Slide 1: Insight Into the Mechanism of Action of AAV-SLB101, a Novel Muscle-Tropic Capsid
Insight Into the Mechanism of Action of AAV-SLB101, a Novel Muscle-Tropic Capsid for Neuromuscular and Cardiac Indications Jessica F Boehler, PhD Principal Scientist, DMD Scientific Lead Solid Biosciences © 2025 Solid Biosciences - Nonconfidential
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding future expectations, plans and prospects for the company; the ability to successfully achieve and execute on t
Slide 3: Disclosures
Disclosures • I am a full-time employee at Solid Biosciences Inc. and hold equity in the company 3 © 2025 Solid Biosciences - Nonconfidential
Slide 4: Rational Capsid Design Can Optimize AAV Therapeutics
Rational Capsid Design Can Optimize AAV Therapeutics AAV is a lead delivery vehicle for genomic medicines1 Gap: Natural capsids (e.g., AAV9) can exhibit inefficient High doses of AAV are transduction to target tissues1 required to reach certain tissues but can be associated with adverse High-dose ad
Slide 5: AAV-SLB101: Next Generation Capsid for Improved AAV Delivery
AAV-SLB101: Next Generation Capsid for Improved AAV Delivery • AAV-SLB101 was engineered by inserting a VR-VIII peptide sequence into the VR-VIII of the AAV9 capsid 3 • The VR-VIII extends outward from the external capsid surface and has been demonstrated to drive AAV-cell interaction1 5 • The inser
Slide 6: AAV-SLB101 Demonstrated Improved Transgene Expression in Skeletal and Cardiac Muscle
AAV-SLB101 Demonstrated Improved Transgene Expression in Skeletal and Cardiac Muscle Across Mice and Non-Human Primates (NHPs) Whole Body Protein Expression in WT Muscle Protein Expression (Luciferase Micea Activity in NHPs)b AAV-SLB101 AAV9 SKELETAL MUSCLE CARDIAC MUSCLE 30.0 40.0 Fold change vs AA
Slide 7: Improved Transgene Expression Correlated with Superior Biodistribution in Skeletal and Cardiac Muscle
Improved Transgene Expression Correlated with Superior Biodistribution in Skeletal and Cardiac Muscle in mice and NHPs Biodistribution in Isolated Tissues (Day Biodistribution in Isolated Tissues (Day 28 28 post-dose)a post-dose)b SKELETAL MUSCLE CARDIAC MUSCLE 6x1035 QUADRICEPS 3.005 6x10 HEART 4.0
Slide 8: AAV-SLB101 Transduction of Human Skeletal Muscle Cells and Cardiomyocytes
AAV-SLB101 Transduction of Human Skeletal Muscle Cells and Cardiomyocytes Resulted in Robust and Superior Protein Expression Human DMD Myotubes (n=3 cell lines) Healthy iPSC-Derived Cardiomyocytes 40 22.5x 25 20.8x 20 30 (relative to AAV9) (relative to AAV9) Fold change Fold change 15 20 10 10 5 1 0
Slide 9: We Hypothesize That the Mechanism of Action of AAV-SLB101
We Hypothesize That the Mechanism of Action of AAV-SLB101 Drives Improvements in Biodistribution, Expression, and Kinetics1,2 Recombinant Versions of the Integrin C2C12 Data Support Integrin Mechanism Conserved Receptora Show Binding to Binding Mechanism Affecting Across Species When AAV-SLB101a AAV
Slide 10: AAV-SLB101 Resulted in Faster Transgene Expression Compared With AAVrh74 and AAV9
AAV-SLB101 Resulted in Faster Transgene Expression Compared With AAVrh74 and AAV9 Capsid Comparison (luciferase expression)a 11 1.2e+10 Vehicle 10 1.0e+10 AAV9 9 AAVrh74 8.0e+9 AAV-SLB101 8 6.0e+9 7 AAV-SLB101 showed 4.0e+9 Total flux, p/s expression beginning 2 days 3.0e+9 6 after administration 5
Slide 11: AAV-SLB101 Transduction Kinetics Allows for Rapid Therapeutic Benefit in mdx Mice
AAV-SLB101 Transduction Kinetics Allows for Rapid Therapeutic Benefit in mdx Mice Robust Expression by Day 4 and Maximal Expression Serum Biomarkers Rapidly Decreased by 1 Month in Microdystrophin-Positive Myofibers; 4 Days Post-Administrationa,b Expression Was Consistent at 3 Months ** 800 ** * 150
Slide 12: Functional Improvements at Doses ≥6.0E12 Vg/Kg Observed After SGT-003 Treatment
Functional Improvements at Doses ≥6.0E12 Vg/Kg Observed After SGT-003 Treatment EDL SPECIFIC FORCE FORELIMB GRIP STRENGTH Grip Strength 11 weeks (KgF/kg) *** *** ** 300 * *** ** Specific Force (kN/m2) 5 4 200 3 100 2 1 0 0 aAsterisks indicate statistical significance between groups (*p<0.05, **p<0.0
Slide 13: AAV-SLB101 Treatment in NHPs Achieved Robust Transgene Expression Compared to AAVrh74
AAV-SLB101 Treatment in NHPs Achieved Robust Transgene Expression When Compared to AAVrh74 Treatment With AAV-SLB101 Results in Increased Microdystrophin Protein Expression QUADRICEPS HEART CK8-Microdystrophin Protein CK8-Microdystrophin Protein (LC/MS) in NHP at (LC/MS) in NHP at 1.0E14 vg/kg 1.0E1
Slide 14: Reduced Liver Biodistribution and Stable GGT in NHPs Treated with AAV-SLB101
Reduced Liver Biodistribution and Stable GGT in NHPs Treated with AAV- SLB101 Biodistribution in Isolated Tissues (Day 28 post-dose)a GGT Levels Remain Unchanged Following AAV-SLB101 Administration Compared to Vehicle Controls LIVER 1.5x1036 LIVER Fold Change Compared to Vehicle 1.5 **** *** 3 0 vg/
Slide 15: INSPIRE DUCHENNE: Study Overview
INSPIRE DUCHENNE: Study Overview Primary Objective: To investigate the safety and tolerability of a single 1.0E14 vg/kg • Single-dose level, open-label, Phase 1/2 study IV dose of SGT-003 • Ambulatory patients with Duchenne Primary Endpoint: Incidence of treatment-emergent adverse events through Day
Slide 16: Microdystrophin Initial Clinical Data Suggest Opportunity For Other Clinical Trial Applications
Initial Clinical Data Suggest Opportunity For Other Clinical Trial Applications(n = 3 Patients, Day 90 analysis) Robust Biodistribution High Protein Expression With Biomarker Profile Shows Observed in Skeletal Muscle Widespread Distributiona Improvements to Muscle MICRODYSTROPHIN EXPRESSION MEASURED
Slide 17: Interim Safety Summary
Interim Safety Summary No treatment-emergent SAEs reported All treatment-related AEs resolved without sequelae in the weeks following dosing Total Participants (N=7) Glucocorticoids alone used for SGT-003 Treatment-Emergent Adverse Events (TEAEs) Data cutoff March 7, 2025 immunosuppression n (%) Ser
Slide 18: GGT Within Normal Range at all Timepoints Evaluated for First 7 Participants
GGT Within Normal Range at all Timepoints Evaluated for First 7 Participants As of a data cutoff of March 7, 2025, no GGT results were above laboratory upper limits of normal at any timepoint after dosing with SGT-003 GGT 100 90 80 70 60 IU/L 50 40 30 20 10 0 -5 0 5 10 15 20 25 30 35 40 45 50 55 60
Slide 19: AAV-SLB101: Next-Generation Capsid for Improved AAV Delivery
AAV-SLB101: Next-Generation Capsid for Improved AAV Delivery Enhanced biodistribution to skeletal and cardiac muscle Accelerated tissue transduction kinetics Differentiated transduction mediated by cell surface receptors Leads to higher transgene expression and improved therapeutic efficacy Increase