Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (June 2021)
42 slides from Foghorn Therapeutics's investor presentation, Jun 1, 2021
Slide 1: Targeting the Chromatin Regulatory System
Targeting the Chromatin Regulatory System Broadening the Impact of Precision Medicines for Oncology and Other Diseases June 2021
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: The Chromatin Regulatory System: The Next Wave of Cancer Therapies
The Chromatin Regulatory System: The Next Wave of Cancer Therapies 3 Cytotoxics Targeted Antibodies IO / Cell Therapy Medicines targeting breakdowns in the chromatin regulatory system Cancer is one of the leading causes of death worldwide 1950s – 1960s Kinases 1990s 2000s 2010s The Future
Slide 4: 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 4 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 5: Our Gene Traffic Control Platform Makes It Possible to Understand and Drug Genetic Dependencies
Our Gene Traffic Control Platform Makes It Possible to Understand and Drug Genetic Dependencies within the Chromatin Regulatory System 5 Integrated, Scalable, Efficient – Repeatable Paradigm Target Identification & Validation Production of Chromatin Regulatory System Components at Scale & Proprietar
Slide 6: Production of Chromatin Regulatory System Components
6 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 Synthesize
Slide 7: Precision Oncology / Breadth and Depth
Program / Target Modality Discovery IND-enabling Phase 1 Phase 2 Phase 3 Global Rights FHD-286 (BRG1 / BRM) Enzyme inhibitor FHD-609 (BRD9) Protein degrader Selective BRM I) Enzyme inhibitor II) Protein degrader Selective ARID1B Protein degrader Synthetic Lethal Targets (multiple) I) Enzyme inhibito
Slide 8: The Chromatin Regulatory System Orchestrates Gene Expression
The Chromatin Regulatory System Orchestrates Gene Expression
Slide 9: The Chromatin Regulatory System Orchestrates Gene Expression
Normal gene expression The Chromatin Regulatory System Orchestrates Gene Expression 9 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 10: Breakdowns in the Chromatin Regulatory System Lead to Disease
Breakdowns in the Chromatin Regulatory System Lead to Disease 10 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 11: Chromatin Regulatory System – Abundance of Targets
Chromatin Regulatory System – Abundance of Targets 11 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 12: Mutations Lead to Disease Specific Genetic Dependencies
Mutations Lead to Disease Specific Genetic Dependencies on the Chromatin Regulatory System 12 Transcription Factor Mutations / Overexpression Chromatin Remodeling Complexes Mutations / Overexpression Mutations that Impinge on the Chromatin Regulatory System Novel Targets / Dependencies Targeted Prot
Slide 13: 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 14: FHD-286 Targets Abnormal Dependencies on BAF in Cancer
FHD-286 Targets Abnormal Dependencies on BAF in Cancer 14 • 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 Indicat
Slide 15: AML Dependent on BRG1 / Lineage Dependent TF Interaction
15 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 – TF Activity AML Dependent on BRG1 / Lineage Dependent TF
Slide 16: AML Dependent on BRG1 / Lineage Dependent TF Interaction
AML Dependent on BRG1 / Lineage Dependent TF Interaction 16 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 Down Regulation of SPI1 (PU.1)
Slide 17: FHD-286 Shows Broad Efficacy Across AML Patient Derived Samples
FHD-286 Shows Broad Efficacy Across AML Patient Derived Samples 17 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 Y AML R/R 1991pA
Slide 18: 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 18 Tumor Volume Body Weight 0 7 14 21 0 250 500 750 1000 1250 Days Post Treatment T u m o r V o lu m e ( m m 3 ) 0 7 14 21 0 800 1600 2400 3200 Days Post Treatment T u m o r V o lu m e ( m m 3 ) 0 7 14 21 80 90
Slide 19: FHD-286 Shows Effect Across Range of Mutations in AML Patient Samples
FHD-286 Shows Effect Across Range of Mutations in AML Patient Derived Samples 19 IC 5 0 ( n M ) Patient samples
Slide 20: Therapeutic Rationale for Uveal Melanoma
Therapeutic Rationale for Uveal Melanoma: Dependency on Overexpression of the MITF / SOX10 Transcription Factors and the BAF Complex 20 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 h
Slide 21: 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 21 0 7 14 21 28 0 300 600 900 1200 Days Post Treatment T u m o r V o lu m e ( m m 3 ) Tumor Volume 0 7 14 21 28 80 90 100 110 120 Days Post Treatment B o d y W e ig h t C h a n g e ( % ) Body
Slide 22: FHD-286 Clinical Development Plan
FHD-286 Clinical Development Plan 22 Clinical data as early as Q4 2021 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 evaluate safety and efficacy • Assess safety, PK,
Slide 23: 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 24: FHD-609 Targets and Degrades the BRD9 Subunit of BAF
FHD-609 Targets and Degrades the BRD9 subunit of BAF which is Required for Synovial Sarcoma Cells to Survive 24 Selective, Potent BRD9 Targeted Protein Degrader SS18-SSX1 / SSX2 / SSX4 mutated subunit Target / Approach • BRD9 • Intravenous Protein Degrader Initial Indication • Synovial Sarcoma Mutat
Slide 25: Robust in vivo Activity in Synovial Sarcoma Model and BRD9 Degradation
Robust in vivo Activity Observed in Synovial Sarcoma Model and BRD9 Degradation Associated with FHD-609 Treatment 25 Weekly Dosing of FHD-609 Achieved Sustained BRD9 Degradation SY01 Synovial Sarcoma CDX Model • Mutation: SS18-SSX2 • Inhibited tumor growth • Dose dependent BRD9 degradation correlate
Slide 26: 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 26 0 10 20 30 40 0 700 1400 2100 2800 Days Post Treatment T u m o r V o lu m e ( m m 3 ) 0 7 14 21 28 80 90 100 110 120 Days Post Treatment % B o d y W e ig h t C h a n g e
Slide 27: FHD-609 Clinical Development Plan
FHD-609 Clinical Development Plan 27 Metastatic Synovial Sarcoma Synovial Sarcoma expansion cohorts Synovial Sarcoma FIH Phase 1 Potential for entry into definitive efficacy trials in synovial sarcoma CLINICAL PLAN Clinical data as early as H1 2022 SMARCB-1 deleted tumors and potentially other indic
Slide 28: Selective BRM Modulators for BRG1 Mutated Cancers
Selective BRM Modulators for BRG1 Mutated Cancers Enzymatic Inhibitor and Protein Degrader Programs
Slide 29: BRG1 Mutations Create a Genetic Dependency on BRM
BRG1 Mutations Create a Genetic Dependency on BRM 29 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
Slide 30: BRG1 Mutated in ~5% of All Tumors
BRG1 Mutated in ~5% of All Tumors – Potential Broad Addressable Patient Populations 30 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
Slide 31: 20X Selective BRM Inhibitor and Targeted Protein Degrader
20X Selective BRM Inhibitor and Targeted Protein Degrader Discovered from Gene Traffic Control Platform 31 Selective BRM Modulators Enzyme assay using BRG1 and BRM subunits Enzyme assay using BRG1 and BRM containing full BAF complexes Cellular assays for BRG1 and BRM BRM Selective Inhibitor Program
Slide 32: Selective ARID1B Protein Degrader for ARID1A Mutated Cancers
Selective ARID1B Protein Degrader for ARID1A Mutated Cancers
Slide 33: ARID1A – Most Mutated Subunit in BAF Complex – Creates Dependency on ARID1B
ARID1A – Most Mutated Subunit in BAF Complex – Creates Dependency on ARID1B 33 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, col
Slide 34: ARID1B Highlights Broad Potential of Gene Traffic Control Platform
ARID1B Highlights Broad Potential of Foghorn Gene Traffic Control Platform 34 Drugging Strategy • Platform produces BAF complexes and subcomplexes containing either ARID1A or ARID1B at scale • Status: Validating hits from multiple High Throughput Screens ARID1B Highly purified ARID1B-BAF Complex Bio
Slide 35: Novel Approach to Targeting Transcription Factors
Novel Approach to Targeting Transcription Factors Disrupting Transcription Factor – Chromatin Remodeling Complex Interactions
Slide 36: 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 36 • Highly involved in gene expression • Implicated in range of cancers and other diseases TFs are compelling drug targets… • Featureless surface: no drugg
Slide 37: Transcription Factor-Chromatin Remodeling Complex Interactions
Transcription Factor-Chromatin Remodeling Complex Interactions 37 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) R U KD = 21 nM 0.1 1 10 100 1000 10000 0 50 100 150 200 250 MYOD1 (nM) R
Slide 38: Merck Collaboration; Potential to Drug >100 TFs
• 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 38 Potential to Drug > 100 TFs Assoc
Slide 39: Investment Highlights
Investment Highlights LARGE MARKET POTENTIAL ➢ Biology implicated in up to 50% of cancer potentially impacting ~2.5 million patients ➢ Potential applications beyond oncology in diseases including virology, autoimmune disease and neurology 39 WELL FUNDED MEANINGFUL UPCOMING MILESTONES ➢ Phase I FHD-2
Slide 40: Appendix
FCGHORN THERAPEUTICS Appendix
Slide 41: Proven Leadership Team
Carl Decicco, Ph.D., CSO Proven Leadership Team 41 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 QA R
Slide 42: Experienced Leadership Team with Industry Leading Advisors and Investors
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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