Entrada Therapeutics, Inc. · NASDAQ:TRDA
Entrada Therapeutics — Targeted Intracellular Delivery Summit 2023
24 slides from Entrada Therapeutics's conference presentation, Mar 8, 2023
Slide 1: Development of Endosomal Escape Vehicles (EEV) to Enhance Functional Delivery of Oligonucleotides
Development of Endosomal Escape Vehicles (EEV™) to Enhance the Functional Delivery of Oligonucleotides Patrick Dougherty, PhD Senior Scientist, Discovery Research Targeted Intracellular Delivery Summit March 8, 2023 1 Targeted Intracellular Delivery Summit 2023
Slide 2: Disclaimer
DISCLAIMER This presentation includes express and implied “forward-looking statements. Forward looking statements include all statements that are not historical facts, and in some cases, can be identified by terms such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,
Slide 3: Entrada's Mission
ENTRADA’S MISSION Treating Devastating Diseases With Intracellular Therapeutics 3 Targeted Intracellular Delivery Summit 2023
Slide 4: The Need for Intracellular Therapeutics
THE NEED FOR INTRACELLULAR THERAPEUTICS Approximately 75% of all disease-causing targets are intracellular and difficult to reach, representing a significant issue when developing effective therapies First Challenge: Cell Entry Early Endosome Second Challenge: ~75% of Disease Targets Escape from the
Slide 5: Endosomal Escape Vehicle (EEV) Platform
ENDOSOMAL ESCAPE VEHICLE (EEV TM ) PLATFORM Entrada seeks to solve a fundamental problem: lack of efficient cellular uptake and escape from the endosome; Both are critical to intracellular target engagement and therapeutic benefit Prolonged duration of effect 3 • Unique chemistry results in improved
Slide 6: A Broadly Applicable Platform
A BROADLY APPLICABLE PLATFORM Entrada has demonstrated intracellular uptake of unique moieties ranging from 1 kDa to 600 kDa Antibodies Enzymes Oligonucleotides 550-600 KDa 150 KDa 98 KDa 96 KDa 86 KDa 46 KDa 37 KDa 32 KDa 16 KDa 6 KDa 1-3 KDa Hybrid frataxin Antibody Thymidine Purine Alanine- Human
Slide 7: EEV Library: Screening and Optimization
EEV LIBRARY: SCREENING AND OPTIMIZATION Discovery Engine for Intracellular Therapeutics Screening Cascade for EEV Candidates Chemically-diverse >500 member EEV library EEV Linker Therapeutic modality In vitro functional validation EEVs with robust target cell uptake and efficacy in relevant cell typ
Slide 8: Functional Delivery for Target Tissues
FUNCTIONAL DELIVERY FOR TARGET TISSUES Entrada’s EEV-therapeutics can be designed to enhance functional delivery to target tissues EGFP-654 Transgenic Mice Functional Delivery to Target Tissues 200 PMO654 138.6 EEV-PMO654 EGFP Protein (a.u.) 150 103.6 69.3 100 33.3 50 27.1 14.6 6.6 4.0 4.1 2.9 0 Tri
Slide 9: Translation from Uptake to Outcomes
TRANSLATION FROM UPTAKE TO OUTCOMES EEV-therapeutics possess favorable pharmacological properties: significant uptake in target tissues, efficient intracellular delivery and potent pharmacodynamic outcomes Tissue Uptake in Muscle Intracellular Delivery Pharmacodynamic Outcome ✓ Skeletal muscle ✓ End
Slide 10: Duchenne Muscular Dystrophy (DMD)
DUCHENNE MUSCULAR DYSTROPHY (DMD) 10 Targeted Intracellular Delivery Summit 2023
Slide 11: DMD Overview and Therapeutic Approach
DMD OVERVIEW AND THERAPEUTIC APPROACH Duchenne is caused by mutations in the DMD gene, which Exon skipping therapeutics have been approved lead to a lack of functional dystrophin, causing based on modest improvement in dystrophin progressive loss of muscle function throughout the body levels ranging
Slide 12: Repeat EEV-PMO Treatment in D2-mdx Mice
REPEAT EEV-PMO TREATMENT IN D2-mdx MICE Robust exon 23 skipping after four monthly IV doses Broad dystrophin expression and restoration of muscle integrity of EEV-PMO-23 in D2-mdx mice after four monthly IV doses of EEV-PMO-23 in D2-mdx mice Representative Immunofluorescence of Gastrocnemius Muscle
Slide 13: ENTR-601-44 for Exon Skip Amenable DMD
ENTR-601-44 FOR EXON 44 SKIP AMENABLE DMD A single IV dose of ENTR-601-44 resulted in robust exon skipping in both skeletal and cardiac muscles in NHP, as well as prolonged duration of effect for at least 12 weeks Exon Skipping in NHP Muscles at Day 7 Duration of Effect in NHP Biceps for at Least 12
Slide 14: ENTR-601-45 for Exon Skip Amenable DMD
ENTR-601-45 FOR EXON 45 SKIP AMENABLE DMD ENTR-601-45 showed robust exon skipping and dystrophin production in patient-derived skeletal and cardiac muscle cells ENTR-601-45 in Skeletal Muscle Cells ENTR-601-45 in Cardiac Muscle Cells 14 ENTR-601-45 is a DMD exon 45 skipping PMO conjugated to the EEV
Slide 15: Myotonic Dystrophy Type 1 (DM1)
MYOTONIC DYSTROPHY TYPE 1 (DM1) 15 Targeted Intracellular Delivery Summit 2023
Slide 16: DM1 Is a Debilitating, Multisystemic Disease with No Available Treatments
DM1 IS A DEBILITATING, MULTISYSTEMIC DISEASE WITH NO AVAILABLE TREATMENTS DM1 is caused by a mutation in the 40,000+ 50,000+ dystrophia myotonica protein kinase (DMPK) gene people in the U.S. have DM11 people in Europe have DM11 Symptoms include: Fatigue and excessive daytime sleepiness Cardiac cond
Slide 17: ENTR-701 Efficacy in HSA-LR Mice
ENTR-701 EFFICACY IN HSA-LR MICE ENTR-701 treatment reduced nuclear foci and CUG-repeat expansion transcript level and corrected aberrant splicing in HSA-LR mice, in a dose dependent manner Nuclear Foci Reduction Atp2a1 Splicing Correction HSA-r(CUG)220 Reduction Nuclei 120 1.5 Relative r(CUG)220 Le
Slide 18: DM1 Data Summary
DM1 DATA SUMMARY ENTR-701 demonstrated potential to treat DM1 via a CUG-repeat steric blocking approach both in vitro and in vivo • Robust in vitro and in vivo data set demonstrating: ▪ Highly specific reduction of pathogenic CUG-repeat containing mRNA ▪ Reduction of nuclear foci ▪ Correction of Mbn
Slide 19: Interferon Regulatory Factor 5 (IRF5)
INTERFERON REGULATORY FACTOR 5 (IRF5) 19 Targeted Intracellular Delivery Summit 2023
Slide 20: EEV-PMO Treatment Reduced IRF5 Expression In Vitro
EEV-PMO TREATMENT REDUCED IRF5 EXPRESSION IN VITRO Interferon regulatory factor 5 (IRF5) overexpression has been implicated in several autoimmune and inflammatory diseases EEV-PMO Approach to Knockdown IRF5 IRF5 Production Relative IRF5 Protein Expression IRF5 pre-mRNA 2.0 With EEV-PMO 2 3 4 5 6 7 8
Slide 21: Summary
SUMMARY Our EEV-PMO approach has broad applicability to upregulate and downregulate target gene expression through distinct mechanisms of action • Increased Dystrophin Production in DMD Models via Exon Skipping ▪ ENTR-601-44a and ENTR-601-45 showed robust exon skipping and dystrophin protein product
Slide 22: Discovery Programs
DISCOVERY PROGRAMS 22 Targeted Intracellular Delivery Summit 2023
Slide 23: Additional Platform Opportunities
ADDITIONAL PLATFORM OPPORTUNITIES Entrada continues to invest in and build upon our EEV Platform to extend our efforts in developing novel EEV-therapeutic candidates Target Platform Approach Goal DNA Gene editing Deliver CRISPR enzyme and repair gene function with guide RNA RNA editing Deliver oligo
Slide 24: Thank you!
ACKNOWLEDGEMENTS Thank you! 24 Targeted Intracellular Delivery Summit 2023
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