On this page of StockholderLetter.com we present the latest annual shareholder letter from Taysha Gene Therapies, Inc. — ticker symbol TSHA. Reading current and past TSHA letters to shareholders can bring important insights into the investment thesis.

 •  4/18/2024 Letter Continued (Full PDF)
 •  5/8/2023 TSHA Stockholder Letter
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TSHA Shareholder/Stockholder Letter Transcript:

Bringing New
Treatments To Life
2023 ANNUAL REPORT


Letter From
The CEO
Sean Nolan
Chairman and Chief Executive Officer
Dear Stockholders,
2023 was a year of exceptional execution for Taysha. We made tremendous progress on
the development of our lead gene therapy candidate, TSHA-102, in clinical evaluation
for the treatment of Rett syndrome. This included generating compelling initial clinical
data in adult patients in Canada and expanding the trial into the adolescent population,
obtaining regulatory clearance to initiate the clinical evaluation of TSHA-102 in pediatric
patients in both the United States (U.S.) and United Kingdom (U.K.) and dosing the
   rst patient in our pediatric trial in the U.S. Additionally, we strengthened our balance
sheet and extended our cash runway into 2026 to further enable our journey to bring a
potentially transformational treatment to the Rett syndrome community. Importantly,
we believe these accomplishments allow us to focus our efforts in 2024 on moving to the
high dose of TSHA-102 and generating critical longer-term clinical data in a broad range
of ages and stages of patients with Rett syndrome across multiple geographies.
The unmet need and burden of care for Rett syndrome is high. Rett syndrome is a
rare neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene
encoding methyl CpG-binding protein 2 (MeCP2), which is essential for regulating
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.
Rett syndrome progression is divided into four key stages, beginning with early-onset
stagnation at six to 18 months of age, followed by rapid regression, plateau and late
motor deterioration. Currently, there are no approved disease-modifying therapies
that treat the genetic root cause of the disease. Rett syndrome caused by a pathogenic
MECP2 mutation is estimated to affect between 15,000 and 20,000 patients in the U.S.,
European Union (EU) and U.K.

The random X-inactivation and subsequent mosaic expression pattern of MECP2 results
in a mixture of cells that are either de   cient in MeCP2 or express MeCP2 normally, which
makes Rett syndrome challenging to treat with traditional small molecule and gene
therapy approaches. We believe our TSHA-102 gene therapy candidate, equipped with
the novel miRNA-Responsive Auto-Regulatory Element, or miRARE technology, has
the potential to appropriately address this challenge and provide therapeutic bene   t.
TSHA-102 is a self-complementary, intrathecally delivered AAV9 gene therapy designed
as a one-time treatment that aims to address the genetic root cause of Rett syndrome
by delivering a functional form of MECP2 to cells in the central nervous system. It utilizes
the innovative miRARE technology, which is designed to mediate MECP2 expression in
the central nervous system on a cell-by-cell basis and overcome the risks associated with
both under- and over-expression of MeCP2. Thus, TSHA-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.
TSHA-102 has received Fast Track, Orphan Drug and Rare Pediatric Disease designations
from the U.S. Food and Drug Administration (FDA) and was granted Orphan Drug
designation from the European Commission for the treatment of Rett syndrome.
Recently, TSHA-102 also received Innovative Licensing and Access Pathway (ILAP)
designation from the U.K. Medicines and Healthcare products Regulatory Agency
(MHRA), which is a program that is designed to accelerate the review path of novel
treatments. Collectively, these designations further reinforce the high unmet medical
need for patients with Rett syndrome and the potential of TSHA-102.
In 2023, we generated initial clinical data in our    rst-in-human REVEAL Phase 1/2
adult trial in Canada that further validated our construct and supported the potential
of TSHA-102 as a one-time, disease-modifying treatment for patients with the most
advanced stage of Rett syndrome. We recently reported longer-term data from both
adult patients treated with the low dose, which demonstrated a well-tolerated safety
pro   le with sustained and new improvements across multiple clinical domains as of the
35-week assessment for the    rst patient and the 19-week assessment for the second
patient. We believe these continued improvements in both adult patients with advanced,
stage four disease support the durability and transformative potential of TSHA-102
across multiple genotypes of Rett syndrome.
Another key priority in 2023 was expanding the clinical evaluation of TSHA-102 across a
broad age range of patients and geographies. We made signi   cant progress toward this
goal as we expanded our REVEAL Phase 1/2 adult trial into the adolescent population,
announced the expansion of the adolescent and adult trial into the U.S., obtained
regulatory clearance to initiate clinical evaluation in the pediatric population in the
U.S. and U.K., and dosed the    rst pediatric patient in our REVEAL Phase 1/2 pediatric
trial in the U.S. With the completion of these milestones, we now have a robust clinical
development program for TSHA-102, including two ongoing clinical trials spanning the
U.S., Canada and the U.K.

TSHA-102 REVEAL Phase 1/2 Adolescent and Adult Trial
Our ongoing REVEAL Phase 1/2 adolescent and adult trial is a    rst-in-human,
open-label, randomized, dose-escalation and dose-expansion trial evaluating the safety
and preliminary efficacy of TSHA-102 in females aged 12-years and older with stage four
Rett syndrome. The trial is taking place in Canada and the U.S. We are currently enrolling
patients in Part A, the dose escalation portion of the trial, which is evaluating a low
dose (cohort one) and high dose (cohort two) of TSHA-102 sequentially. Two patients
have been dosed in the low dose cohort, and the dosing of cohort one is considered
complete. These two patients have quite different genetic mutations. The    rst patient   s
MECP2 mutation manifests in a more severe disease phenotype with patient one being
completely non-ambulatory at baseline, whereas the second patient has a milder
phenotype and could walk with prompting at baseline.
When we initiated the REVEAL trial, the focus was primarily on safety, with little
expectation of efficacy for the stage four adult population among key opinion leaders in
the Rett syndrome community due to the advanced stage of the disease. Therefore, it
was exciting last November to announce the encouraging initial impact that TSHA-102
appeared to have across multiple clinical domains in the    rst two adult patients as early
as four weeks following treatment.
Recently, we presented longer follow-up data, including a six-month post-treatment
assessment for patient one, with clinical observations from week 35 post-treatment.
Importantly, we continued to see a durable response and sustained 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 improvement observed in the Rett Syndrome Behavioral Questionnaire (RSBQ).
Additionally, the second adult patient demonstrated sustained improvement across key
efficacy measures, with new improvement observed in certain measures, including the
Revised-Motor Behavior Assessment (R-MBA) and signi   cantly reduced seizures at 12
weeks post-treatment.
Moreover, 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, socialization and 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    rst patient, and at week 19, at decreased steroid levels for the
second patient.
The longer-term safety pro   le is also encouraging. Data from the    rst two adult patients
showed that TSHA-102 was well-tolerated with no treatment-emergent 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 pro   le 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 TSHA-102 across multiple genotypes of Rett syndrome and further validate
our construct.



 4/18/2024 Letter Continued (Full PDF)