Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (August 2024)
59 slides from Foghorn Therapeutics's investor presentation, Aug 8, 2024
Slide 1: August 2024 Unique biology, Precision therapeutics, Broad impact
August 2024 Unique biology Precision therapeutics Broad impact 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 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: Pipeline of First-in-Class Precision Therapeutics in Oncology
| 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-286 (SMARCA2 / SMARCA4) FHD-909 (Selective SM
Slide 10: Multiple Near-Term Value Inflection Points through 2026
| … with Multiple Near-Term Value Inflection Points through 2026 10 Q4 2024AML Combination Dose Escalation Data FHD-286 H2 2024Phase 1 InitiationFHD-909 (Selective SMARCA2 Inhibitor) ConfidentialIND Filing / Phase 1 InitiationSelective SMARCA2 Degrader Year End 2024Initiate IND-Enabling StudiesSelec
Slide 11: Potential Multi-Billion Dollar Opportunities in Oncology
| Potential Multi-Billion Dollar Opportunities in Oncology 11 Foghorn Owned Selective CBP Degrader Selective EP300 Degrader Lilly Target #3 Selective ARID1B Degrader FHD-286 (R/R AML, Other) Potential for therapeutic area expansion (e.g., immunology and inflammation) Partnered w Lilly $500M to $2B M
Slide 12: Clinical & Pre-Clinical Programs
Clinical & Pre-Clinical Programs • FHD-286 – Dual SMARCA2 / SMARCA4 Inhibitor • FHD-909 (LY4050784) – Selective SMARCA2 Inhibitor • Selective CBP Degrader • Selective EP300 Degrader • Selective ARID1B Program
Slide 13: FHD-286: Dual SMARCA2 / SMARCA4 Inhibition Targeting BAF Dependency in Cancer
FHD-286: Dual SMARCA2 / SMARCA4 Inhibition Targeting BAF Dependency in Cancer FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complexSMARCA2 = BRM SMARCA4 = BRG1
Slide 14: Exploring BAF Dependency in Cancer with FHD-286
| Exploring BAF Dependency in Cancer with FHD-286 – Potent, First-in-Class, Oral Dual Inhibitor of SMARCA2 and SMARCA4 14 Clinical and pre-clinical data demonstrated broad- based differentiation across AML and multiple solid tumors BAF ATPase: SMARCA2 / SMARCA4 FHD-286: • Allosteric modulation inhib
Slide 15: Significant Opportunity for Novel Therapy in R/R AML
| Significant Opportunity for Novel, Effective Therapy in Patients with R/R AML 15 • >50% of patients relapse • Intensive chemo – still standard of care Most cases of AML are not curable 40% of AML cases have no actionable mutations • No meaningful developments for broad AML patient population since
Slide 16: FHD-286 Demonstrated Mutation-Agnostic Differentiation Effects in Phase 1
| FHD-286 Demonstrated Promising Mutation-Agnostic Differentiation Effects in Single Agent Phase 1 Trial 16 Dose Level Mutations Cytogenetics Risk Starting CD11b% Max CD11b% CD11b+ Fold Change Starting CD34% Min CD34% CD34+ % Decrease 10mg N/A Adverse 7 62 9.2x 94 27 (71%) 7.5mg CBFB (locus at 16q22
Slide 17: Dose Escalation Trial Design in Combination with Decitabine in AML
| Dose Escalation Trial Design in Combination with Decitabine in AML 17 Target Indication: • R/R AML Treatment Plan & Dose Escalation: • 3+3 escalation design • Oral FHD-286, QD, 28-day cycles • Standard decitabine dose schedule Key Objectives • Safety/Tolerability • Maximum Tolerated Dose (MTD) and
Slide 18: Pre-Clinical Data Demonstrated Combination Potential in AML
| FHD-286 + decitabine (MLL-AFP + FLT3 TKD Luc/GFP PDX) Pre-Clinical Data Demonstrated Combination Potential with Multiple Agents in AML 18 FHD-286 + BET inhibitor (mtNPM1 + FLT3 ITD Luc/GFP AML PDX) FHD-286 + menin inhibitor (mtNPM1 + FLT3 ITD Luc/GFP AML PDX) FHD-286 + cytarabine (MV4, 11 FLT3 ITD
Slide 19: FHD-286 Has Potential in Multiple High-Value Oncology Indications
| FHD-286 Has Potential in Multiple High-Value Oncology Indications 19 R/R AML combinations (e.g., decitabine, menin inhibitors, others) Other Hematologic and Solid Tumors TKI Combination Front-Line AML Combination
Slide 20: Selective SMARCA2 Modulators For SMARCA4 Mutated Cancers
Selective SMARCA2 Modulators For SMARCA4 Mutated Cancers FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complexSMARCA2 = BRM SMARCA4 = BRG1
Slide 21: SMARCA2 Selective Inhibitor FHD-909 on Track for Phase 1 Initiation
| SMARCA2 Selective Inhibitor FHD-909 on Track for Phase 1 Initiation, Selective SMARCA2 Degrader Continues Late-Stage Pre-Clinical Development 21 SMARCA2 Selective Inhibitor (FHD-909) SMARCA2 Selective Degrader Biology Exploit the synthetic lethal relationship between SMARCA2 and mutated SMARCA4 St
Slide 22: Selective SMARCA2 Inhibition Exploits Synthetic Lethal Relationship
| Selective SMARCA2 Inhibition: Promising Strategy to Exploit Synthetic Lethal Relationship Between SMARCA2 and Mutant SMARCA4 22 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 23: SMARCA4 is Mutated in Up to 10% of NSCLC
| SMARCA4 is Mutated in Up to 10% of NSCLC; Up to 5% of Solid Tumors 23 SMARCA4 mutated across a broad range of tumors Accounts for ~5% of solid tumors AACR GENIE via cBioPortal
Slide 24: 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 24 SMARCA4 10% KRAS 29% EGFR 2
Slide 25: FHD-909 Demonstrated Approximately 33-fold Selectivity Across Cell Lines
| SMARCA4 WT SMARCA4 MUT 0.0001 0.001 0.01 0.1 1 A b so 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-90
Slide 26: FHD-909 Monotherapy Demonstrated Regression in H2126 Model
| FHD-909 Monotherapy Demonstrated Regression In Vivo in H2126 SMARCA4 Mutant NSCLC Model and Was Well Tolerated 26 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 27: FHD-909 Demonstrated 96% TGI in A549 and 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 27 A549 Model NOTE: All doses were well tolerated. Dosing holidays were applied at the high dose, as appropriate SMARCA4 mut p.E1496*, TP53 p.Q104*, NF1 p.E1699* SMARCA4, Q729fs / H
Slide 28: FHD-909 Demonstrated Regression in H1793 Model
| FHD-909 Monotherapy Demonstrated Regression in H1793 SMARCA4 Mutant NSCLC Model 28 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 29: FHD-909 Trial Design
| FHD-909 Trial Design – Phase 1 Initiation On Track • Restricted to SMARCA4 mutated tumors • SMARCA4 mutant status confirmed by standard NGS panel • Further enrichment for NSCLC patients as trial progresses • Tumor histology agnostic 29 Dose Escalation Dose Expansion • Arm 1: SMARCA4 mutant NSCLC •
Slide 30: SMARCA2 Selective Degrader Achieved Complete SMARCA2 Degradation
| SMARCA2 Selective Degrader Achieved Complete SMARCA2 Degradation and Cell Growth Inhibition In Vitro 30 Degraders Caused Time- and Dose-Dependent SMARCA2 Degradation Antiproliferative Effects in A549 Mutant NSCLC Model A549 Ten-Day Proliferation AssaySMARCA2 / SMARCA4 HIBIT Data % Inhibition of Ce
Slide 31: CBP and EP300 Proteins: A Decades Long Challenge in Selectivity
| CBP and EP300 Proteins – A Decades Long Challenge in Selectivity 31 • 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 32: Selective CBP Protein Degrader For EP300 Mutated Cancers
Selective CBP Protein Degrader For EP300 Mutated Cancers
Slide 33: Summary: Selective CBP Protein Degrader for EP300 Mutated Cancers
| Summary: Selective CBP Protein Degrader for EP300 Mutated Cancers 33* 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, br
Slide 34: Selective CBP Degradation Resulted in Tumor Growth Inhibition
| Selective CBP Degradation Resulted in Significant Tumor Growth Inhibition in Colorectal & Bladder and Regression in Gastric EP300 Null Models 34
Slide 35: 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 35 PLT (x109cells/L) 0 500 1,000 1,500 2,000 2,500 Study Day 14 Vehicle FHT-CBPd, 10mg/kg, sc, QD
Slide 36: 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 36 dCBP-9 PK/PD (60mg/kg, sc) dCBP-9 PK/PD (150mg/kg, sc) dCBP-9 PK/PD (150mg/kg, im) C B P L e ve ls / % V e h ic le P la s m a P K (n g /m L )
Slide 37: Selective EP300 Protein Degrader For CBP Mutated and EP300 Dependent Cancers
Selective EP300 Protein Degrader For CBP Mutated and EP300 Dependent Cancers
Slide 38: Summary: Selective EP300 Protein Degrader
| Summary: Selective EP300 Protein Degrader for CBP Mutant & EP300 Dependent Cancers 38 * 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 • DLBCL • Bladder, melanoma
Slide 39: 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 39 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 T u m o r V o lu m e (m m ³ + S E M ) Vehic
Slide 40: Selective EP300 Degradation Does Not Show Thrombocytopenia
| Selective EP300 Degradation Does Not Show Thrombocytopenia In Vivo 40 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 Vehicle FHT-EP300d, 50mg/kg, sc, BID Dual BD inhibitor, 30mg/kg, p.o, BID FHT-EP300d Dual CBP/EP300 Inhibitor Vehicl
Slide 41: Selective ARID1B Protein Degrader For ARID1A Mutated Cancers
Selective ARID1B Protein Degrader For ARID1A Mutated Cancers
Slide 42: 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 42* Per year incidence in the U.S., EU5, Japan. Source: Clarivate DRG Mature Markets Data. • ARID1B • Targeted protein degrader Target / Approach • ARID1A mutated cancersInitial Indication • ARID1A mutations (e.g.
Slide 43: Compound Screening Yielded Selective ARID1B Binders
| Compound Screening and Structure-Based Optimization Yielded Selective ARID1B Binders 43 • 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 44: Structure-Based Optimization Improved ARID1B Binding Affinity
| Structure-Based Optimization Drove Improved ARID1B Binding Affinity from 100 uM to less than 200 nM 44 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 45: Multiple Near-Term Value Inflection Points through 2026
| … with Multiple Near-Term Value Inflection Points through 2026 45 Q4 2024AML Combination Dose Escalation Data FHD-286 H2 2024Phase 1 InitiationFHD-909 (Selective SMARCA2 Inhibitor) ConfidentialIND Filing / Phase 1 InitiationSelective SMARCA2 Degrader Year End 2024Initiate IND-Enabling StudiesSelec
Slide 46: Developing First-In-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| Developing First-In-Class Precision Medicines Targeting Major Unmet Needs in Cancer 46 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 47: August 2024 Unique biology, Precision therapeutics, Broad impact
August 2024 Unique biology Precision therapeutics Broad impact
Slide 48: Appendix
Appendix
Slide 49: Lilly Collaboration Validates Foghorn Approach
| Lilly Collaboration Validates Foghorn Approach: Significant Upfront and Deal Economics 49 $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 50: FHD-286: Dual SMARCA2 / SMARCA4 Inhibition Additional Information
FHD-286: Dual SMARCA2 / SMARCA4 Inhibition Targeting BAF Dependency in Cancer Additional Information
Slide 51: First-in-Class Mutation-Agnostic Differentiation Agent in AML
| Potential First-in-Class Mutation-Agnostic Differentiation Agent With Significant Combination Potential in AML 51 Completed Phase I Monotherapy Safety and Efficacy Results Ongoing Phase I Combination Trial Efficacy • Differentiation observed in heavily pre-treated patients, regardless of mutationa
Slide 52: Blast Count Reduction Led to ANC Recovery in a Subset of Patients
| Peripheral Blood and Bone Marrow Blast Count Reduction Led to ANC Recovery in a Subset of Patients 52 * MDS Patient Diagnosis Dose Level Mutations Cytogenetic Risk Cycles on Study ANC Recovery Peripheral Starting Blast % Peripheral Min Blast % Peripheral Blast % Change BMA Starting Blast % BMA Min
Slide 53: Blast Count Reduction Leading to ANC Recovery in a Subset of Patients
| Peripheral Blood and Bone Marrow Blast Count Reduction Leading to ANC Recovery in a Subset of Patients 53 * MDS Patient Diagnosis Dose Level Mutations Cytogenetic Risk Cycles on Study ANC Recovery Peripheral Starting Blast % Peripheral Min Blast % Peripheral Blast % Change BMA Starting Blast % BMA
Slide 54: Bone Marrow Aspirate: Clear Evidence of Differentiation
| Bone Marrow Aspirate: Clear Evidence of Differentiation Bone Marrow Blast Reduction from 40% to 6% Signs of Differentiation in Heavily Pre-Treated, Secondary AML Patient with Abnormal Karyotype in Phase 1 Dose Escalation Trial 54 Patient Background: • 47-year-old male, secondary AML • Abnormal kar
Slide 55: Clinical Benefit in Heavily Pre-Treated Patient in Phase 1
| Absolute Neutrophil Count (ANC) Peripheral Blast Count Clinical Benefit in Heavily Pre-Treated Patient in Phase 1 Dose Escalation Trial 55 100% 0% 50% 10 5 10/13/21 10/24/21 11/4/21 11/14/21 11/25/21 12/6/21 0 Initiation of FHD 286 1st SCT 2nd SCT Patient Background: • 25-year-old male, treatment-
Slide 56: 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
Slide 57: Foghorn's Novel Approach to Drugging Transcription Factors
| Foghorn’s Novel Approach to Drugging Transcription Factors Enabled by Its Protein Production and Discovery Capabilities 57 • 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 58: 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 58 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
Slide 59: August 2024 Unique biology, Precision therapeutics, Broad impact
August 2024 Unique biology Precision therapeutics Broad impact
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