4D Molecular Therapeutics, Inc. · NASDAQ:FDMT
4D Molecular Therapeutics — ASGCT Symposium 2023
33 slides from 4D Molecular Therapeutics's conference presentation, May 18, 2023
Slide 1: AAV-Mediated Gene Therapy for Cystic Fibrosis (4D-710)
AAV-Mediated Gene Therapy for Cystic Fibrosis (4D-710) Jennifer L.Taylor-Cousar, MD, MSCS, ATSF
Slide 2: Disclosures
Disclosures ▪ Personal financial relationships with commercial interests relevant to medicine, within the past year: • As faculty at an institution that is part of the CF TDN, I am/have been site/national PI on studies for 4DMT, Vertex, and Eloxx. • I have done clinical trial consulting for Vertex.
Slide 3: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gibson et al. Am J Respir Crit Care Med 2003
Slide 4: Multisystem Autosomal Recessive Disorder
Multisystem Autosomal Recessive Disorder Chronic sinusitis Chronic bacterial infection of airways Hepatobiliary disease Pancreatic exocrine and endocrine insufficiency Constipation Elevated sweat chloride Congenital bilateral absence Subfertility of the vas deferens (CBAVD) Slide courtesy of CFF
Slide 5: Video courtesy of CFF
Video courtesy of CFF
Slide 6: Classifying CFTR Mutations
Classifying CFTR Mutations De Boeck, Amaral. Lancet Resp Med 2016
Slide 7: Majority of PwCF are Variant-eligible for Highly Effective Modulator Therapy
Majority of PwCF are Variant-eligible for Highly Effective Modulator Therapy
Slide 8: Modulator Therapy Landscape
Modulator Therapy Landscape ▪ Up to 94% of people with CF could ultimately be eligible for a highly effective modulator ▪ It’s not known (exactly) how many pwCF are not taking modulators (probably >10%) Slide courtesy of JP Clancy; https://www.cff.org/Research/Developing-New-Treatments/CFTR-Modulato
Slide 9: Unequal Eligibility for CFTR Modulator Therapy
Unequal Eligibility for CFTR Modulator Therapy Ethnic Native White Hispanic Black Asian Ancestry American # with 0 2,298 588 458 63 29 copies of (10%) (30%) (38%) (40%) (17%) F508del* # eligible for an 23,940 2089 941 NR NR CFTR (92%) (76%) (70%) modulator^ PwCF from historically marginalized groups
Slide 10: Timeline of Advances in CF
Timeline of Advances in CF 56 NEWBORN SCREENING AVAILABLE IN ALL 50 STATES ELX-TEZ-IVA (TRIKAFTA®) HISTORICAL AND PREDICTED SURVIVAL ADULT CARE STANDARDIZED TEZ/IVA (SYMDEKO®) CREATION OF TDN LUM/IVA (ORKAMBI®) CFTR GENE MAPPED IVACAFTOR (KALYDECO®) PATIENT REGISTRY NEB. AZTREONAM (CAYSTON®) CREATED
Slide 11: CFTR Gene Discovered
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene Discovered
Slide 12: Timeline of CF Gene Therapy 1989–2001
Timeline of CF Gene Therapy 1989–2001 Cooney AL at el. Genes 2018; 9(11):538.
Slide 13: Failure of Conventional AAV Gene Therapy in CF Lung
Failure of Conventional AAV Gene Therapy in CF Lung PREVIOUS CLINICAL TRIAL EXPERIENCE WITH TGAAVCF ▪ Six trials with AAV2-based gene therapy (tgAAVCF) in upper1–6 and lower 5-8 airways ▪ Nasal and sinus administration (n=3 trials): o Participants dosed: 34 o Safe and well tolerated o DNA: detected
Slide 14: Advantages and Disadvantages of Conventional AAV as a Vector
Advantages and Disadvantages of Conventional AAV as a Vector Advantages Disadvantages • Lower risk of pathogenicity • AAV receptor on basolateral (rather • Duration of expression (in non- than apical) surface proliferating cells) • Small genome packaging capacity • Broad range of target organs based
Slide 15: Therapeutic Vector Evolution: A101 Aerosol Delivered Synthetic AAV
Therapeutic Vector Evolution: A101 Aerosol Delivered Synthetic AAV PROPRIETARY SYNTHETIC VECTOR DISCOVERY PLATFORM Route: Aerosol Dose: <3E15 vg/pt Tissue target: Lung epithelium Antibody resistance TVP, Therapeutic Vector Evolution; vg, vector genome
Slide 16: 4D-710: Next-Gen Aerosolized Genetic Medicine for Cystic Fibrosis Lung
4D-710: Next-Gen Aerosolized Genetic Medicine for Cystic Fibrosis Lung A101 TARGET VECTOR PROFILE & 4D-710 PRODUCT DESIGN AND KEY ATTRIBUTES Potential Barriers Limited Transduction Bronchial airway of Airway Cells Nebulizer 4D-710 Design Lungs Defensins A101 Ubiquitous CFTR∆R Antibodies PROMOTER TRA
Slide 17: 4D-710 Preclinical Characterization
4D-710 Preclinical Characterization A101 VECTOR RESISTANCE TO HUMAN IVIG, 4D-710 BIODISTRIBUTION, AND CFTR EXPRESSION IN PRIMATES Human Antibody Resistance: IVIG Delivery and Transduction: Aerosol NHP 4D-710 Biodistribution in NHP Lung (n=3 NHP; 48 samples) 100% 80% 96% 92% (46/48) Genome (qPCR) Pos
Slide 18: Next-Generation 4D-710 AAV Gene Therapy in Cystic Fibrosis
Next-Generation 4D-710 AAV Gene Therapy in Cystic Fibrosis: 4DMT APPROACH TO OVERCOMING HURDLES WITH TGAAVCF ▪ A101 novel synthetic vector: o Directed Evolution in primates for aerosol delivery o Efficient mucus penetration & transgene expression o High resistance to pre-existing human AAV antibodie
Slide 19: 4D-710 Phase 1/2 Clinical Trial Study Design (4D-710-C001)
4D-710 Phase 1/2 Clinical Trial Study Design (4D-710-C001) OPEN-LABEL PHASE 1/2 TRIAL IN MODULATOR-INELIGIBLE ADULTS WITH CYSTIC FIBROSIS Dose Exploration Dose Expansion Cohort 2 Dose Expansion 2E15 vg Selected dose (n=3–6) (n= up to 12) Cohort 1 1E15 vg (n=3–6) SRT Review Observation Period Long-te
Slide 20: 4D-710 Phase 1/2 Clinical Trial: Objectives and Eligibility
4D-710 Phase I/2 Clinical Trial STUDY OBJECTIVES AND ELIGIBILITY CRITERIA Study Objectives Key Inclusion Criteria ▪ Evaluate a single nebulized dose of 4D-710 ▪ Age ≥18 years (1E15, 2E15 vg) ▪ Confirmed diagnosis: CF lung disease o Safety, tolerability, and immunogenicity ▪ Ineligible for CFTR modul
Slide 21: 4D-710 Phase 1/2 Clinical Trial: Major Study Endpoints
4D-710 Phase 1/2 Clinical Trial: Major Study Endpoints ▪ Primary endpoint: o Incidence and severity of adverse events ▪ Key secondary endpoints: o Transgene transfer and expression in bronchoscopy samples (biopsies, brushings) o Change in ppFEV1 from baseline (through Month 12) o Change in Cystic Fi
Slide 22: 4D-710 Phase 1/2 Clinical Trial: Cohort 1 Participants
4D-710 Phase 1/2 Clinical Trial: Cohort 1 Participants DEMOGRAPHICS AND BASELINE CHARACTERISTICS Cohort 1 (1E15 vg dose) Characteristic Participant 1 Participant 2 Participant 3 Age, y 36 24 20 Sex Male Male Female Race/ethnicity Non-Hispanic white Non-Hispanic white Non-Hispanic white CFTR modulato
Slide 23: 4D-710 Phase 1/2 Clinical Trial: Cohort 1 Acute Safety
4D-710 Phase 1/2 Clinical Trial: Cohort 1 Acute Safety SERIAL SPIROMETRY AND ADVERSE EVENTS DURING NEBULIZATION OF 4D-710 Serial Spirometry During 4D-710 Dosing: ▪ Full volume administered (1E15 vg) Through 4 Hours Post-Nebulization ▪ Participant 1: a mild, self-limited AE 110 100 o Grade 1 dry thro
Slide 24: 4D-710 Phase 1/2 Clinical Trial: Cohort 1 Safety Summary
4D-710 Phase 1/2 Clinical Trial: Cohort 1 Safety Summary NO 4D-710–RELATED ADVERSE EVENTS UP TO 12 MONTHS AFTER COMPLETION OF DOSING ▪ No 4D-710–related adverse events ▪ No 4D-710–related serious adverse events ▪ No dose-limiting toxicities Duration of Cohort 1 safety follow-up as of 12-APR-2023: 12
Slide 25: 4D-710 Phase 1/2 Clinical Trial: Bronchoscopic Sampling Plan
4D-710 Phase 1/2 Clinical Trial: Bronchoscopic Sampling Plan Bronchoscopy: Week 4* Trachea Biomarker Right Left Bronchoscopic Sampling Sites ISH PCR 1 Upper Lobe Endobronchial biopsy Apico-posterior Upper Lobe 3 Anterior Apical Superior-lingular 1 Right secondary carina X Anterior Inferior-lingular
Slide 26: Widespread Transgene Delivery & Expression: Biopsies
Widespread Transgene Delivery & Expression: Biopsies CONSISTENT TRANSDUCTION ACROSS PATIENTS, LUNG REGIONS 4D-710 DNA (+) Lung Biopsies 4D-710 RNA Expression (+) Lung Biopsies CFTRDR DNA qPCR1 Results CFTRDR RNA ISH 5 of 5 biopsies (+) (All 3 pts) % Positive Epithelial Cells2 80 36–47% (+) Left Uppe
Slide 27: Widespread CFTR Expression in Lung: All Biopsies (+)
Widespread CFTR Expression in Lung: All 5 Biopsies (+) CFTR∆R RNA EXPRESSION BY ISH Controls DAPB ISH 4D-710–Treated CFTR∆R RNA probe* (negative control probe) Left Secondary Carina Left Secondary Carina Endobronchial Biopsy (40X) Endobronchial Biopsy (80X) CFTR∆R ISH Untreated CF lung tissue *Repre
Slide 28: Multiple Bronchial Epithelial Cell Types Express CFTR Transgene
Multiple Bronchial Epithelial Cell Types Express CFTR Transgene INDEPENDENT PATHOLOGISTS’ REVIEW: CFTR∆R RNA ISH LOCALIZATION Transduced cell types* 1. Basal cells 2. Goblet cells 3. Columnar ciliated cells Image from Participant 1. *Assessed by 2 independent pathologists. ISH, in situ hybridization
Slide 29: Widespread CFTR Expression in Lung: All Brushings (+)
Widespread CFTR Expression in Lung: All 6 Brushings (+) CFTR∆R RNA EXPRESSION BY IN SITU HYBRIDIZATION (ISH) Controls DAPB ISH BRUSHING 4D-710 Treated CFTR∆R RNA probe* (negative control probe) Right Lower Lobe Left Lower Lobe CFTR∆R ISH Untreated CF lung tissue *Representative images from Participa
Slide 30: Widespread CFTR Protein Expression in Lung
Widespread CFTR Protein Expression in Lung CFTR PROTEIN EXPRESSION BY IHC Controls 4D-710–Treated CFTR IHC* Left Secondary Carina (40X) Right Middle Carina (40X) ▪ 3/3 participants positive for CFTR protein expression ▪ CFTR IHC signal higher than that observed in commercially acquired CF (N=20) and
Slide 31: 4D-710 Clinical Data Summary, Implications, and Next Steps
4D-710 Clinical Data Summary, Implications, and Next Steps CLINICAL PROOF OF CONCEPT FOR SAFETY AND WIDESPREAD TRANSGENE EXPRESSION ▪ Cohort 1 Summary: o No 4D-710-related AEs post-dosing o Widespread CFTR transgene and protein expression (all 11 lung samples) o ~40% of cells expressed CFTR by ISH (
Slide 32: Until It's Done
UNTIL IT’S DONE
Slide 33: Acknowledgements
• People with CF and their families • Participating CF clinical and research centers • JP Clancy and 4DMT for slides