Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (February 2025)
53 slides from Foghorn Therapeutics's investor presentation, Feb 3, 2025
Slide 1: Unique biology, Precision therapeutics, Broad impact
February 2025 Unique biology Precision therapeutics Broad impact NASDAQ LISTED FHTX Exhibit 99.1
Slide 2: Forward Looking Statements
| Forward Looking Statements 2 This presentation contains forward-looking statements that are based on management's beliefs and assumptions and on information currently available to management. All statements other than statements of historical facts contained in this presentation are forward- looki
Slide 3: Foghorn is a Leader in Chromatin Biology, Successfully Drugging Challenging Targets
| Foghorn is a Leader in Chromatin Biology, Successfully Drugging Challenging Targets 3 Chromatin Regulation is Implicated in up to 50% of Tumors Foghorn has Unlocked Previously Undruggable Targets Leaders in Targeted Protein Degradation Pioneers in Targeting Chromatin Biology Opening New Biology wi
Slide 4: Chromatin Regulatory System Orchestrates Gene Expression
| Chromatin Regulatory System Orchestrates Gene Expression: Multiple Opportunities for Targets and Therapeutics 4 Chromatin – compacted form of DNA inside the nucleus of the cell Chromatin Remodeling Complexes – specialized multiprotein machines that allow access to DNA Targets: SMARCA2, ARID1B Tran
Slide 5: Foghorn Has Progressed Multiple Programs Against Challenging Targets
| Foghorn Has Progressed Multiple Programs Against Challenging Targets 5 SMARCA2: Potential in up to 10% of NSCLC and up to 5% of all solid tumors Challenge: Industry has failed to develop a selective inhibitor EP300: Role in both solid and heme malignancies Challenge: Toxicities with dual inhibitio
Slide 6: Gene Traffic Control Platform Designed to Deliver Precision, First-in-Class Therapeutics
| Foghorn’s Gene Traffic Control® Platform Designed to Deliver Precision, First-in-Class Therapeutics: Integrated, Scalable, Efficient, Repeatable 6 1. Chromatin Biology • Bioinformatics • Genomics • Epigenomics 2. Assays & Biochemistry Capabilities 3. Chemistry & Drugging • Selective, small molecul
Slide 7: Foghorn's Unique Platform Capabilities Evolved From Drugging BAF
| Foghorn's Unique Platform Capabilities Evolved From Drugging a Specific Chromatin Remodeling Complex (BAF)* 7 • Purification & recombinant production of large proteins and protein complexes • Biochemistry & biophysics of intrinsically disordered proteins • High throughput screening for binders and
Slide 8: Degrader Design, Optimization and Development Platform
| Degrader Design Degrader Optimization Degrader Development Best-in-Class Degrader • In Vitro efficacy • Indication selection • Combinations • Resistance mechanisms • In Vivo models • PK/PD determination, modeling and dose prediction • Proprietary E3 ligase binders o ~ 15 -17 in internal library o
Slide 9: The Next Foghorn Chapter: Delivering Multiple Potential Blockbusters Into the Clinic
| The Next Foghorn Chapter: Delivering Multiple Potential Blockbusters Into the Clinic 9 Pioneering BAF and Chromatin Biology (2016 – 2020) Built platform and developed deep understanding of biology Producing BAF and transcription factors at scale Demonstrated druggability of chromatin regulat
Slide 10: Advancing a Pipeline of First-in-Class Precision Therapeutics
| Foghorn is Advancing a Pipeline of First-in-Class Precision Therapeutics With Potential for Broad Application in Oncology… 10 Modality Program Phase 1 Enzyme Inhibitors Transcription Factor Disruptors Undisclosed Protein Degraders Commercial Rights FHD-909* (Selective SMARCA2) 3 Discovery Programs
Slide 11: Multiple Near-Term Value Inflection Points Through 2026
| …With Multiple Near-Term Value Inflection Points Through 2026 11 April 2025 (AACR)Preclinical Combination Data FHD-909 (LY4050784) (Selective SMARCA2 Inhibitor) ConfidentialIND / Phase 1 InitiationSelective SMARCA2 Degrader 2026IND / Phase 1 InitiationSelective CBP Degrader 2026IND / Phase 1 Initi
Slide 12: Potential Multi-Billion Dollar Opportunities in Oncology
| Potential Multi-Billion Dollar Opportunities in Oncology 12 Foghorn Owned Selective EP300 Degrader Lilly Target #3 Selective ARID1B Degrader Platform has potential for therapeutic area expansion (e.g., immunology and inflammation)Partnered w Lilly Selective SMARCA2 Inhibitor (FHD-909*) Selective S
Slide 13: Clinical & Preclinical Programs
Clinical & Preclinical Programs • FHD-909 (LY4050784) – Selective SMARCA2 Inhibitor • Selective CBP Degrader • Selective EP300 Degrader • Selective ARID1B Degrader 13
Slide 14: Selective SMARCA2 Inhibitor and Degrader For SMARCA4 Mutated Cancers
Selective SMARCA2 Inhibitor and Degrader For SMARCA4 Mutated Cancers SMARCA2 = BRM SMARCA4 = BRG1 14
Slide 15: FHD-909 Selective SMARCA2 Inhibitor in Phase 1 Trial
| FHD-909 Selective SMARCA2 Inhibitor in Phase 1 Trial; Preclinical Combination Data at AACR 2025 15 Selective SMARCA2 Inhibitor FHD-909* Selective SMARCA2 Degrader Biology Exploit the synthetic lethal relationship between SMARCA2 and mutated SMARCA4 Stage / Next Milestone Phase 1 dose escalation tr
Slide 16: Selective SMARCA2 Inhibition Exploits Synthetic Lethal Relationship
| Selective SMARCA2 Inhibition: Promising Strategy to Exploit Synthetic Lethal Relationship Between SMARCA2 and Mutant SMARCA4 16 No SMARCA4 Mutations SMARCA4 Mutation SMARCA4 Mutation and SMARCA2i Cell Survival Cell Death Healthy Cells Cancer Cells SMARCA4 SMARCA2 BAF Complex BAF Complex Mutant SMA
Slide 17: SMARCA4 is Mutated in Up to 10% of NSCLC; Up to 5% of Solid Tumors
| SMARCA4 is Mutated in Up to 10% of NSCLC; Up to 5% of Solid Tumors 17 SMARCA4 mutated across a broad range of tumors Accounts for ~5% of solid tumors AACR GENIE via cBioPortal
Slide 18: SMARCA4 Mutated in Up to 10% of NSCLC Tumors
| SMARCA4 Mutated in Up to 10% of NSCLC Tumors, Minimal Overlap With Other Mutations2Overall Survival for SMARCA4wt vs SMARCA4mut1 Patients With NSCLC Harboring SMARCA4 Mutations Have Significantly Worse Clinical Outcomes and Define a High Unmet Need Patient Population 18 SMARCA4 10% KRAS 29% EGFR 2
Slide 19: FHD-909 Demonstrated Approximately 33-fold Selectivity
| SMARCA4 WT SMARCA4 MUT 0.0001 0.001 0.01 0.1 1 A b s o lu te I C 50 ( μ M ) NCI-H2122 CALU6 NCI-H2172 NCI-H441 NCI-H2170 NCI-H460 NCI-H1703 NCI-H358 NCI-H2009 NCI-H1944 NCI-H1299 A549 RERFLCAI NCI-H1693 NCI-H1568 NCI-H2023 NCI-H838 SMARCA4 (WT) SMARCA4 (MUT) (SMARCA2 Only)(SMARCA2 & SMARCA4) FHD-9
Slide 20: FHD-909 Monotherapy Demonstrated Regression In Vivo in H2126 Model
| FHD-909 Monotherapy Demonstrated Regression In Vivo in H2126 SMARCA4 Mutant NSCLC Model and Was Well Tolerated 20 H2126 Reduction in Tumor Volume H2126 Body Weight Genetic Background: SMARCA4 W764R, TP53 E62*, STK11-/-, CDKN2A-/-, KEAP1 R272C NOTE: All doses were well tolerated. Dosing holidays we
Slide 21: FHD-909 Monotherapy Demonstrated Strong In Vivo Activity Across NSCLC Models
| FHD-909 Monotherapy Demonstrated Strong In Vivo Activity Across SMARCA4 Mutant NSCLC Models at Well Tolerated Doses 21 NOTE: All doses were well tolerated 0 7 14 21 28 100 200 300 400 500 Days of Dosing (Dose Start Day1) Vehicle Control FHD-909, 20mg/kg, BID, PO FHD-909, 40mg/kg, BID, PO FHD-909,
Slide 22: FHD-909 (LY4050784) Trial Design
| FHD-909 (LY4050784) Trial Design • Restricted to SMARCA4 mutated tumors • SMARCA4 mutant status confirmed by standard NGS panel • Further enrichment for NSCLC patients as trial progresses • Tumor histology agnostic • Enrolling in US and Japan 22 Dose Escalation Dose Expansion • Arm 1: SMARCA4 muta
Slide 23: Selective SMARCA2 Degrader Achieved Complete SMARCA2 Degradation
| Selective SMARCA2 Degrader Achieved Complete SMARCA2 Degradation and Cell Growth Inhibition In Vitro 23 Degraders Caused Time- and Dose-Dependent SMARCA2 Degradation Antiproliferative Effects in A549 Mutant NSCLC Model A549 Ten-Day Proliferation AssaySMARCA2 / SMARCA4 HIBIT Data SMARCA2 SMARCA4 %
Slide 24: Selective CBP Protein Degrader For EP300 Mutated Cancers
Selective CBP Protein Degrader For EP300 Mutated Cancers 24
Slide 25: CBP and EP300 Proteins – A Decades Long Challenge in Selectivity
| CBP and EP300 Proteins – A Decades Long Challenge in Selectivity 25 CBP and EP300 Biology • CBP and EP300 are highly homologous, paralog histone acetyltransferases regulating enhancer-mediated transcription and protein stability • Dysregulation of CBP and EP300 has been implicated in multiple canc
Slide 26: Summary: Selective CBP Protein Degrader for EP300 Mutated Cancers
| Summary: Selective CBP Protein Degrader for EP300 Mutated Cancers 26 * Per year incidence in the U.S., EU5, Japan . Source: Clarivate DRG Mature Markets Data. • CREB binding protein (CBP) • Targeted protein degrader Target / Approach • EP300 mutated cancers (e.g., subsets of bladder, colorectal, b
Slide 27: Selective CBP Degradation Results in Significant Anti-Tumor Activity
| EP300mut Lung Cancer CDX (LU99) EP300mut Bladder Cancer CDX (639V) EP300mut Gastric Cancer CDX (AGS) Selective CBP Degradation Results in Significant Anti-Tumor Activity in EP300mut Solid Tumor Models 27Fold Selectivity >1000x EP300 64 nM CBP 0.05 nM Degrader Selectivity FHT-CBPd-9 DC50 @24h 6 12
Slide 28: Long-Acting Injectable Formulation Provides Sustained Target Coverage
| EP300mut (639V) Bladder CDX (Daily Dosing and Single Injection of LAI Formulation) Plasma PK and Tumor PD (CBP) Measured From Bladder CDX Efficacy • Single injection of FHT-CBPd-9 in a LAI resulted in sustained plasma exposure (PK) and CBP degradation (PD) throughout the 3-week experiment, ultimat
Slide 29: Selective CBP Degradation Did Not Show Thrombocytopenia
| Bone Marrow Staining (In Vivo) Platelet Counts Post Two Weeks of Dosing (In Vivo Mice Models) *Dual CBP/EP300 inhibition study used 3 weeks of dosing Preclinical Studies Indicate Selective CBP Degradation Did Not Show Thrombocytopenia and Spared Megakaryocytes In Vivo 29 PLT (x109cells/L) 0 500 1,
Slide 30: Selective EP300 Protein Degrader For CBP Mutated and EP300 Dependent Cancers
Selective EP300 Protein Degrader For CBP Mutated and EP300 Dependent Cancers 30
Slide 31: Summary: Selective EP300 Protein Degrader
| Summary: Selective EP300 Protein Degrader for CBP Mutant & EP300 Dependent Cancers 31 * Per year incidence in the U.S., EU5, Japan. Source: Clarivate DRG Mature Markets Data. • E1A binding protein p300 (EP300) • Targeted protein degrader Target / Approach • AR+ Prostate • Broad range of heme malig
Slide 32: EP300 Degradation Shows Anti-Proliferative Activity in Hematological Malignancies
| Anti-Tumor Activity Across Full Range of Heme Sub-Lineages (~ 70% of All Tested Cell Lines are Sensitive) EP300 Degradation Shows Anti-Proliferative Activity in Broad Range of Hematological Malignancies 32
Slide 33: EP300 Degradation Results in Tumor Growth Inhibition in Myeloma, DLBCL and Prostate Models
| Multiple Myeloma (MM1S) CDX DLBCL (KARPAS422) CDX AR+ Prostate (VCaP) CDX EP300 Degradation Results in Significant Tumor Growth Inhibition in Multiple Myeloma, DLBCL and Prostate Models 33 B o d y W ei g h t C h an g e ( % ) 5 10 15 20 25 30 35 40 45 0 500 1,000 1,500 2,000 Vehicle FHT-EP300d - 32
Slide 34: Selective EP300 Degrader Demonstrated Complete Response in Multiple Myeloma Model
| • Non-selective dual CBP/EP300 inhibitor shows tumor stasis, but clinical safety (i.e., thrombocytopenia) resulted in dosing holidays • Selective EP300 degrader can achieve deeper responses (complete tumor regression) with no thrombocytopenia • Selective EP300 degrader with improved therapeutic wi
Slide 35: Identification of a Patient Selection Biomarker in DLBCL
| Identification of a Patient Selection Biomarker in DLBCL • Screened 28 DLBCL cell lines; ~60% are sensitive • Two-step biomarker of sensitivity: ‒ EP300 present (no high-impact mutations in EP300) and ‒ One of two other mutations • Mechanistic hypothesis being further validated In Vitro Anti-Proli
Slide 36: Oral EP300 Selective Degrader Shows Promising Efficacy
| Multiple Myeloma CDX treated w/ dEP300 - CRBN dEP300-CRBN demonstrates 32% oral bioavailability Multiple Myeloma CDX treated w/ dEP300 - CRBN Multiple Myeloma CDX treated w/ dEP300 - CRBN Oral EP300 Selective Degrader Shows Promising Efficacy; Well Tolerated With No Thrombocytopenia 36 CCS1477 Ino
Slide 37: Selective ARID1B Protein Degrader For ARID1A Mutated Cancers
Selective ARID1B Protein Degrader For ARID1A Mutated Cancers 37
Slide 38: ARID1B is a Major Synthetic Lethal Target; Program Update in 2025
| ARID1B is a Major Synthetic Lethal Target With Potential in Up To 5% of All Solid Tumors; Degradation Achieved, Program Update in 2025 38 * Per year incidence in the U.S., EU5, Japan. Source: Clarivate DRG Mature Markets Data. • ARID1B • Targeted protein degraderTarget / Approach • ARID1A mutated
Slide 39: Compound Screening and Structure-Based Optimization Yielded Selective ARID1B Binders
| Compound Screening and Structure-Based Optimization Yielded Selective ARID1B Binders 39 • Mapped and purified several potential ligandable regions of ARID, which were then screened against various compound libraries • Characterized binding using multiple biochemical and biophysical techniques: e.g
Slide 40: Structure-Based Optimization Drove Improved ARID1B Binding Affinity
| Structure-Based Optimization Drove Improved ARID1B Binding Affinity From 100 uM to Less Than 200 nM 40 1.4 Å co-xtal structure 2.0 Å soak structure 1.7 Å soak structure ARIDb-2 ARID1B Kd: 15 uM ARIDb-1 ARID1B Kd: 100 uM ARIDb-3 ARID1B Kd: 0.5 uM ARIDb-9 ARID1B Kd: 0.2 uM 1.9 Å co-xtal structure Ge
Slide 41: Induced Proximity Platform Evolution
Induced Proximity Platform Evolution FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex 41
Slide 42: Existing Capabilities Setting Foundation for Expansion into Induced Proximity
| Existing Capabilities Have Produced Multiple Degrader Programs and are Setting Foundation for Expansion into Induced Proximity 42 TargetDegrader Machinery (E3 Ligase) TargetEffector Post-Translational modification - dependent Protein Stabilization Modulation of gene activation/repression Induced P
Slide 43: Induced Proximity Platform Demonstrates Initial POC for DUBTAC
| Induced Proximity Platform Demonstrates Initial POC for DUBTAC 43 increase in protein levels DUBTACs (deubiquitinase targeting chimera) are heterobifunctional molecules that recruit a DUB to a target of interest in order to remove the ubiquitin “degradation tag”, thereby resulting in protein stabi
Slide 44: Novel Approach to Activate Cell Death Cascade
| Induced Proximity Platform Demonstrates Potential for Novel Approach to Activate Cell Death Cascade 44 Normal BCL6 Function BCL6 Activation with BAF-BCL6 Heterobifunctional • BCL6 is a proto-oncogene, which binds to promoters of cell death genes and suppresses their expression • We have developed
Slide 45: Induced Proximity Platform Offers Expansion Beyond Oncology
| 48 Nuclear Hormone Receptors Nuclear hormone receptor are implicated in multiple biology processes across most organ systems • Only 10 nuclear hormone receptors have been drugged and approved to date (e.g., AR, ER Glucocorticoids, thyroid HR alpha beta) • Despite decades of development most others
Slide 46: Degrader Platform Uniquely Enables Expansion into Induced Proximity
| Degrader Design Degrader Optimization Degrader Development Best-in-Class Induced Proximity Modulator • Structural prediction/ docking • Well-developed toolkit • Flexibility- rigidity • Charge • Hydrophobicity • Commercial and proprietary covalent and fragment screening libraries • Target binders •
Slide 47: Drugging Transcription Factors Multiple Approaches
Drugging Transcription Factors Multiple Approaches FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex 47
Slide 48: Foghorn's Transcription Factor Platform Approaches
| Foghorn’s Transcription Factor Platform: 4 Approaches 48 Transcription Factor Chromatin Remodeler Modulating TF activity via Protein-Protein Interaction Disruptors Transcription Factor Native E3 Ligase Degrading TFs via recruitment of the native E3 ligase using molecular glue = MG (Molecular Glue)
Slide 49: Multiple Near-Term Value Inflection Points Through 2026
| Multiple Near-Term Value Inflection Points Through 2026 49 April 2025 (AACR)Preclinical Combination Data FHD-909 (LY4050784) (Selective SMARCA2 Inhibitor) ConfidentialIND / Phase 1 InitiationSelective SMARCA2 Degrader 2026IND / Phase 1 InitiationSelective CBP Degrader 2026IND / Phase 1 InitiationS
Slide 50: Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer 50 Large Market Potential Chromatin biology is implicated in up to 50% of tumors, potentially impacting ~2.5 million patients Foghorn’s current pipeline potentially addresses more than 500,000 of these patients Bro
Slide 51: Unique biology, Precision therapeutics, Broad impact
Unique biology Precision therapeutics Broad impact 51 February 2025
Slide 52: Appendix
Appendix 52
Slide 53: Lilly Collaboration Validates Foghorn Approach
| Lilly Collaboration Validates Foghorn Approach: Significant Upfront and Deal Economics 53 $380 Million Up-front $300 million cash $80 million in Foghorn common stock at a price of $20 per share Three Undisclosed Discovery Programs Option to participate in a percentage of the U.S. economics Tiered
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