Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (December 2024)
45 slides from Foghorn Therapeutics's investor presentation, Dec 16, 2024
Slide 1: Unique biology, Precision therapeutics, Broad impact
December 2024 Unique biology Precision therapeutics Broad impact 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 the Pioneer in Chromatin Biology, an Untapped Area for Therapeutics
| Foghorn is the Pioneer in Chromatin Biology, an Untapped Area for Therapeutics 3 What if … It were possible to develop a therapeutic approach to treat half of all cancers? Chromatin biology is implicated in up to 50% of tumors ~2.5 million cancer patients Potential for therapeutic area expansion
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 Complex – specialized multiprotein machineries that allow access to DNA Transcription Factor – prote
Slide 5: Foghorn has Progressed Multiple Programs Against Challenging Targets
| Foghorn has Progressed Multiple Programs Against Challenging Targets 5 SMARCA2: Potential in 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 inhibition, difficulty engineeri
Slide 6: Foghorn's 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: 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: The Next Foghorn Chapter: Delivering Multiple Potential Blockbusters into the Clinic
| The Next Foghorn Chapter: Delivering Multiple Potential Blockbusters into the Clinic 8 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 9: Foghorn Is 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... 9 Modality Program Phase 1 Enzyme Inhibitors Transcription Factor Disruptors Undisclosed Protein Degraders Commercial Rights FHD-909* (Selective SMARCA2) 3 Discovery Program
Slide 10: Multiple Near-Term Value Inflection Points through 2026
| …with Multiple Near-Term Value Inflection Points through 2026 10 October 2024Phase 1: First Patient DosedFHD-909 (Selective SMARCA2 Inhibitor) ConfidentialIND Filing / Phase 1 InitiationSelective SMARCA2 Degrader Year End 2024Initiate IND-Enabling StudiesSelective CBP Degrader 2025Initiate IND-Ena
Slide 11: Potential Multi-Billion Dollar Opportunities in Oncology
| Potential Multi-Billion Dollar Opportunities in Oncology 11 Foghorn Owned Selective EP300 Degrader Lilly Target #3 Selective ARID1B Degrader Potential for therapeutic area expansion (e.g., immunology and inflammation)Partnered w Lilly Selective SMARCA2 Inhibitor (FHD-909) Selective SMARCA2 Degrade
Slide 12: Clinical & Pre-Clinical Programs
Clinical & Pre-Clinical Programs • FHD-909 (LY4050784) – Selective SMARCA2 Inhibitor • Selective CBP Degrader • Selective EP300 Degrader • Selective ARID1B Program 12
Slide 13: Selective SMARCA2 Modulators For SMARCA4 Mutated Cancers
Selective SMARCA2 Modulators For SMARCA4 Mutated Cancers SMARCA2 = BRM SMARCA4 = BRG1 13
Slide 14: FHD-909 in Phase 1 Trial; Selective SMARCA2 Degrader Continues Pre-Clinical Development
| FHD-909, SMARCA2 Selective Inhibitor in Phase 1 Trial; Selective SMARCA2 Degrader Continues Late-Stage Pre-Clinical Development 14 SMARCA2 Selective Inhibitor (FHD-909*) SMARCA2 Selective Degrader Biology Exploit the synthetic lethal relationship between SMARCA2 and mutated SMARCA4 Stage Phase 1 d
Slide 15: Selective SMARCA2 Inhibition Exploits Synthetic Lethality
| Selective SMARCA2 Inhibition: Promising Strategy to Exploit Synthetic Lethal Relationship Between SMARCA2 and Mutant SMARCA4 15 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 16: SMARCA4 is Mutated in Up to 10% of NSCLC
| SMARCA4 is Mutated in Up to 10% of NSCLC; Up to 5% of Solid Tumors 16 SMARCA4 mutated across a broad range of tumors Accounts for ~5% of solid tumors AACR GENIE via cBioPortal
Slide 17: SMARCA4 Mutant NSCLC Patients Have Worse Outcomes and High Unmet Need
| 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 17 SMARCA4 10% KRAS 29% EGFR 2
Slide 18: FHD-909 Demonstrated Approximately 33-fold Selectivity Across Cell Lines
| SMARCA4 WT SMARCA4 MUT 0.0001 0.001 0.01 0.1 1 A bs ol ut e IC 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-909
Slide 19: 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 19 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 20: FHD-909 Demonstrated 96% TGI in A549 and Tumor Stasis in RERF-LC-AI
| RERF-LC-AI Model FHD-909 Monotherapy Demonstrated 96% TGI in A549 and Tumor Stasis in RERF-LC-AI Mutant NSCLC Models 20 A549 Model NOTE: All doses were well tolerated. Dosing holidays were applied at the high dose, as appropriate 0 7 14 21 28 200 400 600 800 1000 1200 Days of Dosing (Dose Start Da
Slide 21: FHD-909 Monotherapy Demonstrated Regression in H1793 Model
| FHD-909 Monotherapy Demonstrated Regression in H1793 SMARCA4 Mutant NSCLC Model 21 H1793 Model • FHD-909 delivered across range of SMARCA4 mut xenograft models • Results ranging from impressive TGI to regression as monotherapy • All doses across all four models were well tolerated NOTE: All doses
Slide 22: FHD-909 Trial Design
| FHD-909 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 22 Dose Escalation Dose Expansion • Arm 1: SMARCA4 mutant NSCLC • Arm 2: Other SMARCA4 mutant t
Slide 23: SMARCA2 Selective Degrader Achieved Complete SMARCA2 Degradation In Vitro
| SMARCA2 Selective 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 0.01 0.1 1 10 100
Slide 24: CBP and EP300 Proteins – A Decades Long Challenge in Selectivity
| CBP and EP300 Proteins – A Decades Long Challenge in Selectivity 24 • CBP and EP300 are chromatin regulators and histone acetyltransferases • CBP and EP300 are virtually identical, thus achieving selectivity is a significant challenge • Dual targeting has revealed tolerability and safety issues Fo
Slide 25: Selective CBP Protein Degrader For EP300 Mutated Cancers
Selective CBP Protein Degrader For EP300 Mutated Cancers 25
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. Target / Approach • CREB binding protein (CBP) • Targeted protein degrader Initial Indication • EP300 mutated cancers (e.g., subsets of blad
Slide 27: Selective CBP Degradation Resulted in Significant Tumor Growth Inhibition
| Selective CBP Degradation Resulted in Significant Tumor Growth Inhibition in Colorectal & Bladder and Regression in Gastric EP300 Null Models 27
Slide 28: Selective CBP Degradation Did Not Show Thrombocytopenia
| Bone Marrow Staining (In Vivo)Platelet Counts Post Two Weeks of Dosing (In Vivo) Pre-Clinical Studies Indicate Selective CBP Degradation Did Not Show Thrombocytopenia and Spares Megakaryocytes In Vivo 28 PLT (x109cells/L) 0 500 1,000 1,500 2,000 2,500 Study Day 14 Pl at el et s (X 10 3 c el ls /u
Slide 29: Long-Acting Injectable Formulations of CBP Degrader
| Pre-Clinical Studies Indicate Long-Acting Injectable Formulations of CBP Degrader Could Enable At Least Once Every 2 Weeks Dosing 29 dCBP-9 PK/PD (60mg/kg, sc) dCBP-9 PK/PD (150mg/kg, sc) dCBP-9 PK/PD (150mg/kg, im) 0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360 0 25 50 75 100 125 10 10
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. Target / Approach • E1A binding protein p300 (EP300) • Targeted protein degrader Initial Indications • AR+ Prostate • DLBCL
Slide 32: EP300 Degradation Results in Tumor Growth Inhibition in Prostate and DLBCL Models
| EP300 Degradation Results in Significant Tumor Growth Inhibition in AR+ VCAP Prostate and KARPAS422 DLBCL Models 32 Prostate AR+ VCAP Model DLBCL KARPAS422 (CBP Null) Model 5 10 15 20 25 30 35 40 45 50 0 500 1,000 1,500 2,000 Days After Tumor Inoculation Tu m or V ol um e (m m ³ + S EM ) Vehicle C
Slide 33: Selective EP300 Degradation Does Not Show Thrombocytopenia In Vivo
| Selective EP300 Degradation Does Not Show Thrombocytopenia In Vivo 33 Platelet Counts Post Two Weeks of Dosing (In-Vivo) PLT (x109cells/L) 0 500 1,000 1,500 2,000 2,500 Study Day 14 Pl at el et s (X 10 3 c el ls /u L) Vehicle FHT-EP300d, 50mg/kg, sc, BID Dual BD inhibitor, 30mg/kg, p.o, BID FHT-EP
Slide 34: Selective ARID1B Protein Degrader For ARID1A Mutated Cancers
Selective ARID1B Protein Degrader For ARID1A Mutated Cancers 34
Slide 35: ARID1B is a Major Synthetic Lethal Target in Up To 5% of Solid Tumors
| ARID1B is a Major Synthetic Lethal Target Implicated in Up To 5% of All Solid Tumors 35* Per year incidence in the U.S., EU5, Japan. Source: Clarivate DRG Mature Markets Data. Target / Approach • ARID1B • Targeted protein degrader Initial Indication • ARID1A mutated cancers Mutation / Aberration •
Slide 36: Compound Screening and Structure-Based Optimization Yielded Selective ARID1B Binders
| Compound Screening and Structure-Based Optimization Yielded Selective ARID1B Binders 36 • 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 37: Structure-Based Optimization Improved ARID1B Binding Affinity
| Structure-Based Optimization Drove Improved ARID1B Binding Affinity from 100 uM to less than 200 nM 37 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 1
Slide 38: Multiple Near-Term Value Inflection Points through 2026
| … with Multiple Near-Term Value Inflection Points through 2026 38 October 2024Phase 1: First Patient DosedFHD-909 (Selective SMARCA2 Inhibitor) ConfidentialIND Filing / Phase 1 InitiationSelective SMARCA2 Degrader Year End 2024Initiate IND-Enabling StudiesSelective CBP Degrader 2025Initiate IND-En
Slide 39: Developing First-In-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| Developing First-In-Class Precision Medicines Targeting Major Unmet Needs in Cancer 39 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 40: Unique biology, Precision therapeutics, Broad impact
Unique biology Precision therapeutics Broad impact 40December 2024
Slide 41: Appendix
Appendix 41
Slide 42: Lilly Collaboration Validates Foghorn Approach
| Lilly Collaboration Validates Foghorn Approach: Significant Upfront and Deal Economics 42 $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
Slide 43: Transcription Factors: A Novel Approach
Transcription Factors A Novel Approach FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex 43
Slide 44: Foghorn's Novel Approach to Drugging Transcription Factors
| Foghorn’s Novel Approach to Drugging Transcription Factors Enabled by Its Protein Production and Discovery Capabilities 44 • Highly involved in gene expression • Implicated in range of cancers and other diseases • Featureless surface: no druggable binding pocket • Tight interactions with DNA: undr
Slide 45: Transcription Factors Bind to BAF Directly with Specificity
| Transcription Factors Bind to BAF Directly with Specificity; Unique Insights into Where and How Transcription Factors Bind 45 Mass spec. foot-printing Pull-down assays Foghorn’s collection of BAF sub-complexes and domains Biophysical Biochemical Structural AUC / SPR / ITC TR-FRET / FP Crystal / NM
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