Dyne Therapeutics, Inc. · NASDAQ:DYN
Dyne Therapeutics — ASGCT Annual Meeting 2021
19 slides from Dyne Therapeutics's conference presentation, May 14, 2021
Slide 1: Splice Correction and Reduction of Toxic DMPK RNA In Vitro and In Vivo
Splice Correction and Reduction of Toxic DMPK RNA In Vitro and In Vivo Utilizing Novel Antibody Targeted Antisense Oligonucleotides ROMESH SUBRAMANIAN, PH.D. Joachim, living with DM1 ASGCT ANNUAL MEETING | MAY 14, 2021
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding Dyne Therapeutics, Inc.’s (the “Company”) strat
Slide 3: Our Mission: Life-transforming therapies for serious muscle diseases
OUR MISSION Life-transforming therapies for patients with serious muscle diseases 3
Slide 4: Dyne FORCE Platform: Modern Oligo Therapeutics for Muscle Diseases
Dyne FORCE Platform: Modern Oligo Therapeutics for Muscle Diseases ANTIBODY Proprietary Fab targets TfR1 to enable muscle delivery PAYLOAD Modularity enables rational selection of payload to target the genetic basis of disease ASO siRNA LINKER Nuclear Cytoplasmic Clinically validated, enables locali
Slide 5: Robust Portfolio Focused on Muscle Diseases
Robust Portfolio Focused on Muscle Diseases PROGRAM TARGET DISCOVERY PRECLINICAL PHASE 1 PHASE 2 PHASE 3 ESTIMATED PATIENTS Myotonic Dystrophy US: >40,000 DMPK (DM1) Europe: >74,000 Exon 51 Duchenne Muscular Exon 53 US: ~12,000-15,000 Dystrophy (DMD) Exon 45 Europe: ~25,000 Exon 44 Facioscapulohumer
Slide 6: DM1 Program: Disease-Modifying Nuclear DMPK Knockdown
DM1 Program Overview Clinical Presentation Population • Mutation in the DMPK gene • Myotonia • >40,000 (US) • Onset at any point, depending • Muscle weakness • >74,000 (Europe) on DM1 phenotype • Cardiac arrhythmia • Life expectancy of 45 - 60 years • Pulmonary abnormalities OUR APPROACH Disease-Mod
Slide 7: FORCE Targets the Genetic Basis of DM1
FORCE Targets the Genetic Basis of DM1 DNA Triplet Toxic RNA RNA Binds Clinical Repeats Forms Foci Splicing Proteins Presentation Cytoplasm 449bp 479bp DMWD DMPK SIX5 Toxic DMPK mRNA MBNL Sequestered • Myotonia proteins Sequestered MBNL Toxic RNA is unable • Muscle weakness to leave the nucleus, seq
Slide 8: FORCE Demonstrated Robust DMPK KD, Foci Reduction, and Splice Correction
2,600 CTG Repeats DM1 Myoblasts: FORCE Demonstrated Robust DMPK KD, Foci Reduction, and Splice Correction DMPK mRNA KD by qPCR DMPK foci reduction by FISH BIN1 splice correction by qPCR 1.2 3.0 BIN1 Exon 11 Inclusion vs. PBS 1.0 2.5 DMPK vs. PBS 0.8 2.0 0.6 1.5 0.4 1.0 0.2 0.5 0.0 0.0 PBS FORCE PBS
Slide 9: Dose-Dependently Corrected Splicing and Reversed Myotonia in HSALR DM1 Mouse Model
FORCE Dose-Dependently Corrected Splicing and Reversed Myotonia in the HSALR DM1 Mouse Model Splicing Correction Near Complete Myotonia Reversal in Multiple Muscles Within 14 Days After a Single Low Dose 3.0 Myotonia Grade (EMG) 2.0 1.0 0.0 PBS ASO Dyne Note: HSALR mice, single dose 14-day study. Ov
Slide 10: FORCE Dose-Dependently Corrected Splicing in Multiple RNAs in HSALR Mouse Model
FORCE Dose-Dependently Corrected Splicing in Multiple RNAs in HSALR DM1 Mouse Model After a Single Dose Gastrocnemius WT Splicing: Splicing Derangement = 0.0 10
Slide 11: Dose-Dependently Corrected Splicing and Reversed Myotonia in HSALR DM1 Mouse Model
FORCE Dose-Dependently Corrected Splicing and Reversed Myotonia in the HSALR DM1 Mouse Model Splicing Correction Near Complete Myotonia Reversal in Multiple Muscles Within 14 Days After a Single Low Dose 3.0 Myotonia Grade (EMG) 2.0 1.0 0.0 PBS ASO Dyne Note: HSALR mice, single dose 14-day study. Ov
Slide 12: hTfR1/DMSXL: Innovative Model to Evaluate Pharmacodynamics
hTfR1/DMSXL: Innovative Model Developed by Dyne to Evaluate Pharmacodynamics By Measuring Toxic Human Nuclear DMPK KD Fully human Expresses human toxic FORCE Uptakes human TfR1 conjugate targeting Fabs DMPK mDMPK ASO 1,000+ CUG hTfR1 repeats ASO hDMPK hTfR1 DMSXL Nucleus mDMPK Cytoplasm • Expresses
Slide 13: Dyne Lead Conjugate Demonstrated Robust Toxic Human DMPK KD in hTfR1/DMSXL Model
Dyne Lead Conjugate Demonstrated Robust Toxic Human DMPK KD in hTfR1/DMSXL Model Fully human FORCE conjugate mDMPK ASO 1,000+ CUG hTfR1 repeats hDMPK ASO Nucleus mDMPK Cytoplasm Note: 2 x 10 mg/kg, d0 and d7, analyzed d14; Data are mean ±SD; *p < 0.05, **p < 0.01,***p < 0.001, ****p < 0.0001, signif
Slide 14: Demonstrated Robust Foci Reduction in the Heart of hTfR1/DMSXL Mice
FORCE Demonstrated Robust Foci Reduction in the Heart of hTfR1/DMSXL Mice DMPK mRNA KD by qPCR DMPK foci reduction by in situ hybridization PBS FORCE DMPK vs. PBS Toxic human DMPK foci Nuclei Note: 10 mg/kg ASO d0 and d7, analyzed d14; data are mean ±SD; n = 6 – 9; ****p < 0.0001, significant by t-t
Slide 15: Single Dose of FORCE Conjugate Achieved Sustained Human Toxic DMPK KD at Week 4
Single Dose of FORCE Conjugate Achieved Sustained Human Toxic DMPK KD at Week 4 in the hTfR1/DMSXL mouse 10 mg/kg hTfR1/DMSXL mice D0 Wk 4 Heart Diaphragm Gastrocnemius Tibialis Anterior 1.4 1.8 51% KD 1.4 1.4 1.6 1.2 1.2 1.2 42% KD 46% KD 46% KD 1.4 DMPK vs. PBS DMPK vs. PBS DMPK vs. PBS DMPK vs. P
Slide 16: Enhanced Distribution and WT DMPK KD Across NHP Muscles
FORCE Achieved Enhanced Distribution and WT DMPK KD Across NHP Skeletal, Cardiac and Smooth Muscles Gastrocnemius Soleus Deep Flexor Bicep Ileum (Near Cecum) 62% KD 39% KD 62% KD 51% KD 70% KD Heart-left Ventricle Diaphragm Masseter Quadricep Jejunum (Duodenum Ends) 36% KD 49% KD 41% KD 52% KD 63% K
Slide 17: FORCE Well-Tolerated in Single Dose NHP Study
FORCE Well-Tolerated in Single Dose NHP Study All CBC measures, including iron homeostasis and platelet counts, within normal range Kidney and liver function, including ALT, AST, and BUN:Creatinine ratio, within normal range Note: ALT: alanine transaminase, AST: aspartate transaminase, BUN: blood ur
Slide 18: DM1 Program Summary
DM1 Program Summary Preclinical Summary Potential Advantages Targeted toxic DMPK in the nucleus in patient cells • Tractable development with rapid path to human PoC Robust and durable toxic human DMPK KD in • Efficient commercial model, addressable with focused novel hTfR1/DMSXL model sales force R
Slide 19: Stop or Reverse Disease Progression
Three INDs planned between Q4 2021 - Q4 2022 Targeting the genetic basis of serious muscle diseases to STOP OR REVERSE DISEASE PROGRESSION FORCE Robust Delivering Exceptional PLATFORM PIPELINE FOR PATIENTS TEAM 19