Taysha Gene Therapies, Inc.

Greetings and welcome to the TASER Gene Therapy's third quarter 2024 earnings call. At this time, all participants are in listen-only mode. A question and answer session will follow the formal presentation. As a reminder, this conference is being recorded. If anyone should require operator assistance during the call, please signal for an operator by pressing star and then zero. It is now my pleasure to introduce Haley Collins, the Director and Head of Investor Relations. Thank you, and you may proceed, Haley.

Thank you. Good afternoon, and welcome to Tayshia's third quarter 2024 financial results and corporate update conference call. Earlier today, Tayshia issued a press release announcing financial results for the third quarter ended September 30th, 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, FACIA's CEO, Zubimar Negandrin, 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 concerning the potential of FACIA 102, including the reproducibility and durability of any favorable results initially seen in patients' dose-to-date and clinical trials 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 the timing of initiating additional trials and reporting data from our clinical trials, the potential for these product candidates to receive regulatory approval from the FDA or equivalent foreign regulatory agencies, The clinical potential of interest-equal administration and our current cash resources supporting our plant operating expenses and capital requirements into the fourth quarter of 2026. These statements may include the expected timing and results of clinical trials for our product candidates and other clinical regulatory plans and the market opportunity for those programs. This call may also contain forward-looking statements relating to CACIA'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 CACIA's actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and regulatory interactions for our product candidates our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for discoveries, limitations imposed by patents owned or controlled by third parties, and the requirements of substantial funding to conduct our research and development activities. For a list and description of the risks and uncertainties that we face, Please see the reports we have filed with the Securities and Exchange Commission, including in our annual report on Form 10-K for the full year ended December 31st, 2023, and our quarterly report on Form 10-Q, the quarter ended September 30th, 2024, that we filed today. This conference call contains sensitive information that is accurate only as of the date of this live broadcast, November 13th, 2024. Patient 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 security laws. With that, I would now like to turn the call over to our CEO, John Nolan.

Thank you, Hailey, and welcome, everyone, to our third quarter 2024 financial results and corporate update conference call. I will begin with a brief update on our recent activities. And then Sugandh Gendron, president and head of R&D of Tayshia, will provide an update on our lead Tayshia 102 program and clinical evaluation for Rett syndrome. Cameron Alam, our chief financial officer, will follow up with a financial update. I will then provide closing remarks and open up the call for questions. In the third quarter, we continued to drive progress across our TASHA 102 program and clinical evaluation for pediatric, adolescent, and adult patients with Rett syndrome. Our accomplishments included achieving important clinical and CMC regulatory progress, collecting additional clinical data, further supporting the safety profile of TASHA 102 across different ages and stages of disease, and enrolling additional patients in the high-dose cohort across both our adolescent adult and our pediatric reveal phase 1-2 trials, which support our expeditious development of TASHA 102 for patients and families suffering from RAD syndrome. We recently completed our initial Type B multidisciplinary meeting with the FDA that was granted as a benefit of receiving Regenerative Medicine Advanced Therapy, or RMAT, designation for TASHA-102. We are pleased with the progress made with the FDA on further elucidating the potential regulatory pathway for TASHA-102 as we advance discussions on trial design, endpoints, and the potential use of an established natural history data set for Part B of our revealed trials. Additionally, we aligned on a meeting cadence with the FDA to expedite the development plan for TASHA-102. We recently completed a Type D CMC meeting, which was well attended by the FDA, including senior officials. We obtained FDA approval to use the pivotal TASHA-102 product in our revealed trials based on a successful demonstration of analytical comparability between the clinical product and the product derived from the final commercial manufacturing process. Subsequently, we released the pivotal product, which we intend to use in Part B of our trials. With this progress, we believe we are in a strong position with our CMC activities for Tayshia-102. Sukhu will discuss this in more detail. We also received approval from the Independent Data Monitoring Committee, or IDMC, to proceed with continued enrollment in cohort 2, evaluating the high dose of TASHA-102 of 1 into the 15 total vector genomes for both review phase 1-2 trials, following the IDMC's review of available clinical data from the three patients treated with the high dose. I am pleased to share that the I am pleased to share the high dose of TASHA-102 continues to demonstrate an encouraging safety profile. TASHA-102 was generally well tolerated with no serious adverse events or dose-limiting toxicities in the first two adolescent adult patients as of 20 weeks and nine weeks post-treatment, respectively, and in the first pediatric patient at six weeks post-treatment. Subsequently, we dosed the third patient in the high-dose cohort of the adolescent adult trial and enrolled the second patient in the high-dose cohort of the pediatric trial, with dosing scheduled for the current quarter. As a reminder, Rett syndrome is a rare neurodevelopmental disorder that afflicts an estimated 15,000 to 20,000 patients in the United States, Europe, and the United Kingdom. Currently, there are no approved disease-modifying therapies to treat the genetic root cause of the disease, and there is significant unmet need. Rett syndrome is caused by mutations in the X-linked ME-CP2 gene, which inhibits neuronal development and leads to multi-system complications. It's characterized by loss of communication and hand function, slowing or regression of development, motor and respiratory impairment, and autonomic dysfunction, seizures, intellectual disabilities, and shortened life expectancy. Individuals with Rett syndrome typically require 24-7 care and lifelong assistance with daily activities, resulting in high caregiver burden and significant impact on quality of life. We remain confident in our differentiated gene therapy candidate which we believe has potential to provide meaningful therapeutic benefit to a broad population of patients with Rett syndrome using a minimally invasive delivery approach that has the potential to be administered in the outpatient setting for both children and adults. Patient 102 is a one-time intrinsically delivered gene therapy that was strategically designed to enable optimal and controlled transgene expression across the central nervous system. Threat syndrome is challenging to treat with traditional small molecules and gene therapy approaches due to the random inactivation and subsequent mosaic expression pattern of MECP2 that results in a mixture of cells that are either deficient in MECP2 or express it normally. We believe patient 102 equipped with the novel MiRAIR technology has the potential to appropriately address this challenge by mediating MeCP2 expression in the central nervous system on a cell-by-cell basis. By silencing the transgene in healthy cells expressing MeCP2 and enabling protein production in deficient cells, MiRAIR is designed to overcome the risks associated with both under and over expression of MeCP2. Importantly, our capsid is paired with a self-complementary viral genome to enhance the effectiveness of gene transduction. We made the decision to utilize the mini-MeCP2 gene, which is a smaller version of the MeCP2 gene that contains the essential functional domains necessary for therapeutic benefit, so that we were able to package our construct with a self-complementary vector. Self-complementary vectors have a smaller packaging capacity than the traditional single-stranded vectors, but they offer the important advantage of faster, more efficient transduction because they're able to entirely bypass the step of converting the vector genome into a double-stranded DNA prior to gene expression. As a result, a self-complementary vector can speed up the onset of transgene expression and potentially improve the efficacy of the gene therapy. We believe these strategic attributes of our construct enable the early and consistent clinical improvements that persisted and strengthened over time, as we've seen in the adult and pediatric patients treated with the low dose of TASHA-102. Since Rett syndrome is a progressive disease, we believe early clinical response increases the likelihood of reversing the disease trajectory and may be predictive of long-term clinical outcomes. Rett syndrome requires an increased MeCP2 protein to activate the neural circuits necessary for regaining function. And it also requires time for patients to strengthen these reactivated circuits to enable deeper learning of the skills affected by the disease. We believe the sooner positive clinical impact is observed following treatment, the greater the trajectory of potential improvement and longer-term outcomes. Therefore, early clinical benefit is a strong indicator that ME-CP2 protein has reached therapeutic levels that, in turn, create the opportunity for patients to further strengthen and gain new skills that can positively impact their activities of daily living. Importantly, The clinical data presented from the adult patients with the most advanced stage of the disease treated with the low dose of TASHA-102 indicate a pattern of early clinical improvements and functional gains across multiple domains within four weeks post-treatment that persisted and strengthened over time. Specifically, improvements in autonomic function, including breathing and sleep, were demonstrated as early as two weeks post-treatment. At four weeks, clinical improvements and functional gains were reported across multiple domains impacting daily activities, including time and gross motor skills, socialization and communication, and seizure events. This includes beginning to use eating utensils, sitting without support, saying mama or daddy, petting a dog, improved attentiveness and social interactions with family members, and improved use of IVs through the communication device as documented by video evidence, efficacy measures, and or clinical observations reported by the principal investigator. As the pediatric data mature, We anticipate that the early clinical improvements and functional gains observed should also persist and strengthen over time in the pediatric patients treated with TASHA-102 as the neural network matures and patients develop the strength to gain more complex skills. We look forward to further evaluating the pediatric patients over time. As clinical evaluation of TASHA-102 further progresses, It is important to note that our program leverages a routine, minimally invasive delivery approach that has the potential to be administered in the outpatient setting. Preclinical findings support the clinical potential of intrathecal administration as an effective delivery method for AAV-based gene therapies that are designed to treat the genetic root cause of CNS diseases as it enables widespread and consistent biodistribution across the brain and spinal cord. We believe this widespread distribution has been demonstrated throughout the clinical data. Through the clinical data, we reported that showed broad improvements across key clinical domains important in disease pathology, including fine and gross motor skills, communication and socialization, autonomic and seizure events. Importantly, we saw this consistently in the two adult and two pediatric patients treated with the low dose of TASHA-102. despite differences in baseline disease severity. This was translationally reinforced with data from the analysis of five non-human primate studies that we recently presented at the ESGTC Annual Congress, which demonstrated that intrathecal delivery of gene therapies reaches key areas of the brain and spinal cord. Sukha will discuss this in more depth. Collectively, we believe the strategic design of our constructs has contributed to the encouraging safety and efficacy data we have reported today in both reveal trials, demonstrating early, sustained, and new clinical improvements and functional gains that strengthen over time and across multiple domains. We believe there is potential to see continued improvements as the data mature, and we look forward to reporting longer-term data from the low-dose cohort and data from the high-dose cohort in both reveal trials in the first half of 2025. We plan to continue working closely with the FDA through the RMAT mechanism to solidify the regulatory pathway for Tayshia-102 based on the totality of data, and we remain focused on the execution as we prepare for what we expect to be an impactful year ahead. I will now turn the call over to Sukhu to provide a more in-depth discussion of TASHA 102. Sukhu?