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Taysha Gene Therapies 2025 Annual Report Bringing New Treatments To Life 2025 ANNUAL REPORT
Letter From The CEO Sean Nolan Chairman and Chief Executive Officer Dear Stockholders, 2025 was a year of significant execution for Taysha as we advanced our gene therapy candidate, TSHA-102, for the treatment of Rett syndrome. Throughout the past year, we generated compelling data across Part A of our REVEAL Phase 1/2 trials and made important regulatory progress in defining a streamlined path to a Biologics License Application (BLA) submission to support a potential broad label for TSHA-102 in individuals aged two years and older with Rett syndrome. We achieved several important milestones, including Breakthrough Therapy designation for TSHA-102 from the United States (U.S.) Food and Drug Administration (FDA), initiation of our REVEAL pivotal trial, FDA clearance to initiate our safety-focused ASPIRE trial, and FDA alignment on chemistry, manufacturing, and controls (CMC) requirements, which collectively will support our planned BLA submission for TSHA-102. In parallel, we strengthened our balance sheet and extended our cash runway into 2028, supporting continued investment across clinical, regulatory and commercial activities. This progress has set the stage for what we believe will be a transformative year ahead as we focus on completing the pivotal development of TSHA-102 and bolstering our commercial readiness efforts as we advance toward potential registration. Rett syndrome is a devastating, rare and progressive neurodevelopmental disease with a high unmet need and a profound, lifelong burden for patients and caregivers. It is well-characterized clinically, defined by impairments across multiple clinical domains, including fine and gross motor function, communication, autonomic function and seizures. Our work is driven by the high unmet needs of those impacted by Rett syndrome. There are currently no approved disease-modifying therapies that treat the genetic root cause of Rett syndrome, which affects an estimated 15,000 to 20,000 patients in the U.S., Europe and the United Kingdom. TSHA 102 is a one-time, intrathecally delivered gene therapy uniquely designed to address the genetic root cause of Rett syndrome, with the potential to meaningfully alter
the natural history of the disease and offer patients the opportunity to achieve functional milestones that would be otherwise impossible, according to natural history data. Based on the clinical data we ve reported to date, we believe TSHA-102 may deliver meaningful and durable functional improvements across a broad population of patients, including pediatrics, adolescents and adults with varying genotypes and severity of disease. Compelling REVEAL Phase 1/2 Clinical Data Across Broad Patient Population Part A of our REVEAL Phase 1/2 trials is evaluating the safety and preliminary efficacy of TSHA-102 at two dose levels, 5.7 10 vector genomes (vg) (low dose) and 1 10 vg (high dose), to determine the dose for the pivotal trial. A total of 12 participants, aged 6 to 21 years, were treated with TSHA-102 in Part A of the studies. Both doses have demonstrated an encouraging safety profile, and TSHA-102 has been generally welltolerated with no treatment-related serious adverse events or dose-limiting toxicities as of the March 2026 data cutoff. In 2025, we presented compelling data from Part A of the trials across pediatric, adolescent and adult patients at the 2025 International Rett Syndrome Foundation (IRSF) Rett Syndrome Scientific Meeting. The data demonstrated that 100% of patients gained one or more defined developmental milestone across the core functional domains of fine motor, gross motor and communication post-treatment, with a consistent pattern of early sustained gains and new achievements continuing to emerge over time. In addition to the developmental milestones achieved across the treatment cohort, patients consistently gained multiple additional skills and improvements in core disease characteristics as well as improvements across multiple clinician-assessed outcome measures, including the Revised Motor Behavior Assessment (R-MBA) and Clinician Global Impression Improvement (CGI-I). The high dose of TSHA-102 consistently outperformed the low dose, with dose-dependent effects deepening over time. Based on Taysha s robust analysis of the National Institutes of Health-funded IRSF natural history study data, patients six years and older with Rett syndrome have a 0% to less than 6.7% likelihood of spontaneously gaining new or regaining developmental milestones that were lost after a defined number of years. We believe the unprecedented functional gains consistently seen post-TSHA-102 reinforce its potentially broad therapeutic impact on activities of daily living that are most important to caregivers and clinicians. Following FDA review of these data, we were pleased to receive Breakthrough Therapy designation for TSHA-102, which we believe highlights the FDA s recognition of both the significant unmet medical need and the therapeutic potential of TSHA-102 to redefine the treatment paradigm for this devastating disease. FDA Alignment on Streamlined Path to BLA Submission Over the past two years, we have maintained ongoing, constructive dialogue with the FDA, which has enabled written alignment on a pathway that we believe reflects the rigorous, systematic data collection and well-controlled study design and endpoint selection required by the FDA for a robust, data-driven application. In 2025, we finalized our REVEAL pivotal trial protocol and statistical analysis plan with the FDA, including agreement that a six-month interim analysis may serve as the
basis for a planned BLA submission. Importantly, our trial design enables us to test our response rate against a low null hypothesis of 6.7%, requiring a minimum 33% response rate to demonstrate efficacy. We initiated the REVEAL pivotal trial in the fourth quarter of 2025, and multiple patients have been dosed to date. We expect to complete dosing in the second quarter of 2026. In addition, we received FDA clearance to initiate the safety-focused ASPIRE trial following written alignment on the trial design and data for inclusion in our BLA submission to support a broad label of TSHA-102 for patients aged two years and older with Rett syndrome. We expect to complete dosing in the ASPIRE trial in the second quarter of 2026 We believe this regulatory alignment supports an efficient and streamlined path to BLA submission and reflects the strength of our clinical dataset as well as the objective and clinically meaningful nature of the proposed endpoints and our natural history data analysis. Written FDA Alignment on CMC Requirements Support Planned BLA Submission In early 2026, we further aligned with the FDA on our proposed comparability approach between TSHA-102 material derived from the clinical and final commercial manufacturing processes. The FDA agreed this approach may support pooling data across our REVEAL Phase 1/2, REVEAL pivotal and ASPIRE trials for the planned BLA submission. We believe this will further strengthen the BLA package by including longerterm data and enabling a comprehensive assessment of data generated across the development program. Additionally, the FDA endorsed our Process Performance Qualification (PPQ) campaign strategy to support process validation for our planned BLA submission. This included the stability data package, potency assay strategy and execution of BLA-enabling PPQ lots using the commercial manufacturing process, which we initiated in the second quarter of 2026. This feedback aligns with the FDA s January 2026 guidance aimed at increasing flexibility on requirements for cell and gene therapies to advance innovation. With this alignment, we are confident that our CMC activities are on track to support our planned BLA submission in step with the pivotal data readout and position us well as we bolster our commercial preparedness in 2026. Advanced Commercial Readiness Activities As we advance toward potential registration, we have taken critical steps to initiate our commercial readiness activities. Recently completed market research demonstrates high anticipated demand for TSHA-102 across pediatric, adolescent and adult patients with Rett syndrome from both clinicians and caregivers in the U.S. and a clear preference for intrathecal administration, reinforcing the substantial market opportunity in Rett syndrome. Additionally, we continued to build out our commercial function in preparation for future launch with the appointment of David McNinch as our Chief Commercial Officer and Brad Martin as our Senior Vice President, Market Access and Value, further strengthening our commercial leadership team. Taysha s commercial function is led by Sean McAuliffe, our Chief Business Officer, who previously led the go-to-market strategy for Zolgensma for
 • shareholder letter icon 4/22/2026 Letter Continued (Full PDF)
 • stockholder letter icon 5/8/2023 TSHA Stockholder Letter
 • stockholder letter icon 4/18/2024 TSHA Stockholder Letter
 • stockholder letter icon 4/21/2025 TSHA Stockholder Letter
 • stockholder letter icon More "Biotechnology" Category Stockholder Letters
 • Benford's Law Stocks icon TSHA Benford's Law Stock Score = 83


TSHA Shareholder/Stockholder Letter Transcript:

Taysha Gene Therapies 2025 Annual Report
Bringing New
Treatments To Life
2025 ANNUAL REPORT


Letter From
The CEO
Sean Nolan
Chairman and Chief Executive Officer
Dear Stockholders,
2025 was a year of significant execution for Taysha as we advanced our gene therapy
candidate, TSHA-102, for the treatment of Rett syndrome. Throughout the past year,
we generated compelling data across Part A of our REVEAL Phase 1/2 trials and made
important regulatory progress in defining a streamlined path to a Biologics License
Application (BLA) submission to support a potential broad label for TSHA-102 in
individuals aged two years and older with Rett syndrome.
We achieved several important milestones, including Breakthrough Therapy designation
for TSHA-102 from the United States (U.S.) Food and Drug Administration (FDA),
initiation of our REVEAL pivotal trial, FDA clearance to initiate our safety-focused ASPIRE
trial, and FDA alignment on chemistry, manufacturing, and controls (CMC) requirements,
which collectively will support our planned BLA submission for TSHA-102. In parallel, we
strengthened our balance sheet and extended our cash runway into 2028, supporting
continued investment across clinical, regulatory and commercial activities. This progress
has set the stage for what we believe will be a transformative year ahead as we focus
on completing the pivotal development of TSHA-102 and bolstering our commercial
readiness efforts as we advance toward potential registration.
Rett syndrome is a devastating, rare and progressive neurodevelopmental disease
with a high unmet need and a profound, lifelong burden for patients and caregivers.
It is well-characterized clinically, defined by impairments across multiple clinical
domains, including fine and gross motor function, communication, autonomic function
and seizures. Our work is driven by the high unmet needs of those impacted by Rett
syndrome. There are currently no approved disease-modifying therapies that treat the
genetic root cause of Rett syndrome, which affects an estimated 15,000 to 20,000
patients in the U.S., Europe and the United Kingdom.
TSHA 102 is a one-time, intrathecally delivered gene therapy uniquely designed to
address the genetic root cause of Rett syndrome, with the potential to meaningfully alter

the natural history of the disease and offer patients the opportunity to achieve functional
milestones that would be otherwise impossible, according to natural history data. Based
on the clinical data we   ve reported to date, we believe TSHA-102 may deliver meaningful
and durable functional improvements across a broad population of patients, including
pediatrics, adolescents and adults with varying genotypes and severity of disease.
Compelling REVEAL Phase 1/2 Clinical Data Across Broad Patient Population
Part A of our REVEAL Phase 1/2 trials is evaluating the safety and preliminary efficacy
of TSHA-102 at two dose levels, 5.7  10      vector genomes (vg) (low dose) and 1  10      vg
(high dose), to determine the dose for the pivotal trial. A total of 12 participants, aged
6 to 21 years, were treated with TSHA-102 in Part A of the studies. Both doses have
demonstrated an encouraging safety profile, and TSHA-102 has been generally welltolerated with no treatment-related serious adverse events or dose-limiting toxicities as
of the March 2026 data cutoff.
In 2025, we presented compelling data from Part A of the trials across pediatric,
adolescent and adult patients at the 2025 International Rett Syndrome Foundation
(IRSF) Rett Syndrome Scientific Meeting. The data demonstrated that 100% of patients
gained one or more defined developmental milestone across the core functional domains
of fine motor, gross motor and communication post-treatment, with a consistent
pattern of early sustained gains and new achievements continuing to emerge over time.
In addition to the developmental milestones achieved across the treatment cohort,
patients consistently gained multiple additional skills and improvements in core disease
characteristics as well as improvements across multiple clinician-assessed outcome
measures, including the Revised Motor Behavior Assessment (R-MBA) and Clinician
Global Impression     Improvement (CGI-I). The high dose of TSHA-102 consistently
outperformed the low dose, with dose-dependent effects deepening over time.
Based on Taysha   s robust analysis of the National Institutes of Health-funded IRSF
natural history study data, patients six years and older with Rett syndrome have a 0%
to less than 6.7% likelihood of spontaneously gaining new or regaining developmental
milestones that were lost after a defined number of years. We believe the unprecedented
functional gains consistently seen post-TSHA-102 reinforce its potentially broad
therapeutic impact on activities of daily living that are most important to caregivers and
clinicians.
Following FDA review of these data, we were pleased to receive Breakthrough Therapy
designation for TSHA-102, which we believe highlights the FDA   s recognition of both the
significant unmet medical need and the therapeutic potential of TSHA-102 to redefine
the treatment paradigm for this devastating disease.
FDA Alignment on Streamlined Path to BLA Submission
Over the past two years, we have maintained ongoing, constructive dialogue with the
FDA, which has enabled written alignment on a pathway that we believe reflects the
rigorous, systematic data collection and well-controlled study design and endpoint
selection required by the FDA for a robust, data-driven application.
In 2025, we finalized our REVEAL pivotal trial protocol and statistical analysis plan
with the FDA, including agreement that a six-month interim analysis may serve as the

basis for a planned BLA submission. Importantly, our trial design enables us to test our
response rate against a low null hypothesis of 6.7%, requiring a minimum 33% response
rate to demonstrate efficacy. We initiated the REVEAL pivotal trial in the fourth quarter
of 2025, and multiple patients have been dosed to date. We expect to complete dosing in
the second quarter of 2026.
In addition, we received FDA clearance to initiate the safety-focused ASPIRE trial
following written alignment on the trial design and data for inclusion in our BLA
submission to support a broad label of TSHA-102 for patients aged two years and older
with Rett syndrome. We expect to complete dosing in the ASPIRE trial in the second
quarter of 2026
We believe this regulatory alignment supports an efficient and streamlined path to BLA
submission and reflects the strength of our clinical dataset as well as the objective and
clinically meaningful nature of the proposed endpoints and our natural history data
analysis.
Written FDA Alignment on CMC Requirements Support Planned BLA Submission
In early 2026, we further aligned with the FDA on our proposed comparability
approach between TSHA-102 material derived from the clinical and final commercial
manufacturing processes. The FDA agreed this approach may support pooling data
across our REVEAL Phase 1/2, REVEAL pivotal and ASPIRE trials for the planned BLA
submission. We believe this will further strengthen the BLA package by including longerterm data and enabling a comprehensive assessment of data generated across the
development program.
Additionally, the FDA endorsed our Process Performance Qualification (PPQ) campaign
strategy to support process validation for our planned BLA submission. This included the
stability data package, potency assay strategy and execution of BLA-enabling PPQ lots
using the commercial manufacturing process, which we initiated in the second quarter
of 2026. This feedback aligns with the FDA   s January 2026 guidance aimed at increasing
flexibility on requirements for cell and gene therapies to advance innovation. With this
alignment, we are confident that our CMC activities are on track to support our planned
BLA submission in step with the pivotal data readout and position us well as we bolster
our commercial preparedness in 2026.
Advanced Commercial Readiness Activities
As we advance toward potential registration, we have taken critical steps to initiate our
commercial readiness activities. Recently completed market research demonstrates high
anticipated demand for TSHA-102 across pediatric, adolescent and adult patients with
Rett syndrome from both clinicians and caregivers in the U.S. and a clear preference
for intrathecal administration, reinforcing the substantial market opportunity in Rett
syndrome.
Additionally, we continued to build out our commercial function in preparation for future
launch with the appointment of David McNinch as our Chief Commercial Officer and Brad
Martin as our Senior Vice President, Market Access and Value, further strengthening our
commercial leadership team. Taysha   s commercial function is led by Sean McAuliffe, our
Chief Business Officer, who previously led the go-to-market strategy for Zolgensma for


shareholder letter icon 4/22/2026 Letter Continued (Full PDF)
 

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