Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (May 2025)
63 slides from Foghorn Therapeutics's investor presentation, May 14, 2025
Slide 1: Unique biology, Precision therapeutics, Broad impact
May 2025 Unique biology Precision therapeutics Broad impact NASDAQ LISTED FHTX Exhibit 99.2
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 Multi-billion Dollar Opportunities First-in-Class and Best-in-Class Approaches Selective Target Engagement Strategic Partnership: Multiple Programs Targeting chromatin regulation, implicated in up to 50% of all t
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 Achieved Selectivity Where Others Have Failed
| Foghorn has Achieved Selectivity Where Others Have Failed 5 Potential in up to 10% of NSCLC and 5% of all solid tumors Challenge: Industry has failed to develop a selective inhibitor Role in both solid and heme malignancies Challenge: Toxicity with dual inhibition, difficulty engineering selectivi
Slide 6: Gene Traffic Control Platform
| 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: Degrader Design, Optimization and Development
| 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 8: First-in-Class Precision Therapies Across Oncology
| Foghorn: First-in-Class Precision Therapies with Potential for Multi-Billion Dollar Opportunities Across Oncology 8 Modality Program Phase 1 Enzyme Inhibitors Transcription Factor Disruptors Undisclosed Protein Degraders Partner FHD-909* (Selective SMARCA2) 3 Discovery Programs Undisclosed Partner
Slide 9: Advancing Multiple Programs with Near-Term Milestones Through 2026
| Advancing Multiple Programs with Near-Term Milestones Through 2026 9 Phase 1 Monotherapy DataFHD-909* (LY4050784) (Selective SMARCA2 Inhibitor) 2026IND / Phase 1 InitiationSelective CBP Degrader 2026IND / Phase 1 InitiationSelective EP300 Degrader ConfidentialIND / Phase 1 InitiationSelective SMAR
Slide 10: FHD-909 Being Developed in Collaboration with Lilly
| FHD-909 is Being Developed in Collaboration with Lilly; Landmark Agreement Signed in December 2021 Significant Upfront and Economics Strong Momentum and Shared Vision Ongoing Discovery Programs • $300 million cash • $80 million in Foghorn common stock at a price of $20 per share • 50/50 U.S. econo
Slide 11: Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer 11 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 12: Selective SMARCA2 Programs For SMARCA4 Mutated Cancers
Selective SMARCA2 Programs For SMARCA4 Mutated Cancers • FHD-909 (LY4050784) – Selective SMARCA2 Inhibitor • Selective SMARCA2 Degrader 12
Slide 13: SMARCA2: FHD-909 Inhibitor and Preclinical Degrader
| SMARCA2: Clinical-stage FHD-909 Selective SMARCA2 Inhibitor and Preclinical Selective SMARCA2 Degrader 13 Selective SMARCA2 Inhibitor FHD-909* Selective SMARCA2 Degrader Biology Exploit the synthetic lethal relationship between SMARCA2 and mutated SMARCA4 Status Phase 1 monotherapy dose escalation
Slide 14: Selective SMARCA2 Inhibition Exploits Synthetic Lethality
| Selective SMARCA2 Inhibition: Promising Strategy to Exploit Synthetic Lethal Relationship Between SMARCA2 and Mutant SMARCA4 14 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 15: SMARCA4 is Mutated in Up to 10% of NSCLC
| SMARCA4 is Mutated in Up to 10% of NSCLC; Up to 5% of Solid Tumors 15 SMARCA4 mutated across a broad range of tumors Accounts for ~5% of solid tumors AACR GENIE via cBioPortal
Slide 16: SMARCA4 Mutations Lead to Worse Clinical Outcomes in NSCLC
| NSCLC patients with SMARCA4 mutations: ─ Poor prognosis ─ Shorter overall survival ─ Less responsive to immune checkpoint inhibitors ─ Clinically definable, high unmet need population SMARCA4 Mutated in Up to 10% of NSCLC Tumors, Minimal Overlap With Other Mutations2Overall Survival for SMARCA4wt
Slide 17: SMARCA4 and KRAS Co-Mutations Have Even Worse Outcomes
| When SMARCA4 and KRAS Mutations Co-Occur, Patients Have Even Worse Outcomes to Standard of Care Treatment In response to PD(L)-1 therapy, Patients with Co-Occurring SMARCA4 and KRAS Mutations have a Shorter ORR, PFS, and OS than Patients with only KRASmut 17 Overall Response Rate (ORR) Source: Ale
Slide 18: FHD-909 is Highly Selective for SMARCA2 Over SMARCA4
| FHD-909 is Highly Selective for SMARCA2 Over SMARCA4 18 FHD-909 Demonstrated Approximately 33-fold Selectivity Across SMARCA4 Mutant and Wild-Type Cell Lines In Vitro Selectivity = 33x Median IC50 (µM) 0.0932SMARCA4 WT 0.0028SMARCA4 MUT NCI-H460, Lung model (NSCLC / SMARCA4-wildtype) FHD-909 is hi
Slide 19: FHD-909 Monotherapy Regression in NCI-H2126 NSCLC Model
| FHD-909 Monotherapy Demonstrated Regression In Vivo in NCI-H2126 SMARCA4 Mutant NSCLC Model at Tolerated Doses 19 NCI-H2126 Reduction in Tumor Volume NCI-H2126 Body Weight Genetic Background: SMARCA4 W764R, TP53 E62*, STK11-/-, CDKN2A-/-, KEAP1 R272C NOTE: All doses were well tolerated. Dosing hol
Slide 20: FHD-909 Strong In Vivo Activity Across SMARCA4 Mutant NSCLC Models
| FHD-909 Monotherapy Demonstrated Strong In Vivo Activity Across SMARCA4 Mutant NSCLC Models at Tolerated Doses 20 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, 60mg/kg, BID, PO A549 Model RERF-LC-AI Mo
Slide 21: FHD-909 Positioned for Combination with Standard Therapies
| Chemotherapy Targeted Therapies FHD-909 is Positioned to Be Evaluated in Combination with Standard Therapies 2025 AACR Data FHD-909 shows significant anti-tumor activity preclinically in combination with standard therapies in NSCLC 21 Cisplatin PemetrexedPaclitaxel KRAS inhibitorsPembrolizumab
Slide 22: FHD-909 Combination Activity in A549 Xenograft Model
| FHD-909 in Combination with Standard Therapies Demonstrates Significant Activity in the A549 (SMARCA4 mutant, KRAS G12S) Xenograft NSCLC Model 22 0 7 14 21 28 200 400 600 800 1000 1200 Days of Dosing (Dose Start Day 1) T u m o r vo lu m e (m m 3 ) * * * * ** ## Note: * p≤0.05 for pairwise comparis
Slide 23: FHD-909 Combination Activity in RERF-LC-AI Xenograft Model
| FHD-909 in Combination with Standard Therapies Demonstrates Significant Activity in the RERF-LC-AI (SMARCA4 mutant) Xenograft NSCLC Model 23 0 7 14 21 28 200 400 600 800 1000 1200 1400 Days of Dosing (Dose Start Day 1) T u m o r V o lu m e (m m 3 ) * * * * **# # Note: * p≤0.05 for pairwise compari
Slide 24: Synergy of FHD-909 with KRAS Inhibitors In Vitro
| Synergistic Activity Observed for FHD-909 in Combination with KRAS Inhibitors In Vitro 24 In h ib it io n ( % ) In h ib it io n ( % ) FHD-909 + olomorasib (KRAS G12C inhibitor) FHD-909 + pan-KRAS inhibitor In h ib it io n ( % ) In h ib it io n ( % ) 1 10 100 1000 10000 -20 0 20 40 60 80 100 120 FH
Slide 25: FHD-909 with Olomorasib in NCI-H2030 Xenograft
| Combination of FHD-909 with KRAS Inhibitors Demonstrates Synergistic Activity in SMARCA4, KRAS Co-Mutated Human NSCLC Xenograft Models in vivo FHD-909 + olomorasib (KRAS G12C inh) NCI-H2030 (SMARCA4mt, KRAS G12C) 25 0 7 14 21 28 0 500 1000 1500 2000 2500 3000 Days of Dosing (Dose Start Day1) T u m
Slide 26: FHD-909 with Pan-KRAS Inhibitor in A549 Xenograft
| Combination of FHD-909 with KRAS Inhibitors Demonstrates Synergistic Activity in SMARCA4, KRAS Co-Mutated Human NSCLC Xenograft Models in vivo FHD-909 + pan-KRAS inh A549 (SMARCA4mt, KRAS G12S) 26 Combination of FHD-909 with pan-KRAS inhibitor resulted in synergistic antitumor activity and sustain
Slide 27: FHD-909 with Pembrolizumab Enhanced Anti-Tumor Activity
| FHD-909 in Combination with Pembrolizumab Shows Significantly Enhanced Anti-Tumor Activity in A549 CD34+ HSC Humanized Xenograft NSCLC Model 27 FHD-909 sensitized the tumor cells to pembrolizumab treatment resulting in enhanced combination activity, while pembrolizumab alone had no effect on tumor
Slide 28: First-in-Human Phase 1 Trial of FHD-909
| A First-in-Human Phase 1 Trial of FHD-909 in Advanced Solid Tumor Patients with SMARCA4 Mutations Phase 1a Dose Escalation Advanced solid tumors with any SMARCA4 alteration (mTPI-2 method with backfillinga) Dose Level 1 Dose Level 2 Dose Level 3 Dose Level n Phase 1b Dose Expansionb Presence of a
Slide 29: Treatment Landscape in NSCLC by Line of Therapy
| Treatment Landscape in NSCLC by Line of Therapy 29 1st Line NSCLC Pembrolizumab-based regimens Other immune checkpoint inhibitor-based regimens Chemotherapy-based regimens 2nd Line NSCLC Chemotherapy-based regimens Ramucirumab (anti-VEGF) + chemotherapy Checkpoint inhibitor monotherapy 3rd Line NS
Slide 30: Treatment Landscape in NSCLC: Agents Evaluated with FHD-909
| Treatment Landscape in NSCLC by Line of Therapy 30 1st Line NSCLC Pembrolizumab-based regimens Other immune checkpoint inhibitor-based regimens Chemotherapy-based regimens 2nd Line NSCLC Chemotherapy-based regimens Ramucirumab (anti-VEGF) + chemotherapy Checkpoint inhibitor monotherapy 3rd Line NS
Slide 31: Selective SMARCA2 Degrader Achieved Complete Degradation In Vitro
| Selective SMARCA2 Degrader Achieved Complete SMARCA2 Degradation and Cell Growth Inhibition In Vitro 31 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 32: Degrader Programs
Degrader Programs • Selective CBP Degrader • Selective EP300 Degrader • Selective ARID1B Degrader 32
Slide 33: Selective CBP Protein Degrader For EP300 Mutated Cancers
Selective CBP Protein Degrader For EP300 Mutated Cancers 33
Slide 34: CBP and EP300 Proteins: A Decades Long Challenge in Selectivity
| CBP and EP300 Proteins – A Decades Long Challenge in Selectivity 34 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 35: Summary: Selective CBP Protein Degrader
| Summary: Selective CBP Protein Degrader for EP300 Mutated Cancers 35 * 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 36: Selective CBP Degradation Anti-Tumor Activity in EP300mut Models
| 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 36 Fold Selectivity >1000x EP300 64 nM CBP 0.05 nM Degrader Selectivity FHT-CBPd-59 DC50 @24h T u
Slide 37: Long-Acting Injectable Formulation Provides Anti-Tumor Activity
| No Significant Difference in Platelet Counts at End of Study Tumor growth inhibition (regression) observed in EP300mut (639V) Bladder CDX Long-Acting Injectable (LAI) Formulation Provides Anti-Tumor Activity With a Single Injection 37 Company Confidential & Proprietary Information T u m o r V o lu
Slide 38: CBP Degrader in Combination in ER+ Breast Cancer Models
| Foghorn Selective CBP Degrader Shows Promise in Combination With Standard Therapies in Preclinical ER+ Breast Cancer Models 38 CDK4/6 Inhibitor + Fulvestrant CBP Degrader (FHT-CBPd-41) + CDK4/6 inhibitor + Fulvestrant Cancer cell growth only significantly inhibited at highest concentrations of SoC
Slide 39: 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 39 PLT (x109cells/L) 0 500 1,
Slide 40: Selective EP300 Protein Degrader
Selective EP300 Protein Degrader For CBP Mutated and EP300 Dependent Cancers 40
Slide 41: Summary: Selective EP300 Protein Degrader
| Summary: Selective EP300 Protein Degrader for CBP Mutant & EP300 Dependent Cancers 41 * 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 42: Anti-Tumor Activity Across Heme Sub-Lineages
| 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 42MM: Multiple Myeloma; DLBCL: Diffuse Large B-Cell Lymphoma; AML: Acute Myeloid Leukemia; BL:
Slide 43: EP300 Degradation Tumor Growth Inhibition in Myeloma, DLBCL and Prostate
| 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 43 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 44: Selective EP300 Degrader 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 45: 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 46: 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 at Tolerated Doses With No Thrombocytopenia 46 CCS1477
Slide 47: Selective ARID1B Protein Degrader
Selective ARID1B Protein Degrader For ARID1A Mutated Cancers 47
Slide 48: ARID1B is a Major Synthetic Lethal Target
| ARID1B is a Major Synthetic Lethal Target With Potential in Up To 5% of All Solid Tumors 48 * Per year incidence in the U.S., EU5, Japan. Source: Clarivate DRG Mature Markets Data. • ARID1B • Targeted protein degraderTarget / Approach • ARID1A mutated cancers (e.g. ovarian, endometrial, colorectal
Slide 49: Foghorn is First to Report Selective Degradation of ARID1B
| Foghorn is First to Report Selective Degradation of ARID1B 49 ARID1A/B BAF Nucleosome PDB ID: 6LTJ Company Confidential & Proprietary Information • Foghorn has developed potent and selective binders • Foghorn is first to report selective degradation • Program update expected in 2025
Slide 50: Compound Screening Yielded Selective ARID1B Binders
| Compound Screening and Structure-Based Optimization Yielded Selective ARID1B Binders 50 • 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 51: Structure-Based Optimization Improved ARID1B Binding Affinity
| Structure-Based Optimization Drove Improved ARID1B Binding Affinity From 100 uM to Less Than 200 nM 51 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 52: Advancing Multiple Programs with Near-Term Milestones Through 2026
| Advancing Multiple Programs with Near-Term Milestones Through 2026 52 Phase 1 Monotherapy DataFHD-909* (LY4050784) (Selective SMARCA2 Inhibitor) 2026IND / Phase 1 InitiationSelective CBP Degrader 2026IND / Phase 1 InitiationSelective EP300 Degrader ConfidentialIND / Phase 1 InitiationSelective SMA
Slide 53: Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer 53 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 54: Unique biology, Precision therapeutics, Broad impact
Unique biology Precision therapeutics Broad impact 54 May 2025
Slide 55: Appendix
Appendix 55
Slide 56: Induced Proximity Platform Evolution
Induced Proximity Platform Evolution FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex 56
Slide 57: 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 57 TargetDegrader Machinery (E3 Ligase) TargetEffector Post-Translational modification - dependent Protein Stabilization Modulation of gene activation/repression Induced P
Slide 58: Induced Proximity Platform Demonstrates Initial POC for DUBTAC
| Induced Proximity Platform Demonstrates Initial POC for DUBTAC 58 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 59: Novel Approach to Activate Cell Death Cascade
| Induced Proximity Platform Demonstrates Potential for Novel Approach to Activate Cell Death Cascade 59 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 60: Induced Proximity Expansion Beyond Oncology: Nuclear Hormone Receptors
| 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 61: 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 62: 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 62
Slide 63: Foghorn's Transcription Factor Platform Approaches
| Foghorn’s Transcription Factor Platform: 4 Approaches 63 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)
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