Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (December 2021)
48 slides from Foghorn Therapeutics's investor presentation, Dec 13, 2021
Slide 1: Targeting the Chromatin Regulatory System
Targeting the Chromatin Regulatory System Broadening the Impact of Precision Medicines for Oncology and Other Diseases December 2021 Exhibit 99.2
Slide 2: Disclaimer, Confidentiality, and Forward-Looking Statements
Disclaimer, Confidentiality, and Forward-Looking StatementsThis presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation are forward-looking statements. In some cases, you can identify forward-looking statements by term
Slide 3: Dysregulation of the Chromatin Regulatory System Implicated in up to 50% of All Cancers
Dysregulation of the Chromatin Regulatory System Has Been Implicated in up to 50% of All Cancers 3 Significant Market Opportunity 2.5M People 50% of All Cancers Based on exome sequencing, the chromatin regulatory system is implicated in ~50% of all cancers $400+ billion 2030 global oncology market o
Slide 4: Foghorn Well Positioned to Discover and Develop First in Class Precision Medicines
Foghorn Well Positioned to Discover and Develop First in Class Precision Medicines Targeting Cancer and Other Diseases Significant Global Partnerships Strategic Collaboration with Loxo Oncology at Lilly Merck collaboration to drug single specified transcription factor target Expertise across drug di
Slide 5: Advancing a Broad Pipeline Across a Range of Targets and Modalities
Advancing a Broad Pipeline Across a Range of Targets and Modalities 5 Precision Oncology / Breadth and Depth Program / Target Modality Discovery IND Enabling Phase 1 Phase 2 Commercial Rights FHD-286 (BRG1/BRM) Enzyme Inhibitor FHD 609 (BRD9) Degrader Selective BRM I) Enzyme Inhibitor 50/50 U.S., Ex
Slide 6: Strategic Collaboration with Loxo Oncology at Lilly
Strategic Collaboration with Loxo Oncology at Lilly 6 Foghorn to Lead Discovery and Research Activities $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. econo
Slide 7: The Chromatin Regulatory System Orchestrates Gene Expression
The Chromatin Regulatory System Orchestrates Gene Expression
Slide 8: The Chromatin Regulatory System Orchestrates Gene Expression
Normal gene expression The Chromatin Regulatory System Orchestrates Gene Expression 8 Two Major Components Work in Concert - Chromatin Remodeling Complexes and Transcription Factors Work together to orchestrate gene expression TF’s guide chromatin remodeling complexes to the right locations Once chr
Slide 9: Breakdowns in the Chromatin Regulatory System can Lead to Disease
Breakdowns in the Chromatin Regulatory System can Lead to Disease 9 Mutations or overexpression in chromatin remodeling complexes result in abnormal gene expression Mutated or overexpressed TF hijacks chromatin remodeling complex to wrong location DISEASE DISEASE
Slide 10: Chromatin Regulatory System – Abundance of Targets
Chromatin Regulatory System – Abundance of Targets 10 28 Chromatin Remodeling Complexes and >1,000 TFs Estimate >100 Transcription Factors Associated with just the BAF Complex BAF Complex and Associated Transcription Factors + BAF Complex Subunits Mutated and Dysregulated in Cancer
Slide 11: Mutations Lead to Disease Specific Genetic Dependencies
Mutations Lead to Disease Specific Genetic Dependencies on the Chromatin Regulatory System 11 Transcription Factor Mutations / Overexpression Chromatin Remodeling Complexes Mutations / Overexpression Mutations that Impinge on the Chromatin Regulatory System Novel Targets / Dependencies Targeted Prot
Slide 12: Foghorn's Gene Traffic Control Platform
Foghorn’s Gene Traffic Control Platform Makes It Possible to Understand and Drug Genetic Dependencies within the Chromatin Regulatory System 12 Integrated, Scalable, Efficient – Repeatable Paradigm Target Identification & Validation Production of Chromatin Regulatory System Components at Scale & Pro
Slide 13: Production of Chromatin Regulatory System Components
Production of Chromatin Regulatory System Components Platform is Powered by Ability to Produce Components at Scale Drives Drug Discovery Pipeline with Cutting Edge Technology Surface Mapping Assembly HTS Biophysics / SPR Affinity Screening and Validation Characterize TF / BAF Binding Sites Synthesiz
Slide 14: Foghorn Pursuing >8 Targeted Protein Degraders
Foghorn Pursuing >8 Targeted Protein Degraders Heterobifunctional Degrader Platform Bioinformatics • Optimal E3 ligase target pairing • Proteomics Chemical Toolbox Screening and Characterization Structural and Computational Approaches to Degrader Design Optimization of Degrader Drug Properties • Pro
Slide 15: Advancing a Broad Pipeline Across a Range of Targets and Modalities
Advancing a Broad Pipeline Across a Range of Targets and Modalities 15 Precision Oncology / Breadth and Depth Program / Target Modality Discovery IND Enabling Phase 1 Phase 2 Commercial Rights FHD-286 (BRG1/BRM) Enzyme Inhibitor FHD 609 (BRD9) Degrader Selective BRM I) Enzyme Inhibitor 50/50 U.S., E
Slide 16: FHD-286: Clinical Entry Point - AML and Uveal Melanoma
FHD-286: Clinical Entry Point - AML and Uveal Melanoma FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex
Slide 17: FHD-286 Targets Abnormal Dependencies on BAF in Cancer
FHD-286 Targets Abnormal Dependencies on BAF in Cancer • BRM / BRG1 is the engine (ATPase) of the BAF chromatin remodeling complex • BRG1 & BRM are highly similar proteins BRG and BRM Subunits BRMBRG1 Target / Approach • BRG1 / BRM ATPase • Small molecule, allosteric, oral enzymatic inhibitor Indica
Slide 18: AML & Dependency on BRG1 / Lineage Dependent TF Interactions
AML & Dependency on BRG1 / Lineage Dependent TF Interactions Disease State Treatment with FHD-286 Loss of blast phenotype / Apoptosis Differentiation AML blasts stuck in BAF / TF dependent proliferative phase HSC Cancerous blast cells rely on BRG1 containing BAF / TF activity BAF – TF Activity BAF –
Slide 19: AML Dependent on BRG1 / Lineage TF Interaction
AML Dependent on BRG1 / Lineage TF Interaction 19 Subtype Sample ID TF #1 SPI1 (PU.1) TF #3 TF #4 SPI1 (PU.1) / BAF Dependency SPI1 ChIPseq TF Association with AML by FAB Classification: 70% BRG1 Inhibition Leads to Loss of SPI1 (PU.1) Occupancy on Chromatin
Slide 20: Preclinical FHD-286 Data Shows Broad Efficacy Across AML Patient Derived Samples
Preclinical FHD-286 Data Shows Broad Efficacy Across AML Patient Derived Samples 20 Notable Patient ID Deep Response Pathology Review Disease Status 1690AML1 Y AML Secondary 1695AML1 Y AML/MDS Secondary 1696AML1 Y AML Secondary 1701AML1 Y AML Secondary 1893AML1 Y AML R/R 1899AML1 Y AML R/R 1990pAML1
Slide 21: FHD-286 Shows Effect Across a Range of Mutations in AML Samples
FHD-286 Shows Effect Across a Range of Mutations in AML Patient-Derived Samples 21 IC 50 (n M ) Patient Samples DNMT3A FLT3 IDH1 IDH2 KIT NF1 NPM1 NRAS RUNX1 TET2 TP53
Slide 22: Dose-Dependent Tumor Growth Inhibition with FHD-286 in AML CDX Models
Dose-Dependent Tumor Growth Inhibition Observed with FHD-286 Treatment in AML CDX Models 22 Tumor Volume Body Weight 0 7 14 21 0 250 500 750 1000 1250 Days Post Treatment Tu m or V ol um e (m m 3 ) 0 7 14 21 0 800 1600 2400 3200 Days Post Treatment Tu m or V ol um e (m m 3 ) 0 7 14 21 80 90 100 110
Slide 23: Tumor Growth Inhibition Observed by Bioluminescence Imaging in Disseminated AML
Tumor Growth Inhibition with FHD-286 Treatment Observed by Bioluminescence Imaging in a Disseminated AML model FHD-286 1.5 mg / kg, BID (5on / 8off) x3 Sorafenib 15 mg / kg, QDx14 Vehicle FHD-286 1.5 mg / kg QDx28 FHD-286 Survival Advantage in Disseminated AML Model 23
Slide 24: Therapeutic Rationale for Uveal Melanoma
Therapeutic Rationale for Uveal Melanoma: Dependency on Overexpression of the MITF / SOX10 Transcription Factors and the BAF Complex 24 Inhibiting BRG1 / BRM to Shut Down the Abnormal TF Interaction with the BAF Complex SOX10 MITF MITF ChIPseq SOX10 ChIPseq Biology Over 85% of uveal melanoma cancers
Slide 25: FHD-286 Dose-Dependent Tumor Regression in Uveal Melanoma CDX Models
FHD-286 was Associated with Dose-Dependent Tumor Regression in Uveal Melanoma CDX Models at Tolerated Doses 25 0 7 14 21 28 0 300 600 900 1200 Days Post Treatment Tu m or V ol um e (m m 3 ) Tumor Volume 0 7 14 21 28 80 90 100 110 120 Days Post Treatment Bo dy W ei gh t C ha ng e (% ) Body Weight 0 5
Slide 26: FHD-286 Clinical Development Plan
FHD-286 Clinical Development Plan 26 Two Parallel Phase 1 Studies Activated Initial clinical data expected in H1’22 Trial Designs • Single patient accelerated titration (n=1) • Convert to 3+3 once relevant PK / PD, safety or clinical activity observed • Retrospective biomarker analysis to further ev
Slide 27: FHD-609: Clinical Entry Point – Synovial Sarcoma
FHD-609: Clinical Entry Point – Synovial Sarcoma FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex
Slide 28: BRD9 is Required for Survival of Synovial Sarcoma Cells
BRD9 is required for the survival of synovial sarcoma cells FHD-609 Targets and Degrades the BRD9 subunit of BAF which is Required for Synovial Sarcoma Cells to Survive Selective, Potent BRD9 Targeted Protein Degrader SS18-SSX1 / SSX2 / SSX4 mutated subunit Target / Approach • BRD9 • Intravenous pro
Slide 29: Robust in vivo Activity Observed in Synovial Sarcoma Model
Robust in vivo Activity Observed in Synovial Sarcoma Model and BRD9 Degradation Associated with FHD-609 Treatment Weekly Dosing of FHD-609 Achieved Sustained BRD9 Degradation SY01 Synovial Sarcoma CDX Model • Mutation: SS18-SSX2 • Inhibited tumor growth • Dose dependent BRD9 degradation correlated w
Slide 30: Superior Tumor Growth Inhibition of FHD-609 vs Ifosfamide and Pazopanib
ASKA CDX Model Superior Tumor Growth Inhibition of FHD-609 in a Synovial Sarcoma Model as Compared to Ifosfamide and Pazopanib 30 Tumor Volume Body Weight • Mutation: SS18-SSX1 • Superior tumor growth inhibition compared to ifosfamide and pazopanib • Complete suppression observed over 30 days at 2 m
Slide 31: FHD-609 Clinical Development Plan
FHD-609 Clinical Development Plan Metastatic Synovial Sarcoma Synovial sarcoma expansion cohorts Synovial Sarcoma FIH Phase 1 Potential for entry into definitive efficacy trials in synovial sarcoma CLINICAL PLAN Initial clinical data as early as H1’22 SMARCB-1 deleted tumors and potentially other in
Slide 32: Selective BRM Modulators for BRG1 Mutated Cancers
Selective BRM Modulators for BRG1 Mutated Cancers Enzymatic Inhibitor and Protein Degrader Programs
Slide 33: BRG1 Mutations Create a Genetic Dependency on BRM
BRG1 Mutations Create a Genetic Dependency on BRM Selective BRM Modulators Overview BRM BRG1 Target / Approach • BRM • Enzymatic inhibitor • Targeted protein degrader Indication • BRG1 mutated cancers (e.g., NSCLC), 30+ cancers with BRG1 mutations Mutation / Aberration • BRG1 Stage • Pre-clinical Ne
Slide 34: BRG1 Mutated in ~5% of All Tumors
BRG1 Mutated in ~5% of All Tumors Broad Addressable Patient Population BRG1 mutated across range of tumors Accounts for ~5% of all tumors BRG1 mutated in up to 10% of NSCLC tumors, minimal overlap with other mutations 34
Slide 35: BRM Selective Inhibitor in vivo Efficacy in BRG1 Mutant Lung Model
BRM Selective Inhibitor in vivo Efficacy Demonstrates PK / PD and In vivo Efficacy in a BRG1 Mutant Lung CDX Model BRG1 cellular IC50 BRM cellular IC50 A549-BRG1 Mutant NSCLC Model Body Weight Plasma Exposure Vehicle Control (BID) Cisplatin 4 mg / kg (IP) FHT-BRMi 15 mg / kg (BID) FHT-BRMi 30 mg / k
Slide 36: Enzymatic Selectivity Approaching 200x Achieved
Enzymatic Selectivity Approaching 200x Achieved 36
Slide 37: Advancing BRM Selective Degraders Achieving Complete BRM Degradation
Advancing BRM Selective Degraders Achieving Complete BRM Degradation Degraders cause time- and dose-dependent BRM degradation, antiproliferative effects in A549 BRG1 mutant NSCLC lung model 0.01 0.1 1 10 100 -50 0 50 100 150 FHX-NSXLX Conc (uM) % in hi bi tio n F T-BRMd BRM / BRG1 HiBit Data A549 Te
Slide 38: Selective ARID1B Protein Degrader for ARID1A Mutated Cancers
Selective ARID1B Protein Degrader for ARID1A Mutated Cancers
Slide 39: ARID1A: Most Mutated Subunit in BAF Complex
ARID1A: Most Mutated Subunit in BAF Complex – Creates Dependency on ARID1B 39 Selective ARID1B Protein Degrader Overview ARID1A ARID1B Target / Approach • ARID1B • Targeted protein degrader Indication • ARID1A mutated cancers Mutation / Aberration • ARID1A mutations (e.g., ovarian, endometrial, colo
Slide 40: Targeting ARID1A Mutated Cancers: ARID1B Protein Degrader
Targeting ARID1A Mutated Cancers: ARID1B Protein Degrader Advantaged by Gene Traffic Control Platform and Protein Degrader Capabilities Gene Traffic Control Platform Protein Degrader Capabilities • Platform produces BAF complexes and subcomplexes containing either ARID1A or ARID1B at scale • Enables
Slide 41: Novel Approach to Targeting Transcription Factors
Novel Approach to Targeting Transcription Factors Disrupting Transcription Factor – Chromatin Remodeling Complex Interactions
Slide 42: A New Approach to Drugging Transcription Factors
A New Approach to Drugging Transcription Factors Enabled by Proprietary Ability to Purify and Synthesize Chromatin Regulatory System Components 42 • Highly involved in gene expression • Implicated in range of cancers and other diseases TFs are compelling drug targets… • Featureless surface: no drugg
Slide 43: Transcription Factor-Chromatin Remodeling Complex Interactions
Transcription Factor-Chromatin Remodeling Complex Interactions 43 Unique Insights in Where and How Transcription Factors Bind TF #2TF #1 TF #3 Transcription Factors (TF): TF #4 0.01 0.1 1 10 100 1000 0 100 200 300 400 SPI1 (nM) RU KD = 21 nM 0.1 1 10 100 1000 10000 0 50 100 150 200 250 MYOD1 (nM) RU
Slide 44: Merck Collaboration; Highly Scalable Approach and Significant Unmet Medical Need
• Merck collaboration to drug single specified transcription factor target • $425 million in up-front, research, development and sales-based milestones • Up to low double-digit royalties on product sales Highly Scalable Approach and Significant Unmet Medical Need 44 Potential to Drug > 100 TFs Assoc
Slide 45: Foghorn Well Positioned to Discover and Develop First in Class Precision Medicines
Foghorn Well Positioned to Discover and Develop First in Class Precision Medicines Targeting Cancer and Other Diseases Significant Global Partnerships Strategic Collaboration with Loxo Oncology at Lilly Merck collaboration to drug single specified transcription factor target Expertise across drug di
Slide 46: Appendix
FCGHORN THERAPEUTICS Appendix
Slide 47: Proven Leadership Team
Carl Decicco, Ph.D., CSO Proven Leadership Team 47 Steve Bellon, Ph.D., SVP, Drug Discovery Adrian Gottschalk, President & CEO Carlos Costa, SVP, HR Sam Agresta, M.D., M.P.H., CMO Jacqueline Cinicola, VP Regulatory Affairs Murphy Hentemann, Ph.D., VP Program Leadership Chong-Hui Gu, VP, CMC and QARy
Slide 48: Industry Leading Board of Directors and Advisors
Charles Sawyers, M.D. MSKCC, HHMI – SAB Chair Gerald Crabtree, M.D. Stanford, HHMI; Founder Faheem Hasnain Gossamer Bio, Chair of Mirati David Schenkein, M.D. General Partner, GV Craig Peterson, Ph.D. Professor UMass Medical School Tony Kouzarides, Ph.D. Gurdon Institute – University of Cambridge Do
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