4D Molecular Therapeutics, Inc. · NASDAQ:FDMT

4D Molecular Therapeutics — Technical Presentation (April 2024)

15 slides from 4D Molecular Therapeutics's technical presentation, Apr 20, 2024

  1. Slide 1: Preclinical Characterization of 4D-175 for Geographic Atrophy

    Preclinical Characterization of 4D-175, a Novel AAV-based Investigational Intravitreal Gene Therapy for Geographic Atrophy Melissa A. Calton, Ph.D. Vice President, Early Stage Product Development 4D Molecular Therapeutics © 2023 4D Molecular Therapeutics. All Rights Reserved.

  2. Slide 2: Geographic Atrophy

    Geographic Atrophy § Major cause of irreversible vision loss— affects an estimated 5 million individuals globally (1 million in the US)1,2 § Characterized by atrophic lesions caused by progressive degeneration of the RPE, photoreceptors, and choroid § Current treatments reduce the rate of growth in

  3. Slide 3: Complement Factor H (CFH)

    Complement Factor H (CFH) § Key regulator of the complement system Classical pathway Lectin pathway Alternative pathway o Inhibits assembly of C3 and C5 convertases via Antibody-antigen complex Serum lectin binding to mannose residues Spontaneous hydrolysis of C3 on pathogen competition with CFB for

  4. Slide 4: CFH Dysfunction in Geographic Atrophy

    CFH Dysfunction in Geographic Atrophy § Variants in the gene encoding CFH are strongly associated with the risk of GA1,2 o Most common variant (Y402H) accounts for nearly 50% of the overall risk2,3 o Rare variant (R1210C) is strongly associated with early onset GA4 § Murine models support a causal r

  5. Slide 5: Gene Therapy for Geographic Atrophy

    Gene Therapy for Geographic Atrophy Therapeutic Rationale § The retina is an opportune target for gene therapy o Small tissue volume Durable therapeutic activity* o Relatively low dose requirements o Stable and non-dividing cell population Transgene Expression Alternative complement pathway activati

  6. Slide 6: Intravitreal AAV-mediated Retinal Gene Therapy

    Intravitreal AAV-mediated Retinal Gene Therapy Retinal Cell Transduction Wild-type AAV R100: Retinotropic AAV Vector Wild-type AAV Blocked by Limited retinal R100 Efficient barrier Enhanced retinal barrier (ILM) transduction penetration transduction Retina Retina Heparan Inner sulfate retina Cytosol

  7. Slide 7: R100: Targeted and Evolved AAV Vector

    R100: Targeted and Evolved AAV Vector Extensive Characterization in Preclinical and Clinical Studies R100 Human RPE Cell Transduction Retinal Transduction in NHPs Retinotropic AAV Vector 50 * R100 1 Week 3 Weeks 8 Weeks AAV2 * EGFP+/PMEL17+ (%) 40 * 30 * *p<0.05 * 20 10 * 0 1 2 3 4 5 6 7 Intravitrea

  8. Slide 8: 4D-175 Transgene Design and Function

    4D-175 Transgene Design and Function Short-form Complement Factor H (sCFH) Transgene Design Pharmacological Activity Heparin Binding C3b Cleavage Full-length Human CFH1 3 sCFH NT Control Heparin binding CFH Heparin C3b binding CFH + + + - + - Supernatant sCFH C3b binding binding C3d binding CFI + +

  9. Slide 9: 4D-175 Design

    4D-175 Design Intravitreal Gene Therapy for Geographic Atrophy § Clinically validated retinotropic AAV vector (R100) § Codon-optimized sequence encoding a Promoter (Ubiquitous) Transgene (sCFH) shortened form of human complement R100 factor H (sCFH) § Ubiquitous promotor to drive transgene 1 500 1,0

  10. Slide 10: 4D-175 Preclinical Characterization: Human Retinal Cells In Vitro

    4D-175 Preclinical Characterization Robust Transgene Expression and Functional Activity in Human Retinal Cells In Vitro Transgene Expression* MAC (C5b–9) Formation in iPSC-derived RPE Cells† 250 NT MOI 800 MOI 2,000 MOI 5,000 ECU 200 nM 25 p<0.001 p<0.01 200 20 sCFH concentration (nM) MAC+ cells (%)

  11. Slide 11: NHP Ocular Pharmacodynamics and Tolerability

    4D-175 Preclinical Characterization NHP Ocular Pharmacodynamics and Tolerability 4D-175 Ocular Biodistribution 4D-175 Safety and Tolerability Aqueous Humor* Ocular Distribution‡ Fluorescein Angiography Intraocular Pressure (IOP) 40 Vehicle (n=3) NHP 2502 (1.5x1011 vg/eye) Mean ±SD IOP (mm Hg) 3x1010

  12. Slide 12: Conclusions

    Conclusions § In vitro experiments demonstrated that the sCFH transgene-derived protein exhibits functional activity consistent with wild type full-length CFH o Proper heparin and C3b binding o Appropriate C3b cleavage and corresponding inhibition of alternative complement pathway activity § Transdu

  13. Slide 13: Acknowledgments

    Acknowledgments 4D Molecular Therapeutics University of Pennsylvania Roxanne Croze Caralee Schaefer Wenchao Song Devi Khoday An Song Laura Kovacs Ted Sullivan David Kirn Joseph Vacca Domokos Lauko Christian Vettermann Maria Osuna Kathrine Yoh © 2023 4D Molecular Therapeutics. All Rights Reserved. 13

  14. Slide 14: Back-up

    Back-up ©© 2023 4D4D 2023 Molecular Therapeutics. Molecular AllAll Therapeutics. Rights Reserved. Rights Reserved. 14

  15. Slide 15: Confirmed Pharmacological Function of sCFH In Vivo

    Confirmed Pharmacological Function of sCFH In Vivo Phenotypic Correction in Mouse Model of aHUS AAV.sCFH (n=11) 60 100 Experimental Design AAV.Control (n=11) 50 45 AAV.sCHF (n=11) 80 CFHR/R mice 40 36 Incidence (%) Survival (%) 60 30 Age (weeks) 4 8 16 24 32 AAV.Control (n=11) 40 18 20 Murine anti-C

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