Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (November 2023)
35 slides from Foghorn Therapeutics's investor presentation, Nov 2, 2023
Slide 1: Corporate Overview November 2023
CORPORATE OVERVIEW November 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
| FORWARD LOOKING STATEMENTS 2 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,” “m
Slide 3: First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| FIRST-IN-CLASS PRECISION MEDICINES TARGETING MAJOR UNMET NEEDS IN CANCER 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 MAJOR STRATEGIC C
Slide 4: Unique Insights into Chromatin Biology
| NOVEL TARGETS GUIDED BY GENETIC DEPENDENCIES TAILORED DRUGGING APPROACHES UNIQUE INSIGHTS INTO CHROMATIN BIOLOGY Transcription Factor Mutations / Overexpression Chromatin Remodeling Complex Mutations / Overexpression Helicases & Other Chromatin Binding Proteins involved in gene expression / functi
Slide 5: 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 6: 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 Combination Study BRG1 Mutated Cancers, e.g. , NSCLC & Bladder Undisclosed FHD-286 (B
Slide 7: FHD-286: Targeting BAF Dependency in Cancer
FHD-286: Targeting BAF Dependency in Cancer FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex
Slide 8: FHD-286: Targeting BAF Dependency in Cancer
| FHD-286: TARGETING BAF DEPENDENCY IN CANCER Potent, Selective, Allosteric, Small Molecule Inhibitor of BRG1 / BRM 8 BAF ATPase: BRG1/BRM • FHD-286: Allosteric modulation inhibiting the activity of BRM/BRG1 Differentiation • Clinical and pre-clinical and data demonstrate broad- based differentiatio
Slide 9: FHD-286: First-in-Class Broad-Based Differentiation Agent in AML
| PHASE I MONOTHERAPY SAFETY AND EFFICACY RESULTS PHASE I COMBINATION STUDY FHD-286: FIRST-IN-CLASS BROAD-BASED DIFFERENTIATION AGENT WITH SIGNIFICANT COMBINATION POTENTIAL IN AML SIGNIFICANT OPPORTUNITY • ~27,000 drug treated relapsed and/or refractory (R/R) AML patients*, with significant unmet ne
Slide 10: FHD-286 Demonstrated Differentiation Across Broad Range of Genotypes
| 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 59.4x 70 2 (97%) 7.5mg KMT2A rearrangement Adverse 3 58 21.4x 85 9 (90%) 7.5mg RUNX1, KRAS, ASXL1,
Slide 11: Patient Bone Marrow Shifts to Differentiated Phenotype During FHD-286 Therapy
| PATIENT BONE MARROW SHIFTS FROM LEUKEMIC STEM CELL-LIKE TO DIFFERENTIATED PHENOTYPE DURING FHD-286 THERAPY • Single-cell RNA-seq of patient bone marrow aspirates show that marrow is heavily infiltrated with leukemic stem cell-like blasts at screening • On treatment aspirates demonstrate that the b
Slide 12: Patient 7: 47-Year-Old with Secondary AML
| PATIENT 7: 47-YEAR-OLD WITH SECONDARY AML SHOWED CLEAR SIGNS OF DIFFERENTIATION BONE BLAST REDUCTION FROM 40% TO 6% BONE MARROW ASPIRATE DEMONSTRATING CLEAR EVIDENCE OF DIFFERENTIATION 47-YEAR-OLD MALE WITH SAML WITH AN ABNORMAL KARYOTYPE (DEL (7Q), INV (3), DER (7;12), -8, ADD(1)) • Prior AML Tre
Slide 13: Patient 5: 25-Year-Old with AML
| PATIENT 5: 25-YEAR-OLD WITH AML OBSERVED MEANINGFUL CLINICAL BENEFIT 25-YEAR-OLD MALE WITH TREATMENT-RELATED AML WITH A KMT2A REARRANGEMENT • Prior AML Treatment: • Progressive disease with CNS Leukemia: 7 lines prior treatment and 2 bone marrow transplants • Prior Non-AML Treatment: • Ewing’s sar
Slide 14: Pre-Clinical Data Show Combination Potential in AML
| MV4, 11 FLT3 ITD CDX PRE-CLINICAL DATA DEMONSTRATE SIGNIFICANT COMBINATION POTENTIAL WITH MULTIPLE AGENTS IN AML 0 20 40 60 0 25 50 75 100 MLL-AF9 + FLT3-TKD Luc/GFP PDX Days, post-infusion % S ur vi va l FHD-286 + decitabine (n=8) 1 mg/kg decitabine (n=7) 1.5 mg/kg FHD-286 (n=7) Vehicle (n=7)6 we
Slide 15: 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 16: Selectively Targeting BRG1 Mutant Cancers
| SELECTIVELY TARGETING BRG1 MUTANT CANCERS Up to 5% of all Solid Tumors Harbor BRG1 Mutations Partner / Approach • BRM Selective Programs part of the Loxo@Lilly collaboration • Two Drugging Approaches: • Selective Inhibition • Selective Degradation Opportunity • BRG1 mutated cancer • ~8-10% of NSCL
Slide 17: 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 17 Tumor Volume Tu m or V ol um e (m m 3 ) Da
Slide 18: Degraders Cause Time- and Dose-Dependent BRM Degradation
| 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 18 BRM / BRG1 HIBIT DATA A549 TEN-DAY PROLIFERATION ASSAY BRM BRG1 % D eg ra da tio n (% ) Concentration (uM
Slide 19: Selective EP300 Protein Degrader for CBP Mutant Cancers
SELECTIVE EP300 PROTEIN DEGRADER FOR CBP MUTANT & EP300 DEPENDENT CANCERS (E.G., BLADDER, NSCLC, VARIOUS LYMPHOMAS AND LEUKEMIAS)
Slide 20: Advancing Highly Selective EP300 Protein Degrader
| ADVANCING HIGHLY SELECTIVE EP300 PROTEIN DEGRADER FOR CBP MUTANT & EP300 DEPENDENT CANCERS 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 Indications • AR+ Prostate • DL
Slide 21: EP300 Degradation Results in Tumor Growth Inhibition in Prostate Model
| EP300 DEGRADATION RESULTS IN SIGNIFICANT TUMOR GROWTH INHIBITION IN AR+ VCAP PROSTATE MODEL 21 VCAP PROSTATE MODEL BODY WEIGHT LOSS FHT-EP300d 50 mg / kg (BID) Enzalutamide, 30mg/kg, QD Vehicle Control
Slide 22: Selective Degradation of EP300 and CBP Does Not Show Thrombocytopenia
| SELECTIVE DEGRADATION OF EP300 AND CBP DOES NOT SHOW THROMBOCYTOPENIA IN MICE AT RELEVANT DOSES 22 PLT (x109cells/L) 0 500 1000 1500 2000 2500 3000 Study Day 14 Pl at el et s (X 10 3 ce lls /u L) Vehicle, sc, BID GNE-781, 30mpk, PO, BID GNE-781 dCBP-3 dEP300-2 dCBP-3, 50mpk, sc, BID dEP300-2, 50mp
Slide 23: 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 24: 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 bla
Slide 25: Selective CBP Degrader Demonstrates CBP-Dependent Cell Killing
| HIGHLY SELECTIVE DEGRADER OF CBP DEMONSTRATES CBP-DEPENDENT CELL KILLING ACROSS MULTIPLE CANCERS 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 C pd [nM] HT29 (CB /EP300 WT) RFO (EP300 mutant) % C e
Slide 26: CBP Selective Degraders Result in Tumor Growth Inhibition in Colorectal Model
| RKO (EP300 NULL) BODY WEIGHT CHANGE (%) CBP SELECTIVE DEGRADERS RESULT IN SIGNIFICANT TUMOR GROWTH INHIBITION IN EP300MUT COLORECTAL MODEL 26 RKO (EP300 NULL) MODEL 5 10 15 20 25 30 0 500 1000 1500 2000 2500 Days After Tumor Inoculation Tu m or V ol um e (m m ³+ S EM ) Vehicle Control FHT-CBPd, 50
Slide 27: 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 28: ARID1A: Most Mutated Subunit in BAF Complex
| 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 29: 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 30: 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 31: 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 32: 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 33: Transcription Factors Bind to BAF Directly with High Specificity
| TRANSCRIPTION FACTORS BIND TO BAF DIRECTLY WITH HIGH DEGREE OF SPECIFICITY 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 / FP C
Slide 34: 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 Combination Study BRG1 Mutated Cancers, e.g. , NSCLC & Bladder Undisclosed FHD-286 (B
Slide 35: First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| FIRST-IN-CLASS PRECISION MEDICINES TARGETING MAJOR UNMET NEEDS IN CANCER 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 MAJOR STRATEGIC C
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