Entrada Therapeutics, Inc. · NASDAQ:TRDA
Entrada Therapeutics — Boulder Peptide Symposium 2022
29 slides from Entrada Therapeutics's conference presentation, Nov 10, 2022
Slide 1: Development of Endosomal Escape Vehicles to Enhance the Intracellular Delivery of Oligonucleotides
Development of Endosomal Escape Vehicles to Enhance the Intracellular Delivery of Oligonucleotides Patrick Dougherty, PhD Senior Scientist, Discovery Research Boulder Peptide Symposium November 10 th , 2022 1 BPS 2022
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 BPS 2022
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’s EEV platform consists of a library of proprietary cyclic peptides with unique chemistry that enable improved uptake and endosomal escape 3 Prolonged duration of effect • Unique chemistry results in improved uptake 1 High intracellular uptake (int
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 BPS 2022
Slide 11: DMD Overview
DMD OVERVIEW Duchenne muscular dystrophy (DMD) is a progressive, devastating muscle wasting disease with significant unmet need. Entrada’s first DMD program is for exon 44 skipping • DMD is caused by mutations in the DMD gene that encodes for dystrophin1 • Progressive muscle degeneration, wasting an
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: Repeat EEV-PMO Treatment Results in CK Correction and Functional Improvement
REPEAT EEV-PMO TREATMENT RESULTS IN CK CORRECTION AND FUNCTIONAL IMPROVEMENT Repeat EEV-PMO-23 treatment normalized serum CK levels and showed significant improvements in muscle function when compared to PMO alone after four monthly IV doses in D2-mdx mice Serum CK Levels Wire Hang Time Grip Strengt
Slide 14: Exon Skipping and Dystrophin Production in Patient-Derived Cells
EXON SKIPPING AND DYSTROPHIN PRODUCTION IN PATIENT-DERIVED CELLS Robust dose-dependent exon 44 skipping and dystrophin protein production were observed in DMD patient-derived muscle cells treated with clinical candidate, ENTR-601-44 Exon Skipping Dystrophin Protein Production 120 **** 120 **** DMD E
Slide 15: ENTR-601-44 in Human DMD Mice (hDMD)
ENTR-601-44 IN HUMAN DMD MICE (hDMD) A single IV dose of ENTR-601-44 resulted in high and durable levels of exon 44 skipping across major muscle groups in hDMD mice for at least 12 weeks Heart Diaphragm Tibialis Anterior Triceps 100 100 100 100 Exon skipping (%) 80 80 80 80 60 60 60 60 40 40 40 40 2
Slide 16: ENTR-601-44 in NHP
ENTR-601-44 IN NHP 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 Weeks 120 100 Cohort 1
Slide 17: Entrada DMD Data Summary
ENTRADA DMD DATA SUMMARY Entrada’s murine and NHP data represent a robust set of translational data; IND application in Q4 2022 • High levels of exon skipping across mdx, D2-mdx, human dystrophin mouse and NHP studies • Exon skipping translates to promising dystrophin production in heart and skeleta
Slide 18: Myotonic Dystrophy Type 1 (DM1)
MYOTONIC DYSTROPHY TYPE 1 (DM1) 18 BPS 2022
Slide 19: DM1 Overview
DM1 OVERVIEW DM1 is a debilitating multi-systemic disease with no available treatments; CUG repeats in DMPK mRNA sequester MBNL proteins, resulting in nuclear foci, aberrant splicing, and disease • DM1 occurs in 1:8,000 people worldwide and affects ~40,000 patients in US and over 50,000 in Europe ▪
Slide 20: ENTR-701 in DM1 Cell Line with Repeat Expansion
ENTR-701 IN DM1 CELL LINE WITH REPEAT EXPANSION DM1 clinical candidate, ENTR-701, showed reduction of nuclear foci and selective reduction of repeat expansion-containing DMPK transcript in the HeLa480 cell line Nuclear Foci Reduction Selective Reduction of Mutant DMPK mRNA Nuclei Endogenous DMPK Foc
Slide 21: ENTR-701 in DM1 Patient-Derived Myotubes
ENTR-701 IN DM1 PATIENT-DERIVED MYOTUBES ENTR-701 treatment in DM1 patient-derived muscle cells resulted in significant nuclear foci reduction and correction of aberrant splicing Nuclear Foci Reduction Correction of Aberrant Splicing Nuclei MBNL1 SOS1 Foci 100 60 (normalized to DM1 untreated) 1.25 E
Slide 22: Efficacy of ENTR-701 in HSA-LR Mice
EFFICACY OF ENTR-701 IN HSA-LR MICE ENTR-701 treatment reduced nuclear foci and CUG-repeat expansion transcript level and corrected aberrant splicing in HSA-LR mice Nuclear Foci Reduction Atp2a1 Splicing Correction HSA-r(CUG)220 Reduction Nuclei 120 1.5 Relative r(CUG)220 Levels Foci 40 Exon 22 Incl
Slide 23: ENTR-701 Corrected Spliceopathy in HSA-LR Mice
ENTR-701 CORRECTED SPLICEOPATHY IN HSA-LR MICE Mbnl1 (54 nt) Nfix (123 nt) Atp2a1 (42 nt) Ldb3 (186 nt) Camk2g (114 nt) Trim55 (288 nt) Fbxo31 (87 nt) Slc8a3 (18 nt) Map3k4 (156 nt) Dctn4 (21 nt) 1.0 0.8 0.6 0.4 0.2 Splicing Index 0.0 T T EN L R EN -LR 01 01 01 T T EN -LR EN LR 01 T T T T T EN -LR E
Slide 24: Durability of ENTR-701 in HSA-LR Mice
DURABILITY OF ENTR-701 IN HSA-LR MICE A single dose of ENTR-701 resulted in splicing correction in HSA-LR mice for at least 8 weeks Mbnl1 Exon 5 Inclusion Atp2a1 Exon 22 Inclusion Nfix Exon 7 Inclusion ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱ ✱✱ 30 120 40 Exon 22 Inclusion (
Slide 25: Myotonia Correction in HSA-LR Mice
MYOTONIA CORRECTION IN HSA-LR MICE A single dose of ENTR-701 ameliorated pinch-induced myotonia for at least 8 weeks HSA-LR Mouse: Non-treated HSA-LR Mouse: ENTR-701 Treated 25 ENTR-701 is the clinical candidate selected for DM1, composed of CUG-repeat blocking PMO conjugated to EEV BPS 2022
Slide 26: Entrada DM1 Data Summary
ENTRADA DM1 DATA SUMMARY ENTR-701 demonstrated potential to treat DM1 via a CUG-repeat steric blocking approach both in vitro and in vivo; IND application planned in 2023 • Robust in vitro and in vivo data set demonstrating: ▪ Highly specific reduction of pathogenic CUG-repeat containing mRNA ▪ Redu
Slide 27: Discovery Programs
DISCOVERY PROGRAMS 27 BPS 2022
Slide 28: 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 29: Thank you!
ACKNOWLEDGEMENTS Thank you! 29 BPS 2022
Entrada Therapeutics — Boulder Peptide Symposium 2022 on 6ix