Dyne Therapeutics, Inc. · NASDAQ:DYN
Dyne Therapeutics — Muscle Study Group Annual Scientific Meeting 2021
29 slides from Dyne Therapeutics's conference presentation, Nov 4, 2021
Slide 1: FORCE Platform Delivers Exon Skipping PMO, Leads to Durable Increases in Dystrophin Protein
FORCETM Platform Delivers Exon Skipping PMO, Leads to Durable Increases in Dystrophin Protein in mdx Mice and Is Well Tolerated in NHPs Oxana Beskrovnaya, Ph.D. Muscle Study Group Annual Scientific Meeting | Oct. 1, 2021 Ravi, living with DMD
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’s strategy, future operations, prospects a
Slide 3: Agenda
Agenda • FORCE platform to enable muscle-targeted delivery of oligonucleotides • Application of FORCE platform for the treatment of DMD Functional benefit in the mdx mouse model FORCE platform achieves high level dystrophin expression across cardiac and skeletal muscle in mdx model • On path to
Slide 4: Dyne FORCE Platform: Modern Oligo Therapeutics for Muscle Diseases
Dyne FORCETM 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 LINKER Clinically validated, enables precise conjugation of payloads to
Slide 5: Rationally Select Payload to Target Genetic Basis of Disease
Rationally Select Payload to Target Genetic Basis of Disease ASO acts in the Subcellular distribution of ASO and siRNA siRNA acts in the cytoplasm nucleus and cytoplasm Cell Membrane ASO siRNA Exogenous dsRNA Cell Membrane mRNA-Antisense Duplex Dicer mRNA complex RNaseH1 Recognizes Duplex RNase H1 E
Slide 6: FORCE Platform Designed to Deliver Significant Advantages
FORCE Platform Designed to Deliver Significant Advantages Targeted Muscle Delivery Targets Genetic Basis of Disease Leverages TfR1 expression Rationally select payloads on skeletal, cardiac and smooth muscle to match target biology Stop or Reverse Redosable Administration Enhanced Tolerability Disea
Slide 7: Building a Global DMD Franchise of Transformative Therapies
Building a Global DMD Franchise of Transformative Therapies Overview Clinical Presentation Population • Mutation in the DMD gene that • Muscle weakness • ~12,000 - 15,000 (US) encodes for dystrophin • Progressive loss of function • ~ 25,000 (Europe) • Onset in first few years of life • Loss of ambul
Slide 8: ASO-Mediated Exon Skipping: Mechanism for Disease Correction
ASO-Mediated Exon Skipping: Mechanism for Disease Correction DMD patient ASO-treated DMD patient Healthy ∆ex49-50 ∆ex49-50 DMD 48 49 50 51 52 48 51 52 48 51 52 Pre-mRNA Ex 51 ASO Premature stop codon DMD 48 49 50 51 52 48 51 52 48 52 Mature mRNA Out-of-frame Protein Dystrophin Truncated, produced NO
Slide 9: Agenda
Agenda • FORCE platform to enable muscle-targeted delivery of oligonucleotides • Application of FORCE platform for the treatment of DMD Functional benefit in the mdx mouse model FORCE platform achieves high level dystrophin expression across cardiac and skeletal muscle in mdx model • On path to
Slide 10: FORCE Dose-Dependently Increased Dystrophin Expression
FORCE Dose-Dependently Increased Dystrophin Expression 0 1 2 weeks Quadriceps FORCE-M23D 10, 20, or 30 mg/kg FORCE-M23D IV dose Tissue analysis Dose-Dependent Increase in Dystrophin Expression Restored Dystrophin Expression Std. Curve (% WT) 10 20 30 64 32 16 4 1 0 mg/kg mg/kg mg/kg Dystrophin 427 k
Slide 11: Demonstrated Functional Benefit with a Single Dose
FORCE Demonstrated Functional Benefit with a Single Dose Distance Traveled in Distance Traveled in Open Field Home Cage Running Wheel Following Hind Limb Fatigue Challenge (Assessed 4 weeks after treatment) (Assessed 2 weeks after treatment) 1250 Light Dark Active Period Light Period Period Distance
Slide 12: Study Evaluated Dynamic of FORCE on Dystrophin Expression up to 12 Weeks After a Single Dose
Study Evaluated Dynamic of FORCE on Dystrophin Expression up to 12 Weeks After a Single Dose Study Timeline (Weeks) Endpoints 0 1 2 3 4 5 6 7 8 9 10 11 12 • ASO muscle concentration • Exon skipping by PCR 10 or 30 mg/kg • Dystrophin protein by WB 10 or 30 mg/kg • Dystrophin localization by IF 10 or
Slide 13: Achieved Robust and Durable Skipping and Dystrophin Expression in Cardiac and Skeletal Muscle
FORCE Achieved Robust and Durable Skipping and Dystrophin Expression in Cardiac and Skeletal Muscle Quadriceps Diaphragm Heart 50 50 50 40 40 40 % Skipping % Skipping % Skipping 30 30 30 20 20 20 10 10 10 0 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 We
Slide 14: Achieved Robust and Durable Skipping and Expression of Dystrophin in Quadriceps
FORCE Achieved Robust and Durable Skipping and Expression of Dystrophin in Quadriceps % Skipping by PCR Dystrophin by WB FORCE-M23D FORCE-M23D 10 mg/kg 10 mg/kg 50 60 30 mg/kg 30 mg/kg % Dystrophin Protein 40 50 % Skipping 40 30 30 20 20 10 10 0 0 Weeks: 0.4 1 4 8 12 Weeks: 0.4 1 4 8 12 Note: Single
Slide 15: Robust Dystrophin Expression and Localization to Sarcolemma in Quadriceps at 8 Weeks
FORCE Achieved Robust Dystrophin Expression and Localization to Sarcolemma in Quadriceps at 8 Weeks Dystrophin Expression by WB Dystrophin Localization to Sarcolemma 30 mg/kg 8 Weeks Post-Dose Vehicle FORCE-M23D % WT Dystrophin FORCE M23D Dystrophin 16 4 1 0 Dystrophin αActinin Laminin 41% of wild-t
Slide 16: Achieved Durable Dystrophin Localization to Sarcolemma in Quadriceps
FORCE Achieved Durable Dystrophin Localization to Sarcolemma in Quadriceps Dystrophin Dystrophin-positive fibers: 68% 83% 45% 100 µm Laminin WT mdx vehicle 4 weeks 8 weeks 12 weeks mdx FORCE-M23D 30 mg/kg Note: Single IV 30 mg/kg dose of FORCE-M23D in mdx mouse model on day 0, analysis at specified
Slide 17: Achieved Robust and Durable Skipping and Expression of Dystrophin in Diaphragm
FORCE Achieved Robust and Durable Skipping and Expression of Dystrophin in Diaphragm % Skipping by PCR Dystrophin by WB FORCE-M23D FORCE-M23D 10 mg/kg 10 mg/kg 40 100 30 mg/kg 30 mg/kg 90 % Dystrophin Protein 80 30 70 % Skipping 60 20 50 40 30 10 20 10 0 0 Weeks: 0.4 1 4 8 12 Weeks: 0.4 1 4 8 12 Not
Slide 18: Robust Dystrophin Expression and Localization to Sarcolemma in Diaphragm at 4 Weeks
FORCE Achieved Robust Dystrophin Expression and Localization to Sarcolemma in Diaphragm at 4 Weeks Dystrophin Expression by WB Dystrophin Localization to Sarcolemma 30 mg/kg 4 Weeks Post-Dose Vehicle FORCE-M23D % WT Dystrophin Dystrophin 16 4 1 0 FORCE-M23D Dystrophin αActinin Laminin 90% of wild-ty
Slide 19: Achieved Robust and Durable Skipping and Expression of Dystrophin in Heart
FORCE Achieved Robust and Durable Skipping and Expression of Dystrophin in Heart % Skipping by PCR Dystrophin by WB FORCE-M23D FORCE-M23D 10 mg/kg 10 mg/kg 50 100 30 mg/kg 30 mg/kg 90 % Dystrophin Protein 40 80 70 % Skipping 30 60 50 20 40 30 10 20 10 0 0 Weeks: 0.4 1 4 8 12 Weeks: 0.4 1 4 8 12 Note
Slide 20: Robust Dystrophin Expression and Localization to Sarcolemma in Heart at 4 Weeks
FORCE Achieved Robust Dystrophin Expression and Localization to Sarcolemma in Heart at 4 Weeks Dystrophin Expression by WB Dystrophin Localization to Sarcolemma 30 mg/kg 4 Weeks Post-Dose Vehicle FORCE-M23D % WT Dystrophin Dystrophin 16 4 1 0 FORCE-M23D Dystrophin αActinin Laminin 78% of wild-type d
Slide 21: Achieved Robust and Durable Dystrophin Expression and Sarcolemma Localization in Muscle
FORCE Achieved Robust and Durable Dystrophin Expression and Sarcolemma Localization in Muscle Quadriceps Diaphragm Heart Dystrophin expression by WB 46% of wild-type dystrophin 90% of wild-type dystrophin 78% of wild-type dystrophin Vehicle FORCE-M23D Vehicle FORCE-M23D Vehicle FORCE-M23D Dystrophin
Slide 22: Distinctive Pharmacokinetic Profile Delivered Substantial and Durable Dystrophin Expression with a Single Dose
FORCE Distinctive Pharmacokinetic Profile Delivered Substantial and Durable Dystrophin Expression with a Single Dose Pharmacokinetics Pharmacodynamics Muscle ASO concentration Exon skipping Dystrophin restoration FORCE-M23D 10 mg/kg FORCE-M23D 30 mg/kg 200 60 200 60 % Dystrophin or Skipping % Dystro
Slide 23: Agenda
Agenda • FORCE platform to enable muscle-targeted delivery of oligonucleotides • Application of FORCE platform for the treatment of DMD Functional benefit in the mdx mouse model FORCE platform achieves high level dystrophin expression across cardiac and skeletal muscle in mdx model • On path to
Slide 24: DYNE-251 Achieved Robust and Dose-Dependent Exon Skipping in DMD Patient Myotubes
DYNE-251 Achieved Robust and Dose-Dependent Exon 51 Skipping in DMD Patient Myotubes Exon 51 Skipping in del52 DMD Myotubes 80 % Exon 51 Skipping 60 40 20 0 Low Medium High DYNE-251 Note: DYNE-251 exposure in DMD patient myotubes for 10 days. N = 3. 24
Slide 25: Dose Regimen Study in NHPs to Inform Clinical Dose
Dose Regimen Study in NHPs to Inform Clinical Dose Endpoints Study Timeline (Weeks) • Exon skipping by PCR 0 1 2 3 4 5 6 7 8 2 x 30 mg/kg Tissues analyzed 4 x 30 mg/kg • Quadriceps 5 x 30 mg/kg • Diaphragm DYNE-251 IV dose • Heart Tissue analysis 25
Slide 26: DYNE-251 Achieved Robust Exon Skipping in NHP Skeletal and Cardiac Muscles
DYNE-251 Achieved Robust Exon Skipping in NHP Skeletal and Cardiac Muscles Study Timeline (Weeks) 0 1 2 3 4 5 6 7 8 2 x 30 mg/kg DYNE-251 IV dose 4 x 30 mg/kg Tissue analysis 5 x 30 mg/kg Quadriceps Diaphragm Heart 18% 52% 43% 25 80 60 % Exon 51 Skipping % Exon 51 Skipping % Exon 51 Skipping 20 60 4
Slide 27: DYNE-251 NHP GLP Toxicology Results Demonstrated Favorable Safety Profile That Support Advancement to Clinic
DYNE-251 NHP GLP Toxicology Results Demonstrated Favorable Safety Profile That Support Advancement to Clinic • No dose limiting toxicity observed after five weekly doses up to a maximally feasible dose • No changes in cardiac, respiratory, neurologic or ophthalmic endpoints • No effect on kidney fun
Slide 28: Summary
Summary • In mdx mouse model FORCE achieved: Dose-dependent, robust, and durable skipping and dystrophin expression Long-lasting dystrophin localization to sarcolemma Functional benefit • DYNE-251 demonstrated robust and dose-dependent exon 51 skipping in DMD patient myotubes • DYNE-251 demons
Slide 29: 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 29
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