Taysha Gene Therapies, Inc. · NASDAQ:TSHA
Taysha Gene Therapies — Investor Day (June 2021)
98 slides from Taysha Gene Therapies's investor day presentation, Jun 28, 2021
Slide 1: Research & Development Day, Day 1
RESEARCH & DEVELOPMENT DAY DAY 1 – June 28, 2021 | 9:00 AM – 12:00 PM CT Bringing New Cures to Life Exhibit 99.1
Slide 2: Legal disclosure: forward-looking statements
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 operation
Slide 3: Introductions & Company Overview
RA Session II President, Founder & CEO Introductions & Company Overview
Slide 4: Unparalleled gene therapy pipeline focused exclusively on monogenic CNS disorders
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 Regulatory guidance YE 2021 TSHA-101 GRT GM2 Gangliosidosis Currently open
Slide 5: Three distinct franchises could address over 500,000 patients (US+EU)
Our three distinct franchises have the potential to address over 500,000+ patients (US+EU) Neurodegenerative Estimated Patient Population (US + EU) 1Tauopathies only include MAPT-FTD, PSP, CBD 2Additional programs include TSHA-107, TSHA-108, and TSHA-109 500,000 CLN1 900 Lafora 700 SURF1 300-400 APB
Slide 6: Strategy focused on rapid clinical and commercial development
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 Our scient
Slide 7: Approach and ability to deliver various payloads
Approach and ability to deliver various payloads Replace gene of interest to treat diseases or disorders with limited gene expression Comprised of a codon-optimized DNA transgene that encodes the wild type gene of interest Transgene (or mini-gene) coupled with a promoter selected to ensure expressio
Slide 8: Novel platform technology that powers our research engine
Novel platform technology that powers our research engine Potential to facilitate redosing via vagus nerve Efficient targeting of vagal neurons demonstrated in adult rats, with potential to improve autonomic nervous system symptoms in humans Normal vagal nerve fibers and neurons post AAV delivery to
Slide 9: Our strategic partnership with UTSW
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 neur
Slide 10: Manufacturing strategy allows flexibility and scalability
Manufacturing strategy allows flexibility and scalability to support broad pipeline Support the UTSW viral vector core to supply early-phase clinical material Active technical collaboration and knowledge sharing for process information and analytical methods First program is ongoing Capabilities 50L
Slide 11: TSHA-120 for Giant Axonal Neuropathy
TSHA-120 for Giant Axonal Neuropathy TSHA-120 GAN Steven Gray, PhD Chief Scientific Advisor, UTSW Gene Therapy Program Suyash Prasad, MBBS, MSc, MRCP, MRCPCH, FFPM Chief Medical Officer and Head of R&D
Slide 12: Giant axonal neuropathy is a rare inherited genetic disorder
Giant axonal neuropathy (GAN) is a rare inherited genetic disorder that affects both central and peripheral nervous systems Rare autosomal recessive disease of the central and peripheral nervous systems caused by loss-of-function gigaxonin gene mutations No approved disease-modifying treatments avai
Slide 13: GAN natural history and disease progression
GAN natural history and disease progression Delayed early motor development Tightly curled hair Unsteady gait, foot deformity Progressive motor weakness Ataxia and dysarthria Nystagmus (cerebellar), optic neuropathy / decreased visual acuity Scoliosis and progressive contractures Loss of independent
Slide 14: Clinical manifestations of GAN
Clinical manifestations of GAN Tightly curled hair are hallmark of early-onset GAN cohort– characterized by a dull appearance and course texture with tight curls Rapid progression of rotational and S-shaped scoliosis in the same male with GAN at age 12 and 15 years Severe finger flexor contractures
Slide 15: MRIs demonstrate progression of CNS symptoms with age
MRIs demonstrate progression of CNS symptoms with age Distinctive increased T2 signal abnormalities within cerebellar white matter surrounding the dentate nucleus of the cerebellum observed One of the earliest brain imaging findings in individuals with GAN Findings precede the more widespread perive
Slide 16: Impaired pulmonary function in GAN patients
Impaired pulmonary function in GAN patients Forced vital capacity ( FVC%) correlated well with several functional outcomes MFM32 Neuropathy impairment score FARS Ambulatory status With independently ambulant individuals having better performance than the non-ambulant group Nocturnal hypoventilation
Slide 17: GAN patients report significant autonomic nervous system impairments
GAN patients report significant autonomic nervous system impairments GAN patients in this study reported significant autonomic dysfunction Patient or parent report of autonomic dysfunction were based upon the COMPASS 31 self-assessment questionnaire, specifically affecting the domains of autonomic f
Slide 18: Neurophysiology in GAN
Neurophysiology in GAN Nerve conduction function showed progressive sensorimotor polyneuropathy with age Significantly diminished Compound Motor action potential (CMAP) amplitudes Overall, upper extremity CMAP amplitudes correlated significantly to the MFM32% score and the total NIS score, and appea
Slide 19: Giant Axonal Neuropathy (GAN)
Giant Axonal Neuropathy (GAN) Sensory and Motor Peripheral Neuropathy, “ALS in kids” Cognition is mostly unaffected in the early stages of disease 3-4 yrs old: clumsiness, loss of coordination ~10 yrs old: unable to walk Late teens: highly reduced coordination and use of arms/hands ~20 yrs old: Fata
Slide 20: Rationale for targeting the GAN gene
Rationale for targeting the GAN gene Gigoxonin is an E3 ligase enzyme that attach ubiquitin to substrate proteins (Ubiquitination), marking them for degradation by either proteosome or autophagy Mutations affect production of the protein gigaxonin Leads to dysregulation and the progressive accumulat
Slide 21: Molecular underpinnings of GAN
Molecular underpinnings of GAN Evidence that gigaxonin targets itself, providing some amount of theoretical autoregulation of gigaxonin protein levels Full list of gigaxonin targets unknown, with lack of clarity around whether gigaxonin targets intermediate filaments for degradation directly Loss of
Slide 22: TSHA-120 program overview and construct
TSHA-120 program overview and construct Construct invented in the Gray Lab AAV9 viral vector with engineered transgene encoding the human gigaxonin protein Self-complementary AAV capsid (scAAV) for rapid activation and stable expression JeT promoter drives ubiquitous expression Designed to deliver a
Slide 23: Preclinical data supported intrathecal dosing of TSHA-120
Preclinical data supported intrathecal dosing of TSHA-120 Comprehensive preclinical results demonstrated: Efficacy of gigaxonin gene replacement demonstrated in vitro and in vivo Resolution of intermediate filaments and improved disease pathology in GAN mice, including DRG and peripheral nerve Pheno
Slide 24: TSHA-120 improved pathology of the sciatic nerve in GAN KO mice
TSHA-120 improved pathology of the sciatic nerve in the GAN KO mice TSHA-120 GAN Bailey, R. et al, MTMCD 2018 Intact unmyelinated fibers and associated Schwann cells Normal Schwann cell cytoplasm associated with myelinated fibers Dense, disorganized accumulations of NFs in fibers Accumulation of IFs
Slide 25: TSHA-120 improved pathology of the DRG in GAN KO mice
TSHA-120 improved pathology of the DRG in the GAN KO mice TSHA-120 GAN GAN KO – AAV9-GAN Normal control GAN KO – vehicle injected D C Significant reduction in % neuronal inclusions Bailey, R. et al, MTMCD 2018
Slide 26: TSHA-120 normalized performance of 18-month-old GAN rodent model
TSHA-120 normalized performance of 18-month-old GAN rodent knockout model Untreated GAN rodents performed significantly worse than heterozygous controls GAN rodents treated at 16 months old performed significantly better than untreated GAN rodents at 18 months old GAN rodents treated at 16 months ol
Slide 27: Primary efficacy endpoint is the Motor Function Measure (MFM32)
Primary efficacy endpoint is the Motor Function Measure (MFM32) – A validated quantitative scale Validated instrument used in multiple regulatory approvals A 32-item scale for motor function measurement developed for neuromuscular diseases Assesses severity and progression of motor function across a
Slide 28: MFM32 correlations across motor and demographic assessments
MFM32 correlations across various motor and demographic assessments Multiple measures of disease severity were evaluated with MFM32 identified as having the highest correlation between all tested measures of mobility, neurophysiologic measures, force (by myometry measures), and distal grip and pinch
Slide 29: GAN natural history study data as a comparator
GAN natural history study data as a dependable 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 MFM32 MFM32 total score shows uniform decline between patients of all age groups over time Av
Slide 30: GAN natural history study data: cohort characteristics
GAN natural history study data – Cohort characteristics Of ninety total alleles analyzed in this cohort, forty-six different pathogenic variants (mutations) in the GAN gene were observed, and included: Missense mutations (53.3%) Splice site mutations (16.7%) Frameshifting deletions (15.6%) In-frame
Slide 31: Total MFM32 score correlated with ambulatory status
Total MFM32 score correlated with ambulatory status Only includes individuals over age 6 where MFM32 was performed (n=37) Eighteen individuals were independently ambulant, 10 required assistance to walk, and 9 were non-ambulant Independently ambulant individuals having better performance and higher
Slide 32: Clinical Trial NCT02362438
Clinical Trial: NCT02362438 TSHA-120 GAN NOTE: Subsequent slides only show data from 1.2 x 1014 vg and 1.8 x 1014 vg doses Goals and Targets of Trial Product Details and Dose Cohorts Route and Method of Administration Dose Cohorts* 3. 5 x 1013 total vg (n=2) 1. 2 x 1014 total vg (n=4) 1. 8 x 1014 to
Slide 33: TSHA-120 interventional study endpoints
TSHA-120 interventional study endpoints Disease-Specific/Global Assessments Motor Function Measure 32 (MFM32) total score (and domains) Motor symptoms (10m walk, 4 stair climb, 4 stair descent) Muscle strength (myometry) Sensory symptoms (NIS, FARS, clinical examination, reflexes) Neurophysiology As
Slide 34: TSHA-120 achieved sustained improvement in primary efficacy endpoint
TSHA-120 achieved sustained improvement in primary 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 1.8x1014 total vg dose and 1.2x1014 total v
Slide 35: Treatment resulted in arrest of disease progression at therapeutic doses
Treatment with TSHA-120 resulted in a clear arrest of disease progression at therapeutic doses and long-term durability TSHA-120 GAN Arrest of disease progression at therapeutic doses TSHA-120 was well tolerated at multiple doses 6 patients treated for 3+ years supporting long-term durability Plan t
Slide 36: Bayesian analysis confirmed arrest of disease progression
Additional analysis using Bayesian methodology confirmed arrest of disease progression Bayesian analysis Enables direct probability statements about any unknown quantity of interest Enables immediate incorporation of data gathered as the trial progresses Useful and accepted by regulatory agencies wh
Slide 37: TSHA-120 halted pre-treatment rate of decline at 1.8x10^14 vg dose
TSHA-120 halted patient pre-treatment rate of decline at 1.8x1014 total vg dose TSHA-120 GAN Bönnemann, C. et al; 2020 Treated population average annual post-treatment decline for both the 1.8x1014 total vg cohort and 1.2x1014 total vg cohort 1.8x1014 vg halted patient pre-treatment rate of decline,
Slide 38: Nearly 100% probability of clinically meaningful slowing of disease
Further analyses confirmed nearly 100% probability of clinically meaningful slowing of disease compared to natural history Further analyses were conducted to assess the probability of clinically meaningful slowing of disease as compared to natural history A 4-point decline in MFM32 is considered cli
Slide 39: Exploratory endpoints: ophthalmology biomarkers
Exploratory endpoints – Ophthalmology biomarkers Data from 11 patients were analyzed for visual acuity via the Logarithm of the Minimum Angle of Resolution (LogMar) Dose-dependent trend towards stabilization of visual acuity, i.e., a slowed increase in LogMAR values, observed and appeared to be inde
Slide 40: Summary of safety findings
Summary of safety findings Clinically well tolerated Some evidence of asymptomatic cerebrospinal fluid pleocytosis in earlier dosed patients No dose-limiting toxicity No transaminitis No sign by neuroimaging or clinically of new enhancement or inflammation No clinical signs of acute or subacute infl
Slide 41: Anticipated next steps for TSHA-120 by end of 2021
Anticipated next steps for TSHA-120 by the end of 2021 Complete transfer data from the NIH Initiate manufacturing of commercial-grade GMP material Discuss the regulatory pathway for TSHA-120 Request regulatory guidance from EMA and MHRA Initiate new clinical sites in US and EU Update on regulatory i
Slide 42: Opportunity to achieve human POC for vagus nerve redosing
Parasympathetic System Constricts pupils Stimulates flow of saliva Constricts bronchi Slows Heartbeat Stimulates peristalsis and secretion Stimulates Bile Release Contracts bladder Nerve X (Vagus) Nerve IX Nerve VII Nerve III Stimulates vasodilation Pelvic splanchnic nerves Opportunity to achieve hu
Slide 43: Vagus nerve redosing study design and GFP expression
GFP – green fluorescent protein Courtesy of Dr. Diane Armao IT Injection: AAV9/GAN 0 20 Study 2 Tissue Analysis 16 VN Injection: AAV9/GFP Weeks: Vagus Nerve Nodose Ganglia IT Injection: AAV9/GAN 0 8 Study 1 Tissue Analysis 4 VN Injection: AAV9/GFP Weeks: TSHA-120 GAN
Slide 44: Successful transduction of brain neurons following redosing via vagus nerve
Medulla Nucleus Ambiguous Pre-Botzinger Complex Courtesy of Dr. Diane Armao Successful transduction of relevant brain neurons following redosing via vagus nerve injection TSHA-120 GAN
Slide 45: Vagus nerve injection permits AAV9 redosing in immunized rats
DMN X Sol N med Sol N lat NTS Area Postrema XII DMN X NTS Sol N lat XII Naive AAV9 Pre-immunized Area Postrema Vagus nerve injection permits AAV9 redosing confirmed in brain slices of AAV9-immunized rats Courtesy of Dr. Diane Armao TSHA-120 GAN
Slide 46: Q & A
Q & A TSHA-120 GAN
Slide 47: TSHA-101 for GM2 Gangliosidosis
TSHA-101 for GM2 Gangliosidosis TSHA-101 GM2 Suyash Prasad, MBBS, MSc, MRCP, MRCPCH, FFPM Chief Medical Officer and Head of R&D
Slide 48: GM2 gangliosidosis is a severe neurodegenerative disease
GM2 gangliosidosis is a severe 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 Mutation
Slide 49: Residual Hex A activity determines the severity of GM2
Residual Hex A activity determines the severity of GM2 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
Slide 50: What does natural history tell us about disease progression?
What does natural history tell us about disease progression? Bley A.E. et al; A retrospective study through NTSAD Patients experience significant diagnostic delays: Mean age at onset of earliest symptom was 5 +/- 3.3 months Average age of diagnosis was 13.3 +/- 5.3 months Diagnosis usually occurs on
Slide 51: Natural history and motor development delay
What does natural history tell us about motor development delay? Utz J. et al; Prospective Nat Hx. study Similar age of diagnosis reported compared to Bley et al.: Median age of diagnosis was 15 mo. Most patients experienced motor developmental delays within the first 6 months of life, and all patie
Slide 52: Motor developmental delay timeline
What does natural history tell us about motor development delay? Motor Developmental Delay Timeline Motor Skills Diagnosis (N=# of patients assessed) % Never Gained % Experienced Age (months) divided into 6 month intervals at which motor developmental milestones occurred 0–6 7–12 13–18 19–24 Age unk
Slide 53: Novel bicistronic vector design for HEXA and HEXB expression
Novel bicistronic vector design allows consistent expression of HEXA and HEXB genes HEXA and HEXB genes are required to produce the subunits of the beta-hexosaminidase A enzyme The novel bicistronic vector design enables 1:1 expression of the alpha-subunit, HEXA, and the beta-subunit, HEXB, under th
Slide 54: Dose-dependent improvement in survival in mice treated with TSHA-101
Preclinical Pharmacology: Significant, dose-dependent improvement in survival observed in mice treated with TSHA-101 TSHA-101 GM2
Slide 55: Dose-dependent improvements in rotarod assessments
Preclinical Pharmacology: Dose-dependent improvements observed in rotarod assessments in mice treated with TSHA-101 TSHA-101 GM2
Slide 56: GM2 accumulation significantly reduced in brain following treatment
Preclinical Pharmacology: GM2 accumulation significantly reduced in mid-section of brain following treatment with TSHA-101 after 16 weeks TSHA-101 GM2
Slide 57: Phase 1/2 adaptive trial for TSHA-101 in GM2 gangliosidosis
Phase 1/2 adaptive trial for TSHA-101 in GM2 gangliosidosis TSHA-101 GM2 Goals and Targets of Trial Product Details and Dose Cohorts Route and Method of Administration Dose Cohorts 5 x 1014 total vg (n=4) Goals Primary – Safety: clinical and laboratory assessments Secondary – Efficacy: pathologic, p
Slide 58: TSHA-101 Canadian IST endpoints
TSHA-101 Canadian IST endpoints Disease-Specific/Global Assessments Hypotonia Dysphagia Head Control Scale CHOP INTEND Modified Ashworth scale Vineland-3 Bayley-III/WPPSI-IV Quality of Life/Other Assessment PedsQL Infant Scales PedsQL Family Impact Module CGI – Improvement (CGI-I) Imaging Echocardio
Slide 59: Anticipated next steps for TSHA-101 by end of 2021
Anticipated next steps for TSHA-101 by the end of 2021 Preliminary Phase 1/2 biomarker data (Queen’s University study) in 2H 2021 Initiate U.S. Phase 1/2 study in 2H 2021 TSHA-101 GM2 Submit IND in 2H 2021 US study utilized material from commercial process
Slide 60: Q & A
Q & A TSHA-101 GM2
Slide 61: TSHA-118 for CLN1 Disease
TSHA-118 for CLN1 Disease TSHA-118 CLN1 disease Steven Gray, PhD Chief Scientific Advisor, UTSW Gene Therapy Program Suyash Prasad, MBBS, MSc, MRCP, MRCPCH, FFPM Chief Medical Officer and Head of R&D
Slide 62: CLN1 disease is a severe neurodegenerative lysosomal storage disease
CLN1 disease is a severe neurodegenerative lysosomal storage disease Severe, progressive, neurodegenerative lysosomal storage disease, with no approved treatment Caused by mutations in the CLN1 gene, encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) The absence of PPT1 le
Slide 63: CLN1 disease onset and progression
CLN1 disease onset and progression Typically between 2-24 months of age when mental and motor development declines Late infantile onset between 2-4 years Juvenile onset between 4-10 years ONSET Developmental regression; rapid loss of motor function and cognitive abilities Decreased muscle tone (hypo
Slide 64: CLN1 disease phenotypes and symptom progressions
CLN1 disease phenotypes and symptom progressions Ages of symptom onset derived from clinical experience and recently published guidelines Specific occurrence, order, and age at symptom onset are variable In general, individuals with the infantile phenotype have the most aggressive course, with age a
Slide 65: Clinical spectrum of CLN1 disease phenotypes varies
Clinical spectrum of CLN1 disease phenotypes varies CLN1 disease phenotypes vary by age at onset, order of symptom onset, rate of disease progression, and life expectancy There are at least 71 different disease-causing pathogenic variants in CLN1 reported to date, with strong genotype-phenotype corr
Slide 66: No clinical management guidelines specific to CLN1 disease
No clinical management guidelines or consensus statements specific to CLN1 disease 15 CLN1 disease experts and 39 caregivers responded to the surveys, and 14 experts met to develop consensus-based recommendations Found a limited evidence base for treatment and no clinical management guidelines speci
Slide 67: CLN1 disease natural history data
CLN1 disease natural history data Ongoing observational study that aims to assess natural history of NCL diseases (including CLN1) as part of the international DEM-CHILD Database (Angela Schulz, Universitätsklinikum Hamburg-Eppendorf) University of Rochester NHS used a combined retrospective and pro
Slide 68: Rochester natural history: age and order of symptom onset
Rochester CLN1 disease natural history data – Age and order of symptom onset TSHA-118 CLN1 disease Retrospective (n=8) Prospective (n=12) Sex Female Male 7 (87.5%) 1 (12.5%) 6 (50%) 6 (50%) Age-at-Onset Infantile (0 - 1.5 years): Late Infantile (>1.5 - <5 years): Juvenile (≥5 years): 2 (mean 1.2 yea
Slide 69: Rochester natural history: change in disease severity over time
Rochester CLN1 disease natural history data – Change in disease severity over time Age-at-onset, initial symptom type, and order of symptom presentation variable and inconsistent across individuals with CLN1 disease Severity could be quantified for each individual in prospective arm Progression appe
Slide 70: TSHA-118 preclinical studies to date
TSHA-118 preclinical studies to date # Study Scope (ID) Model System Age at dosing Route of Administration & Dose (vg/animal) Major Findings 1 Proof of Concept; (UNC-2014-001) PPT1-/- mice 1, 4, 12, 20, 26 weeks IT: 7E+10, 2.2E+11, 7E+11 Elevated levels of active PPT1 in serum Significant survival b
Slide 71: TSHA-118-treated CLN1 KO mice had improved survival rates
TSHA-118-treated CLN1 KO mice had improved survival rates TSHA-118 CLN1 disease IT administration of TSHA-118 significantly extended survival of PPT1 KO mice for all ages and at all dose levels Percent Survival Age (Months) Untreated Het Untreated KO 4 week IT TSHA-118 12 week IT TSHA-118 100 75 50
Slide 72: Higher doses and earlier intervention mediated stronger rescue
Higher doses of TSHA-118 and earlier intervention mediated stronger rescue of CLN1 KO mice TSHA-118 CLN1 disease
Slide 73: Sustained preservation of motor function in treated mice
TSHA-118-treated CLN1 KO mice had sustained preservation of motor function TSHA-118 CLN1 disease
Slide 74: Increased and sustained plasma PPT1 activity
TSHA-118-treated CLN1 mice had increased and sustained plasma PPT1 activity 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 WT-Untreated Het-Untr
Slide 75: Phase 1/2 adaptive trial for TSHA-118 in CLN1
Phase 1/2 adaptive trial for TSHA-118 in CLN1 TSHA-118 CLN1 disease Goals and Targets of Trial Product Details and Dose Cohorts Route and Method of Administration Dose Cohorts 5 x 1014 total vg (n=3) 1.0 x 1015 total vg (n=3) Dose expansion – TBD Goals Primary – Safety: clinical and laboratory asses
Slide 76: TSHA-118 Phase 1/2 clinical assessments
TSHA-118 Phase 1/2 clinical assessments Disease-Specific/Global Assessments Unified Batten Disease Rating Scale (UBDRS) CHOP INTEND Hamburg Scale: motor, visual, language, and seizure scores Seizures assessed by UBDRS and seizure diary Adaptive score assessed by Vineland-III Bayley-III / WPPSI-IV /
Slide 77: Anticipated next steps for TSHA-118 by end of 2021
Anticipated next steps for TSHA-118 by the end of 2021 Initiate Phase 1/2 clinical study in 2H 2021 under open IND Patient finding activity in collaboration with UTSW, Rochester, Hamburg CTA scientific advice meetings underway to open European site TSHA-118 CLN1 disease
Slide 78: Q & A
Q & A TSHA-118 CLN1 disease
Slide 79: TSHA-102 for Rett Syndrome
TSHA-102 for Rett Syndrome TSHA-102 Rett Syndrome Steven Gray, PhD Chief Scientific Advisor, UTSW Gene Therapy Program Suyash Prasad, MBBS, MSc, MRCP, MRCPCH, FFPM Chief Medical Officer and Head of R&D
Slide 80: Rett syndrome is one of the most common genetic causes of intellectual disability in women
Rett syndrome is one of the most common genetic causes of intellectual disabilities in women Rett Syndrome is caused by mutations in the X-linked MECP2 gene MeCP2 regulates the expression of many genes involved in normal brain function A brief period of normal development is followed by a devastatin
Slide 81: Rett syndrome is an X-linked neurodevelopmental disorder
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder Characterized by mutations in methyl CpG-binding protein 2 (MECP2), a protein that is essential for neuronal and synaptic function in the brain. Female heterozygous RTT patients are mosaic carriers of normal and mutated MECP2 RTT falls a
Slide 82: Regulated MECP2 expression with AAV9 and miRARE
AAV9 capsid Brain tropism & favorable safety profile Development of a gene therapy for Rett syndrome requires regulated expression of MECP2 AAV9/MECP2 caused dose-dependent side effects after intraCSF administration in WT and KO mice We have developed a novel miRNA-responsive target sequence (miRARE
Slide 83: miRARE targets endogenous miRNAs regulating MECP2 expression
miRARE is a targeting panel for endogenous miRNAs which regulate MECP2 expression TSHA-102 Rett Syndrome
Slide 84: Approaches to create a miRNA target panel for MECP2
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 regul
Slide 85: Preclinical data for TSHA-102 recently published in Brain
Preclinical data for TSHA-102 in Rett syndrome recently published in Brain TSHA-102 Rett Syndrome
Slide 86: miRARE reduced overall miniMeCP2 expression versus unregulated
miRARE reduced overall expression of miniMeCP2 transgene expression compared to unregulated miniMeCP2 in WT mice CC: Cervical Cord; TC: Thoracic Spinal Cord; LC: Lumbar Cord TSHA-102 Rett Syndrome
Slide 87: miRARE regulated genotype-dependent MECP2 expression across brain regions
miRARE regulated genotype-dependent MECP2 expression across different brain regions in wild type and Rett KO mouse models TSHA-102 Rett Syndrome
Slide 88: miRARE regulated expression in pons and midbrain cell-by-cell
miRARE regulated expression in pons and midbrain based on a cell-by-cell basis TSHA-102 Rett Syndrome
Slide 89: TSHA-102 mouse study results
Diamond = vet-requested euthanasia for prolapse or bullying-related injury TSHA-102 Rett Syndrome Mice were dosed P28-35
Slide 90: Safety: no adverse behavioral side effects in WT mice
Safety: TSHA-102 did not cause adverse behavioral side effects in WT mice TSHA-102 Rett Syndrome Mice were dosed P28-35
Slide 91: Efficacy: TSHA-102 outperformed unregulated AAV9/mini in MECP2 KO mice
Efficacy: TSHA-102 outperformed unregulated AAV9/mini in MECP2 KO mouse survival study 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. TSHA-1
Slide 92: TSHA-102 Phase 1/2 study design plan
TSHA-102 Phase 1/2 study design plan TSHA-102 Rett Syndrome Goals and Targets of Trial Product Details and Dose Cohorts Route and Method of Administration Dose Cohorts Each cohort randomized 3:1 (one patient is a delayed treatment control) 5 x 1014 total vg (n=4) 1.0 x 1015 total vg (n=4) Goals Prim
Slide 93: TSHA-102 Phase 1/2 clinical assessments
TSHA-102 Phase 1/2 clinical assessments Rett-Specific/Global Assessments Motor Behavior Assessment Scale (MBA) Rett Syndrome Hand Apraxia Scale (RHAS) Rett Syndrome Behavior Questionnaire (RSBQ) Functional Mobility Scale in Rett Syndrome (FMS) Clinical Global Impression Behavior/Mood Assessments Anx
Slide 94: Anticipated next steps for TSHA-102 by end of 2021
Anticipated next steps for TSHA-102 by the end of 2021 Submit IND/CTA in 2H 2021 Complete GMP manufacturing using commercial process Pre-IND/CTA and Scientific Advice meetings underway Initiate Phase 1/2 study by YE 2021 TSHA-102 Rett Syndrome
Slide 95: Q & A
Q & A TSHA-102 Rett Syndrome
Slide 96: Closing Remarks
Closing Remarks RA Session II President, Founder & CEO
Slide 97: Taysha
TAYSH GENE dA
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