Modalis Therapeutics Corporation · TSE:4883
Modalis Therapeutics — Investor Presentation (December 2023)
53 slides from Modalis Therapeutics's investor presentation, Dec 6, 2023
Slide 1: Corporate Presentation For investors
Corporate Presentation For investors （TSE︓4883） Modalis therapeutics Corporation December 2023 Copyright Copyrightand andproprietary proprietaryto toModalis Modalis
Slide 2: Disclaimer
Disclaimer This document has been prepared by Modalis Therapeutics corporation and Modalis Therapeutics Inc. (the “Companies”) solely for information purpose only. This document does not constitute or form part of and should not be construed as, an offer to sell or issue or the solicitation of an of
Slide 3: Modalis at a glance
Modalis at a glance • The first and most advanced company developing CRISPR- based epigenome editing therapeutics • Founded in 2016 • Publicly listed on Tokyo Stock Exchange (Ticker: 4883) • Headquartered in Tokyo and R&D operated in Waltham MA • ~40 FTE • President and CEO: Haru Morita, formerly at
Slide 4: Modalis' Value Highlights
MODALIS’ Value Highlights Established the first robust epigenetic platform for activation and inhibition of endogenous genes using CRISPR-GNDM ® platform Demonstrated sustained modulation of gene expression in multiple species (mouse, cyno) resulting in functional efficacy without toxicities Pipelin
Slide 5: What is the epigenome?
What is the epigenome? Modifications that control where, when, and how much each gene is expressed by adapting regions of the genome, without changing the DNA sequence ~20,000 genes Gene X Gene Y Gene Z Switch box (Transcription Regulatory Region) Organisms are controlled by transcription machinery
Slide 6: Potential benefits of CRISPR-GNDM Technology
CRISPR-GNDM® is a promising new therapeutic modality that controls the epigenome Potential benefits of CRISPR-GNDM® Technology X1 Single dose Long-lasting Disease Modifying Does not require Sustained effect Not just reduction of Repeated dosing for years or decades symptoms but potential to cure CRI
Slide 7: Non-cleaving CRISPR = CRISPR-GNDM
Non-cleaving CRISPR = CRISPR-GNDM® Enables treatment of genetic disorders by controlling epigenetic ON/OFF switch CRISPR-GNDM® (Guide Nucleotide-Directed Modulation) platform Modulator ON/OFF gRNA Target gene Designed not to cleave DNA dCas9 (enzyme null) 7 Copyright and proprietary to Modalis
Slide 8: GNDM-MDL-101 has been validated in mouse models and monkey
GNDM-MDL-101 has been validated - efficacy in mouse disease models and target engagement in monkey ④Resulted ②GNDM ③ Modulate level of expression expression protein level of target reverses gene/protein abnormality ①Transduction ①AAV Transduction ②GNDM expression ③Modulation of target ④Efficacy 8 Co
Slide 9: Delivery of CRISPR-GNDM to target
Delivery of CRISPR-GNDM® to target AAV vector to deliver GNDM to target cell +GNDM U6 gRNA Cas9 pA -GNDM AAV vector 1 2 3 4 Package GNDM gene Local or systemic GNDM GNDM modulates into AAV vector injection transduced into target gene in cells target cell 9 Copyright and proprietary to Modalis
Slide 10: CRISPR-GNDM targets genes that cannot be addressed by other modalities
CRISPR-GNDM® targets genes that cannot be addressed by other modalities Conventional ASO Gene Editing Gene therapy siRNA CRISPR-GNDM Delivered to off- Precise targeting Yes Yes Yes target tissues Require repeated Durability Years Permanent Years injection Applications LoF ONLY Mostly GoF GoF only Lo
Slide 11: Epigenome editing competitive landscape
Epigenome editing competitive landscape Modalis is in the lead Year Company Funding Platform Pipeline/Target indication Stage of Development Founded • MDL-101/LAMA2-CMD IND enabling Modalis CRISPR-GNDM x 2016 Public • MDL-202/Myotonic PreIND completed Therapeutics AAV Dystrophy Type 1(DM1) ZFN and d
Slide 12: Modalis pipeline strategy focuses on musculoskeletal diseases
Modalis pipeline strategy focuses on musculoskeletal diseases Discovery/Preclinical Clinical Discovery Lead IND Code Indication Ownership Phase I/II Pivotal Research Optimization Enabling MDL-101 LAMA2-CMD*1 Modalis MDL-202 DM1 *2 Modalis Muscular MDL-201 DMD *3 Modalis disorders MDL-103 FSHD *4 Mod
Slide 13: CNS and cardiomyopathy are additional active areas
CNS and cardiomyopathy are additional active areas Target selection criteria for Modalis’ gene therapies Unmet Need Muscle Liver Cardiomyopathy Eye CNS Low-replicating Tissue Accessibility Cell Types 13 Copyright and proprietary to Modalis
Slide 14: Gene therapy expanding from local to systemic administration
With the initial success, gene therapy has begun to expand targets from local to systemic administration Gene therapies approved by US FDA WW market Trade Name Approval cost Indication Manufacturer Patient Population size* (mil USD) Lxturna 2017 $850k RPE65 Spark/Roche 2 per 100,000 $65M♭ 1 in 10,00
Slide 15: Current AAV capsids provide tissue tropic delivery
Current AAV capsids provide tissue tropic delivery • Previous AAV 2, 6, 8,9 vectors were used across all tissues and diseases • Systemically delivered capsids sequestered in the liver, causing hepato- and dose limiting toxicities • Novel, engineered vectors have high target tissue tropism for muscle
Slide 16: All muscle programs share the same platform as MDL-101
All muscle programs share the same platform as MDL-101 Muscle targeting AAV GNDM platform MDL-202 MDL-201 MDL-103 MD-101 16 Copyright and proprietary to Modalis
Slide 17: Pipeline
Pipeline 17 Copyright and proprietary to Modalis
Slide 18: MDL-101 LAMA2-CMD
LAMA2-CMD (aka CMD1a) Severe muscular dystrophy caused by loss of function mutation in LAMA2 gene MDL-101 Prevalence 1 in 30,000* 10,000 in US Potential to be the first Disease Apparent at birth or LAMA2-CMD Onset within a few months treatment after birth Disease Patients do not • Severe muscle weak
Slide 19: MDL-101 activates LAMA-1 to compensate for missing LAMA2
MDL-101 activates LAMA-1, compensates for the missing function of LAMA2, which is too large for classical gene therapy approach LAMA1/2 protein structure LAMA1 CRISPR-GNDM® targeting LAMA1 LAMA2 Muscle cell Exspression pattern of LAMA1and LAMA2 by tissues Transcription LAMA1 LAMA2 modulator RNA Prot
Slide 20: MDL-101 Development
MDL-101 Development ØCurrent status n Mouse efficacy in two disease strains (dy2j and dyW) and wild type • Upregulation of LAMA–1 gene and protein along with GNDM expression • Improvement in biochemical and physiological readouts and prolonged survival • Sustained expression of GNDM in WT mice for 2
Slide 21: mMDL-101 is efficacious in severe MDC1a model
mMDL-101 is efficacious in severe MDC1a model Increased lifespan, body weight and grip strength of dyw mice Extended lifespan Improved growth (% Survival) (Weight) mMDL-101 mMDL-101 Vehicle Vehicle p<0.005, log rank test p<0.0001, Mann-Whitney test 21 Copyright and proprietary to Modalis
Slide 22: MDL-202 Myotonic dystrophy type 1 (DM1)
Myotonic dystrophy type 1(DM1) extension of CTG repeat in 3’ UTR of DMPK gene MDL-202 Prevalence 1-4.8 in 10,000 DM is the most common muscular dystrophy among (1 in 2,300*) adults of European ancestry Potential to be the first- Disease DM1 can occur from Age at onset is between 20 and in-class and
Slide 23: DM1 is caused by abnormal splicing from CTG extension
DM1 is caused by abnormal splicing rooted from CTG extension in 3’UTR of DMPK gene DM1disease causing mechanism Splicing in healthy people Expanded CTG repeat MBNL1 1 14 15 3’UTR DMPK gene Abnormally expanded (CUG)n repeats form hairpin-like MBNL1 contributes structures normal splicing DMPK mRNA Wit
Slide 24: MDL-202 silences DMPK expression and releases MNBL
MDL-202 silences DMPK expression and releases splicing protein MNBL to function properly in muscle cells MDK-202’s mechanism of action Expanded CTG repeat 1 14 15 3’UTR GNDM-DMPK GNDM silences DMPK 5’ CAP AAA expression MNBL is released 5’ CAP AAA From CTG MNBL goes back repeat to contribute normal
Slide 25: MDL-201 Duchenne Muscular Dystrophy (DMD)
Duchenne Muscular Dystrophy (DMD) A type of muscular dystrophy caused by mutation in Dystrophin gene MDL-201 Prevalence 1 in 3,500 to 5,000 Relatively high in genetic disorders Potentially best-in-class male newborns molecule by rebooting Disease most commonly UTRN gene expression onset appears betw
Slide 26: UTRN-GNDM reactivates Utrophin gene in DMD patients
UTRN-GNDM reactivates Utrophin gene to compensate non- functional Dystrophin gene in DMD patients Concept of GNDM-UTRN to re-activate UTRN gene Newborn Early DMD patient DMD patient childhood With GNDM Utrophin Gene (fetal version of Restore Dystrophin) function スイッチの Dystrophin 切替 gene Impaired Imp
Slide 27: Competitors developing mini-dystrophins with low functionality
Competitors are developing mini-dystrophins, with known low functionality, as wt Dystrophin is too large to fit into the AAV Dystrophin/Utrophin Structure and mini-Dystrophins ABD2 DgBD SBD DbBD R1~3 R4~19 R20~24 Dystrophin ABD1 11 17 CR CT 11kbp H1 H2 H3 H4 nNOS Utrophin ABD1 CR CT 10kbp Basal lami
Slide 28: MDL-103 Facioscapulohumeral Muscular Dystrophy (FSHD)
Facioscapulohumeral Muscular Dystrophy (FSHD) A type of muscular dystrophy caused by impaired Dux4 gene expression Prevalence 1 in 10,000-20,000 Muscular dystrophy most MDL-103 frequent in adults Potentially first-in-class treatment by silencing Disease Often not recognized Progression of disease to
Slide 29: FSHD disease mechanism
FSHD disease mechanism Inappropriate over-expression of Dux4 in skeletal muscles • The D4Z4 repeat region at OFF location 4q35 on chr4 Healthy Dux4 • Healthy individuals have numerous highly methylated D4Z4 repeats D4Z4 repeat • FSHD-1 and -2 affected 11-100 repeats 5meC individuals have ON hypometh
Slide 30: MDL-104 Tauopathy (incl. Alzheimer's Disease)
Tauopathy (incl. Alzheimer's Disease) Neurodegenerative disorders caused by misfolding of the tau protein MDL-104 Prevalence 1 in 9 above 65* 60-80% of cognitive disorders 55 million in ww Potentially best-in-class Disease Progressed in 6-8 yrs Slow and chronic progression, molecule by silencing Ons
Slide 31: Product concept of Tau suppressor by CRISPR-GNDM
Product concept of Tau suppressor by CRISPR-GNDM® GNDM-Tau • Reversing the pathogenic conditions of Transcription suppressor Tauopathy by partial or full suppression of Tau specific Gene suppression Tau gene that leads to reduction of Tau gRNA protein in the brain Tau dCas9 • GNDM-Tau, driven by neu
Slide 32: Tau is a center of attention in treating Alzheimer disease
Tau is a center of attention in treating Alzheimer diseases Ø Tau correlates with clinical symptoms and neuronal loss in Alzheimer's disease and other primary tauopathies. n Tau aggregates and tangles are thought to induce neuronal degeneration, synaptic loss and cell death n Tauopathies include a r
Slide 33: GNDM mediated suppression of MAPT in humanized Tau mice
GNDM mediated suppression of MAPT in humanized Tau mice Humanized ICV injection@P2 MAPT mice 1.4e+11 8wk RNA-FISH vg/head GNDM Tau GNDM+Tau GNDM -Tau GNDM -対照gRNA 33 Copyright and proprietary to Modalis
Slide 34: MDL-206 Angelman Syndrome
Angelman Syndrome CNS disorder caused by impaired UBE3A gene expression Prevalence 1 in 10,000 to MDL-206 • 60,000 patients WW（2017） Potentially first-in-class 20,000 live birth • 20,000 in US treatment by Disease typically diagnosed Seizures may begin at 2 to 3 unsilencing UBE3A Onset at 6 to 12 mo
Slide 35: By blocking ATS transcript, GNDM un-silences UBE3A expression
By blocking ATS transcript, GNDM un-silences UBE3A expression 6 5 ATS IC 11 11 - S- RPN or d or d E3A PW SN Sn IP W Sn UB Paternal STOP Normal Neurons UBE3A Maternal UBE3A protein Angelman Paternal STOP Patient Impaired Neurons Maternal STOP expression UBE3A mutation GNDM Patient UBE3A Paternal prot
Slide 36: UBE3A is successfully unsilenced in Cortex
UBE3A is successfully unsilenced in Cortex UBE3A staining in un-inject- ed WT mice brains (left) and HET (UBE3Amat-/pat+) mice injected with AAV9-hSyn1-Control sgRNA-GNDM® (middle) or AAV9- hSyn1-Targeting sgRNA-GNDM® (right). UBE3A staining alone (black and white; top), UBE3A (red) and DAPI (blue)
Slide 37: Business and Development Strategy
Business and Development Strategy 37 Copyright and proprietary to Modalis
Slide 38: Development stage of Modalis pipeline
Development stage of Modalis pipeline Current status Next milestones • Animal PoC in mouse disease models • Target engagement in NHP (ASGCT • GLP-Tox MDL-101 LAMA2-CMD • GMP manufacturing 2023 Late-breaking Abstracts #2) • IND (2H 2024) • PreIND meeting with FDA (June 2023) • Animal PoC in disease m
Slide 39: Status of the muscular dystrophy pipeline
Status of the muscular dystrophy pipeline MDL-201 and 202 prioritized upon regaining rights Code Indication 2023/12 2024/12 2025/12 MDL-101 LAMA2-CMD Pre-IND filing response IND filing MDL-202 DM1 Pre-IND filing IND filing Conditional on funding from partnering, grant * Milestone events are informat
Slide 40: MODALIS GNDM platform provides a diversified pipeline
MODALIS GNDM platform provides a diversified pipeline Expand approach to Pioneering gene Apply technology to challenging modulation products with larger applications applied to high unmet opportunities need indication MDL-202 CNS, CV and other MDL-101 MDL-201 programs 40 Copyright and proprietary to
Slide 41: Modalis' pipelines and market size
Modalis’ pipelines and market size MDL-101 paves the clinical path to larger indication programs Modalis programs and market size MDL-103 MDL-201 FSHD DMD MDL-105 DCM MDL-202 DM1 MDL-104 MDL-206 Tauopathy Angelman Syndrome MDL-101 LAMA2-CMD Stage of development ※ Size of circles represent market siz
Slide 42: Growth Strategy for Modalis
Growth Strategy for Modalis Opportunities expand two dimensionally Potential Growth for GNDM technology ~2,200 potential targets >100 core target Expansion appropriate for GNDM indications identified MDL-206 MDL-104 Pipeline License opportunities MDL-105 M/S payments over time MDL-103 MDL-201 MDL-20
Slide 43: Partnering strategy
Partnering strategy • CRISPR-GNDM® has demonstrated applicability to many high value diseases • Partnering allows risk / profit sharing for programs developed beyond early PoC • Partnering will be undertaken when conditions and timing are appropriate based on value and business characteristics of ea
Slide 44: Finance
Finance 44 Copyright and proprietary to Modalis
Slide 45: Value increase through future pre-clinical and clinical trials
Value increase through future pre-clinical and clinical trials Expected milestone events and impact on corporate value To include program numbers to give concreteness Partnering Clinical PoC (2~3yrs) Orphan designation • Reasonable patient recruitment • Safety PreIND • Reasonable biomarker response
Slide 46: Why MODALIS?
Why MODALIS? • Innovator in the hot space=epigenetic editing • High interest in this approach due to applicability to genetic diseases for which other platforms are not feasible • Wide applications in musculoskeletal, CNS, cardiovascular and in other areas • Validated technology • Established animal
Slide 47: Q&A
Q&A 47 Copyright and proprietary to Modalis
Slide 48: Q1: The partnership is gone, but is the GNDM over?
Q1: The partnership is gone, but is the GNDM over? • Rather, we believe that this is just the beginning. • First of all, the field of epigenome editing is attracting a great deal of attention, as other companies backed by huge VC funds are entering the field one after another. • Among these companie
Slide 49: Q2: No partnering? Can't do it?
Q2: No partnering? Can't do it? • Once successfully developed, partnering is almost always possible. On the other hand, "when" it can be done before the product is marketed is uncertain, depending on various factors. • For those partnering, the development costs incurred in addition to the license f
Slide 50: Q3: Has MODALIS abandoned platform model?
Q3: Has MODALIS abandoned platform model? • When we say "platform-based," the benefit or expectation is that it will scale, or reduce the risk, cost, and development time of a second or subsequent pipeline. • With CRISPR-GNDM® technology, what Modalis is trying to achieve is to demonstrate with MDL-
Slide 51: Q4: Any implications to the coming milestones?
Q4: Any implications to the coming milestones? • The current PIPES fundraising will allow us to bridge the funding needed to start clinical trials. • In the meantime, the Company expects that, • Partnering for MDL-101 will be in place to cover the costs of the clinical trial and/or • partnering and
Slide 52: Q5: What is the current status of non-muscle programs?
Q5: What is the current status of non-muscle programs? • In CNS diseases, AAV based delivery into the brain can be done by either by 1) ICM (intracranial) or ICV (intracerebroventricular) administration, in which AAVs are delivered into the spinal fluid and infiltrated from outside the brain, or 2)
Slide 53: Q6: How will the funds from this fundraising be used?
Q6: How will the funds from this fundraising be used? • The Company plans to use the money to fund the research and development required for its own pipeline, including the re-acquired DM1 pipeline. Specifically, the Company plans to place the highest priority on the funds required for the MDL-101 I
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