Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (June 2024)
59 slides from Foghorn Therapeutics's investor presentation, Jun 3, 2024
Slide 1: June 2024 Unique biology, Precision therapeutics, Broad impact
June 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 BRM: 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 engineering s
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: 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-286 (BRG1/BRM) FHD-909 (Selective BRM) 3 Disc
Slide 10: Multiple Near-Term Value Inflection Points through 2026
| … with Multiple Near-Term Value Inflection Points through 2026 10 H2 2024AML Combination Dose Escalation Data FHD-286 H2 2024Phase 1 InitiationFHD-909 (Selective BRM Inhibitor) ConfidentialIND Filing / Phase 1 InitiationSelective BRM Degrader Year End 2024Initiate IND-Enabling StudiesSelective CBP
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 BRM/BRG1 Inhibitor • FHD-909 (a.k.a. LY4050784) – Selective BRM Inhibitor • Selective CBP Degrader • Selective EP300 Degrader • Selective ARID1B Program
Slide 13: FHD-286: Dual BRM/BRG1 Inhibition Targeting BAF Dependency in Cancer
FHD-286: Dual BRM/BRG1 Inhibition Targeting BAF Dependency in Cancer FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex
Slide 14: Exploring BAF Dependency in Cancer with FHD-286
| Exploring BAF Dependency in Cancer with FHD-286 – Potent, Oral Dual Inhibitor of BRM and BRG1 14 Clinical and pre-clinical data demonstrated broad- based differentiation across AML and multiple solid tumors BAF ATPase: BRG1/BRM FHD-286: • Allosteric modulation inhibiting the activity of both BRM a
Slide 15: Significant Opportunity for Novel Therapy in Patients with 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 Induced Differentiation Across Broad Genetic Backgrounds in Phase 1
| FHD-286 Induced Differentiation Across a Broad Range of Genetic Backgrounds in Phase 1 Study 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) 2 94 59.
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 Primary • Safety/Tolerability • Maximum Tolerated Dose (
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 TumorsTKI Combination Front-Line AML Combination
Slide 20: Selective BRM Modulators For BRG1 Mutated Cancers
Selective BRM Modulators For BRG1 Mutated Cancers FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex
Slide 21: BRM Selective Inhibitor FHD-909 on Track for Phase 1 Initiation
| BRM Selective Inhibitor FHD-909 on Track for Phase 1 Initiation, BRM Selective Degrader Continues Late-Stage Pre-Clinical Development 21 BRM Selective Inhibitor (FHD-909) BRM Selective Degrader Biology Exploit the synthetic lethal relationship between BRM (SMARCA2) and mutated BRG1 (SMARCA4) Stage
Slide 22: BRM Selective Inhibition Exploits Synthetic Lethal Relationship
| BRM Selective Inhibition is a Promising Strategy to Exploit the Synthetic Lethal Relationship Between BRM and Mutated BRG1 22 No BRG1 Mutations BRG1 Mutation BRG1 Mutation and BRMi Cell Survival Cell Death Healthy Cells Cancer Cells BRG1 BRM BAF Complex BRM BAF Complex Mutant BRG1 BAF Complex BRMi
Slide 23: BRG1 is Mutated in Up to 10% of NSCLC; Up to 5% of Solid Tumors
| BRG1 is Mutated in Up to 10% of NSCLC; Up to 5% of Solid Tumors 23 BRG1 mutated across a broad range of tumors Accounts for ~5% of solid tumors AACR GENIE via cBioPortal
Slide 24: NSCLC Patients with BRG1 Mutations Have Worse Outcomes
| BRG1 mutated in up to 10% of NSCLC tumors, minimal overlap with other mutations2Overall Survival for BRG1wt vs BRG1mut1* Patients with NSCLC Harboring BRG1 Mutations Have Significantly Worse Clinical Outcomes and Define a High Unmet Need Patient Population 24 BRG1 10% KRAS 29% EGFR 26% ALK 7% RET
Slide 25: FHD-909 Demonstrated Approximately 33-fold Selectivity
| BRG1 WT BRG1 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 BRG1 (WT) BRG1 (MUT) (BRM Only)(BRM and BRG1) FHD-909 Demonstrated Approxim
Slide 26: FHD-909 Monotherapy Demonstrated Regression in H2126 Model
| FHD-909 Monotherapy Demonstrated Regression In Vivo in H2126 BRG1 Mutant NSCLC Model and Was Well Tolerated 26 H2126 Reduction in Tumor Volume H2126 Body Weight Genetic Background: BRG1 W764R, TP53 E62*, STK11-/-, CDKN2A-/-, KEAP1 R272C NOTE: All doses were well tolerated. Dosing holidays were app
Slide 27: FHD-909 Monotherapy Demonstrated 96% TGI in A549
| 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 0 7 14 21 28 200 400 600 800 1000 1200 Days of Dosing (Dose Start Da
Slide 28: FHD-909 Monotherapy Demonstrated Regression in H1793 Model
| FHD-909 Monotherapy Demonstrated Regression in H1793 BRG1 Mutant NSCLC Model 28 H1793 Model • FHD-909 delivered across range of BRG1 mut xenograft models • Results ranging from impressive TGI to regression as monotherapy • All doses across all four models were well tolerated NOTE: All doses were w
Slide 29: FHD-909 Trial Design
| FHD-909 Trial Design – Phase 1 Initiation On Track • Restricted to BRG1 mutated tumors • BRG1 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: BRG1 mutant NSCLC • Arm 2: O
Slide 30: BRM Selective Degrader Achieved Complete BRM Degradation In Vitro
| BRM Selective Degrader Achieved Complete BRM Degradation and Cell Growth Inhibition In Vitro 30 Degraders Caused Time- and Dose-Dependent BRM Degradation Antiproliferative Effects in A549 Mutant NSCLC Model A549 Ten-Day Proliferation AssayBRM/BRG1 HIBIT Data BRM BRG1 % D eg ra da tio n Concentrati
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. Target / Approach • CREB binding protein (CBP) • Targeted protein degrader Initial Indication • EP300 mutated cancers (e.g., subsets of blad
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 Pl at el et s (X 10 3 c el ls /u
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) 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 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. Target / Approach • E1A binding protein p300 (EP300) • Targeted protein degrader Initial Indications • AR+ Prostate • DLBCL
Slide 39: EP300 Degradation Results in Tumor Growth Inhibition in VCAP and KARPAS422
| 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 Tu m or V ol um e (m m ³ + S EM ) Vehicle C
Slide 40: Selective EP300 Degradation Does Not Show Thrombocytopenia In Vivo
| 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 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 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. Target / Approach • ARID1B • Targeted protein degrader Initial Indication • ARID1A mutated cancers Mutation / Aberration •
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 1
Slide 45: Multiple Near-Term Value Inflection Points through 2026
| Multiple Near-Term Value Inflection Points through 2026 45 H2 2024AML Combination Dose Escalation Data FHD-286 H2 2024Phase 1 InitiationFHD-909 (Selective BRM Inhibitor) ConfidentialIND Filing / Phase 1 InitiationSelective BRM Degrader Year End 2024Initiate IND-Enabling StudiesSelective CBP Degrad
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: June 2024 Unique biology, Precision therapeutics, Broad impact
June 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 BRM/BRG1 Inhibition Additional Information
FHD-286: Dual BRM/BRG1 Inhibition Targeting BAF Dependency in Cancer Additional Information FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex
Slide 51: Potential First-in-Class Broad-Based Differentiation Agent in AML
| Potential First-in-Class Broad-Based Differentiation Agent With Significant Combination Potential in AML 51 Completed Phase I Monotherapy Safety and Efficacy Results Ongoing Phase I Combination Study Efficacy • Differentiation observed in heavily pre-treated patients, regardless of mutational stat
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 Study 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 Study 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: June 2024 Unique biology, Precision therapeutics, Broad impact
June 2024 Unique biology Precision therapeutics Broad impact
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