Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (May 2024)
44 slides from Foghorn Therapeutics's investor presentation, May 6, 2024
Slide 1: May 2024 Unique biology Precision therapeutics Broad impact
May 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: Developing First-In-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| Developing First-In-Class Precision Medicines Targeting Major Unmet Needs in Cancer 3 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 Broa
Slide 4: Unique Insights into Chromatin Biology to Prosecute Untapped Area for Novel Targets and Therapeutics
| Unique Insights into Chromatin Biology to Prosecute Untapped Area for Novel Targets and Therapeutics 4 Novel Targets Guided by Genetic Dependencies Tailored Drugging Approaches Transcription Factor Mutations / Overexpression Chromatin Remodeling Complex Mutations / Overexpression Helicases & Other
Slide 5: Foghorn's Validated Gene Traffic Control Platform Enables an Integrated, Scalable, Efficient Paradigm
| Foghorn’s Validated Gene Traffic Control© Platform Enables an Integrated, Scalable, Efficient and Repeatable Paradigm 5 Deep mechanistic understanding of the chromatin regulatory system Biology first, small molecule modality agnostic Targeting Disease Selective Therapeutics What to Drug: Identify
Slide 6: Foghorn Is 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 6 Modality Program Phase 1 Enzyme Inhibitors Transcription Factor Disruptors Undisclosed Protein Degraders Commercial Rights FHD-286 (BRG1/BRM) FHD-909 (Selective BRM) 3 Discov
Slide 7: 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 8: Exploring BAF Dependency in Cancer with FHD-286
| Exploring BAF Dependency in Cancer with FHD-286 – Potent, Small Molecule Inhibitor Targeting BRM and BRG1 8 Clinical and pre-clinical data demonstrate broad- based differentiation across AML and multiple solid tumors BAF ATPase: BRG1/BRM FHD-286: • Allosteric modulation inhibiting the activity of
Slide 9: First-in-Class Broad-Based Differentiation Agent With Significant Combination Potential in AML
| First-in-Class Broad-Based Differentiation Agent With Significant Combination Potential in AML 9 Completed Phase I Monotherapy Safety and Efficacy Results Ongoing Phase I Combination Study Efficacy • Differentiation observed in heavily pre-treated patients, regardless of mutational status • Multip
Slide 10: Significant Opportunity for Novel, Effective Therapy in Patients with R/R AML
| Significant Opportunity for Novel, Effective Therapy in Patients with R/R AML 10 • More than half of patients will relapse post frontline treatment • Intensive chemotherapy has been standard of care for four decades with no meaningful improvement Most cases of AML are not curable 40% of AML cases
Slide 11: Study Design for FHD-286 Phase 1 Dose-Escalation in Combination with Decitabine in AML
| Study Design for FHD-286 Phase 1 Multicenter Dose-Escalation in Combination with Decitabine in AML 11 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 •
Slide 12: FHD-286 Demonstrated Differentiation Across a Broad Range of Genetic Backgrounds
| FHD-286 Demonstrated Differentiation Across a Broad Range of Genetic Backgrounds in Phase 1 Trial 12 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 9
Slide 13: 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 Trial 13 Patient Background: • 47-year-old male, secondary AML • Abnormal karyotype: Del (7Q)
Slide 14: Clinical Benefit in Heavily Pre-Treated Patient in Phase 1 Trial
| Absolute Neutrophil Count (ANC) Peripheral Blast Count Clinical Benefit in Heavily Pre-Treated Patient in Phase 1 Trial 14 100% 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-related AML • KM
Slide 15: Pre-Clinical Data Demonstrated Combination Potential with Multiple Agents in AML
| FHD-286 + decitabine (MLL-AFP + FLT3 TKD Luc/GFP PDX) Pre-Clinical Data Demonstrated Combination Potential with Multiple Agents in AML 15 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 16: 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 17: BRM Selective Inhibitor FHD-909 IND Submitted in Q2'24, BRM Selective Degrader Continues Development
| BRM Selective Inhibitor FHD-909 IND Submitted in Q2’24, BRM Selective Degrader Continues Late-Stage Pre-Clinical Development 17 BRM Selective Inhibitor (FHD-909) BRM Selective Degrader Biology Exploit the synthetic lethal relationship between BRM (SMARCA2) and mutated BRG1 (SMARCA4) Stage IND subm
Slide 18: BRM Selective Inhibition Exploits the Synthetic Lethal Relationship Between BRM and Mutated BRG1
| BRM Selective Inhibition is a Promising Strategy to Exploit the Synthetic Lethal Relationship Between BRM and Mutated BRG1 18 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 19: 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 19 BRG1 mutated across a broad range of tumors Accounts for ~5% of solid tumors AACR GENIE via cBioPortal
Slide 20: Patients with NSCLC Harboring BRG1 Mutations Define a High Unmet Need Population
| BRG1 mutated in up to 10% of NSCLC tumors, minimal overlap with other mutations2Overall Survival for SMARCA4wt vs SMARCA4mut1 Patients with NSCLC Harboring BRG1 Mutations Have Significantly Worse Clinical Outcomes and Define a High Unmet Need Patient Population 20 BRG1 10% KRAS 29% EGFR 26% ALK 7%
Slide 21: FHD-909 Demonstrated Approximately 30-fold Selectivity Across 17 Cell Lines
| BRG1 WT BRG1 MUT 0.0001 0.001 0.01 0.1 1 A b so lu te 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) FHD-909 Demonstrated Approximately 30-fold Selectivit
Slide 22: FHD-909 Monotherapy Demonstrated In Vivo Activity in H2126 BRG1 Mutant NSCLC Model
| FHD-909 Monotherapy Demonstrated In Vivo Activity in H2126 BRG1 Mutant NSCLC Model; Well Tolerated 22 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 applied at t
Slide 23: FHD-909 Monotherapy Demonstrated 96% TGI in A549 and Tumor 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 23 A549 Model NOTE: All doses were well tolerated. Dosing holidays were applied at the high dose, as appropriate BRG1 Q729fs / H736Y, KRAS G12S, STK11-/-, CDKN2A-/-, KEAP1 G333C BRG
Slide 24: FHD-909 Monotherapy Demonstrated Regression in H1793 BRG1 Mutant NSCLC Models
| FHD-909 Monotherapy Demonstrated Regression in H1793 BRG1 Mutant NSCLC Models 24 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
Slide 25: BRM Selective Degrader Achieved Complete BRM Degradation and Cell Growth Inhibition In Vitro
| BRM Selective Degrader Achieved Complete BRM Degradation and Cell Growth Inhibition In Vitro 25 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 d a ti o n Concentra
Slide 26: Selective CBP Protein Degrader For EP300 Mutated Cancers
Selective CBP Protein Degrader For EP300 Mutated Cancers
Slide 27: Summary: Selective CBP Protein Degrader for EP300 Mutated Cancers
| Summary: Selective CBP Protein Degrader for EP300 Mutated Cancers 27* Per year incidence in the U.S., EU5, Japan Source: Clarivate RDG Mature Markets Data • CREB binding protein (CBP) • Targeted protein degrader Target / Approach • EP300 mutated cancers (e.g., subsets of bladder, colorectal, breas
Slide 28: Selective CBP Degradation Resulted in Significant Tumor Growth Inhibition in Colorectal & Bladder Models
| Colorectal RKO (EP300 Null) Model Selective CBP Degradation Resulted in Significant Tumor Growth Inhibition in Colorectal & Bladder in EP300 Null Models 28 Bladder 639V (EP300 Null) Model B o d y W ei g h t C h a n g e (% ) T u m o r V o lu m e ( m m ³ + S E M ) T u m o r V o lu m e ( m m ³ + S E
Slide 29: Selective CBP Degradation Resulted in Tumor Regression in Gastric EP300 Null Models
| Selective CBP Degradation Resulted in Tumor Regression in Gastric EP300 Null Models 29 Gastric AGS (EP300 Null) Model B o d y w e ig h t C h a n g e ( % ) 20 30 40 50 60 0 500 1,000 1,500 Days After Tumor Inoculation T u m o r V o lu m e ( m m ³ + S E M ) Vehicle (BID) FHT-CBPd - 9, 10mg/kg (QD) F
Slide 30: Selective CBP Degradation Did Not Show Thrombocytopenia and Spared Megakaryocytes
| Bone Marrow Staining (In Vivo)Platelet Counts Post Two Weeks of Dosing (In Vivo) Preclinical Studies Indicated Selective CBP Degradation Did Not Show Thrombocytopenia and Spared Megakaryocytes In Vivo 30 PLT (x109cells/L) 0 500 1,000 1,500 2,000 2,500 Study Day 14 Vehicle FHT-CBPd, 10mg/kg, sc, QD
Slide 31: Long-Acting Injectable Formulations of CBP Degrader Could Enable Less Frequent Dosing
| Preclinical Studied Indicated Long-Acting Injectable Formulations of CBP Degrader Could Enable Once Every 2 Weeks, or Less Frequent, Dosing 31 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 ev el s / % V e h ic le P la sm a P K (n g /m L )
Slide 32: Selective EP300 Protein Degrader For CBP Mutated and EP300 Dependent Cancers
Selective EP300 Protein Degrader For CBP Mutated and EP300 Dependent Cancers
Slide 33: Summary: Selective EP300 Protein Degrader for CBP Mutant & EP300 Dependent Cancers
| Summary: Selective EP300 Protein Degrader for CBP Mutant & EP300 Dependent Cancers 33 * Per year incidence in the U.S., EU5, Japan Source: Clarivate RDG Mature Markets Data • E1A binding protein p300 (EP300) • Targeted protein degrader Target / Approach • AR+ Prostate • DLBCL • Bladder, melanoma,
Slide 34: EP300 Degradation Resulted in Significant Tumor Growth Inhibition in Prostate and DLBCL Models
| EP300 Degradation Resulted in Significant Tumor Growth Inhibition in AR+ VCAP Prostate and KARPAS422 DLBCL Models 34 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 ) Veh
Slide 35: Selective EP300 Degradation Does Not Show Thrombocytopenia In Vivo
| Selective EP300 Degradation Does Not Show Thrombocytopenia In Vivo 35 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 36: Selective ARID1B Protein Degrader For ARID1A Mutated Cancers
Selective ARID1B Protein Degrader For ARID1A Mutated Cancers
Slide 37: ARID1B is a Major Synthetic Lethal Target Implicated in Up To 5% of All Solid Tumors
| ARID1B is a Major Synthetic Lethal Target Implicated in Up To 5% of All Solid Tumors 37* Per year incidence in the U.S., EU5, Japan Source: Clarivate RDG Mature Markets Data • ARID1B • Targeted protein degrader Target / Approach • ARID1A mutated cancersInitial Indication • ARID1A mutations (e.g.,
Slide 38: Compound Screening and Structure-Based Optimization Yields Selective ARID1B Binders
| Compound Screening and Structure-Based Optimization Yields Selective ARID1B Binders 38 • 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 39: Structure-Based Optimization Drives Improved ARID1B Binding Affinity
| Structure-Based Optimization Drives Improved ARID1B Binding Affinity from 100 uM to less than 200 nM 39 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 G
Slide 40: 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 41: Foghorn's Novel Approach to Drugging Transcription Factors
| Foghorn’s Novel Approach to Drugging Transcription Factors Enabled by Its Protein Production and Discovery Capabilities 41 • 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 42: Transcription Factors Bind to BAF Directly with High Degree of Specificity
| Transcription Factors Bind to BAF Directly with High Degree of Specificity; Unique Insights into Where and How Transcription Factors Bind 42 Mass spec. foot-printing Pull-down assays Foghorn’s collection of BAF sub-complexes and domains Biophysical Biochemical Structural AUC / SPR / ITC TR-FRET /
Slide 43: Foghorn Is 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 43 Modality Program Phase 1 Enzyme Inhibitors Transcription Factor Disruptors Undisclosed Protein Degraders Commercial Rights FHD-286 (BRG1/BRM) FHD-909 (Selective BRM) 3 Disco
Slide 44: Developing First-In-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| Developing First-In-Class Precision Medicines Targeting Major Unmet Needs in Cancer 44 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
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