Modalis Therapeutics Corporation · TSE:4883
Modalis Therapeutics — Investor Presentation (March 2023)
70 slides from Modalis Therapeutics's investor presentation, Mar 17, 2023
Slide 1: FY2023 Corporate Presentation
English translation for reference purposes only FY2023 Corporate Presentation （TSE︓4883）Modalis therapeutics Corporation Corporate and Technology summary March 17, 2023 In case of any discrepancy, the Japanese version shall prevail Copyright and Copyright andproprietary proprietaryto Modalis to Moda
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: Table of contents
Table of contents 1. Corporate Overview 2. Gene Therapy, Gene Editing 3. MDL-101 for LAMA2-CMD 4. Other Programs 5. Growth Strategy 6. Sustainability 3 Copyright and proprietary to Modalis
Slide 4: 1. Corporate Overview
1. Corporate Overview 4 Copyright and proprietary to Modalis
Slide 5: Corporate Overview (As of December 31, 2022)
1. Corporate Overview Corporate Overview (As of December 31, 2022) Modalis Therapeutics is a biotech company to develop CRISPR-based gene therapies Date History Modalis Therapeutics Corporation Name Jan 2016 Founded in Tokyo as EdiGENE Corporation (Ticker symbol: 4883) Established 100% owned US subs
Slide 6: Every life deserves attention
1. Corporate Overview︓Modalis Modalis is a gene therapy company dedicated to translating evolutional science into life-changing treatments for rare disease patients. Novel The first CRISPR Leading precision medicines based company in for genetic disorders gene modulation epigenetic for which Therape
Slide 7: Potential benefits of CRISPR-GNDM Technology
1. Corporate Overview︓CRISPR-GNDM® CRISPR-GNDM® is a promising new therapeutic modality Potential benefits of CRISPR-GNDM® Technology X1 Single dose Long-lasting Disease Modifying Doesn’t require Sustained effect Not just to reduces Repeated dosing for years or decades symptoms but gives cure 7 Copy
Slide 8: Modalis Value Highlights
1. Corporate Overview︓Modalis Value Highlights Modalis Value Highlights Ø Pioneering CRISPR-based epigenetic editing technology with development pipelines • First and the leading CRISPR-based gene modulation/epigenetic editing technology that enables therapeutic applications Ø Muti-layered IP protec
Slide 9: Genetic Disorders
1. Corporate Overview︓ Genetic Disorders Genetic Disorders They are caused by LoF or GoF LoF GoF (loss-of-function) (Gain-of-(mal)function) Supplement missing function Silence malfunction GTx 9 Copyright and proprietary to Modalis
Slide 10: Provides solution for the long tail of disease
1. Corporate Overview︓Every life deserves attention Provides solution for the long tail of disease It is believed that of10,000* human diseases, about 7,000#are rare diseases which consist of “long tail” diseases. Of these, 80%† overlap with genetic disorders and 95％ remain untreated. The company is
Slide 11: Gene Modulation is CRISPR 2.0
1. Corporate Overview︓Gene Modulation is CRISPR 2.0 Gene Modulation is CRISPR 2.0 “I think one interesting possibility is that we’ll see CRISPR being used not to edit genomes, or at least not to make permanent changes to genomes, but instead to regulate them, to control levels of human proteins that
Slide 12: Non-cleaving CRISPR = CRISPR-GNDM
1. Corporate Overview : Mechanism Non-cleaving CRISPR = CRISPR-GNDM® Enables treatment of genetic disorders by controlling ON/OFF switch CRISPR-GNDM® (Guide Nucleotide-Directed Modulation) platform Modulator ON/OFF gRNA Target gene Designed not to cleave DNA dCas9 (enzyme null) 12 Copyright and prop
Slide 13: GNDM is efficient approach both for LoF and GoF mutation
1. Corporate Overview : Advantages over other technologies GNDM is efficient approach both for LoF and GoF mutation In LoF disorders In GoF disorders single Limited only Targets for suppression to ex vivo application Base editing DNA RNA Protein Point of Mutation(s) Gene editing • GNDM (CRISPR) 1 mu
Slide 14: Precision technologies are not one-thing-fits-all
1. Corporate Overview : Precision medicine Precision technologies are not one-thing-fits-all 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 M
Slide 15: Business Model
1. Corporate Overview︓Business Model Business Model Hybrid of own pipeline and collaboration pipeline Early Stage Research Preclinical Clinical Animal IND enabling studies Clinical Target GNDM GNDM 動物モデル Sales Model による検証 GMP manufacturing Trial selection prototyping optimization Manufacturing evalu
Slide 16: CV is our next horizon
1. Corporate Overview︓CV is our next horizon Therapeutic area that Modalis targets Target tissue for gene therapy Brain by local injection • Modalis has focused High mainly on CNS and muscle muscle disease area Cardiomyopathy • Our accumulated know Invasiveness eye how allow us to explorer new disea
Slide 17: CRISPR-GNDM platform efficiently identifies optimal gRNA
1. Corporate Overview︓CRISPR-GNDM® platform CRISPR-GNDM® platform efficiently identifies optimal gRNA Lead candidate screening in human primary myoblast cells ~3mo 17 Copyright and proprietary to Modalis
Slide 18: Pipeline
1. Corporate Overview︓Pipeline Pipeline Preclinical Clinical Disease Lead IND- PhaseⅠ Code Partner Structure Discovery Pivotal /Indication*1 Optimization Enabling /PhaseⅡ Astellas MDL-201 Muscle License Pharma Inc. Collaboration Astellas MDL-202 Muscle License Pharma Inc. Fully controlled MDL-101 LA
Slide 19: IP position
1. Corporate Overview︓IP position IP position Established IP with foundational CIRPSR IP from Broad and engineered Cas9 from Univ of Tokyo Modalis’ IP position Upstream Allergan abbvie Licensors Ophthalmology JUNO Tx MASSACHUSETTS Bristol-Myers Squibb MGH GENERAL HOSPITAL CART Beam Tx Base Editing B
Slide 20: Each product will be protected by multiple layers of IP
1. Corporate Overview︓IP position Each product will be protected by multiple layers of IP Licensed Patents to partner for each Target Target B Target C Target D (optimal gRNA use of gRNA with GNDM, vector, etc) GNDM IP (covers engineered Cas9, Modulator, etc.) CRISPR Foundation IP AAV vector IP 20 C
Slide 21: Diversified pipeline with their own missions
1. Corporate Overview︓Diversified pipeline with their own missions Diversified pipeline with their own missions Pioneer the gene Expand technology Further approach to modulation opportunity with challenging With highly products for larger applications suitable indications opportunity MDL-101 MDL-104
Slide 22: Management Team and Board of Directors
1. Corporate Overview︓Board members Management Team and Board of Directors Seasoned team Executive Officers Haru Morita Co-founder, President, CEO, and Chair of the board • REGiMMUNE, Founder, President and CEO • Y’s Therapeutics, Booz Allen and Company, Kyowa-KIRIN Tetsuya Yamagata MD PhD: SVP, Chi
Slide 23: 2. Gene Therapy and Gene Editing
2. Gene Therapy and Gene Editing 23 Copyright and proprietary to Modalis
Slide 24: How multiple cell types are created from the same DNA code
2. Gene Therapy and Gene Editing︓Switching genes How multiple cell types are created from the same DNA code Each of 20,000 genes have ON/OFF switches that control cell type specific expression Switch box Gene X Gene Y Gene Z • There are 37.2 Trillion cells in our body Cell A translation • 200 cell t
Slide 25: CRISPR is a novel gene editing technology
2. Gene Therapy and Gene Editing︓About CRISPR CRISPR is a novel gene editing technology Faster and higher throughput due to limited variable region which is easily synthesizable as gRNA Old gene editing technologies CRISPR ZFN TALEN Targeting with RNA (easier and faster) ZFN TALEN gRNA Cas9 Target p
Slide 26: Major players in CRISPR field
2. Gene Therapy and Gene Editing︓Players of CRISPR Major players in CRISPR field Modalis established unique position in CRISPR companies, most of which reached >$1B Dx Platformer Tx KSQ VERTEX Intellia TX $3.5B Exonics ~$1B CRISPR Tx Tx Canonical Caribou $3.5B ? CASEBIA TX $0.3B BAYER Editas $0.6B B
Slide 27: Delivery of CRISPR-GNDM to target
2. Gene Therapy and Gene Editing︓ Delivery Delivery of CRISPR-GNDM® to target Use AAV vector to deliver GNDM to target cell +GNDM A driver works only in specific tissues U6 gRNA Cas9 pA -GNDM AAV vector 1 2 3 4 Package gene Local or systemic GNDM GNDM modulates Into AAV vector injection transduced i
Slide 28: Big innovations in AAV vectors
2. Gene Therapy and Gene Editing︓ Big innovations in AAV vectors Big innovations have been brought to AAV vectors recently AAV vector • Previously, generic vectors such as AAV2, 6, 8, and 9 were universally used for all target diseases Capsid Transgene • Those capsids are predominantly sequestered i
Slide 29: Transition to specialized capsid is the need of the field
2. Gene Therapy and Gene Editing︓ Big innovations in AAV vectors Transition to specialized capsid is the need of the field and will be beneficial in the long run In musclular disorders like MDL-101 • Does of generic capsids were limited Cannot 2 by the off-target toxicity of capsid itself, deliver 1
Slide 30: Scalability of GNDM
2. Gene Therapy and Gene Editing︓ Scalability Scalability of GNDM gRNA is the only variable which is unique for each target. Other components are off-the-shelf to assemble. For ON For OFF gRNA dCas9 Modulator 30 Copyright and proprietary to Modalis
Slide 31: Key Progress and anticipated milestones
2. Gene Therapy and Gene Editing︓ Key Progress and anticipated milestones Key Progress and anticipated milestones 2022 Achievement Upcoming milestones ü INTERACT meeting p PreIND request filing (1Q) ü implemented specialized capsid p Data presentation on NHP study MDL-101 strategy (2Q) ü Initiated N
Slide 32: 3. MDL-101 for LAMA2-CMD
3. MDL-101 for LAMA2-CMD 32 Copyright and proprietary to Modalis
Slide 33: MDL-101 for LAMA2-CMD
3. MDL-101 for 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 in-class and the first Onset within a few months LAMA2-CMD after birth treatm
Slide 34: Loss of LAMA2 causes congenital muscular dystrophy type 1A
3. MDL-101 for LAMA2-CMD Loss of LAMA2 causes congenital muscular dystrophy type 1A (LAMA2- 3 4 CMD) Normal LAMA2 Function LAMA2 Loss-of-function LAMA2 ECM a Collagen Laminins LAMB1 LAMC1 b g Integrins Cell membrane • Strongly expressed in skeletal muscle. • Most common form of congenital Laminin-21
Slide 35: LAMA1 can compensate the loss of LAMA2 function in vivo
3. MDL-101 for LAMA2-CMD 3 LAMA1 can compensate the loss of LAMA2 function in vivo 5 LAMA2 (3,122 a.a.) 45% Identity / 75% Similarity LAMA1 (3,075 a.a.) Expression in High None muscle tissue 35 Copyright and proprietary to Modalis
Slide 36: By activating LAMA1, GNDM compensates missing LAMA2 function
3. MDL-101 for LAMA2-CMD By activating the sister gene, LAMA1, GNDM compensates missing function of LAMA2, which is too big to be addressed by regular GTx Exspression pattern of LAMA1and LAMA2 by tissues CRISPR-GNDM® targeting LAMA1 LAMA1 LAMA2 Muscle cell protein Tissue RNA Protein RNA Transcriptio
Slide 37: Conducting IND enabling studies as well as process development
3. MDL-101 for LAMA2-CMD Conducting IND enabling studies as well as process development Path to clinic for CRISPR-GNDM® IND enabling In vitro Preclinical PoC clinical (screening/ evaluation) (in vivo) Rodent NHP WT PK/PD GNDM w/ gRNA screening Disease (expression, Toxicity Mouse gRNA (murine cell li
Slide 38: Mice study demonstrated significant improvement in muscle function
3. MDL-101 for LAMA2-CMD Mice study demonstrated significant improvement in muscle function Grip Grip Strength Strength Forepaws Forepaws Average 40 1e14 5e13 Peak Force(gf) 30 force (gf) • dyW (severe MDC1a model) mice 1e14 control injected with GNDM (control gRNA, 20 UNT or active gRNA at low and
Slide 39: INTERACT Meeting summary
3. MDL-101 for LAMA2-CMD INTERACT* Meeting summary n Held in Mid July 2022 n Non-binding n Modalis provided development summary and questions to FDA and FDA answered to them in writing and follow them up in a web meeting. n Primary agenda includes • Manufacturing process and method to assess clearan
Slide 40: Prevalence of LAMA2-CMD
3. MDL-101 for LAMA2-CMD Prevalence of LAMA2-CMD Ø Exact prevalence of LAMA2-CMD is still unknown but... CMD n The prevalence of congenital muscular 1 in 10,000 dystrophies (CMD) has been estimated between • 1-9/100,000 LAMA2-CMD n LAMA2-CMD is about ~30% of CMD: = 25~30% of CMD =~1/30,000 • ~1/30,0
Slide 41: LAMA2-CMD is about the same size as DMD caused by Exon 51 mutation
3. MDL-101 for LAMA2-CMD LAMA2-CMD is about the same size to DMD caused by Exon 51 mutation May not be a mena ble to ex on skipp ing O th er ex on skipp ing Exon 51 2% 4%2% 4% 20% Exo n 53 4% Exo n 45 6% Exo n 44 8% Exo n 50 8% 29% DMD Exo n 52 =1 in 3,500# Exo n 43 13% Exo n 55 CMD Exo n 8 1 in 10,
Slide 42: Status of Development of MDL-101 for LAMA2-CMD
3. MDL-101 for LAMA2-CMD : Status of Development Status of Development of MDL-101 for LAMA2-CMD Ø Reported by 4Q/2022 n Mouse model data in two disease strains (dy2j and dyW) and wildtype • Upregulation of LAMA–1 gene and protein along with GNDM expression • Improvement in biochemical and physiologi
Slide 43: 4. Other Development pipelines
4. Other Development pipelines 43 Copyright and proprietary to Modalis
Slide 44: Summary of other R&D activity
4. Other Development pipelines : Summary in R&D Summary of other R&D activity n MDL-104 (Tau) • Evaluation of the human version molecule with hTau and humanized Tau mice − Initiation of biodistribution study in NHP • Discussion on target indications with KOLs − Alzheimer’s disorder(AD) and/or Fronto
Slide 45: MDL-104 for Tauopathy
4. Other Development pipelines : MDL-104 for Tauopathy Tauopathy (incl. Alzheimer's Disease) Neurodegenerative disorders caused by misfolding of the tau protein MDL-104 Prevalence 1 in 9 above 65* 55 million in ww Potentially best-in-class Disease Progressed in 6-8 yrs molecule by silencing Onset Ta
Slide 46: AD and FTD are primary choice for initial indication
4. Other Development pipelines : MDL-104 for Tauopathy AD and FTD are our primary choice for the initial indication but multiple potential diseases Prevalence Target in Brain Major symptom Progression memory, movement, language, 1 in 9 above 65 AD 1 in 3 above 85 cortex and hippocampus judgment, beh
Slide 47: Product concept of Tau suppressor by CRISPR-GNDM
4. Other Development pipelines : MDL-104 for Tauopathy 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 p
Slide 48: Tau mRNA suppression in transduced brain regions
4. Other Development pipelines : Tau mRNA suppression Tau is strongly suppressed in the brain regions that GNDM is transduced humanized ICV@P2 MAPT 1.4e+11 vg/helm 8wk RNA-FISH GNDM Tau GNDM+Tau GNDM -Tau GNDM -control 48 Copyright and proprietary to Modalis
Slide 49: hTau protein is suppressed to ~50%
4. Other Development pipelines : Tau protein suppression hTau protein is suppressed to ~50% in both Cortex and Hippocampus CORTEX Hippocampus Uncorrected 4×106 3×106 Signal Intensity 2×106 1×106 0 PBS AAV9 C1 AAV9 sg57 PBS PBS Control Control gRNA gRNA gRNA gRNA hTau hTau AAV AAV P2 ICV 8wk takedown
Slide 50: MDL-105 for DCM
4. Other Development pipelines : MDL-105 for DCM Dilated Cardiomyopathy (DCM) A condition in which the heart becomes enlarged • ~20% of DCM is estimated to MDL-105 Prevalence 1 in 250-2,500# be caused by TTN variant • Half is by truncated variant Potential first-in-class Disease Middle age around pr
Slide 51: TTN is the largest human protein
4. Other Development pipelines : MDL-105 for DCM TTN is the largest human protein - which is too large for AAV packaging Largest human protein • 35,000 amino acids /17kb myofibril • 363 exons • Acts as spring in sarcomere • Tension during relaxation Sarcomere Abundant in human body • Third most abun
Slide 52: Product concept: Activate TTN gene to boost TTN protein
4. Other Development pipelines : MDL-105 for DCM Product concept: Activate TTN gene to boost TTN protein in DCM patients Working hypothesis of GNDM based DCM therapy DNA RNA Protein TTN Sufficient Healthy Amount of TTN Functional sarcomere TTN Insufficient DCM with Amount of TTN TTNtv Nonsense Insta
Slide 53: Why GNDM for TTN?
4. Other Development pipelines : MDL-105 for DCM Why GNDM for TTN? n TTN mutations are “definitive” for DCM (ClinGen) n TTN mutations are associated with 15-23% of DCM cases n TTNtv is a haploinsufficiency rather than dominant negative • produce non-functional protein n No direct approach to target
Slide 54: 5. Growth Strategy
5. Growth Strategy 54 Copyright and proprietary to Modalis
Slide 55: Growth Strategy: opportunity expands two dimensionally
5. Growth Strategy : Expansion of pipeline Growth Strategy opportunity expands two dimensionally Potential Growth for GNDM technology ~2,200 target opportunity >100 core target Expansion indications MDL-XXX MDL-105 MDL-104 pipelines MDL-102 License opportunity MDL-101 MDL-206 MDL-205 MDL-202 M/S pay
Slide 56: Modalis' pipelines and market size
5. Growth Strategy : Expansion of pipeline Modalis’ pipelines and market size Large indication programs follow MDL-101 which paves the clinical path Modalis’ pipelines and market size MDL-201 Muscle disease MDL-205 CNS MDL-105 MDL-202 DCM Muscle disease MDL-104 MDL-206 Tauopathy Angelman syndrome MD
Slide 57: Composition of Modalis' value and measures for advance
5. Growth Strategy : Composition of Modalis’ value and measures for advance Composition of Modalis’ value and measures for advance measures for advancement • Aspiration of good talents • Completion of value chain Ø Partnering for future • Acquisition of commercialization additional business Ø Establ
Slide 58: Stricter decision on transition from R to D
5. Growth Strategy : GNDM Upon transition from R to D, which cost time and money, stricter decision is made for higher ROI and better resource allocation. CDMO PoS* patient number management clinical path competition Process Discovery/Research Engine Development Gate filter CRISPR-GNDM® Clinical Pre
Slide 59: The future Modalis envisioned
5. Growth Strategy : The future Modalis envisioned The future Modalis envisioned Short Term Mid Term Long Term (2023) (3yrs) (>3yrs) • MDL-101 PreIND(1Q) • Initiation of clinical trial • Market approval and launch of GNDM-based • MDL-104 target • Clinical PoC（2024〜25） product(S) engagement in NHP •
Slide 60: Expected milestone events and impact on corporate value
5. Growth Strategy : Expected milestone events and impact on corporate value Future pre-clinical and clinical trials are expected to increase the value of the company. Expected milestone events and impact on corporate value Partnering Clinical PoC Orphan designation • Reasonable patient recruitment
Slide 61: Pipeline Status
5. Growth Strategy : Pipeline Pipeline Status MDL-101 on track to file PreIND in 1H 2023 Portfolio under review for the acquisition of assets related to MDL-205 Code Indication 2023/12 2024/12 2025/12 MDL-201 muscle Collaboration Nonclinical and IND-enabling studies, CMC activities# pipeline MDL-202
Slide 62: 6. Sustainability
6．Sustainability 62 Copyright and proprietary to Modalis
Slide 63: Every life deserves attention
6．Sustainability Social︓Initiatives for Rare Disease Corporate Philosophy Every life deserves attention The company group, through drug discovery using the core platform technology “non-cutting CRISPR technology” (CRISPR-GNDM ® technology) to invent therapeutics targeting rare genetic disorders. Tru
Slide 64: Social: Initiatives for Rare Disease
6．Sustainability Social︓Initiatives for Rare Disease It is believed that of10,000* human diseases, about 7,000#are rare diseases which consist of “long tail” diseases. Of these, 80%† overlap with genetic disorders and 95％ remain untreated. The company is committed to identifying cures with our power
Slide 65: Efficient Use & Preservation of Water
6．Sustainability Environment Efficient Use & Preservation of Water To preserve water and ensure it is used efficiently, wastewater from the laboratory is treated in accordance with environmental laws at our R&D facility in the US. ※ pH Neutralization System 65 Copyright and proprietary to Modalis
Slide 66: Global Warming: Measures to Reduce Carbon Footprint
6．Sustainability Environment Global Warming・Measures to Reduce Carbon Footprint With facilities that combine function and needs of our personnel, we are promoting reduction and optimization of energy consumption. The company supports telework, and our recent relocation allows us to carry out busines
Slide 67: Valuing Human Rights & Diversity
6．Sustainability Social Valuing Human Rights・Diversity The company group values the human rights and diversity of our employees and believes that improvement of the working environment is essential. The employees of our R&D facility in the US come from a wide range of backgrounds, regardless of nati
Slide 68: Securing Human Resources & Way of Working
6．Sustainability Social Securing Human Resources & Way of Working Flexible schedules and ongoing efforts to improve the working environment provide employees a source of motivation and sense of security as they carry out their duties. Additionally, we are making efforts to secure and develop talent
Slide 69: Corporate Governance System
6．Sustainability Governance Corporate Governance System Five in six members of our Board of Directors are Outside Directors（of these, one is of foreign nationality and one is female) which creates a system that allows for in- house checks and ensures accountability toward shareholders. Our company h
Slide 70: Copyright and proprietary to Modalis
70 Copyright and proprietary to Modalis
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