Corporate Presentation
March 2024
Legal disclosure
FORWARD LOOKING STATEMENTS
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This presentation includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties as well as our own estimates of potential market opportunities. All of the market data used in this prospectus involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such data. Industry publications and third- party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. Our estimates of the potential market opportunities for our product candidates include several key assumptions based on our industry knowledge, industry publications, third-party research and other surveys, which may be based on a small sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no independent source has verified such assumptions
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Key investment highlights
• Ongoing REVEAL Phase 1/2 adolescent and adult trial in Canada and ongoing REVEAL Phase 1/2 pediatric trial in U.S. and U.K. | ||
TSHA-102: | • Novel miRARE technology designed to mediate MECP2 expression on a cell-by-cell basis (enables protein production in MECP2- | |
defieicnt cells, silences transgene expression in healthy cells) to address risks associated with under- and over-expression of MECP2 | ||
Lead Clinical Program | ||
• High unmet medical need and significant market opportunity of 15,000-20,000 (U.S., EU+U.K.)1 with typical Rett syndrome caused | ||
in Rett Syndrome | ||
by a MECP2 mutation | ||
• Potential to obtain Priority Review Voucher (PRV) | ||
Transformative | • Data from first two adult patients dosed support TSHA-102 was generally well-tolerated with no treatment-emergent SAEs | |
• Sustained and new improvements demonstrated across key efficacy measures and clinical domains | ||
Potential | ||
• Similar patterns of response in patients with different genetic mutations and phenotypic expression | ||
Proven and Well- | • Clinically and commercially proven AAV9 capsid with clinical activity and tolerability across multiple CNS indications | |
• | Intrathecal delivery in an outpatient setting targets key CNS regions and minimizes viral load, potentially reducing risk of systemic | |
Characterized Delivery | inflammatory response | |
• Self-complementary technology facilitates more rapid transgene expression | ||
Well-Capitalized | • $150 million private placement from new and existing investors along with cash and cash equivalents expected to extend cash | |
runway into 2026 | ||
Proven Leadership | • Led by former AveXis management, who developed and launched ZOLGENSMA, the second one-time gene therapy FDA approved | |
• Strong relationships with key gene therapy stakeholders, including regulatory authorities, suppliers and other third parties | ||
Near-Term Catalysts | • Q1 '24 - Expect updated clinical data from completed cohort one (low dose, n=2) in REVEAL adolescent and adult trial | |
• | Mid-2024 - Expect initial clinical data from pediatric low dose cohort (n = 3) in REVEAL pediatric trial | |
Source: 1IRSF; NORD; Amir RE, Van den Veyver IB, Wan M, et al. Rett Syndrome Is Caused by Mutations in X-Linked Mecp2, | 3 |
Encoding Methyl-Cpg-Binding Protein 2. Nat Genet 232:185-188. 1999. |
Progress in clinical-stageTSHA-102 program supports clinical evaluation across a broad range of ages and stages of Rett syndrome
REVEAL Phase 1/2 Adolescent and Adult Trial
in U.S. and Canada
- Completed dosing in cohort one (low dose, n=2) in Canada; encouraging initial safety and efficacy data
- Presented initial clinical data from the first two adult patients at the BPNA 2024 Annual Conference
- Health Canada authorized protocol amendment to include patients ≥12 years of age
- Received IDMC approval of Company's request to proceed to the high dose cohort earlier than planned
- Trial now expanding into the U.S. following submission of 12+ protocol to U.S. FDA
REVEAL Phase 1/2 Pediatric Trial in U.S. and
U.K.
- U.S. FDA cleared IND for TSHA-102 in pediatric patients
- Dosed first pediatric patient in the U.S.
- Received IDMC approval to dose second patient in cohort one (low dose)
- U.K. MHRA authorized CTA for TSHA-102 in pediatric patients
- ODD, RPDD and FTD from the U.S. FDA and ODD from the EU EMA
2024: significant clinical data generation expected in adult, adolescent and pediatric patients across three
geographies
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Rett syndrome: a rare, progressive X-linked neurodevelopmental disease
⚬
⚬
⚬
⚬
Caused by mutations in the X-linked MECP2 gene, a critical transcriptional regulator required for proper neuronal development and brain function1
Mutations in MECP2 inhibit neuronal development, leading to impaired brain development and function1 Primarily occurs in females
Female heterozygous patients are mosaic carriers of normal and mutated MECP2, and symptoms and severity vary, due in part to random X-inactivation2
Rett syndrome is divided into four key stages3
STAGE I
Developmental Arrest
6-18 months (typical)
≤6 months (early)
Symptom onset
= | ||
STAGE II | STAGE III | STAGE IV |
Rapid Deterioration | Pseudo Stationary | Late Motor Deterioration |
1-4 years | 4-10 years | >10 years |
Symptom progression | Symptom stabilization | Muscle wasting with age |
Sources: 1Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185-188.2Braunschweig D, Simcox T, Samaco RC, LaSalle JM. X-Chromosome inactivation ratios affect wild-type MeCP2 expression within mosaic Rett
syndrome and Mecp2-/+ mouse brain. Hum Mol Genet. 2004;13(12):1275-1286.3Gold WA, Krishnarajy R, Ellaway C, Christodoulou J. Rett Syndrome: A Genetic Update and 5
Clinical Review Focusing on Comorbidities. ACS Chem Neurosci. 2018 Feb 21;9(2):167-176. doi: 10.1021/acschemneuro.7b00346. Epub 2017 Dec 15. PMID: 29185709.
Hallmark characteristics of Rett syndrome appear across multiple clinical domains impacting activities of daily living
The cortical architecture and function abnormalities observed across the CNS in Rett syndrome can have a significant impact on motor function, socialization and autonomic function
Gross Motor Function
- Mobility issues
- Loss of movement
and coordination abilities
-
Gait disturbances o Hypotonia
o Dystonia
Fine Motor Function
-
Loss of hand function o Loss of purposeful
hand use
o Repetitive hand movements
Socialization
- Loss of speech/ communication
-
Social withdraw o Behavioral issues
o Intellectual disability
Autonomic Function
- Seizures
-
Sleep disturbances o Breathing issues o Gastrointestinal
issues
o Cardiac function o Vasomotor
disturbances
Sources: Gold WA, Krishnarajy R, Ellaway C, Christodoulou J. Rett Syndrome: A Genetic Update and Clinical Review Focusing on
Comorbidities. ACS Chem Neurosci. 2018 Feb 21;9(2):167-176. doi: 10.1021/acschemneuro.7b00346. Epub 2017 Dec 15. PMID:6 29185709. 2Armstrong, DD. J Child Neurol. 2005;20(9):747-753
No approved disease-modifying treatments address the genetic root cause of Rett syndrome
High unmet medical need
- Current standard of care focused on symptom management2
- High caregiver burden and significant impact on quality of life
Significant market opportunity
- Estimated prevalence of typical Rett syndrome caused by a MECP2 mutation is between 15,000 and 20,000 in major global markets (U.S., EU+U.K.)1
- Rett syndrome occurs worldwide in 1 of every 10,000 female births1
Sources: 1IRSF; NORD; Amir RE, Van den Veyver IB, Wan M, et al. Rett Syndrome Is Caused by Mutations in X-Linked Mecp2, | 7 |
Encoding Methyl-Cpg-Binding Protein 2. Nat Genet 232:185-188. 1999 .2 Fu C, Armstrong D, Marsh E, et al. Consensus guidelines |
on managing Rett syndrome across the lifespan. BMJ Paediatrics Open 2020;4:e000717. doi:10.1136/ bmjpo-2020-000717.
Gene Therapy Challenge: too much or too little MECP2 expression is harmful in Rett syndrome
Rett syndrome
WT
WT
WT
WT
Healthy individual
WT
WT
WT
WT
WT WT
MECP2 duplication syndrome
Some MECP2 deficiency | Normal MECP2 levels | Overexpressed MECP2 |
occurs due to random X-inactivation | in all cells | leads to harmful effects and |
leading to a mixture of wild-type and | duplication syndrome | |
deficient cells |
TSHA-102's novel miRNA-ResponsiveAuto-Regulatory Element (miRARE) technology
is designed to correct MECP2 deficiency and avoid toxic overexpression
Source: Van Esch H, Bauters M, Ignatius J, et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation | 8 |
and progressive neurological symptoms in males. Am J Hum Genet. 2005;77(3):442-453. | |
TSHA-102: an investigational one-time gene therapy that regulates MECP2
⚬ TSHA-102 delivers a functional form of | |
⚬ | MECP2 to cells in the CNS |
Equipped with novel miRNA-responsive | |
target sequence (miRARE) designed to | |
mediate levels of MECP2 in the CNS on a | |
cell-by-cell basis without risk of | |
overexpression | |
- Senses transgene and endogenous | |
MECP2 levels to provide a superior | |
therapeutic profile to that of unregulated | |
⚬ | MECP2 gene replacement3 |
Delivered via intrathecal (IT) administration | |
to target key CNS regions and minimize viral |
AAV9 capsid
Clinically and commercially proven across multiple CNS indications
miniMECP2 allows for packaging of miRARE technology for
sophisticated regulatory control in a self-complementary design1
load using a routine, minimally invasive |
procedure in an outpatient setting |
MEP426 promoter allows targeted neuronal expression and capitalizes on endogenous transcriptional regulation
Self-complementary technology enables more rapid transgene expression due to ability to bypass the rate-limitingsecond-strand synthesis in host cells2
Sources: 1Tillotson R et al. 2017 Nature; 550:398-401; Sinnett SE et al. A New Approach for Designing a Feedback-Enabled AAV Genome Improves Therapeutic Outcomes of MiniMeCP2 Gene Transfer in | |
Mice Modeling RTT. 23rd Annual meeting for the American Society of Gene & Cell Therapy; April 28,2020. 2McCarty DM. Self-complementary AAV vectors: Advances and applications. Mol Ther. | 9 |
2008;16(10):1648-1656.3Haque E et al. The microRNA-responsive autoregulatory element from TSHA-102 for Rett Syndrome modulates therapeutic transgene expression in response to cellular MeCP2 in |
mouse and human cell lines. 30th Annual Congress of the European Society for Gene and Cell Therapy, 24-27 Oct 2023, Brussels, Belgium. Poster #P435.
miRARE prevents overexpression through RNA interference with binding sites for endogenous microRNA responsive to MeCP2 levels1
MeCP2-deficient cell | |||||||||||
TSHA-102 | Healthy, MeCP2-expressing cell | TSHA-102 | |||||||||
X
Designed to silence the miniMECP2 transgene in
cells that already express MeCP2
Designed to enable miniMeCP2 protein production
in MeCP2-deficient cells
TSHA-102 has demonstrated the ability to produce and maintain safe transgene expression levels in the CNS
in preclinical models1
Source: 1Sinnet, SE, et al. Engineered microRNA-based regulatory element permits safe high- | 10 |
dose miniMECP2 gene therapy in Rett mice. Brain. 2021 awab182. | |
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Taysha Gene Therapies Inc. published this content on 08 March 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 08 March 2024 13:21:04 UTC.