ReCode Therapeutics Corporate Presentation 39th JP Morgan Healthcare Conference January 2021 FIRST-IN-CLASS TARGETED, GENETIC MEDICINES FOR RESPIRATORY DISEASES Powered by Best-in-Class, Non-Viral LNP Delivery Platform
THERAPEUTIC PROGRAMS FOCUSED ON HIGH, UNMET NEEDS NON-VIRAL LNP PLATFORM FIRST-IN-CLASS BEST-IN-CLASS & NEW CLASS CAPABILITIES
Genetic Respiratory Diseases 4 Proprietary Classes of LNPs Well Positioned to Execute
• SORT LNPs – Best-in-Class with • Series A, $80M – March 2020 Tissue-Specific Delivery • Primary Ciliary Dyskinesia (PCD) • Strong Patent Protection (2035 plus) • Engineered for Gene Delivery or • Scalable Manufacturing • Cystic Fibrosis (CF) Editing • Proven Management Team, Top • Broad Range of Therapeutic Cargos Industry Investors and Advisors
NON-CONFIDENTIAL 2 Experienced Drug Development Leadership and Industry Advisors
MANAGEMENT
DAVID LOCKHART, PhD JULIE EASTLAND, BRANDON WUSTMAN, CEO & President MBA PhD CFO & COO Senior Vice President of R&D VLADIMIR KHARITONOV, PhD Senior Vice President, CMC MICHAEL TORRES, PhD Vice President, R&D, Texas Site Head
BOARD OF DIRECTORS SCIENTIFIC ADVISORS and KOLs
ED HURWITZ, HELEN S. KIM, DAVID LOCKHART, DANIEL SIEGWART, JD, MBA MBA PhD PhD MPM Capital Vida Ventures ReCode Therapeutics Associate Professor, UTSW ARTHUR JOHNSON, RA SESSION II PETER THOMPSON, MICHAEL TORRES, ROBERT BRIDGES, PhD Taysha Gene Therapies MD PhD PhD Professor Emeritus, Texas OrbiMed ReCode Therapeutics Professor, RFUM PHILIP THOMAS, A&M PhD Professor, UTSW NON-CONFIDENTIAL 3 Best-in-Class and NEW Class of Non-Viral LNPs Customizable to Enable Targeted Delivery of Genetic Medicines
ADVANTAGES DIFFERENTIATED
• RE-DOSABLE, TITRABLE • NO AAV-RELATED SAFETY 5-COMPONENT SORT TECHNOLOGY ISSUES DELIVERS BEYOND THE LIVER
• LARGE PAYLOAD CAPACITY Lungs Spleen Liver • BROAD PAYLOAD DIVERSITY • TARGETS SPECIFIC TISSUES AND CELLS • SCALABLE MANUFACTURING
ReCode’s LNPs enable precise gene replacement, silencing, and correction
NON-CONFIDENTIAL 4 Therapeutic Focus on Genetic Respiratory Diseases Address Underlying Genetic Cause in High Unmet Need Diseases with Potential to Transform Patient Lives
Indications with established endpoints and clear path to human POC and approval
PHASE 1/2 MODALITY TARGET DELIVERY DISCOVERY PRECLINICAL (SAD/MAD/OLE)
mRNA DNAI1 Inhaled IND in 2022 PCD mRNA PCD gene 2 Inhaled Primary Ciliary mRNA PCD gene 3 Inhaled Dyskinesia tRNA PCD nonsense Inhaled tRNA CFTR Inhaled IND in 2022 CF mRNA CFTR Inhaled Cystic Gene CFTR Fibrosis IV; Lung-SORT Correction (F508del) Non-Viral Various IV; Various Platform LNPs Organs/Tissues
Primary endpoint (change in FEV1) with potential to demonstrate rapid improvement applies to current leads and future PCD and CF programs NON-CONFIDENTIAL 5 Lead Therapeutic Programs PCD and CF PCD: Addressing High Unmet Need with ReCode Solutions
The Cause The Solution DNAI1 mutations impair ciliary activity and result in loss of mucociliary clearance (MCC) Repeated delivery of DNAI1 mRNA to the epithelial cells of the conducting airways (e.g., trachea, bronchi, and bronchioles). Challenges Cells targeted by LNP-formulated mRNA delivered as an • Gene editing & gene therapy approaches not well-suited: aerosol using existing methods and devices. Frequent cell turnover (half-life of weeks to months) Basal (stem) cells difficult to access ⎼ Need broad coverage with a single administration to Targeted Delivery: Epithelial cells of the lower airways ⎼ a diseased lung with accumulated mucus ⎼ DNAI1 is a component of the ciliary axoneme required for ciliary beating
NON-CONFIDENTIAL 7 Ciliary Function Restored in Human Cells and Delivered to the Lung as an Inhaled Aerosol Rescued human DNAI1-deficient ciliated cells Well Tolerated
Repeat administration well tolerated Single administration, escalating dose well tolerated
Cellular uptake in the presence of mucus Expression levels constant with repeat dosing
Normal beat frequency recovered Histopathology Results Show No Findings
Synchronized wave-like motion restored Whole-body images of mice treated with luciferase mRNA formulated in a ReCode LNP and nebulized using an Activity comparable to normal controls Aerogen mesh nebulizer
DNAI1 incorporated into cilia of human respiratory epithelial cells
Green: Acetylated alpha-tubulin (microtubules) Human DNAI1 knock-out cells treated with a single Red: HA tagged dose of formulated DNAI1- DNAI1 HA and immuno-stained with anti-acetylated tubulin and anti-HA 72 hrs after dosing.
NON-CONFIDENTIAL 8 PCD and CF Have Clear and Similar Paths for Clinical Development and Approval Endpoints
Indication / Inclusion criteria Phase 1/2 Study* Primary Outcome Measures
PCD Lead mRNA Program SAD ∙● MAD (6 mo.) ● OLE (6 mo.) − Adults Placebo − Safety and tolerability − Pathogenic mutation in DNAI1 − Low Dose Absolute change in percent predicted − FEV1 between 40% and 90% FEV1 High Dose
CF Lead tRNA Program SAD ∙● MAD (3 mo.) ● OLE (9 mo.) − Adults Placebo − Safety and tolerability − CFTR mutation R553X, R1162X, or G542X − Low Dose Absolute change in percent predicted − FEV1 between 40% and 90% FEV1 High Dose
Same primary endpoints, same clinical sites & PIs, similar paths to approval *Phase 1/2 study could be the basis of drug approval
Precedent for clinical path established by approved drugs for CF
NON-CONFIDENTIAL 9 CF Therapeutic Program First-in-Class tRNA Program Targets Subset of the CF Population with No Approved Therapy CF Patients with Nonsense Mutations Do Not Benefit From Approved Therapies
Prevalence Development Path
Global CF patients by mutation/genotype WW Prevalence 70-100K* Currently No approved drugs to treat patients with CFTR nonsense mutations
• tRNA program focuses on a subset of ~5% of patients who do not adequately respond to currently approved drugs
• Trial endpoints well established based on approved therapies Global Patient Population with Nonsense Mutations Development Path Mutation *Number of patients Addressed by lead tRNA
Yes G542X 3,475 (demonstrated)
W1282X 1,552 No
R553X 1,298 Yes (demonstrated) Potential to be First-in-Class for targeted
Yes subset of patients R1162X 612 (expected**)
*Patients identified and tracked through global CF registry (CFTR2.org database) **Patient cells with R116X mutation not available; expected that NanoCorrector should work for all arginine nonsense mutations
NON-CONFIDENTIAL 11 Addressing High Unmet Need in CF
The Need The Solution
CF patients with nonsense (premature stop) mutations tRNA NanoCorrectors Restore Full-length Functional CFTR Protein have no therapeutic options (~5% of CF patients)
The Challenges Wild-type mRNA
Gln Val Arg Val lle Delivery to the right cells in the airway epithelium Full-length functional protein ⎼ Specificity of read-through: consistent amino acid insertion and recognition of true stops ⎼ mRNA with nonsense mutation (C to U resulting in “STOP”) Gln Val Truncated non-functional protein
NanoCorrector tRNAs LNP + tRNA Lead program (tRNA) supported by a $3.4M Arg “read through” the stop mutation and restore full- Therapeutic Development Award by the length functional protein Cystic Fibrosis Foundation (since 2017) GO Normal Restored full-length protein Gln Val Arg Val lle
Repeated delivery of tRNA to the epithelial cells of the conducting airways using existing inhaled aerosol delivery methods and devices
NON-CONFIDENTIAL 12 tRNA Restores CFTR Function in Patient-derived Cells
G542X/F508del R553X/F508del tRNA restores function in human (1) bronchial cells (hBEs) derived from hBEs hBEs patients with G542X and R553X nonsense mutations
Restores current in hBEs comparable to that seen with Lumacaftor (VX-809)
1 Heterozygote cell line from patients with G542X and F508del alleles: tRNA is affecting G542X while Lumacaftor is affecting F508del. NON-CONFIDENTIAL 13 Non-Viral LNP Delivery Technology Proprietary LNP Platform Based on Decades of Research and Deep Understanding of Lipid Chemistry Platform Includes Thousands of Novel Lipids
ZNPs CSAL dLNPs Selective ORgan Targeting Zwitterionic amino lipid (ZAL) Cationic quaternary ammonium Degradable and ionizable amino dendritic lipid nanoparticles sulfonamide amino lipid lipid nanoparticles (SORT LNPs)
Utilizes organ targeting (SORT) molecules to redirect LNPs
• Hybrid 3-component LNPs; multi-organ tropism • Traditional 4-component LNPs • Novel 5-component LNPs with programmed degradability • Optimized for structured cargos such as tRNA and mRNA; • Tissue-specific delivery nebulized delivery to lungs • Optimized for RNA delivery and gene editing in the liver • Optimized for delivery of RNA, gene editing agents, and • In vivo POC with repeated protein delivery in the lungs administrations shown for a and spleen (IV), muscle and broad range of targets brain (local).
NON-CONFIDENTIAL 15 Delivery Differentiator: SORT LNPs Deliver a Broad Range of Payloads to Specific Tissues and Cell Types
Exemplary Results (in vivo and in vitro)
• Preferential delivery to lung cells • Rescue of CFTR chloride transport in hBEs • Delivery of CRISPR/Cas9 to endothelium and epithelium via IV administration
• Delivery of CRISPR/Cas9 to the spleen • Editing in T cells, B cells, and macrophages • Editing observed in lymphatic tissue Delivery of Luciferase mRNA • Gene editing in liver hepatocytes (>95%) • Complete knockout of PCSK9 (serum & tissue) • Delivery of Epo, Klotho and IL-10 mRNA
Cheng et al. Nature Nanotechnology 2020, 15, 313. NON-CONFIDENTIAL 16 Proprietary SORT Platform Enables Tissue-specific CRISPR/Cas9 Gene Editing
Delivery of CRISPR / Cas9 to tdTom Reporter Mice • Novel 5-component LNPs with unique Lung-specific Liver-specific Spleen-specific biodistribution and packaging properties PBS SORT LNP SORT LNP SORT LNP • Standard 4-component LNP technology Heart limited to liver delivery Lungs • SORT LNPs utilize novel in vivo mechanisms to access other tissues and cell types Liver
• Applicable for gene editing by IV Spleen administration of Cas9 mRNA or protein (plus sgRNA and donor DNA) Kidneys
Cheng et al. Nature Nanotechnology 2020, 15, 313. NON-CONFIDENTIAL 17 SORT Delivery - Potential to Transform Treatment of CF
Enable durable CF gene correction with SORT
Broaden CF franchise Transform CF with mRNA platform landscape using Selective ORgan NEAR-TERM FOCUS Targeting (SORT) Potentially address the delivery of gene editing CF tRNA for nonsense entire CF patient components to mutation population population with progenitor (basal) cells mutation-agnostic for a long-lasting CFTR mRNA therapy Initial focus on patients correction with nonsense mutations using a tRNA read- through therapy
Near-term Mid-term Long-term
SORT unlocks the future of genetic medicines Improved Lung Delivery: IV delivery to the lung epithelium bypasses mucus and may further improve delivery in patients with impaired lung function Opportunities for Curative Therapies: Editing of long-lived stem cells (e.g., basal epithelial cells in the airways) NON-CONFIDENTIAL 18 Differentiated Non-Viral LNP Technology Delivers Diverse Cargos Beyond the Liver
Arbutus, Acuitas, Arcturus, ReCode Translate Bio Generation Bio BioNTech, CureVac, Ethris, Genevant, Moderna liver extrahepatic liver extrahepatic liver extrahepatic liver extrahepatic RNA mRNA, siRNA, miRNA tRNA Gene editing co-delivery of Cas9 mRNA + sgRNA +/- donor DNA Gene editing Cas9 RNPs* +/- donor DNA Gene therapy large DNA constructs 3-, 4-component LNPs, ligand conjugated LNPs 3-, 4-components LNPs1 4-component LNPs Class of LNPs 5-component SORTs1,2 for cell targeting
1Can be delivered as an inhaled aerosol 2Thousands of proprietary lipids available
NON-CONFIDENTIAL 19 Opportunity and Milestones Broad Therapeutic and Delivery Platform Enables Partnering Opportunities Outside of Genetic Respiratory Disease
Diverse Cargo Types Applicable Disease Areas
CRISPR(RNA or RECODE’s Focus Genetic respiratory diseases protein)/Cas Chronic inflammatory lung mRNA, tRNA, siRNA, disease, Pulmonary fibrosis miRNA CNS (including gene editing) mABs, other proteins Target Gene therapy targets requiring repeated administration Small molecules Organs/Tissue LNP Classes Immunodeficiency & Lungs autoimmune diseases 3-component ZALs & Immuno-oncology CSALs Spleen ReCode Integrated Platform In vivo CAR T-cell therapies 4-component Lymphatic Tissue dendrimer (dLNPs) Infectious disease/vaccines Liver 5-component SORT Liver fibrosis and cirrhosis Administration Route Brain / CNS Metabolic disorders IV Muscle Muscular dystrophies Inhaled aerosol Reactivation of tumor Intramuscular suppressors (oncology)
Intrathecal
NON-CONFIDENTIAL 21 Key Upcoming Milestones
Primary Ciliary Dyskinesia - DNAI1 Therapeutic Program Estimated Timing PCD – Formulation Selection in NHPs 1H 2021
PCD – Clinical Candidate Selection 2H 2021
PCD – IND-enabling Tox Studies 2H 2021 / 1H 2022
Cystic Fibrosis Therapeutic Programs CF – tRNA Formulation/Nebulization Optimization 2H 2021
CF – mRNA Formulation Selection 1H 2021
CF – Clinical Candidate Selection 2H 2021
CF – IND-enabling Tox Studies 2H 2021 / 1H 2022
Platform Technology SORT: Biodistribution and Tolerability Studies in NHPs 1H 2021
SORT: Delivery to Other Organs and Tissues; Gene Editing in Basal Cells Ongoing
NON-CONFIDENTIAL 22 ReCode Delivering the Future of Genetic Medicines
Programs Platform Capabilities First-in-Class Best-in-Class, NEW Class Ability to Deliver
• Genetic Medicines for Patients • Proprietary Non-viral LNP • Drug Development Expertise with High Unmet Needs Technology [SORT]
• Scalable Manufacturing • Drug Development and • Targeted Delivery Approval Paths Clear • Seasoned Management Team • Diverse Cargos, Mixed Cargos and Industry-leading Investors • Platform Technology to Expand and Advisors Solutions for PCD and CF… and Beyond!
NON-CONFIDENTIAL 23 A Differentiated Delivering the Future Therapeutic Company of Genetic Medicines Thank You!