Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (May 2023)
56 slides from Foghorn Therapeutics's investor presentation, May 8, 2023
Slide 1: Corporate Overview May 2023
CORPORATE OVERVIEW May 2023 Leveraging unique insights into the chromatin regulatory system to pioneer a new class of precision therapies in oncology and beyond Exhibit 99.2
Slide 2: Forward-looking statements
This 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 terms such as “could,” “may,” “might,” “will,” “likely,” “antic
Slide 3: Large market potential, well-funded collaborations, value drivers in 2023
| LARGE MARKET POTENTIAL WELL- FUNDED COLLABORATIONS WITH MAJOR ONCOLOGY PLAYERS SIGNIFICANT VALUE DRIVERS IN 2023 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
Slide 4: Foghorn: significant value creation opportunities
| FOGHORN: SIGNIFICANT VALUE CREATION OPPORTUNITIES 4 >500K PATIENTS >2M PATIENTSBy 2026 POTENTIAL PATIENTS IMPACTED BY PIPELINE Today 2 NME INDs 8 NME INDs NEW MOLECULAR ENTITIES TO IND / CLINIC• Validated platform with first-in-class target in the clinic (FHD-286), with Phase 1 dose escalation dat
Slide 5: Unique insights into chromatin biology
| UNIQUE INSIGHTS INTO CHROMATIN BIOLOGY Transcription Factor Mutations / Overexpression Chromatin Remodeling Complex Mutations / Overexpression Helicases & Other Chromatin Binding Proteins involved in gene expression / function Enzymatic Inhibitors Highly selective and allosteric small molecule inh
Slide 6: Foghorn's validated Gene Traffic Control platform
| FOGHORN’S VALIDATED GENE TRAFFIC CONTROL® PLATFORM Integrated, Scalable, Efficient – Repeatable Paradigm Deep Mechanistic Understanding of the Chromatin Regulatory System Small Molecule and Degrader Platform Biochemistry, Biophysics and Assays of Large Complexes and Proteins UNIQUE TARGETS SPECIAL
Slide 7: Broad pipeline across a range of targets and modalities
| Selective CBP BROAD PIPELINE ACROSS A RANGE OF TARGETS AND MODALITIES Modality Program Discovery Phase 1 Phase 2 Phase 3 Patient Population* Enzyme Inhibitors Transcription Factor Disruptors Partnered Program AML & MDS Uveal Melanoma BRG1 Mutated Cancers, e.g. , NSCLC & Bladder Undisclosed Undiscl
Slide 8: Inhibition of the BRG1 and BRM Subunits of the BAF Complex
Inhibition of the BRG1 and BRM Subunits of the BAF Complex FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex IN PHASE 1 DOSE ESCALATION FOR METASTATIC UVEAL MELANOMA & AML/MDS FHD-286 is a Potent, Selective, Allosteric, Small Molecul
Slide 9: Targeting BAF dependency in cancer
| TARGETING BAF DEPENDENCY IN CANCER BRG1 AND BRM SUBUNITS BRMBRG1 BAF CHROMATIN REMODELING COMPLEX • BRM / BRG1 is the engine (ATPase) of the BAF chromatin remodeling complex • Dependency on BRM / BRG1 is well- established with multiple tumor types, including uveal melanoma, AML / MDS, NSCLC and pr
Slide 10: Significant unmet need in uveal melanoma
| SIGNIFICANT UNMET NEED IN UVEAL MELANOMA Most Common Form of Eye Cancer 10 UVEAL MELANOMA OVERVIEW Market Opportunity: • Over 2,500 new metastatic UM patients impacted per year in the U.S. / over 5,000 U.S. and E.U. • Potential additional opportunity in the adjuvant and neo- adjuvant settings Limi
Slide 11: FHD-286 for metastatic uveal melanoma clinical development plan
| POTENTIAL DEFINITIVE EFFICACY TRIALS & INDICATION EXPANSIONPHASE 1 DOSE ESCALATION STUDY PHASE 1 EXPANSION STUDIES 11 • Evaluate identified dose(s) • Consider refined patient population, if necessary • Consider exploration of combination partners • Assess safety, PK, biomarkers and therapeutic act
Slide 12: Therapeutic rationale for uveal melanoma
| THERAPEUTIC RATIONALE FOR UVEAL MELANOMA Dependency on Two Lineage Transcription Factors: MITF / SOX10 SOX10 MITF OVER 85% OF UVEAL MELANOMA CANCERS HAVE GNAQ OR GNA11 MUTATIONS VALIDATION OF DEPENDENCY AND APPROACHBIOLOGY CANCER CELL LINES CANCER CELL LINES 12 MITF CHIPseq SOX10 CHIPseq
Slide 13: Dose-dependent tumor regression in uveal melanoma CDX models
| DOSE-DEPENDENT TUMOR REGRESSION IN UVEAL MELANOMA CDX MODELS AT TOLERATED DOSES WITH FHD-286 MP-46 UVEAL MELANOMA CDX MODEL o Dose-dependent tumor growth inhibition o Well-tolerated 92-1 UVEAL MELANOMA CDX MODEL o Dose-dependent tumor growth inhibition o Tumor regression at 1.5 mg / kg, PO, QD o W
Slide 14: Significant unmet need remains in R/R AML & MDS
| SIGNIFICANT UNMET NEED REMAINS IN R/R AML & MDS Most Common Type of Acute Leukemia in Adults 14 AML OVERVIEW Mutation: • Elevated BRG1-BAF / TF activity in AML blast cells Market Opportunity: • Over 27,000 relapsed and/or refractory patients impacted per year* Treatment Options: • Limited options
Slide 15: FHD-286 for relapsed/refractory AML & MDS clinical development plan
| POTENTIAL DEFINITIVE EFFICACY TRIALS & INDICATION EXPANSIONPHASE 1 DOSE ESCALATION STUDY PHASE 1 EXPANSION STUDIES 15 • Evaluate identified dose(s) • Consider refined patient population if necessary • Consider exploration of combination partners • Assess safety, PK, biomarkers and therapeutic acti
Slide 16: AML: dependency on BRG1 / lineage TF interactions
| AML: DEPENDENCY ON BRG1 / LINEAGE TF INTERACTIONS HSC AML blasts stuck in BAF / TF dependent proliferative phase Loss of blast phenotype/Apoptosis Differentiation Cancerous blast cells rely on BRG1 containing BAF / TF activity BAF - TF activity BAF - TF activity DISEASE STATE TREATMENT WITH FHD-28
Slide 17: FHD-286 effect across mutations in AML patient-derived samples
| FHD-286 SHOWS EFFECT ACROSS A BROAD RANGE OF MUTATIONS IN AML PATIENT-DERIVED SAMPLES DNMT3A FLT3 IDH1 IDH2 KIT NF1 NPM1 NRAS RUNX1 TET2 TP53 IC 50 (n M ) 17 Mutation Type
Slide 18: Preclinical FHD-286 data shows efficacy across AML samples
| 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 1991pAML1 Y AML de novo 2041AML1 Y N/A de novo 2043pAML1 Y AML R/R 2059
Slide 19: Dose-dependent tumor growth inhibition in AML CDX models
| DOSE-DEPENDENT TUMOR GROWTH INHIBITION OBSERVED WITH FHD-286 TREATMENT IN AML CDX MODELS MV4-11 CDX Model (FLT3 ITD, MLL-AF4) OCI-AML2 CDX MODEL (MII-AF6, DNMT3A MUT.) 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 Treatmen
Slide 20: Survival advantage in disseminated AML model
| TUMOR GROWTH INHIBITION WITH FHD-286 TREATMENT OBSERVED BY BIOLUMINESCENCE GENE TRAFFIC CONTROL PLATFORM PROTEIN DEGRADER CAPABILITIES Imaging in a Disseminated AML Model VEHICLE FHD-286 1.5 MG / KG QDX28 FHD-286 1.5 MG / KG, BID (5ON / 8OFF) X3 SORAFENIB 15 MG / KG, QDX14 FHD-286 SURVIVAL ADVANTA
Slide 21: Selective BRM modulators for BRG1 mutated cancers
SELECTIVE BRM MODULATORS FOR BRG1 MUTATED CANCERS Enzymatic Inhibitor and Protein Degrader Programs Targeting BRG1 Mutated Cancers (e.g., NSCLC), 30+ Cancers with BRG1 Mutations FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex
Slide 22: BRG1 mutations create a genetic dependency on BRM
| BRG1 MUTATIONS CREATE A GENETIC DEPENDENCY ON BRM BRG1 B R M D ep en de nc y Sc or e CANCER CELL LINES Selective BRM Modulators Overview BRM Target / Approach • BRM • Enzymatic inhibitor • Targeted protein degrader Indications • BRG1 mutated cancers (e.g., NSCLC), 30+ cancers with BRG1 mutations M
Slide 23: BRG1 mutated across a range of tumors
| Cancer Of Unknown Primary Skin Cancer, Non-Melanoma Non-Small Cell Lung Cancer Bladder Cancer Endometrial Cancer Colorectal Cancer Melanoma Cervical Cancer Thymic Tumor Esophagogastric Cancer Peripheral Nervous System Small Cell Lung Cancer 0% 5% 10% 15% BRG1 MUTATED ACROSS RANGE OF TUMORS BRG1 MU
Slide 24: BRM selective inhibitor in vivo efficacy
| BRM SELECTIVE INHIBITOR IN VIVO EFFICACY Demonstrates PK / PD and In Vivo Efficacy in a BRG1 Mutant Lung CDX Model Plasma Exposure A549-BRG1 MUTANT NSCLC MODEL Cisplatin 4 mg / kg (IP) FHT-BRMi 15 mg / kg (BID) FHT-BRMi 30 mg / kg (BID) Vehicle Control (BID) 24 Tumor Volume Tu m or v ol um e (m m
Slide 25: Enzymatic selectivity approaching 200x achieved
| ENZYMATIC SELECTIVITY APPROACHING 200X ACHIEVED BRG1 vs BRM ATPase activity BRM IC50 (uM) B R G 1 IC 50 (u M ) 25
Slide 26: Advancing BRM selective degraders
| DEGRADERS CAUSE TIME- AND DOSE-DEPENDENT BRM DEGRADATION, ANTIPROLIFERATIVE EFFECTS IN A549 BRG1 MUTANT NSCLC LUNG MODEL ADVANCING BRM SELECTIVE DEGRADERS Achieving Complete BRM Degradation BRM / BRG1 HIBIT DATA A549 TEN-DAY PROLIFERATION ASSAY 26 0.01 0.1 1 10 100 -50 0 50 100 150 FHX-NSXLX Conc
Slide 27: Selective CBP protein degrader for EP300 mutated cancers
SELECTIVE CBP PROTEIN DEGRADER FOR EP300 MUTATED CANCERS Implicated in Subsets of Cancers Including Bladder, Colorectal, Breast, Gastric and Lung
Slide 28: Advancing highly selective CBP protein degrader
| ADVANCING HIGHLY SELECTIVE CBP PROTEIN DEGRADER FOR EP300 MUTATED CANCERS Selective CBP Protein Degrader Overview * Per year incidence in the U.S., EU5, Japan Target / Approach • CREB binding protein (CBP) • Targeted protein degrader Initial Indication • EP300 mutated cancers (e.g., subsets of pro
Slide 29: Advancement of highly selective CBP degraders
| ADVANCEMENT OF HIGHLY SELECTIVE CBP DEGRADERS 29 SELECTIVE CBP DEGRADATION Osteosarcoma Cell Line Endogenous IF 0 1 2 3 4 5 0 25 50 75 100 125 Selective CBP Degrader U2OS log[nM] av er ag e in te ns ity no rm al iz ed to D M S O CBP EP300 Av er ag e In te ns ity N or m al iz ed to D M SO Log [nM]
Slide 30: CBP-dependent cell killing across multiple cancers
| HIGHLY SELECTIVE DEGRADER OF CBP DEMONSTRTES CBP-DEPENDENT CELL KILLING ACROSS MULTIPLE CANCERS 30 Colorectal CancerGastric Cancer 0.1 1 10 100 1000 10000 100000 0 50 100 150 Cmpd[nM] RKO (EP300 mutant) HT29 (CBP/EP300 Wt) % C el l V ia bi lit y Cmpd [nM] HT29 (CBP/EP300 WT) RFO (EP300 mutant) % C
Slide 31: Selective EP300 protein degrader for CBP mutant cancers
SELECTIVE EP300 PROTEIN DEGRADER FOR CBP MUTANT CANCERS & EP300 DEPENDENT MALIGNANCIES Implicated in CBP Mutated Cancers and Subsets of EP300 Dependent Malignancies (e.g., Bladder, NSCLC, Various Lymphomas and Leukemias)
Slide 32: Advancing highly selective EP300 protein degrader
| ADVANCING HIGHLY SELECTIVE EP300 PROTEIN DEGRADER FOR CBP MUTANT CANCERS & EP300 DEPENDENT MALIGNANCIES Selective EP300 Protein Degrader Overview * Per year incidence in the U.S., EU5, Japan Target / Approach • E1A binding protein p300 (EP300) • Targeted protein degrader Initial Indication • CBP m
Slide 33: Advancement of highly selective EP300 degraders
| ADVANCEMENT OF HIGHLY SELECTIVE EP300 DEGRADERS 33 SELECTIVE EP300 DEGRADATION (Osteosarcoma Cell Line) CELL PROLIFERATION ASSAYS (EP300 Dependent vs. Non-Dependent Cell Lines) HiBiT-CBP U2OS HiBiT-EP300 U2OS Time (hr) Time (hr) HiBiT Assay 1 10 100 1000 10000 0 50 100 150 Cmpd [nM] % L um in es c
Slide 34: Selective ARID1B protein degrader for ARID1A mutated cancers
SELECTIVE ARID1B PROTEIN DEGRADER FOR ARID1A MUTATED CANCERS Protein Degrader Targeting ARID1A Mutated Cancers, the Most Mutated Subunit in the BAF Complex (e.g., Ovarian, Endometrial, Colorectal, Bladder and Other Cancers)
Slide 35: ARID1A most mutated subunit in BAF complex, creates ARID1B dependency
| ARID1A: MOST MUTATED SUBUNIT IN BAF COMPLEX – CREATES DEPENDENCY ON ARID1B Selective ARID1B Protein Degrader Overview * Per year incidence in the U.S., EU5, Japan ARID1A ARID1B AR ID 1B D ep en de nc y Sc or e CANCER CELL LINES Target / Approach • ARID1B • Targeted protein degrader Initial Indicat
Slide 36: ARID1A mutated cancers: significant opportunity
| ~5% of all solid tumors harbor ARID1A mutations ARID1A MUTATED CANCERS: SIGNIFICANT OPPORTUNITY ARID1A Mutated Across Range of Tumors Cancer Types C om pl ex s ub un its ACTL6A ACTL6B ARID1A ARID1B ARID2 BCL11A BCL11B BCL7A BCL7B BCL7C BRD7 BRD9 BAF45B BAF45D BAF45C PBRM1 BAF45A BRM BRG1 BAF47 BAF
Slide 37: Targeting ARID1A mutated cancers: ARID1B protein degrader
| TARGETING ARID1A MUTATED CANCERS: ARID1B PROTEIN DEGRADER GENE TRAFFIC CONTROL PLATFORM PROTEIN DEGRADER CAPABILITIES • Platform produces BAF complexes and subcomplexes containing either ARID1A or ARID1B at scale • Enables proprietary screens against ARID1B • Utilize protein degrader toolbox to cr
Slide 38: 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 39: TFs are compelling drug targets but historically difficult to target
| TFS ARE COMPELLING DRUG TARGETS… …BUT HISTORICALLY DIFFICULT TO TARGET • Highly involved in gene expression • Implicated in range of cancers and other diseases • Featureless surface: no druggable binding pocket • Tight interactions with DNA: undruggable affinities A NEW APPROACH TO DRUGGING TRANSC
Slide 40: Transcription factors bind to BAF directly with high specificity
| TRANSCRIPTION FACTORS BIND TO BAF DIRECTLY WITH HIGH DEGREE OF SPECIFICITY 40 Unique Insights into Where and How Transcription Factors Bind MASS SPEC. FOOT-PRINTING PULL-DOWN ASSAYS Foghorn’s collection of BAF sub-complexes and domains BIOPHYSICAL BIOCHEMICAL STRUCTURAL AUC / SPR / ITC TR-FRET / F
Slide 41: Highly scalable approach drives Merck collaboration
| • >100 TFs estimated associated with BAF • Foghorn pursuing multiple TFs in parallel • Approach highly scalable and potential broad application – other chromatin remodeling complexes and other diseases HIGHLY SCALABLE APPROACH TO ADDRESS SIGNIFICANT UNMET MEDICAL NEED DRIVES MERCK COLLABORATION Po
Slide 42: Broad pipeline across a range of targets and modalities
| Selective CBP BROAD PIPELINE ACROSS A RANGE OF TARGETS AND MODALITIES Modality Program Discovery Phase 1 Phase 2 Phase 3 Patient Population* Enzyme Inhibitors Transcription Factor Disruptors Partnered Program AML & MDS Uveal Melanoma BRG1 Mutated Cancers, e.g. , NSCLC & Bladder Undisclosed Undiscl
Slide 43: Large market potential, well-funded collaborations, value drivers in 2023
| LARGE MARKET POTENTIAL WELL- FUNDED COLLABORATIONS WITH MAJOR ONCOLOGY PLAYERS SIGNIFICANT VALUE DRIVERS IN 2023 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
Slide 44: Appendix
APPENDIX FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex
Slide 45: Strategic Partnership Loxo Oncology at Lilly
STRATEGIC PARTNERSHIP LOXO ONCOLOGY AT LILLY FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex
Slide 46: Strategic collaboration with Loxo Oncology at Lilly
| 50/50 U.S. ECONOMICS ON TWO PROGRAMS 50/50 U.S. economic split on BRM-Selective and another undisclosed program Tiered ex-U.S. royalties starting in the low double-digit range and escalating into the twenties based on revenue levels $380 MILLION UPFRONT $300 million cash payment $80 million invest
Slide 47: The chromatin regulatory system orchestrates gene expression
THE CHROMATIN REGULATORY SYSTEM ORCHESTRATES GENE EXPRESSION FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex
Slide 48: The chromatin regulatory system orchestrates gene expression
| THE CHROMATIN REGULATORY SYSTEM ORCHESTRATES GENE EXPRESSION Two Major Components Work in Concert: Chromatin Remodeling Complexes and Transcription Factors CHROMATIN Chromatin – compacted form of DNA inside the nucleus of the cell 1 | CHROMATIN REMODELING COMPLEX AND TRANSCRIPTION FACTOR Work toge
Slide 49: Breakdowns in the chromatin regulatory system can lead to disease
| Mutation or overexpression in chromatin remodeling complex results in abnormal gene expression Mutated or overexpressed TF hijacks chromatin remodeling complex to wrong location DISEASE Abnormal Gene Expression DISEASE Abnormal Gene Expression BREAKDOWNS IN THE CHROMATIN REGULATORY SYSTEM CAN LEAD
Slide 50: BAF complex subunits mutated and dysregulated in cancer
| BAF Complex Subunits Mutated and Dysregulated in Cancer 28 Chromatin Remodeling Complexes and >1,000 TFs CHROMATIN REGULATORY SYSTEM Estimate >100 Transcription Factors Associated with Just the BAF Complex BAF COMPLEX AND ASSOCIATED TRANSCRIPTION FACTORS Abundance of Targets within the BAF Complex
Slide 51: Platform & Drugging Capabilities
PLATFORM & DRUGGING CAPABILITIES FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex
Slide 52: 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 BENEFITS Surface Mapping Assembly Affinity Screening & Validation HTS Biophysics/SPR Characterize TF / BAF Binding Sites Sy
Slide 53: Optimization of degrader drug properties
| CURRENT APPROACH OPTIMIZATION OF DEGRADER DRUG PROPERTIES DEGRADER CHEMICAL TOOLBOX • A leader in developing heterobifunctional degraders for clinical evaluation in oncology • Employing PROTAC and non-CRBN based molecular glue degradation approaches • Guidelines for both of oral and IV-administere
Slide 54: Leadership Team, Board & Advisors
Leadership Team, Board & Advisors FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex EXPERTISE ACROSS DRUG DISCOVERY, CLINICAL DEVELOPMENT AND COMMERCIALIZATION
Slide 55: Proven leadership team
| PROVEN LEADERSHIP TEAM 55 ADRIAN GOTTSCHALK President & CEO SAM AGRESTA, M.D., M.P.H & TM Chief Medical Officer MICHAEL LACASCIA Chief Legal Officer ALLAN REINE, M.D. Chief Financial Officer STEVE BELLON, PH.D. Chief Scientific Officer FANNY CAVALIE Chief Strategy and Business Operations Officer C
Slide 56: Industry-leading board of directors and advisors
| INDUSTRY-LEADING BOARD OF DIRECTORS AND ADVISORS DOUG COLE, M.D. Flagship Pioneering – Board Chair; Founder BOARD OF DIRECTORS SCOTT BILLER, PH.D. Former CSO and Strategic Advisor, Agios SIMBA GILL, PH.D. Evelo Biosciences, Partner at Flagship Pioneering ADRIAN GOTTSCHALK Foghorn President & CEO C
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