4d Molecular Therapeutics, Inc. · NASDAQ:FDMT

4d Molecular Therapeutics — Gene Therapy for Ophthalmic Disorders Summit 2023

25 slides from 4d Molecular Therapeutics's conference presentation, Nov 28, 2023

  1. Slide 1: Targeting the Complement Pathway with AAV-Based Gene Therapy for Geographic Atrophy

    Targeting the Complement Pathway with AAV-Based Gene Therapy for Geographic Atrophy Melissa A. Calton, Ph.D. Senior Director, Head of Early-Stage Product Development 4D Molecular Therapeutics © 2021 4D Molecular Therapeutics. All Rights Reserved.

  2. Slide 2: 4D Molecular Therapeutics (4DMT)

    4D Molecular Therapeutics (4DMT) BOLDLY INNOVATING TO UNLOCK THE POTENTIAL OF GENETIC MEDICINES FOR MILLIONS OF PATIENTS ~140 Employees Emeryville, Company GMP Facilities FDMT CA R&D Headquarters Customized and evolved vectors Technology ~1 Billion Directed Evolution Payload design and engineering P

  3. Slide 3: Pipeline: 5 Clinical-stage Product Candidates

    Pipeline: 5 Clinical-stage Product Candidates 3 THERAPEUTIC AREAS, INCLUDING RARE AND LARGE PATIENT POPULATIONS VECTOR PRODUCT EPIDEMIOLOGY RESEARCH PRODUCT Delivery CANDIDATE INDICATION (PREVALENCE) CANDIDATE IND-ENABLING PHASE 1/2 PHASE 3 RIGHTS R100 OPHTHALMOLOGY Intravitreal 4D-150 Wet AMD ~3M U

  4. Slide 4: AAV-Based Gene Therapy for GA

    AAV-Based Gene Therapy for GA PRESENTATION SYNOPSIS ▪ Addressing the challenges associated with efficient transgene delivery to the retina via intravitreal injection ▪ The role of the complement pathway and complement factor H (CFH) in the pathogenesis of geographic atrophy ▪ Therapeutic potential o

  5. Slide 5: Addressing the Challenges Associated with Retinal Transgene Delivery

    Addressing the Challenges Associated with Retinal Transgene Delivery Therapeutic Vector Evolution © 2021 4D Molecular Therapeutics. All Rights Reserved. 5

  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: Therapeutic Vector Evolution

    Therapeutic Vector Evolution COMPETITIVE SELECTION FOR TARGET VECTOR PROFILE FITNESS IDENTIFY DESIGN PACKAGE ADMINISTER COMPETITIVE SELECTION* LEAD R100 DISEASE TARGET VECTOR 4DMT AAV 4DMT AAV TARGET VECTOR PROFILE FITNESS VECTOR Retinotropic AAV Vector TARGET(S) PROFILE LIBRARIES LIBRARIES Dose Fro

  8. Slide 8: R100: Evolved Retinotropic Intravitreal AAV Vector

    R100: Evolved Retinotropic Intravitreal AAV Vector PROOF OF CONCEPT NHP Retinal Transduction (IVT Delivery) Transduction of Human RPE Cells In Vitro 50 * R100 Vitreous Retina * Superior transduction eGFP+/PMEL17+ (%) AAV2 40 humor Choroid * of human RPE cells in 30 * vitro compared to the 20 * wild-

  9. Slide 9: R100-mediated Transgene Expression

    R100-mediated Transgene Expression ROBUST PAN-RETINAL EXPRESSION FOLLOWING IVT ADMINISTRATION IN NONHUMAN PRIMATES Central Retina Peripheral PR Peripheral PR ▪ NHP retina 3 weeks after IVT administration of R100.CAG-EGFP (1×1012 vg/eye) ▪ R100 demonstrated Retinal Pigment Epithelium Photoreceptors R

  10. Slide 10: R100 Intravitreal Retinotropic AAV Vector

    R100 Intravitreal Retinotropic AAV Vector IN-LIFE IMAGING IN NONHUMAN PRIMATES FOLLOWING IVT ADMINISTRATION OF R100.CAG-EGFP* 1 Week 3 Weeks 16 Weeks ▪ Durable and widespread retina transduction observed across all regions of the eye *1x1012 vg/eye. EGFP, enhanced green fluorescent protein; IVT, int

  11. Slide 11: R100 Biodistribution and Safety

    R100 Biodistribution and Safety GLP TOXICOLOGY AND BIODISTRIBUTION STUDIES—NONHUMAN PRIMATES 4D-110 4D-125 4D-150 Species NHP NHP NHP NHP* Eyes dosed, N 27 (unilateral) 34 (bilateral) 30 (unilateral) 42 (bilateral) Route of administration IVT IVT IVT IVT Highest dose to date 1E12 vg/eye 1E12 vg/eye

  12. Slide 12: Vector Modularity

    Vector Modularity BROAD APPLICATION ACROSS MULTIPLE RETINAL DISEASES Candidate Transgene Promotor Target Indication Patients Treated* Aflibercept R100 4D-150 VEGF-C miRNA Ubiquitous Wet AMD, DME >60 4D-110 CHM Ubiquitous Choroideremia 13 Photoreceptor- X-linked retinitis 4D-125 RPGR specific pigment

  13. Slide 13: Therapeutic Rationale for Targeting the Complement System

    Geographic Atrophy Therapeutic Rationale for Targeting the Complement System © 2021 4D Molecular Therapeutics. All Rights Reserved. 13

  14. Slide 14: Geographic Atrophy (GA)

    Geographic Atrophy (GA) OVERVIEW ▪ Advanced form of age-related macular Normal Geographic Atrophy degeneration that leads to irreversible vision loss ▪ Affects an estimated 5 million individuals globally (1 million in the US)1,2 ▪ Characterized by atrophic lesions in the outer retina caused by degen

  15. Slide 15: Complement Inhibition is a Validated Therapeutic Approach in GA

    Complement Inhibition is a Validated Therapeutic Approach in GA ▪ Complement-mediated inflammation is recognized Classical Lectin Alternative pathway pathway pathway as a main contributor to the pathogenesis of GA Antibody-antigen Serum lectin binding Pathogenic surface complex to mannose residues s

  16. Slide 16: Complement Factor H (CFH)

    Complement Factor H (CFH) ▪ A key regulator of the complement system Classical Lectin Alternative pathway pathway pathway o Inhibits assembly of C3 and C5 convertase enzymes via Antibody-antigen Serum lectin binding Pathogenic surface complex to mannose residues spontaneous hydrolysis competition wi

  17. Slide 17: Rationale for CFH Gene Transfer in GA

    Rationale for CFH Gene Transfer in GA SUPPORTED BY MULTIPLE LINES OF EVIDENCE ▪ Variants in the gene encoding CFH are strongly associated with the risk of GA1,2 o Most common CFH variant (Y402H) accounts for nearly 50% of the overall risk2,3 o Rare CFH variant (R1220C) is strongly associated with ea

  18. Slide 18: 4D-175 Investigational Intravitreal Gene Therapy for Geographic Atrophy

    4D-175 Investigational Intravitreal Gene Therapy for Geographic Atrophy © 2021 4D Molecular Therapeutics. All Rights Reserved. 18

  19. Slide 19: 4D-175 Transgene Selection

    4D-175 Transgene Selection SHORT-FORM COMPLEMENT FACTOR H (sCFH) ▪ Full-length human CFH gene and promoter exceed the payload capacity of the AAV capsid ▪ To reduce payload size, 4D-175 employs an engineered short-form CFH transgene Heparin binding C3b binding C3b binding Heparin binding C3d binding

  20. Slide 20: 4D-175 Product Design

    4D-175 Product Design INTRAVITREAL GENE THERAPY FOR GEOGRAPHIC ATROPHY ▪ Intravitreal AAV-based gene therapy ▪ Clinically validated retinotropic R100 AAV capsid variant Promoter (Ubiquitous) Transgene (sCFH) ▪ Codon-optimized sequence encoding a shortened form of human complement R100 factor H (sCFH

  21. Slide 21: 4D-175 for the Treatment of GA: Pharmacological Function of sCFH

    4D-175 for the Treatment of GA CONFIRMED PHARMACOLOGICAL FUNCTION OF sCFH PROTEIN 4D-175 sCFH Binds Heparin and C3b 4D-175 sCFH Cleaves C3b Appropriately Heparin Binding CFH sCFH ▪ The C3b alpha chain is degraded into iC3b in the presence of MW (kDa) CFH + CFI Protein Conc (nM) ▪ iC3b is detected as

  22. Slide 22: 4D-175 for the Treatment of GA: In Vivo Function

    4D-175 for the Treatment of GA 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.sCFH (n=11) 80 40 36 Incidence (%) Survival (%) CFHR/R mice 60 30 Age (weeks) 4 8 16 24 32 40 AAV.Con

  23. Slide 23: 4D-175 for the Treatment of GA: In Vitro Data

    4D-175 for the Treatment of GA PRELIMINARY IN VITRO DATA SUPPORT TRANSGENE EXPRESSION AND ACTIVITY sCFH Expression Transgene Expression* MAC Formation in iPSC-derived RPE Cells† 250 NT MOI 800 MOI 2,000 MOI 5,000 Eculizumab 2.25 mM 25 200 sCFH concentration (nM) 20 MAC+ cells (%) 150 15 100 10 50 5

  24. Slide 24: Summary

    Summary ▪ R100: Synthetic retinotropic AAV vector o Enhanced capacity to penetrate vitreoretinal barriers following IVT administration o Widespread transduction of retina cells allows efficient transgene delivery at low doses o Clinically validated: 4 clinical trials evaluating 3 separate investigat

  25. Slide 25: Thank You

    THANK YOU 5858 Horton Street, Suite 455 Emeryville, California 94608 (510) 505-2680 | info@4DMT.com 4DMT.com © 2021 4D Molecular Therapeutics. All Rights Reserved.

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