syndrome, enabling expansion of our ongoing pediatric trial in the US into the UK. And we're currently focused on site initiation activities. We are pleased to share that Tayshia 102 receives Innovative Licensing and Access Pathway Designation, or ILAP, from the MHRA, which is a program that's designed to accelerate the review path of novel treatments. We believe this further reinforces the high unmet medical need for patients with Rett syndrome. As a reminder, Tayshia 102 has already received Fast Track Designation and Orphan drug and rare pediatric disease designations from the FDA and has been granted orphan drug designation from the European Commission for the Treatment of Rett Syndrome. Lastly, we are pleased to share that we have strengthened our clinical and regulatory leadership with the promotion of Dr. Meredith Schultz to Chief Medical Officer and Rumana Haq Ahmed to Chief Regulatory Officer. Dr. Schultz And Ms. Hakamed will continue to report to Suku. Dr. Schultz is a board-certified licensed pediatric neurologist who is experienced in treating patients with Rett syndrome. Dr. Schultz brings more than 17 years of clinical experience and has led numerous gene therapy clinical trials for rare diseases in her career. As chief medical officer, Dr. Schultz will lead the company's clinical development, clinical operations, medical affairs, and safety activities. Ramanahaka Med brings nearly 30 years of experience in global regulatory strategy and product development in multiple therapeutic areas. She has been instrumental in the development and execution of our regulatory strategies for TASHA 102, including obtaining IND and CTA clearances across three countries, and she's led the regulatory interactions across TASHA's gene therapy portfolio. She will continue to lead the company's regulatory affairs department and regulatory interactions. Dr. Schultz and Ms. Haka Ahmed have been instrumental to the clinical development of our Tayshia 102 program, and we look forward to continuing to partner with them in their new leadership positions. With a significant focus on execution in the year ahead, we believe our team is well-positioned to continue to accelerate the development of Tayshia 102. As you can see, we have made exciting progress across our TASHA 102 program over the past year. The sustained and new improvements in both adult patients with advanced stage four syndrome, coupled with the initial six-week clinical data from the first pediatric patient that was reviewed by the IDMC, support the therapeutic potential of TASHA 102 for a broad population of patients with Rett syndrome. Looking ahead, we are focused on generating clinical data across a broad range of ages and stages of patients with Rett syndrome in multiple geographies with multiple value inflection catalysts anticipated in 2024. We look forward to further evaluating the therapeutic potential of TASHA-102 for patients and families living with Rett syndrome. I will now turn the call over to Sukhu to provide more in-depth discussion on our clinical program in Rett syndrome. Sukhu?