UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): April 14, 2021
Taysha Gene Therapies, Inc.
(Exact name of registrant as specified in its Charter)
| Delaware | 001-39536 | 84-3199512 | ||
| (State or Other Jurisdiction of Incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) | ||
| 2280 Inwood Road Dallas, Texas |
75235 | |||
| (Address of Principal Executive Offices) | (Zip Code) | |||
(214) 612-0000
(Registrant’s Telephone Number, Including Area Code)
Not Applicable
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instructions A.2. below):
| ☐ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ☐ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ☐ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ☐ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class |
Trading Symbol(s) |
Name of each exchange on which registered | ||
| Common Stock, $0.00001 par value | TSHA | The Nasdaq Stock Market LLC |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 7.01 Regulation FD Disclosure.
On April 14, 2021, Taysha Gene Therapies, Inc. (the “Company”) updated its corporate presentation for use in meetings with investors, analysts and others. The presentation is available through the Company’s website and a copy is attached as Exhibit 99.1 to this Current Report on Form 8-K.
The information in this Item 7.01 of this Current Report on Form 8-K, including Exhibit 99.1, is being furnished pursuant to Item 7.01 and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”) or otherwise subject to the liabilities of that section, and it shall not be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or under the Exchange Act, whether made before or after the date hereof, except as expressly set forth by specific reference in such filing to this item of this report.
Item 8.01 Other Events.
On April 14, 2021 the Company issued, and posted to its website, a press release entitled “Taysha Gene Therapies Announces New Data on Multiple Preclinical Programs and Upcoming R&D Day.” The full text of the press release is attached as Exhibit 99.2 to this Current Report on Form 8-K and incorporated herein by reference.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
| Exhibit No. |
Description | |
| 99.1 | Corporate presentation, dated April 14, 2021. | |
| 99.2 | Press release, dated April 14, 2021. | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Taysha Gene Therapies, Inc. | ||||||
| Dated: April 14, 2021 | By: | /s/ Kamran Alam | ||||
| Kamran Alam | ||||||
| Chief Financial Officer | ||||||
Exhibit 99.1 Bringing New Cures to Life Corporate Presentation April 2021
Legal Disclosure FORWARD LOOKING STATEMENTS This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward- looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are subject to a number of risks, uncertainties and assumptions. Risks regarding our business are described in detail in our Securities and Exchange Commission filings, including in our Annual Report on Form 10-K for the year ended December 31, 2020. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. The forward-looking statements contained in this presentation reflect our current views with respect to future events, and we assume no obligation to update any forward-looking statements except as required by applicable law. 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.
Driven by a relentless focus on discovering, developing, and commercializing novel AAV-based gene therapies for devastating disorders of the central nervous system 3
Taysha Summary Overview – First in human clinical data for TSHA-101 in GM2 gangliosidosis in 2H 2021 – Additional clinical data for TSHA-120 in GAN in 2H 2021 Multiple product candidates with anticipated – Open IND for TSHA-118 in CLN1 disease; initiation of Phase 1/2 trial in 2H 2021 near-term catalysts to enhancevalue – Submit four IND/CTA filings, including Rett syndrome, in 2021 – Advancement of four product candidates in IND-enabling studies, four in discovery in 2021 – Current pipeline of 26 AAV gene therapy programs Portfolio of 26 CNS gene therapy – Portfolio addressing over 500,000 patients (US+EU) across monogenic CNS diseases, including programs across 3 distinct franchises neurodegenerative diseases, neurodevelopmental disorders, and genetic epilepsies – Led by Drs. Steven Gray and Berge Minassian; established to accelerate R&D, with integration of UT Southwestern Gene Therapy translational research, clinical development and GMP manufacturing Program strategic alliance – Exclusive access to resources, expertise, and novel technology platforms for delivery and dosing of gene therapies – Clinically and commercially proven AAV9 vector platform Validated capsid, manufacturing system – Highly scalable suspension HEK293 manufacturing process with excellent yield and route of delivery – Intrathecal delivery enables direct targeting to the CNS with validated biodistribution and safety – Deep expertise in the development of gene therapies for rare diseases Proven management team – Key leadership team members and investors previously led the development and commercialization of Zolgensma®, and investorsyndicate the first FDA-approved gene therapy for CNS disease 4
Leadership team uniquely positioned to deliver on corporate mission Leadership Advisors RA Session II Steven Gray, PhD Founder, President & CEO Chief Scientific Advisor Suyash Prasad, MBBS, MSc, MRCP, MRCPCH, FFPM Berge Minassian, MD Chief Medical Officer and Head of R&D Chief Medical Advisor Kamran Alam, CPA, MBA Chief Financial Officer Board of Directors Fred Porter, PhD Sean Nolan Chief Technical Officer Chairman Mishima Gerhart Paul Manning Chief Regulatory Officer and Head of Quality Sean McAuliffe Phillip Donenberg Chief Commercial Officer Jim Rouse Sukumar Nagendran, MD Chief Information Officer Emily McGinnis Laura Sepp-Lorenzino, PhD Chief Patient Officer & Head of Government Affairs Tim Douros, JD Kathleen Reape, MD Chief Legal Officer and Corporate Secretary Tracy Porter, M.Ed., SPHR RA Session II Chief People Officer 5
Scientific Advisory Board of preeminent international scientific and clinical thought leaders in gene therapy, CNS diseases and drug discovery and development Scientific Advisory Board University of Utah Registry of Autism and Developmental Deborah Bilder, MD Disabilities (URADD); Utah Regional Education; BioMarin Pharmaceutical Boyd Consultants; Royal Colleges of Physicians; University of Alan Boyd, BCc, MB, ChB, Birmingham Medical School; AstraZeneca; FRSB, FFLM, FRCP, FFPM Ark Therapeutics Ltd Columbia University; Simons Foundation Autism Wendy K. Chung, MD, PhD Research Initiative (SFARI) David P. Dimmock, MD Rady Children’s Institute for Genomic Medicine; FDA; CDC The Neuroscience Research Center Michael W. Lawlor, MD, PhD at the Medical College of Wisconsin; Solid Biosciences David Geffen School of Medicine at University of California, Los Gerald S. Lipshutz, MD, MS Angeles; Wellcome Trust, UK; NIH 6
Taysha by the numbers 500,000+ 1 1 4 26 pivotal-stage program programs in US+EU patients IND/CTAs expected differentiated further diversifying development with addressable through strategic partnership to be submitted by portfolio options to acquire an current pipeline with a world class the end of 2021 additional 4 programs programs academic institution 7
Diverse pipeline focused exclusively on monogenic disorders of the central nervous system Neurodevelopmental Neurodegenerative Genetic Disorders Diseases Epilepsies Diseases characterized by the Multi-faceted conditions Disorders characterized by recurrent progressive degeneration of the characterized by impairments in seizures often leading to abnormal structures and function of the CNS cognition, behavior, and motor development of the brain and PNS function 8
Unparalleled gene therapy pipeline focused exclusively on monogenic CNS disorders PROGRAM INDICATION DISCOVERY PRECLINICAL PHASE 1/2 Pivotal GLOBAL COMM. RIGHTS NEURODEGENERATIVE DISEASES TSHA-120 GRT Giant Axonal Neuropathy TSHA-101 GRT GM2 Gangliosidosis Currently open CTA TSHA-118 GRT CLN1 Disease Currently open IND TSHA-119 GRT GM2 AB Variant TSHA-104 GRT SURF1-Associated Leigh Syndrome IND/CTA submission 2H21 TSHA-112 miRNA APBD TSHA-111-LAFORIN miRNA Lafora Disease TSHA-111-MALIN miRNA Lafora Disease TSHA-113 miRNA Tauopathies TSHA-115 miRNA GSDs Undisclosed GRT/shRNA Undisclosed Undisclosed GRT Undisclosed NEURODEVELOPMENTAL DISORDERS TSHA-102 Regulated GRT Rett Syndrome IND/CTA submission 2H21 TSHA-106 shRNA Angelman Syndrome TSHA-114 GRT Fragile X Syndrome TSHA-116 shRNA Prader-Willi Syndrome TSHA-117 Regulated GRT FOXG1 Syndrome TSHA-107 GRT Autism Spectrum Disorder TSHA-108 GRT Inborn Error of Metabolism TSHA-109 GRT Inherited Metabolism Disorder Undisclosed GRT Undisclosed Undisclosed mini-gene Undisclosed GENETIC EPILEPSY TSHA-103 GRT SLC6A1 Haploinsufficiency Disorder TSHA-105 GRT SLC13A5 Deficiency TSHA-110 mini-gene KCNQ2 Undisclosed mini-gene Undisclosed GRT: Gene replacement therapy miRNA: microRNA shRNA: short hairpin RNA 9
Genetic Epilepsy Our three distinct franchises have the potential to address over 500,000+ patients (US+EU) KCNQ2 37,000 500,000 SLC6A1 Neurodevelopmental 17,000 Additional 2 SLC13A5 Programs 1,900 200,000 Fragile X syndrome 100,000 Angelman Syndrome Neurodegenerative 55,000 Alzheimer’s Prader- ~14M Willi 40,000 Rett syndrome 25,000 FOXG1 20,000 GSDs Tauopathies 20,000 (MAPT-FTD, PSP, CBD) 13,000 APBD 10,000 GAN CLN1 2,400 GM2, Lafora 900 GM2 AB variant SURF1 700 650 300-400 1 Tauopathies only include MAPT-FTD, PSP, CBD. 10 2 Additional programs include TSHA-107, TSHA-108 and TSHA-109 Estimated Patient Population (US + EU)
Our strategy is focused on rapid clinical and commercial development – We leverage a clinically and commercially proven capsid, manufacturing process, and delivery method – Our strategy is designed to accelerate development timelines and increase the probability of success across our pipeline – Program couples validated technology with novel Intrathecal (IT) route of administration targeted payload design (GRT, miRNA, shRNA, regulated – Enables direct targeting to CNS GRT, mini-gene) – Validated biodistribution and safety profile Proven HEK293 Suspension Process – Highly scalable and excellent yields – 3-pronged approach to manufacturing including UTSW, Catalent and internal cGMP facility AAV9 vector for delivery of therapeutic transgene – Demonstrated safety and efficacy across multiple CNS indications 11
Creating a sustainable business model for gene therapy Taysha’s sustainable Traditional chronic dosing One-time dosing gene therapy platform business model business model business model 12
Approach and ability to deliver various payloads Gene Vectorized Regulated Gene Mini-Gene Replacement RNA Replacement Payloads ⎯ Replace gene of interest to treat ⎯ Transgenes designed to ⎯ Regulate expression of a ⎯ Many genes are too large to fit diseases or disorders with express miRNA (small, non- therapeutic transgene in AAV capsids limited gene expression coding sequences of RNA that result in silencing of ⎯ Built-in regulation system to ⎯ Mini-genes designed to gene expression) replace dose-sensitive genes overcome limited AAV ⎯ Comprised of a codon-optimized safely and at therapeutic packaging capacity DNA transgene that encodes the ⎯ Transgenes designed to levels wild type gene of interest express short-hairpin RNA ⎯ Collaboration with Cleveland (shRNA), which reactivate a ⎯ Uses miRARE, our novel Clinic to advance next- ⎯ Transgene (or mini-gene) silenced gene upon binding miRNA target panel generation mini-gene payloads coupled with a promoter to the target of interest initially for genetic epilepsies selected to ensure expression in and neurodevelopmental the cell or tissue-type of interest disorders 13
Novel platform technology that powers our research engine Novel AAV Dosing Platform Novel Capsid Identification miRARE Platform ⎯ Potential to facilitate redosing via ⎯ Novel miRNA target panel derived from ⎯ Improves targeted delivery through use vagus nerve high-throughput miRNA profiling and of machine learning, capsid shuffling and genome mining directed evolution ⎯ Efficient targeting of vagal neurons demonstrated in adult rats, with ⎯ Designed for safely regulated transgene ⎯ Allows rapid identification of capsids potential to improve autonomic expression levels in the brain with improved properties in mice and nervous system symptoms in humans Non- Human Primates (NHPs) to ⎯ Needed in disorders like Rett syndrome maximize translational relevance ⎯ Normal vagal nerve fibers and where high doses of transgene- neurons post AAV delivery to the expressing vectors may be harmful ⎯ Potential to drive new product vagus nerve in dogs while low doses may avoid toxicity but candidates with novel biodistribution be sub-therapeutic and transduction profiles into pipeline ⎯ Built-in regulation system harnesses endogenous systems 14
Our strategic partnership with UTSW We have access to a world-class team of scientists and cutting-edge technology through an exclusive, worldwide royalty-free license to discover, develop, and commercialize gene therapies led by: – Berge Minassian, MD, Division Chief of Child Neurology – Pediatric neurologist with expertise in neurodegenerative diseases, neurodevelopmental disorders, and genetic forms of epilepsy – Discovered MECP2 CNS isoform (Rett syndrome) – Steven Gray, PhD, Director of Viral Vector Core, Associate Professor Dept of Peds – AAV-based vector engineering expertise and optimizing CNS delivery of transgenes – Administered the first AAV9-based therapy to patients via intrathecal route – Exclusive access to a flexible, scalable, and well-characterized GMP manufacturing suite that utilizes a suspension HEK293 process – Exclusive access to next generation platform technologies, including novel redosing platform, transgene regulation (miRARE), and capsid development 15
Manufacturing strategy allows flexibility and scalability to support broad pipeline ⎯ Support the UTSW viral vector core to ⎯ Establish collaborations with leading ⎯ Build internal manufacturing facility to supply early-phase clinical material CDMO to provide additional capacity for support clinical and commercial early-phase and pivotal supply manufacturing ⎯ Active technical collaboration and knowledge sharing for process information and ⎯ Strategic partnership in place with Catalent ⎯ Initial build includes two vector analytical methods Gene Therapies manufacturing trains, one fill/finish suite, QC and technical development labs ⎯ First program is ongoing ⎯ Two programs ongoing ⎯ Building secured in Durham, NC ⎯ Able to leverage process, methods and ⎯ Capabilities materials across programs ⎯ Growing hub for gene therapy ⎯ 50L tox production manufacturing ⎯ Current Capabilities ⎯ 200L available by EOY ⎯ Facility timing ⎯ 200/400L tox production ⎯ 500L GMP manufacturing ⎯ Kicked off 1Q 2021 ⎯ 800L GMP manufacturing ⎯ GMP operations began in December 2020 ⎯ Office and development labs operational in ⎯ Full support for release and stability testing ⎯ In-house support for critical release and 1Q 2022 stability testing ⎯ GMP ready in 2023 16
Neurodegenerative Disease Franchise 17
TSHA-120 GAN Rationale for targeting the GAN gene Normal Healthy Axon GAN Axon ⎯ Mutations affect production of the protein gigaxonin ⎯ Leads to accumulation of neurofilaments in giant axons causing signal interruption and neurodegeneration ⎯ Genetic changes in the GAN gene have been shown to cause Giant Axonal Neuropathy Neuron Cell Body ⎯ Good candidate for gene transfer approach ⎯ Small gene that is easy to package into AAV9 capsid ⎯ High transduction to target organ ⎯ Low-level expression may restore function Abnormal Accumulation of Axon ⎯ A clear model for other disorders with similar mechanism such Neurofilaments as GM2 gangliosidosis, CLN1 disease, SURF1-associated Leigh Axonal Neurofilaments Degenerated Swelling syndrome and amyotrophic lateral sclerosis (ALS) and Thin Myelin Sheath CNS Myelin Sheath PNS Normal GAN 18
TSHA-120 Giant axonal neuropathy (GAN) is a rare inherited genetic disorder GAN that affects both the central and peripheral nervous systems Progressive ⎯ Rare autosomal recessive disease of the central and Tightly Curled Hair Contractures Scoliosis peripheral nervous systems caused by loss-of-function gigaxonin gene mutations ⎯ Majority of children with GAN show symptoms and features before age 5 ⎯ Dull, tightly curled hair ⎯ Progressive scoliosis ⎯ Contractures ⎯ Giant axons ⎯ Spinal cord atrophy Spinal Cord White Matter ⎯ White matter abnormality Giant Axons Atrophy Abnormality ⎯ No approved disease-modifying treatments available ⎯ Symptomatic treatments attempt to maximize physical development and minimize deterioration ⎯ Early- and late-onset phenotypes – shared physiology ⎯ Late-onset often categorized as Charcot-Marie-Tooth Type 2 (CMT2), with lack of tightly curled hair and CNS symptoms, and relatively slow progression ⎯ Represents 1% to 6% of all CMT2 diagnosis ⎯ Late-onset poor quality of life but not life-limiting Murphy SM et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry 2012;83:706–10. Gess B et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes in a German neuromuscular center population. Neuromuscul Disord 2013;23:647–51. 19 ⎯ Estimated prevalence of GAN is 2,400 patients (US+EU) Antoniadi et al 2014 Bacquet J et al. Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation. BMJ Open. 2018
TSHA-120 GAN GAN natural history and disease progression Age 0 5 10 15 20 25 30 35 40 45 50 … Early-onset GAN • Delayed early motor development 0-2 yrs • Tightly curled hair • Unsteady gait, foot deformity 3-8 yrs • Progressive motor weakness • Ataxia and dysarthria 7-9 yrs • Nystagmus (cerebellar), optic neuropathy / decreased visual acuity • Scoliosis and progressive contractures 8-11 yrs • Loss of independent ambulation • Dysphagia • Stridor and respiratory insufficiency 13-18 yrs • CNS – intellectual disability, seizures, spasticity 20+ yrs *** Respiratory failure, death *** Late-onset GAN 0-5 yrs • Asymptomatic 5-25 yrs • Delayed early motor development, unsteady gait 25-50+ yrs • Variable foot deformity • Progressive imbalance • Distal weakness, atrophy, hypotonia • Ambulation issues (stairs, uneven surfaces) • Decreased deep tendon reflexes • Fine motor skills issues (gripping objects) • Considerable impact to Quality of Life 20 Disease progression
TSHA-120 Maximizing patient access and identification to GAN address the estimated 2,400 patients in US and EU Earlier diagnosis Increased awareness Genotyping • Educate HCPs on GAN • Partner with genetic testing • Establish newborn phenotypes (early vs. late providers (ex. Invitae and screening onset) with the potential to GeneDX) to identify patients • Partner with and create key identify patients earlier in with GAN mutation centers of excellence the disease • Screen patients with unknown • Publications to create etiology in CMT clinics • Engage with patient awareness for GAN worldwide advocacy groups phenotypes Murphy SM et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry 2012;83:706–10. 21 Gess B et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes in a German neuromuscular center population. Neuromuscul Disord 2013;23:647–51. Antoniadi et al 2014 Bacquet J et al. Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation. BMJ Open. 2018
TSHA-120 Primary efficacy endpoint is the Motor Function Measure GAN (MFM32) – a validated quantitative scale ⎯ Validated instrument used in multiple regulatory approvals Examples of tasks ⎯ A 32-item scale for motor function measurement developed for neuromuscular diseases No. Domain Starting Position Exercise Requested 1 D1 Supine, lower limbs half-flexed, kneecaps Raise the pelvis; the lumbar spine, the pelvis and the thighs are aligned and ⎯ Assesses severity and progression of motor function at zenith, and feet resting on mat the feet slightly apart across a broad spectrum and in 3 functional domains 2 D1 Supine Without upper limb support, sits up ⎯ Standing, transfers and ambulation 3 D1 Seated on the mat Stands up without upper limb support ⎯ Proximal and axial function 4 D1 Standing Without upper limb support, sits down on the chair with the feet slightly apart ⎯ Distal function 5 D1 Seated on chair Stands up without upper limb support and with the feet slightly apart 6 D1 Standing with upper limb supported Releases the support and maintains a standing position for 5s with the feet ⎯ 32 items scored between 0 and 3 for a maximum slightly apart, the head, trunk, and limbs in the midline position score of 96 7 D1 Standing with upper limb supported on Without upper limb support, raises the foot for 10s ⎯ A higher score means that an individual was able to equipment complete the task 8 D1 Standing Without support, touches the floor with 1 hand and stands up again ⎯ Sometimes, the score is converted to a percentage 9 D1 Standing without support Takes 10 steps forward on both heels ⎯ A 4-point change is considered clinically meaningful in the following indications: 10 D1 Standing without support Takes 10 steps forward on a line ⎯ DMD 11 D1 Standing without support Runs for 10m ⎯ SMA 12 D1 Standing on 1 foot without support Hops 10 times in place ⎯ LAMA2-related muscular dystrophy ⎯ Cerebral palsy 22
TSHA-120 GAN natural history study data as a dependable GAN comparator for future studies ⎯ 45 GAN patients (2013-present) ages 3-21 years ⎯ Can be accessed for treatment study ⎯ Will be used as comparator for treatment study 8-point decline ⎯ MFM32 8 point decline annually annually ⎯ MFM32 total score shows uniform decline between patients of all age groups over time ⎯ Average decline is ~8 points per year ⎯ 4-point change is considered clinically meaningful ⎯ MFM32 selected as primary endpoint due to least variability and its use in confirmatory trials • Natural history data: 8-point decline annually in MFM32 • 4-point change in MFM32 considered clinically meaningful 23 Bönnemann, C. et al; 2020
TSHA-120 GAN TSHA-120 program overview and construct ⎯ Construct invented by Dr. Steven Gray (UTSW) ⎯ AAV9 viral vector with engineered transgene AAV9 capsid encoding the human gigaxonin protein Brain tropism & ⎯ Self-complementary AAV capsid (scAAV) for rapid favorable safety profile activation and stable expression ⎯ JeT promoter drives ubiquitous expression ⎯ Designed to deliver a functional copy of the GAN gene with optimal tropism and rapid expression ⎯ Received orphan drug and rare pediatric disease designations ⎯ Clinical study ongoing at NIH, led by Carsten Bönnemann, MD 24
TSHA-120 Preclinical data supported intrathecal GAN dosing of TSHA-120 Comprehensive preclinical results demonstrated: ⎯ Function of gigaxonin demonstrated in vitro and in vivo ⎯ Phenotypic rescue in GAN mice after intrathecal injection, improving motor function and nerve pathology ⎯ No toxicities in mice or non-human primates (NHPs) up to 1 year post injection ⎯ No toxicities observed in rats at a 10-fold overdose up to 6 months post injection ⎯ Improved DRG pathology in GAN knockout (KO) mice ⎯ Preclinical data published in several scientific journals 25
TSHA-120 TSHA-120 normalized performance of 18-month-old GAN GAN rodent knockout model ⎯ Untreated GAN rodents performed significantly worse than heterozygous controls Rotarod Performance ⎯ GAN rodents treated at 16 months old performed significantly better than untreated GAN rodents at Control n=14 18 months old GAN KO+AAV9/GAN (n=6) Historic GAN KO (n=4) ⎯ GAN rodents treated at 16 months old performed equivalently to heterozygous controls p ≤ 0.05 26 Gray, S.J., unpublished
TSHA-120 TSHA-120 improved pathology of the DRG GAN in the GAN KO mice Normal control GAN KO – vehicle injected GAN KO – AAV9-GAN 27 Bailey, R. et al, 2018, MTMCD
TSHA-120 TSHA-120 improved pathology of the DRG GAN in the GAN KO mice Significant reduction in % neuronal inclusions 28 Bailey, R. et al, 2018, MTMCD
Groundbreaking, historic dose escalation clinical trial – First intrathecally-dosed gene therapy Goals Target Recruitment Target Areas to Transduce • Primary – Safety: clinical and laboratory assessments • 14 subjects injected • Secondary – Efficacy: pathologic, physiologic, • > 5 years old functional and clinical markers Dose Cohorts* 1x 13 • 3.5 x 10 total vg (N=2) 14 3.3x • 1.2 x 10 total vg (N=4) 14 5x • 1.8 x 10 total vg (N=5) 14 10x • 3.5 x 10 total vg (N=3) Administration Technique to Improve transduction • Lumbar Intrathecal Infusion (IT) o • Amount and Rate: 10.5 ml; • Trendelenburg position (15 ) 1 mL/minute • During infusion & 1 hour post • Immunosuppression regimen infusion of prednisolone and rapamycin *Doses calculated by qPCR 29 NOTE: Subsequent slides only show data from 14 14 Clinical Trial: NCT02362438 1.2 x 10 vg and 1.8 x 10 vg doses Route and Product Details Goals and Method of and Dose Cohorts Targets of Trial Administration
TSHA-120 TSHA-120 achieved sustained improvement in primary GAN efficacy endpoint and was well tolerated at multiple doses ⎯ First successful in-human intrathecal gene transfer ⎯ 14 patients dosed ⎯ Positive efficacy results support a dose-response relationship with TSHA-120 14 14 ⎯ 1.8x10 total vg dose and 1.2x10 total vg cohorts demonstrated statistically significantly slowing of disease progression ⎯ Data only recently publicly presented ⎯ Treatment with TSHA-120 was well tolerated ⎯ No signs of significant acute or subacute inflammation ⎯ No sudden sensory changes ⎯ No drug-related or persistent elevation of transaminases 14 1.8 x 10 total vg ⎯ 6 patients beyond 3+ years initial treatment 14 1.2 x 10 total vg 30 Bönnemann, C. et al; 2020
TSHA-120 Treatment with TSHA-120 resulted in a clear arrest of disease GAN progression at therapeutic doses and long-term durability 14 14 1.8 x 10 total vg 1.2 x 10 total vg ⎯ Arrest of disease progression at therapeutic doses⎯ 6 patients treated for 3+ years supporting long-term durability ⎯ TSHA-120 was well tolerated at multiple doses⎯ Plan to engage with agencies in US, EU and Japan to discuss regulatory pathway as soon as possible 31 Bönnemann, C. et al; 2020
TSHA-120 Additional analysis using Bayesian methodology GAN confirmed arrest of disease progression ⎯ Bayesian analysis ⎯ Enables direct probability statements about any unknown quantity of interest 14 1.8 x 10 total vg ⎯ Enables immediate incorporation of data gathered as the 14 1.2 x 10 total vg trial progresses ⎯ Useful and accepted by regulatory agencies when treating rare diseases and small patient populations ⎯ Can be used as a sensitivity analysis to support the more commonly accepted frequentist approach ⎯ Can be used as a way of statistically increasing the power of a clinical trial in a small patient population when used to incorporate auxiliary information ⎯ Confirmed documented natural history data of an 8-point decline in the MFM32 total % score per year ⎯ 4-point decline in the MFM32 is clinically meaningful 14 ⎯ TSHA-120 dose of 1.8x10 total vg resulted in an arrest of disease progression that was statistically significant Bayesian Analysis Frequentist Analysis Mean Std Dev Estimate Std Error p-Value 14 Post infusion: 1.8x10 total vg 7.78 1.94 7.78 1.89 <0.001 14 Post infusion: 1.2x10 total vg 6.09 2.11 6.07 2.05 0.004 Natural history decline -8.19 0.74 -8.18 0.72 <0.001 32 Bönnemann, C. et al; 2020
TSHA-120 TSHA-120 halted patient pre-treatment rate of GAN 14 decline at 1.8x10 total vg dose Bayesian Efficacy Analysis Compared to individual historical data 14 14 Posterior distribution of ���� (1.8 x 10 total vg dose, noninformative prior) Posterior distribution of ���� (1.2 x 10 total vg dose, noninformative prior) 3 2 14 1.8 x 10 total vg 14 1.2 x 10 total vg X-axis = change in slope compared to pre-gene transfer Blue line = pre-treatment change in slope = 0 14 14 ⎯ Graphs depict treated population average annual post-treatment decline for both the 1.8x10 total vg cohort and the 1.2x10 total vg cohort 14 ⎯ 1.8x10 vg halted patient pre-treatment rate of decline, avg annual slope improvement of 7.78 points 14 ⎯ 1.2x10 vg resulted in clinically meaningful slowing of disease progression confirming dose response, avg annual slope improvement of 6.09 points ⎯ Both doses showed superior result compared to natural decline of GAN patients 33 Bönnemann, C. et al; 2020 Change in pre-treatment slope Change in pre-treatment slope
TSHA-120 Further analyses confirmed nearly 100% probability of clinically GAN meaningful slowing of disease compared to natural history 14 Posterior distribution of ���� (1.8 x 10 total vg dose, flat prior) 2 14 ⎯ Further analyses were conducted to assess the probability of 1.8 x 10 total vg clinically meaningful slowing of disease as compared to natural history ⎯ A 4-point decline in the MFM32 is considered clinically meaningful ⎯ Graphs depict treated population annual decline for both the 14 14 1.8x10 total vg cohort and the 1.2x10 total vg cohort as compared to natural history 14 14 Posterior distribution of ���� (1.2 x 10 total vg dose, flat prior) 3 ⎯ 1.8x10 total vg dose confirmed nearly 100% probability of clinically meaningful slowing of disease compared to natural history decline of 14 1.2 x 10 total vg GAN patients 14 ⎯ 1.2x10 total vg dose confirmed approximately 85% probability of clinically meaningful slowing of disease and 100% probability of any slowing of disease X-axis = annual decline in MFM32 total % score Blue line = natural history decline (-8 points per year) Values = % Probability 14 14 Change in disease progression 1.8x10 total vg 1.2x10 total vg Any Slowing 99.9 99.8 Clinically meaningful slowing 50% or more 98.3 84.9 34 Bönnemann, C. et al; 2020 Natural history decline Natural history decline
TSHA-120 GAN Anticipated next steps for TSHA-120 by the end of 2021 Complete transfer data from the NIH Request regulatory guidance from EMA and PMDA Initiate manufacturing of commercial-grade GMP material Initiate new clinical sites in US and EU Request an end-of-Phase meeting; Update on regulatory interactions discuss the regulatory pathway for and current clinical program, 14 TSHA-120 including 3.5x10 total vg cohort 35
TSHA-101 GM2 gangliosidosis is a severe GM2 gangliosidosis neurodegenerative disease ⎯ GM2 gangliosidosis results from a deficiency in the β- hexosaminidase A (Hex A) enzyme ⎯ Hex A is comprised of 2 subunits encoded by the alpha-subunit, HEXA, coded for by the HEXA gene, and the beta-subunit, HEXB, coded for the HEXB gene ⎯ Mutations of the HEXA gene cause Tay-Sachs disease (TSD) while mutations of the HEXB gene cause Sandhoff disease (SD) ⎯ The estimated prevalence is 500 patients (US+EU) ⎯ Preliminary Phase 1/2 safety & biomarker data (Queen’s University) expected in 2H 2021 ⎯ IND filing and initiation of US Phase 1/2 trial expected in 2H 2021 ⎯ Preliminary Phase 1/2 clinical data (Queen’s University) expected by the end of 2021 36
TSHA-101 Residual Hex A activity determines GM2 gangliosidosis the severity of GM2 Normal life span ⎯ Small increases in Hex A activity may lead to significant improvements in clinical outcomes and quality of life ⎯ Infantile onset is the most severe form of GM2 ⎯ Infantile forms may die within the first 4 years of life, and juvenile onset patients rarely survive beyond mid-teens 37
TSHA-101 Novel bicistronic vector design allows GM2 gangliosidosis consistent expression of HEXA and HEXB genes ⎯ HEXA and HEXB genes are required to produce the subunits of the beta-hexosaminidase A enzyme AAV9 capsid Brain tropism & ⎯ The novel bicistronic vector design enables 1:1 favorable safety profile expression of the alpha-subunit, HEXA, and the beta- subunit, HEXB, under the control of a single promoter with a P2A-self-cleaving linker ⎯ SD mice received vehicle or varying doses of TSHA-101 after 6 weeks: 11 ⎯ High dose (2.5x10 vg/mouse) 11 ⎯ Medium dose (1.25x10 vg/mouse) 11 ⎯ Low dose (0.625x10 vg/mouse) ⎯ Vehicle controls 38
TSHA-101 Significant, dose-dependent improvement in GM2 gangliosidosis survival observed in mice treated with TSHA-101 100 Heterozygote/Vehicle (n=6) Knockout/TSHA-101 low dose(n=6) Knockout/TSHA-101 medium dose (n=6) ** * ** **** Knockout/TSHA-101 high dose (n=11) 50 Knockout/Vehicle (n=6) * p-value=0.0141 ** p-value=0.0012 **** p-value<0.0001 0 0 20 40 60 80 100 Time (weeks) 39 Survival (%)
TSHA-101 Dose-dependent improvements observed in GM2 gangliosidosis rotarod assessments in mice treated with TSHA-101 Heterozygote/Vehicle Knockout/TSHA-101 low dose Knockout/Vehicle Knockout/TSHA-101 medium dose Knockout/TSHA-101 high dose 40
TSHA-101 GM2 accumulation was significantly reduced in the mid-section GM2 gangliosidosis of the brain following treatment with TSHA-101 after 16 weeks Heterozygote/Vehicle (n=6) Knockout/TSHA-101 low dose (n=6) Knockout/TSHA-101 medium dose (n=6) Knockout/TSHA-101 high dose (n=11) Knockout/Vehicle (n=6) **** p-value<0.0001 * p-value = 0.0179, 0.0295 41
TSHA-101 Phase 1/2 adaptive trial for TSHA-101 GM2 gangliosidosis in GM2 gangliosidosis • Open-label, single center, Phase 1/2 trial Study design and duration • Patients evaluated for one year, followed by longer-term extension • Age younger than 1 year Patient cohort (n=4) • Pathogenic confirmation of mutation in HEXA or HEXB gene • Patients not on ventilator support 14 • Single total dose of 5x10 vg of TSHA-101 (AAV9/HEXB-P2A-HEXA) Intervention • Delivered intrathecally • Safety and tolerability • Gross motor and fine motor milestones • Bayley score, CHOP-INTEND • Bulbar function/vocalization Key clinical assessments • Respiratory function • Seizure frequency/medications • Ophthalmological assessments • QOL and caretaker burden assessments • Hex A enzyme in CSF and serum Key biomarker assessments • GM2 accumulation in CSF • MRI changes 42
TSHA-118 CLN1 disease is a severe neurodegenerative CLN1 disease lysosomal storage disease ⎯ Severe, progressive, neurodegenerative lysosomal storage disease, with no approved treatment AAV9 capsid Brain tropism & ⎯ Caused by mutations in the CLN1 gene, encoding the favorable safety profile soluble lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) ⎯ The absence of PPT1 leads to the accumulation of palmitoylated substrate within the lysosome ⎯ Disease onset is typically within 6-24 months, with progression visual failure, cognitive decline, loss of fine and gross motor skills, seizures, and death usually occurring by 7 years of age ⎯ The estimated prevalence of CLN1 disease is 900 patients (US+EU) ⎯ Currently an open IND for this program ⎯ Initiation of Phase 1/2 trial expected in 2H 2021 43
TSHA-118 TSHA-118-treated CLN1 KO mice CLN1 disease had improved survival rates 100 Untreated Het 75 Untreated KO 50 4 week IT TSHA-118 12 week IT TSHA-118 25 0 0 3 6 9 12 15 18 21 24 Age (Months) IT administration of TSHA-118 significantly extended survival of PPT1 KO mice for all ages and at all dose levels 44 Percent Survival
TSHA-118 TSHA-118-treated CLN1 mice had increased CLN1 disease and sustained plasma PPT1 activity WT-Untreated Het-Untreated KO-Untreated TSHA-118 • Supraphysiological levels of active PPT1 were observed in all TSHA-118 treated mice and persisted through the study endpoint • Persistence of effect after animal sacrificed up to 8.5 months post-treatment 45
TSHA-118 Phase 1/2 adaptive trial for CLN1 disease TSHA-118 in CLN1 disease • Open-label, dose finding, adaptive design trial Study design and duration • Patients evaluated for one year, followed by longer-term extension • Infantile and juvenile patients Patient cohort (n=18) • Pathogenic confirmation of mutation in CLN1 gene • Patients not on ventilator support • TSHA-118 Intervention 14 • Starting dose 5x10 total vg IT • Safety and tolerability • Gross motor and fine motor milestones • UBDRS and Hamburg Battens scale • Bayley score, Vineland scale Key clinical assessments • Bulbar function/vocalization • Visual loss • Seizure frequency/medications • QOL and caretaker burden assessments • PPT1 enzyme in CSF and serum Key biomarker assessments • Accumulation of palmitoylated substrate in CSF • MRI changes 46
TSHA-104 SURF1 deficiency is the most SURF1 deficiency common cause of Leigh syndrome – A monogenic mitochondrial disorder – Most common cause of cytochrome c oxidase deficient Leigh syndrome – Leigh syndrome – severe neurological disorder that presents in the first year of life – Initially often presents with gastrointestinal symptoms – Progressive loss of mental and movement abilities, often regression is episodic in nature – Can result in death within two to three years – ~10-15% have SURF1 mutation – No approved therapies – Estimated prevalence of SURF1 deficiency is 300 to 400 patients (US+EU) 47
TSHA-104 TSHA-104 IND or CTA filing SURF1 deficiency expected in 2H 2021 – Recombinant AAV9 viral vector with engineered transgene encoding the human SURF1 protein AAV9 capsid Brain tropism & – Designed to deliver a functional copy of the SURF1 gene favorable safety profile – Received orphan drug and rare pediatric disease designations – IND/CTA filing expected in 2H 2021 – Initiation of Phase 1/2 trial expected by the end of 2021 48
TSHA-104 TSHA-104 increased COX1 activity in brain and muscle and restored elevation of SURF1 deficiency blood lactate on exhaustive exercise in dose-dependent manner in SURF1 KO mice 2 2 Change of blood lactate after exhaustive Change in relative COX1 activity running 9∆ lactate 10 months 1.5 1.5 Muscle Cerebrum 8 * 7 * 6 1 * 1 ** 5 *** **** 4 **** 3 0.5 0.5 2 1 0 0 0 WT HET KO+ vehicle KO+ low KO+ high Change in lactate (post exhaustion lactate-pre-exhaustion lactate) of mice from all tested groups at 10 months old. Data shown as mean +SEM **p<0.01, ***p<0.001, and ****p<0.0001 49 Ling, Q. et al. Gene Therapy for SURF1-Related Leigh Syndrome. ASGCT 2020. Relative Activity Relative Activity Δ lactate (mmol/L) – post-pre treadmill)
TSHA-104 TSHA-104 MR spectroscopy analysis – Reduction in SURF1 deficiency choline levels reflective of reduction in brain inflammation CHO/CR+pCR Amplitude 5 4 3 2 1 0 WT KO+Vehicle KO+Low KO+High 50
TSHA-104 SURF1 deficiency Phase 1/2 trial for TSHA-104 in SURF1 deficiency • Open-label, single center, Phase 1/2 trial Study design and duration • Patients evaluated for one year, followed by longer-term extension • Pathogenic confirmation of mutation in SURF1 gene Patient cohort (n=4) • Patients not on ventilator support 14 • Single total dose of 5x10 total vg of TSHA-104 Intervention • Delivered intrathecally • Safety and tolerability • Gross motor and fine motor milestones • Bayley score, CHOP-INTEND, GMFM and vineland Key clinical assessments • Bulbar function/vocalization • Respiratory function • Seizure frequency/medications/EEG • QOL and caretaker burden assessments • Lactate and pyruvate in serum and CSF Key biomarker assessments • COX1 activity • MRI and MRS Spectroscopy 51
Lafora disease is a progressive and fatal TSHA-111 Lafora disease neurodegenerative disorder – Inherited, severe form of progressive myoclonus epilepsy – Caused by loss of function mutations in the EPM2A (laforin) or EPM2B (malin) genes responsible for glycogen metabolism – Absence of laforin or malin results in aggregates of polyglucosans or abnormally shaped glycogen molecules known as Lafora bodies – Signs and symptoms include recurrent epileptic seizures in late childhood or adolescence, difficulty walking, muscle spasms and dementia – Fatal within 10 years of onset – No approved therapies – Estimated prevalence of Lafora disease is 700 patients (US+EU) 52
TSHA-111-LAFORIN and TSHA-111-MALIN, TSHA-111 Lafora disease miRNA approaches – Recombinant AAV9 viral vector designed for AAV9 capsid Brain tropism & miRNA-mediated knockdown of the GYS1 gene favorable safety profile – GYS1 knockdown designed to reduce Lafora bodies and improve clinical condition – Self-complementary AAV capsid (scAAV) for rapid activation and stable expression – CBh promoter drives high levels of expression – Currently in IND/CTA-enabling studies 53
TSHA-111-LAFORIN and TSHA-111-MALIN reduced TSHA-111 Lafora disease GYS1 expression in the laforin and malin KO models laforin knock out model laforin ✱✱✱✱ PBS miRNA 1.0 0.8 GYS1 0.6 GFP 0.4 0.2 SatinFree 0.0 PBS miRNA PBS miRNA malin malin knock out model ✱✱✱ PBS miRNA 1.0 0.8 GYS1 0.6 GFP 0.4 0.2 SatinFree 0.0 PBS miRNA PBS miRNA 54 Relative Expression of GYS1 Relative Expression of GYS1 RR el e a la titv ive e E Exp xpr res ess siio on n o off G G Y YS S1 1
TSHA-111-LAFORIN and TSHA-111-MALIN decreased TSHA-111 Lafora disease Lafora body formation in mice brain Knockdown of GYS1 decreased lafora bodies 8 8 laforin malin *** * 6 6 4 4 2 2 0 0 miRNA PBS miRNA PBS 55 L B % in H i p p o c a m p u s LB % in Hippocampus L B in i p p o c a m p u s LB % in Hippocampus
TSHA-112 APBD Adult polyglycosan body disease (APBD) ⎯ Caused by a mutation in the GBE1 gene, responsible for the creation of branches during glycogen synthesis ⎯ Reduction in glycogen synthesis yields elongated glycogen changes that form poorly Histopathology soluble aggregates in the liver, muscle and CNS of APBD ⎯ Prime of life disease, with onset between 40- 50 years ⎯ Signs and symptoms include sensory loss in the legs, progressive muscle weakness, gait disturbances, mild cognitive impairment and urinary difficulties ⎯ Often misdiagnosed as multiple sclerosis ⎯ No approved therapies ⎯ Estimated prevalence of APBD is 10,000 patients (US+EU) 56
TSHA-112 expected to advance in TSHA-112 APBD IND/CTA-enabling studies in 2021 – Recombinant AAV9 viral vector designed for AAV9 capsid miRNA-mediated knockdown of the GYS1 gene Brain tropism & to treat APBD favorable safety profile – Self-complementary AAV capsid (scAAV) for rapid activation and stable expression – CBh promoter drives high levels of expression – Currently in IND/CTA-enabling study 57
TSHA-112 reduced GYS1 expression in the TSHA-112 APBD APBD KO model * PBS miRNA 1.0 0.8 GYS1 0.6 GFP 0.4 0.2 SatinFree 0.0 PBS miRNA PBS miRNA Gumusgoz, E. 2020 58 Relative Expression of GYS1
TSHA-112 decreased polyglucosan body TSHA-112 APBD formation in mice hippocampus ** 8 6 4 2 0 miRNA PBS TSHA-112 decreased polyglucosan body formation in the hippocampus 59 PB% in Hippocampus PB%inHippocampus
TSHA-119 GM2 AB Variant GM2 gangliosidosis, AB variant – Characterized by a mutation in the GM2A Hex A gene, leading to a deficiency of the GM2- HexA activator protein (GM2AP), a required co- factor for the breakdown of GM2- gangliosides by the protein Hex A HexB – Loss-of-function mutations result in a deficiency of GM2AP causing intra- Hex B lysosomal accumulation of GM2 and other glycolipids in neuronal cells ultimately resulting in cell death. GM2A – Signs, symptoms and progression mirror that of infantile GM2, and include seizures, vision and hearing loss, intellectual disability and paralysis and early death – No approved therapies 60
TSHA-119 GM2 AB Variant TSHA-119 in preclinical development – Self-complementary AAV9 viral vector for AAV9 capsid rapid activation and stable expression CNS tropism & – Designed to deliver a functional copy of the favorable safety profile GM2A gene – CAG promoter drives high levels of expression – Proof-of-concept demonstrated in GM2A KO mouse model – Currently in IND/CTA-enabling studies 61
TSHA-119 caused a dose-dependent TSHA-119 GM2 AB Variant reduction of GM2 accumulation in mice GM2 Accumulation at 20 Weeks in Midsection of Brain 0.15 ** 0.10 0.05 0.00 62 GM2/Total Gangliosides
TSHA-113 Tauopathies Tauopathies – Microtubule associated Protein Tau (MAPT) – Tauopathies are characterized by the accumulation of toxic tau protein in the brain that results in widespread neuronal dysfunction and loss – Tau accumulation is thought to underpin several neurodegenerative diseases, including Alzheimer’s, frontotemporal dementia (FTD), progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy and parkinsonism linked to chromosome 17 – Tau isoforms are expressed in the central and peripheral nervous systems – We are employing tau-specific miRNA shuttles that have been designed to target mRNA for all six isoforms of tau found in the human brain and/or mouse brain – Estimated prevalence of 13,000 patients with MAPT-FTD, PSP, CBD in the US and EU – Estimated 6.2 million Americans and 7.8 million Europeans are living with Alzheimer’s disease 63 FTD – frontotemporal dementia; PSP – progressive supranuclear palsy; CBD – corticobasal degeneration
TSHA-113 Tauopathies TSHA-113 in preclinical development – Self-complementary AAV9 viral vector for rapid AAV9 capsid activation and stable expression CNS tropism & – Utilizes AAV-mediated gene silencing to deliver favorable safety profile life-long reduction of tau protein levels in neurons following administration of a single dose – U6 promoter drives ubiquitous expression – Currently in preclinical development 64
TSHA-113 Tauopathies Primary screen of human tau miRNA candidates Human MAPT Knock-down Secondary screening of top candidates: hTau4i, hTau5i, and hTau7i HumanTau miRNA Candidates Scr = scrambled tau miRNA 65 hTau = human-specific tau miRNA Relative Renilla/Firefly
TSHA-113 Tauopathies TSHA-113 reduced K18 tau expression miRNA Shuttles 66
Mice dosed with TSHA-113 demonstrated widespread TSHA-113 Tauopathies function and GFP expression in neurons and glia ** 1.5 1.0 0.5 0.0 67 scAAV9/Tau5i-CBh-GFP Vehicle Relative hMAPT/GAPDH
Additional candidates targeting neurodegenerative diseases • miRNA targeting GYS1 to inhibit glycogen synthase in the brain to decrease abnormal glycogen formation TSHA-115 miRNA • This approach may enable the treatment of several glycogen storage disorders GSDs • Identical construct as TSHA-111-LAFORIN and TSHA-111-MALIN for Lafora disease Preclinical and TSHA-112 in APBD • Estimated prevalence of 20,000 patients in the US and EU 68
Neurodevelopmental Disorder Franchise 69
= TSHA-102 Rett syndrome is one of the most common genetic Rett Syndrome causes of intellectual disabilities in women STAGE I ⎯ Rett Syndrome is caused by mutations in the X-linked 6-18 months (typical) Infants are generally described as MECP2 gene ≤6 months (early) having normal development until Developmental Arrest Symptom approximately 6 to 18 months of age ⎯ MeCP2 regulates the expression of many genes involved Onset in normal brain function ⎯ A brief period of normal development is followed by a Hallmark Rett symptoms appear: STAGE II devastating loss of speech and purposeful hand use along Hand wringing or squeeze, clapping, 1-4 years with the emergence breathing abnormalities rubbing, washing, or hand to mouth Rapid Deterioration Symptom movements progression-regression ⎯ Disease reversibility described in animal models as 1 demonstrated by Sir Adrian Bird ⎯ The estimated prevalence of Rett syndrome is 25,000 After a period of rapid deterioration STAGE III patients in the US and EU neurological symptoms stabilize, with 4-10 years some even showing slight Pseudo stationary Symptoms ⎯ IND/CTA filing expected in 2H 2021 improvements stabilize/improve ⎯ Initiation of Phase 1/2 trial expected by the end of 2021 STAGE IV 85-90% of affected people may >10 years experience growth failure and muscle Late Motor Deterioration Muscle wasting that worsens with age wasting with age 70 1. Guy J et al. Science 2007
TSHA-102 Rett syndrome (RTT) is an X-linked Rett Syndrome neurodevelopmental disorder ⎯ Characterized by mutations in methyl CpG-binding protein 2 (MECP2), a protein that is essential for WT neuronal and synaptic function in the brain. WT WT WT WT ⎯ Female heterozygous RTT patients are mosaic carriers WT of normal and mutated MECP2 WT WT WT ⎯ RTT falls along a spectrum of MECP2 activity and WT toxicity from gene therapies is linked to unregulated expression of MECP2 Rett syndrome normal (WT) MeCP2 duplication ⎯ MECP2 expression must be regulated to correct the deficiency, while avoiding toxicity associated with overexpression 71
TSHA-102 Development of a gene therapy for Rett syndrome Rett Syndrome requires regulated expression of MECP2 ⎯ AAV9/MECP2 caused dose-dependent side effects after intraCSF administration in WT and KO mice AAV9 capsid Brain tropism & ⎯ We have developed a novel miRNA-responsive target sequence (miRARE) that regulates the expression of the favorable safety profile MECP2 transgene ⎯ Our approach provides a superior therapeutic profile to that of competitor unregulated MECP2 gene replacement 72
TSHA-102 miRARE is a targeting panel for endogenous Rett Syndrome miRNAs which regulate MECP2 expression 73
TSHA-102 Safety: Intrathecal TSHA-102 was not Rett Syndrome associated with early death in WT mice 100 80 60 0 vg, n=13 40 Low dose AAV9/MECP2(v2), n=12 Low dose AAV9/mini, n=12 Low dose TSHA-102, n=12 High dose AAV9/MECP2(v2), n=6 20 High dose AAV9/mini, n=8 High dose TSHA-102, n=9 0 15 20 0 5 10 25 30 35 Age (weeks) Mice were dosed P28-35 Diamond = vet-requested euthanasia for prolapse or bullying-related injury 74 % Survival
TSHA-102 Safety: TSHA-102 did not cause adverse Rett Syndrome behavioral side effects in WT mice 0 vg, n=20 Low dose AAV9/MECP2(v2), n=12 8 Low dose AAV9/mini, n=12 6 Low dose TSHA-102, n=12 High dose AAV9/MECP2(v2), n=10 4 High dose AAV9/mini, n=12 2 High dose TSHA-102, n=9 0 4 8 12 16 20 24 28 32 *p<0.05 Age (weeks) Mice were dosed P28-35 75 Aggregate score
TSHA-102 Efficacy: TSHA-102 outperformed unregulated Rett Syndrome AAV9/mini in MECP2 KO mouse survival study 100 80 WT, 0 vg, n=13 60 KO, 0 vg, n=18 40 KO, High dose AAV9/MECP2(v2), n=12 20 KO, High dose AAV9/mini, n=12 KO, High dose TSHA-102, n=12 0 0 5 10 15 20 25 30 35 Age (weeks) Mice were dosed P28-35 Diamond = vet-requested euthanasia, primarily for lesions. Lesions have been observed with varying frequencies among saline-treated KO mice, virus-treated WT and KO mice, as well as untreated RTT weanlings. 76 % Survival
TSHA-102 IND/CTA filing for TSHA-102 in Rett Rett Syndrome syndrome expected in 2H 2021 • Open-label, dose-ranging, randomized, multi-center Phase 1/2 trial Study design and duration• Safety and preliminary efficacy • Each cohort randomized 3:1 (one patient is a delayed treatment control) Key inclusion/exclusion criteria• Adults with pathogenic confirmation of mutation in MECP2 14 • First cohort (n=4): single dose of 5x10 total vg of TSHA-102 (AAV9/MECP2-miRARE) 15 Intervention• Second cohort (n=4): single dose of 1x10 total vg of TSHA-102 (AAV9/MECP2-miRARE) • Delivered intrathecally Rett-Specific/Global Assessments Respiratory Assessments • Motor Behavior Assessment Scale (MBA) • Respiratory Disturbance Index (RDI) • Rett Syndrome Hand Apraxia Scale (RHAS)• Sleep apnea, sleep study • Rett Syndrome Behavior Questionnaire (RSBQ) • Functional Mobility Scale in Rett Syndrome (FMS) Communication Assessments • Clinical Global Impression• Observer Reported Communication Assessment (ORCA) Key clinical assessments Behavior/Mood Assessments Quality of Life/Other Assessment • Anxiety, Depression, and Mood Scale (ADAMS)• SF-36 – Quality of life assessment from principal • Aberrant Behavior Checklist (ABC) caregiver • RTT-CBI – Caregiver burden inventory Seizure Assessments • EEG and neurophysiology Wearables • Seizure diary• Hexoskin: cardiac, respiratory, sleep & activity 77
TSHA-106 Angelman syndrome is a rare, neurogenic Angelman Syndrome disorder due to genomic imprinting – Caused by a deletion or loss of function of the maternally inherited allele of the UBE3A gene resulting in loss of the UBE3Q protein expression in neurons and abnormal communications between neurons – Maternal-specific inheritance pattern due to genomic imprinting of UBE3A in neurons – Maternal UBE3Q allele is expressed; paternal allele is silenced by a long non-coding RNA, UBE3A antisense transcript, or UBE3A-ATS 78 UPD – Uniparental disomy Scheiffele, P. et al. Nature. 2010
TSHA-106 There are currently no approved Angelman Syndrome treatments for Angelman syndrome – Signs and symptoms include developmental delay, severe impairments in behavior, motor function, communication and sleep as well as intellectual disability, debilitating seizures and ataxia – Normal lifespan but unable to live independently – No currently approved therapies – The estimated prevalence of Angelman syndrome is 55,000 patients (US+EU) www.frontiersin.org UPD – Uniparental disomy 79
TSHA-106 TSHA-106 for Angelman targets UBE3A- Angelman Syndrome ATS transcript through shRNA knock-down – AAV9 viral vector designed for shRNA-mediated knockdown of UBE3A-ATS, the antisense transcript AAV9 capsid governing the expression of UBE3A through the CNS tropism & favorable safety profile paternal allele. – Using AAV-based strategy to achieve broad distribution of the shRNA expression cassette across the entire CNS – Single intrathecal dose – Delivery of an ASO targeting UBE3A-ATS has shown promising results in ameliorating Angelman symptoms in transgenic mouse model – Additional testing in iPSC-derived neurons leading to candidate selection anticipated by mid-2021 – Interim expression and safety data from confirmatory NHP studies expected by the end of 2021 80
TSHA-106 TSHA-106 targets UBE3A-ATS transcript Angelman Syndrome through shRNA knock-down shRNA Candidates 4.0 UBE3A UBE3A-ATS 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Testing in neuroblast cell line demonstrated consistent knockdown of UBE3A-ATS and a subsequent increase in UBE3A expression across 26 distinct shRNA candidates 81 Folds compared to control
Additional candidates targeting neurodevelopmental disorders • FMR1 is the most common single gene cause of autism and cognitive impairment TSHA-114 GRT • Fragile X Syndrome is characterized by anxiety, aggression, hyperactivity, attention deficits, Fragile X syndrome and sleep/communication disruption Preclinical • Estimated prevalence of 100,000 patients in the US and EU • Loss of function of genes along 15q11-q13 chromosome region due to an imprinting defect TSHA-116 shRNA • Patients have developmental delay, insatiable eating habits accompanied by obesity and overt Prader-Willi syndrome diabetes Preclinical • Estimated prevalence of 40,000 patients in the US and EU • Newly discovered gene with prevalence expected to steadily rise as more children as tested with autism spectrum disorder TSHA-117 regulated GRT FOXG1 syndrome • Development and intellectual disabilities, growth restriction with microcephaly, epilepsy, and Preclinical hyperkinetic-dyskinetic movement disorder • Estimated prevalence of 20,000 patients in the US and EU 82
Genetic Epilepsy Franchise 83
TSHA-105 SLC13A5 deficiency results in persistent SLC13A5 deficiency seizures and developmental delays NORMAL SLC13A5 mutation ⎯ Bi-allelic loss of function in the SLC13A5 gene, resulting in a loss or reduction in citrate transport and aberrant cellular metabolism ⎯ Patients have impaired motor function, speech production and seizures ⎯ Signs and symptoms include seizures within a few days of birth, persisting through life, encephalopathy, delayed speech/language development, developmental regression and abnormalities in tooth enamel ⎯ First-line treatment is anti-seizure medications ⎯ Estimated prevalence of SLC13A5 deficiency is 1,900 patients in the US and EU 84 Bhutia, Molecules 2017
TSHA-105 TSHA-105 currently in IND/CTA- SLC13A5 deficiency enabling studies – Recombinant single-stranded AAV9 AAV9 capsid expressing human SLC13A5 protein under the CNS tropism & control of a single promoter vector design favorable safety profile – Delivered intrathecally – Received orphan drug and rare pediatric disease designations – Currently in IND/CTA-enabling studies 85
TSHA-105 TSHA-105 decreased plasma citrate SLC13A5 deficiency levels in SLC13A5 KO mice KO Veh 0.8 0.8 KO + AAV9 CSF * 0.6 0.6 ** 0.4 0.4 0.2 0.2 0.0 0.0 WT Months Post-injection KO 86 Bailey, R. 2020 Citrate (mM) Citrate (mM)
TSHA-105 TSHA-105 improved EEG activity in SLC13A5 deficiency SLC13A5 KO mice Dark Cycle Dark Cycle WT + Vehicle 0.0262 0.0568 * 30 WT + Vehicle KO + Vehicle KO + Vehicle KO + TSHA-105 IC CS M F 20 KO + TSHA-105 IT 10 KO + TSHA-105 CSF 0 87 Bailey, R. 2020 Spike Trains
TSHA-105 TSHA-105 reduced seizure susceptibility SLC13A5 deficiency in SLC13A5 KO mice TSHA-105 reduced seizure susceptibility in SLC13A5 KO mice 100 75 WT + Vehicle (n=8) 50 KO + Vehicle (n=9) KO + TSHA-105 CSF (n=6) 25 0 0 1 2 3 4 5 6 7 8 PTZ Injection 88 Bailey, R. 2020 Survival (%)
TSHA-103 SLC6A1 haploinsufficiency disorder results in SLC6A1 haploinsufficiency disorder persistent seizures and developmental delays ⎯ Autosomal dominant genetic disorder characterized by the loss of function of one copy of the SLC6A1 gene ⎯ SLC6A1 encodes the GABA transporter protein type 1 (GAT1), which is responsible for the reuptake of GABA into presynaptic neurons and glia ⎯ Clinical manifestations include epilepsy, developmental delays, including mild or moderate intellectual disability, ataxia and autism ⎯ No approved therapies ⎯ Estimated prevalence of SLC6A1 haploinsufficiency disorder is 1,900 patients in the US and EU 89
TSHA-103 SLC6A1 haploinsufficiency disorder TSHA-103 in IND/CTA-enabling studies – Self-complementary AAV9 viral vector designed to deliver AAV9 capsid a functional copy of hSLC6A1 CNS tropism & favorable safety profile – JeT promoter drives ubiquitous expression, clinically validated in GAN – Proof-of-concept demonstrated in knockout SLC6A1 mouse model – Delivered intrathecally – Received orphan drug and rare pediatric disease designations – Currently in IND/CTA-enabling studies 90
TSHA-103 TSHA-103 improved nesting and EEG SLC6A1 haploinsufficiency disorder activity in SLC6A1 KO mouse model WT + Vehicle Nesting 2 months post-injection SLC6A1 KO Vehicle WT KO Vehicle KO TSHA-103 SLC6A1 KO TSHA-103 91
Deep pipeline of gene therapies targeting genetic epilepsies • Diminished KCNQ2 function results in seizures in the first week of life, accompanied by TSHA-110 GRT developmental delay involving one or more domains of motor, social, language, or cognition KCNQ2 • Some children may have autistic features Preclinical • Estimated prevalence of 37,000 patients in the US and EU 92
Platform Technologies 93
miRARE is a targeting panel for endogenous miRNAs which can regulate various transgenes 94
Approaches to create a miRNA target panel for regulating MECP2 expression ⎯ High-throughput screening of mouse CNS miRNAs upregulated after MECP2 gene therapy overdose ⎯ Identify endogenous miRNA targets that are conserved across species and appear frequently among the UTRs of dose-sensitive genes regulating intellectual ability ⎯ Use positive results from high-throughput screening to filter and rank bioinformatics data ⎯ Merged screening data and genomic sequence information ⎯ Create a small synthetic (and potentially broadly applicable) regulatory panel 95
451 targets annotated across both species for selected 3’UTRs ⎯ Many targets appear frequently among the 3’UTRs of dose-sensitive genes mediating disorders characterized by intellectual disability ⎯ Bounded area: targets appear across ≥ 6 selected 3’UTRs ⎯ Orange data points: corresponding miRNAs expressed in CNS tissue ⎯ Squares: corresponding miRNAs are potentially MeCP2-responsive . New target panel miRARE RDH1pA with miRARE insertion miRARE 96
Opportunity to achieve human POC for vagus nerve redosing Parasympathetic System ⎯ The vagus nerve represents the main component of the autonomic nervous system Constricts pupils ⎯ Direct delivery to the vagus nerve may provide broad Nerve III coverage of the autonomic nervous system and enable Stimulates flow of saliva Nerve VII redosing by subverting the humoral immune response Nerve IX Nerve X (Vagus) ⎯ Proof-of-concept established in rodent and canine models; Constricts bronchi oral presentation of data at ASGCT 2020 ⎯ Plan to execute confirmatory preclinical studies in canines Slows Heartbeat ⎯ Platform may be utilized to facilitate redosing of previously treated patients in the GAN AAV9 clinical trial as well as Stimulates peristalsis and other indications secretion Stimulates Bile Release Stimulates vasodilation Pelvic splanchnic nerves Contracts bladder 97
Robust expression of GFP in the vagus nerve and associated nodose ganglia in rats support redosing via vagus nerve injection Vagus Nerve Nodose Ganglia Study 1 0 4 8 Weeks: Tissue IT Injection: VN Injection: Analysis AAV9/GAN AAV9/GFP Study 2 0 16 20 Weeks: IT Injection: VN Injection: Tissue AAV9/GAN AAV9/GFP Analysis GFP – green fluorescent protein 98 Courtesy of Dr. Diane Armao
Successful transduction of relevant brain neurons following redosing via vagus nerve injection Nucleus Ambiguous Medulla Pre-Botzinger Complex 99 Courtesy of Dr. Diane Armao
Vagus nerve injection permits AAV9 redosing confirmed in brain slices of AAV9-immunized rats NTS NTS Area Postrema Area Postrema DMN X Sol N lat Sol N med DMN X Sol N lat XII XII AAV9 Pre-immunized Naive 100 Courtesy of Dr. Diane Armao
Vagus nerve injection of increasing doses of AAV delivery were well-tolerated in hounds observed over 13 days Post-surgery Afternoon Fecal Output Testing VN Delivery Rates High Mid Low High Mid Post-surgery Vocalization Low High Mid Low Post-mortem vagal nerves and brain were microscopically normal 101 1 Taysha has exclusive rights to the vagus nerve redosing platform in select indications.
Utilizing machine learning, DNA shuffling, and directed evolution for capsid discovery ⎯ High-content sequencing of recovered capsid pools Rep Cap ITR ITR Capsid genes of ⎯ Using sequencing data from in vivo selection to feed machine AAV1-6, 8, 9, rh10, + lab variants learning algorithms, for in silico design of novel capsids ⎯ Development of new libraries, based on capsid-spanning DNasel fragmentation modifications rather than just peptide insertions Assembly and amplification ⎯ Directed evolution to generate CNS-directed capsids, cross- compatible between mice and NHPs Directed evolution of novel AAV variants Selection of cell type-specific AAV variants for vector development 102
Focused on achieving anticipated near-term milestones in 2021 and building long-term value 14 GAN clinical program update, including 3.5 x 10 total vg cohort GM2 gangliosidosis preliminary biomarker data in 2H 2021 CLN1 program to dose first patient in 2021 under open IND 4 open IND/CTAs expected by the end of 2021, including Rett syndrome Initiated construction of internal cGMP facility in 1H 2021 5 additional programs currently in IND-enabling studies R&D Day in June 2021 Numerous value generating catalysts over the next 18 months 103
Exhibit 99.2
Taysha Gene Therapies Announces New Data on Multiple Preclinical Programs
and Upcoming R&D Day
TSHA-113 significantly reduced tau mRNA and protein levels in mouse models of human tauopathies via cerebral spinal fluid (CSF) delivery supporting further preclinical development
TSHA-105 significantly reduced plasma citrate levels, normalized EEG brain activity, and reduced the number of seizures and seizure susceptibility in SLC13A5 knockout mice
TSHA-106 increased UBE3A expression through shRNA-mediated knockdown of UBE3A-ATS in in vitro cell lines across 26 distinct shRNA candidates for the treatment of Angelman disease
TSHA-112 generated significant reductions in GYS1 protein, abnormal glycogen accumulation and polyglucosan bodies in the APBD knockout mouse model
TSHA-111-LAFORIN and TSHA-111-MALIN achieved effective knockdown of GYS1 expression and insoluble glycogen and decreased Lafora body formation in laforin and malin mouse models
TSHA-119 caused a dose-dependent reduction of GM2 accumulation at 20 weeks in GM2A knockout mice
Positive proof-of-concept data for gene therapy candidates in SCL13A5 deficiency, APBD, Lafora disease and GM2 AB variant support advancement into clinical testing
Expect to submit IND/CTA for one of the following programs by the end of 2021: SLC13A5 deficiency, APBD, Lafora disease or GM2 AB variant
Taysha’s virtual Research and Development Day in June 2021 will highlight progress across R&D pipeline
Dallas – April 14, 2021 - Taysha Gene Therapies, Inc. (Nasdaq: TSHA), a patient-centric, pivotal-stage gene therapy company focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the central nervous system (CNS) in both rare and large patient populations, today announced new data for multiple preclinical programs and a planned R&D Day, which will be held in June 2021.
“Collectively, these new preclinical data highlight Taysha’s next wave of novel gene therapies that have the potential to impact meaningful patient populations. The promising data underscore our ability to rapidly and reproducibly investigate disease biology, design innovative gene therapies and efficiently advance the development of these drug candidates,” said RA Session II, President, Founder and Chief Executive Officer of Taysha. “Among the compelling new data, for the first time, we have shown that TSHA-113, an AAV9 gene therapy that utilizes AAV-mediated gene silencing, reduced tau expression in mouse models of human tauopathies. The potential implications of these data are far reaching, and we intend to further evaluate TSHA-113 in additional preclinical studies. The totality of the preclinical data
presented today support the fundamental elements of our scientific approach of coupling validated technology with novel targeted payload design while utilizing a proven HEK293 suspension manufacturing process. We believe our deep pipeline and innovative scientific engine hold tremendous potential, and we are poised to continue delivering meaningful value to patients with monogenic CNS diseases.”
“Today’s data demonstrate the breadth, depth and velocity of our development engine as a sustainable pivotal-stage gene therapy company. There are no approved disease modifying therapies for any of the programs in our portfolio and we are encouraged by the results of our gene therapy approach of vectorized RNA and gene replacement therapies across our portfolio,” said Suyash Prasad, MBBS, M.SC., MRCP, MRCPCH, FFPM, Chief Medical Officer and Head of Research and Development of Taysha. “We are very excited to further develop TSHA-113 in tauopathies, including Alzheimer’s disease, MAPT-associated frontotemporal dementia and progressive supranuclear palsy, based on the significant reduction in tau expression demonstrated in transgenic mouse models of human tauopathies. In addition, to date, we have advanced five programs into IND/CTA-enabling studies, including TSHA-105 in SLC13A5 deficiency, TSHA-111-LAFORIN in Lafora disease, TSHA-111-MALIN in Lafora disease, TSHA-112 in APBD and TSHA-119 in GM2 AB variant. We intend to file an IND/CTA for one of these five named programs by the end of 2021. By mid-year, we intend to select a development candidate for Angelman syndrome and obtain interim expression and safety data from confirmatory non-human primate studies by year-end. We remain on track to report Phase 1/2 biomarker data for TSHA-101 in GM2 gangliosidosis in the second half of this year and to provide a clinical and regulatory update for TSHA-120 in giant axonal neuropathy by year-end. Finally, in the second half of the year, we continue to expect dosing of the first patient with CLN1 disease in a Phase 1/2 trial for TSHA-118 under an already open IND, filing an IND/CTA for TSHA-102 in Rett syndrome and TSHA-104 in SURF1-associated Leigh syndrome, and filing an IND for TSHA-101 in GM2 gangliosidosis in the U.S. These anticipated clinical and regulatory milestones are expected to be followed by the initiation of Phase 1/2 clinical trials for each of these indications. We look forward to providing additional updates at our R&D Day in June.”
TSHA-113 for Tauopathies
Taysha is developing tau-specific microRNA (miRNA) shuttles designed to target tau mRNA for all six isoforms found in the human brain and/or mouse brain. TSHA-113 is an AAV9 capsid that packages these miRNA shuttles and is delivered in the CSF for the treatment of tauopathies.
| • | In transgenic mouse models carrying human tau, TSHA-113 significantly reduced tau mRNA and protein levels, while demonstrating widespread expression in neurons and glia |
| • | Together with previous in vitro findings, these data further validate selective reduction of tau mRNA and protein levels and warrant further preclinical development |
| • | An estimated 6.2 million Americans and 7.8 million Europeans are living with Alzheimer’s disease |
| • | There are an estimated 13,000 patients in U.S. and Europe affected by MAPT-associated frontotemporal dementia, progressive supranuclear palsy and corticobasal degeneration, which represent a significant commercial opportunity |
TSHA-105 for SLC13A5 deficiency
TSHA-105 is a recombinant self-complementary AAV9 vector that expresses the human SLC13A5 protein under the control of a ubiquitous promoter. The drug candidate is being developed for the treatment of SLC13A5 deficiency.
| • | In SLC13A5 knockout mice, treatment with TSHA-105 resulted in a significant, sustainable decrease of plasma citrate levels up to three months post-injection compared to age-matched, wildtype controls |
| • | TSHA-105 normalized electroencephalogram (EEG) brain activity, reduced the number of seizures, and reduced seizure susceptibility compared to vehicle-treated controls |
| • | The company has advanced TSHA-105 into IND/CTA-enabling studies |
| • | There are an estimated 1,900 patients with SLC13A5 deficiency in the United States and in Europe |
TSHA-106 for Angelman syndrome
TSHA-106 is an intrathecally delivered AAV9 viral vector designed for shRNA-mediated knockdown of UBE3A-ATS, the antisense transcript governing the expression of UBE3A through the paternal allele.
| • | In vitro testing in a neuroblast cell line demonstrated consistent knockdown of UBE3A-ATS and a subsequent increase in UBE3A expression across 26 distinct shRNA candidates |
| • | Selection of development candidate expected by mid-year |
| • | Interim expression and safety data from confirmatory non-human primate (NHP) studies expected by the end of 2021 |
| • | There are an estimated 55,000 patients with Angelman syndrome in the United States and Europe |
TSHA-112 for Adult Polyglucosan Body Disease (APBD)
TSHA-112 is an intrathecally delivered AAV9 viral vector designed for miRNA-mediated knockdown of the GYS1 gene to treat APBD.
| • | In preclinical studies, miRNA knockdown of GYS1 induced significant reductions in GYS1 mRNA, GYS1 protein, abnormal glycogen accumulation, and polyglucosan bodies throughout the brain in an APBD knockout mouse model |
| • | TSHA-112 decreased neuroinflammatory markers across three distinct mouse models |
| • | The company has advanced TSHA-112 into IND/CTA-enabling studies |
| • | There are an estimated 10,000 patients with APBD in the United States and in Europe |
TSHA-111-LAFORIN for EPM2A and TSHA-111-MALIN for EPM2B for Lafora disease
TSHA-111-LAFORIN and TSA-111-MALIN are intrathecally delivered AAV9 viral vectors designed for miRNA-mediated knockdown of the GYS1 gene to treat Lafora disease.
| • | In preclinical studies, TSHA-111-LAFORIN and TSHA-111-MALIN achieved effective knockdown of GYS1 expression and insoluble glycogen in the Lafora disease laforin and malin mouse models, respectively |
| • | Both product candidates decreased Lafora body formation within the brain in their respective mouse models |
| • | The company has advanced TSHA-111-LAFORIN and TSHA-111-MALIN into IND/CTA-enabling studies |
| • | There are an estimated 700 patients with Lafora disease in the United States and in Europe |
TSHA-119 for GM2 AB variant
TSHA-119 is a self-complementary AAV9 vector designed to deliver a functional copy of the GM2A gene to treat GM2 AB variant.
| • | In preclinical studies, TSHA-119 caused a significant, dose-dependent reduction of GM2 accumulation at 20 weeks in mice that were dosed intrathecally at postnatal day 1 or at 6 weeks of age |
| • | Long-term follow up studies, which include bi-monthly behavioral, as well as biochemical and histological analyses, are currently ongoing |
| • | The company has advanced TSHA-119 into IND/CTA-enabling studies |
| • | There are approximately 200 patients with GM2 AB variant in the United States and in Europe |
About Taysha Gene Therapies
Taysha Gene Therapies (Nasdaq: TSHA) is on a mission to eradicate monogenic CNS disease. With a singular focus on developing curative medicines, we aim to rapidly translate our treatments from bench to bedside. We have combined our team’s proven experience in gene therapy drug development and commercialization with the world-class UT Southwestern Gene Therapy Program to build an extensive, AAV gene therapy pipeline focused on both rare and large-market indications. Together, we leverage our fully integrated platform—an engine for potential new cures—with a goal of dramatically improving patients’ lives. More information is available at www.tayshagtx.com.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “anticipates,” “believes,” “expects,” “intends,” “projects,” and “future” or similar expressions are intended to identify forward-looking statements. Forward-looking statements include statements concerning the potential of our product candidates, including our preclinical product candidates, 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, the potential for these product candidates to receive regulatory approval from the FDA or equivalent foreign regulatory agencies, and whether, if approved, these product candidates will be successfully distributed and marketed, and the potential market opportunity for these product candidates. Forward-
looking statements are based on management’s current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission (“SEC”) filings, including in our Annual Report on Form 10-K for the full-year ended December 31, 2020, which is available on the SEC’s website at www.sec.gov. Additional information will be made available in other filings that we make from time to time with the SEC. Such risks may be amplified by the impacts of the COVID-19 pandemic. These forward-looking statements speak only as of the date hereof, and we disclaim any obligation to update these statements except as may be required by law.
Company Contact:
Kimberly Lee, D.O.
SVP, Corporate Communications and Investor Relations
Taysha Gene Therapies
klee@tayshagtx.com
Media Contact:
Carolyn Hawley
Canale Communications
carolyn.hawley@canalecomm.com