Slide 1: A Targeted AAV Gene Therapy Product Candidate, 4D-310, for the Treatment of Fabry Disease
A Targeted AAV Gene Therapy Product Candidate, 4D-310, for the Treatment of Fabry Disease: Intravenous Biodistribution, Transgene Expression & Safety in Non-Human Primates Kevin Whittlesey1, Gabriel Brooks1, Paul Szymanski1, Ghezal Beliakoff1, Julie Nye1, Jessica Sepulveda1, Rozanne Croze1, Chris Sc
Slide 2: Legal Disclaimer
Legal Disclaimer 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 our clinical development plans, strategy, future operatio
Slide 3: Presenter Disclosures
Presenter Disclosures ▪ The presenter is Vice President of Translational Medicine and a full-time employee of 4D Molecular Therapeutics, Inc. © 2021 4D Molecular Therapeutics. All Rights Reserved. 3
Slide 4: 4D-310: Dual Mechanism-of-Action Gene Therapy for Fabry Disease
4D-310: Dual Mechanism-of-Action Gene Therapy for Fabry Disease Ubiquitous GLA PROMOTER TRANSGENE HIGH UNMET MEDICAL NEED EPIDEMIOLOGY: US & EU-5 PRODUCT DESIGN • Monogenic X-linked (GLA) • ~ 19,000 total addressable patients • Vector: C102 • Heart disease: main cause of death • 50,000 - 70,000 newb
Slide 5: Invention of C102 by Therapeutic Vector Evolution
Invention of C102 by Therapeutic Vector Evolution TARGET VECTOR PROFILE (TVP): ENHANCED LOW DOSE DELIVERY & TRANSDUCTION WITHIN HEART TISSUE *Capsid library placed under varying selective pressures // Actual number of selection rounds varies by target © 2021 4D Molecular Therapeutics. All Rights Res
Slide 6: 4D-310 Therapeutic Objectives in Fabry Disease
4D-310 Therapeutic Objectives in Fabry Disease DESIGNED FOR DUAL MECHANISM-OF-ACTION ERT Gene Therapy AGA Enzyme Patient-derived AAV-mediated MOA Product Design Infusions Stem Cells Liver-directed 4D-310 Pharmacokinetics Normal Time of dose Lifelong AGA Delivery Cross-correction endothelial cells +
Slide 7: Efficacy in Fabry Knockout Mice
4D-310 Efficacy in Fabry Knockout Mice DOSE-DEPENDENT SUBSTRATE REDUCTION; NO 4D-310 RELATED TOXICITY OBSERVED Plasma LysoGb3 Substrate Reduction Tissue Gb3 Substrate Reduction Conc. of lysoGb3 (nM) (Response Ratio) Amount of Gb3 ** ** ** ** ** ** ** ** N = 15 mice per group N = 12 mice per group *
Slide 8: 4D-310 NHP Dose-Ranging Study Design
4D-310 NHP Dose-Ranging Study Design DOSE GROUP N TREATMENT ROUTE IN-LIFE ENDPOINTS (VG/KG) 1 1 Vehicle IV N/A 8 wks ▪ Clinical evaluation 2 3 4D-310 IV 3E12 8 wks ▪ Clinical chemistry ▪ Vector distribution & expression 3 3 4D-310 IV 1E13 8 wks ▪ AGA activity in plasma & tissues 4 3 4D-310 IV 5E13 8
Slide 9: Summary of 4D-310 Key Safety Endpoints in NHPs
Summary of 4D-310 Key Safety Endpoints in NHPs NO 4D-310 RELATED TOXICITY OBSERVED PARAMETER KEY OBSERVATIONS Body Weight Normal over time in all dose groups 3E12 and 1E13 dose groups: no change Liver Enzymes 5E13 dose group: minimal transient increase in ALT activity on Day 7 (fully resolved) Total
Slide 10: 4D-310 Pharmacodynamics in NHPs
4D-310 Pharmacodynamics in NHPs DOSE-DEPENDENT STABLE AGA ACTIVITY IN PLASMA 70-fold over baseline level 3.4-fold over baseline level 1.9-fold over baseline level *one NHP in the low dose cohort has been excluded from the dataset as a positive statistical outlier as it exhibited AGA activity that wa
Slide 11: 4D-310 Biodistribution in NHPs
4D-310 Biodistribution in NHPs SUCCESSFUL DELIVERY TO & TRANSDUCTION OF KEY TISSUES TO TREAT FABRY DISEASE GROUP HEART (LV) KIDNEYS LIVER CAROTID Genomes 18/18 (100%) 18/18 (100%) 18/18 (100%) 8/8 (100%) (qPCR) mRNA 18/18 (100%) 18/18 (100%) 18/18 (100%) 6/6 (100%) (RT-qPCR) ▪ In all NHPs administer
Slide 12: Biodistribution in NHPs: Transgene RNA Expression in Heart
4D-310 Biodistribution in NHPs TRANSGENE RNA EXPRESSION SHOWN IN HEART AT ALL DOSE LEVELS Frequency of Expression in Heart Samples Dose-Related Expression in Heart Samples 1.E+09 3E12 1E13 5E13 GROUP VG/KG VG/KG VG/KG 1.E+08 Copies per μg RNA 3/3 3/3 3/3 Left Ventricle (100%) (100%) (100%) 1.E+07 Ve
Slide 13: Pharmacology in NHPs
4D-310 Pharmacology in NHPs AGA ACTIVITY IN KEY FABRY TISSUES 20 3E12 vg/kg 1E13 vg/kg 5E13 vg/kg 15 (fold change from vehicle) AGA Activity 10 8 6 4 2 0 Heart, LV Kidneys Liver © 2021 4D Molecular Therapeutics. All Rights Reserved. 13
Slide 14: Biodistribution in NHPs: Immunohistochemistry of AGA in Heart
4D-310 Biodistribution in NHPs REPRESENTATIVE IMMUNOHISTOCHEMISTRY OF AGA IN HEART LEFT VENTRICLE 20X magnification © 2021 4D Molecular Therapeutics. All Rights Reserved. 14
Slide 15: Summary and Conclusions
Summary and Conclusions ▪ C102 vector invented for low dose IV delivery to the heart, cardiomyocyte transduction, and resistance to neutralizing antibodies ▪ 4D-310 designed for unique dual mechanism-of-action: high AGA blood levels, high AGA expression in heart ▪ 4D-310 showed dose-dependent cleara
Slide 16: Acknowledgements
Acknowledgements ▪ Dr. Christiane Auray-Blais (University of Sherbrooke) for lysoGb3 and Gb3 substrate analysis ▪ Dr. Raphael Schiffmann (4DMT) ▪ Dr. Jinsong Shen (4DMT) © 2021 4D Molecular Therapeutics. All Rights Reserved. 16
Slide 17: Thank you! Questions?
Thank you! QUESTIONS? © 2021 4D Molecular Therapeutics. All Rights Reserved. 17