Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (June 2023)
70 slides from Foghorn Therapeutics's investor presentation, Jun 5, 2023
Slide 1: Corporate Overview June 2023
CORPORATE OVERVIEW June 2023 Leveraging unique insights into the chromatin regulatory system to pioneer a new class of precision therapies in oncology and beyond Exhibit 99.1
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 >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 data
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 Combination Study Uveal Melanoma BRG1 Mutated Cancers, e.g. , NSCLC & Bladder Undiscl
Slide 8: FHD-286 Phase 1 combination study for AML
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 PHASE 1 COMBINATION STUDY FOR AML FHD-286 Is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM S
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: FHD-286: first-in-class broad-based differentiation agent
| PRE-CLINICAL AND CLINICAL DATA DEMONSTRATES BROAD-BASED DIFFERENTIATION FHD-286: FIRST-IN-CLASS BROAD-BASED DIFFERENTIATION AGENT WITH SIGNIFICANT COMBINATION POTENTIAL IN AML INITIATING PHASE 1 COMBINATION STUDY SIGNIFICANT OPPORTUNITY ~27,000 drug treated relapsed and/or refractory (R/R) AML pat
Slide 11: FHD-286 potential to differentiate leukemic stem cells
| FHD-286 HAS THE POTENTIAL TO DIFFERENTIATE LEUKEMIC STEM CELLS WHICH ARE DRIVERS OF RELAPSE IN AML N O R M AL LSC AM L Hematopoietic Stem Cells (HSC) Normal Blood Cells Mutation Leukemic Stem Cell (LSC) Blasts Chemotherapy Therapy-resistant LSCs capable of regenerating new leukemia RELAPSE LSC-tar
Slide 12: FHD-286 Phase 1 monotherapy dose escalation overview
| FHD-286 PHASE 1 MONOTHERAPY DOSE ESCALATION OVERVIEW DESIGN PATIENTS • Oral daily dosing of FHD-286 as monotherapy • R/R AML and R/R MDS patients who exhausted all treatment options • Doses tested: 2.5mg, 5.0mg, 7.5mg, 10.0mg once daily • 40 patients enrolled: 36 R/R AML and 4 R/R MDS • 67.5% had
Slide 13: Most common TRAEs and differentiation syndrome assessment
| MOST COMMON TRAES MOST COMMON ≥ GRADE 3 TRAES • Dry mouth, increased blood bilirubin, increased ALT, rash • Increased blood bilirubin, hypocalcemia, DS, stomatitis, increased ALT • Number of subjects with DS • 1 R/R AML subject adjudicated as having definitive DS; this subject also had 2 events of
Slide 14: Blast count reduction leading to ANC recovery
| PERIPHERAL BLOOD AND BONE MARROW BLAST COUNT REDUCTION LEADING TO ANC RECOVERY IN A SUBSET OF PATIENTS 14* MDS Patient Diagnosis Dose Level Mutations Cytogenetic Risk Cycles on Study ANC Recovery Peripheral Starting Blast % Peripheral Min Blast % Peripheral Blast % Change BMA Starting Blast % BMA
Slide 15: Blast count reduction leading to ANC recovery (continued)
| PERIPHERAL BLOOD AND BONE MARROW BLAST COUNT REDUCTION LEADING TO ANC RECOVERY IN A SUBSET OF PATIENTS 15* MDS Patient Diagnosis Dose Level Mutations Cytogenetic Risk Cycles on Study ANC Recovery Peripheral Starting Blast % Peripheral Min Blast % Peripheral Blast % Change BMA Starting Blast % BMA
Slide 16: 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 17: 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 18: 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 19: Bone marrow shifts to differentiated phenotype during 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 20: Preclinical single agent AML activity and combination potential
| PRE-CLINICAL DATA DEMONSTRATE BROAD SINGLE AGENT AML ACTIVITY WITH SIGNIFICANT POTENTIAL FOR COMBINATION 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 weeks Rx ✱
Slide 21: FHD-286 Phase 1 combination study overview
| FHD-286 PHASE 1 COMBINATION STUDY OVERVIEW Plans to commence in Q3’2023 VALIDATION OF DEPENDENCY AND APPROACH 21 DESIGN DS MANAGEMENT • Standard 3+3 dose escalation design • Oral daily dosing of FHD-286 in combination with either fixed dose decitabine or fixed dose cytarabine • R/R AML patients •
Slide 22: FHD-286 Phase 1 dose escalation for metastatic uveal melanoma
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 PHASE 1 DOSE ESCALATION FOR METASTATIC UVEAL MELANOMA FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor o
Slide 23: Significant unmet need in uveal melanoma
| SIGNIFICANT UNMET NEED IN UVEAL MELANOMA Most Common Form of Eye Cancer 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 Limited
Slide 24: Potential definitive efficacy trials and indication expansion
| POTENTIAL DEFINITIVE EFFICACY TRIALS & INDICATION EXPANSIONPHASE 1 DOSE ESCALATION STUDY PHASE 1 EXPANSION STUDIES 24 • Evaluate identified dose(s) • Consider refined patient population, if necessary • Consider exploration of combination partners • Assess safety, PK, biomarkers and therapeutic act
Slide 25: 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 25 MITF CHIPseq SOX10 CHIPseq
Slide 26: 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 27: 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 28: 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 29: BRG1 mutated across 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 30: 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) 30 Tumor Volume Tu m or v ol um e (m m
Slide 31: 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 ) 31
Slide 32: Degraders cause BRM degradation and antiproliferative effects
| 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 32 0.01 0.1 1 10 100 -50 0 50 100 150 FHX-NSXLX Conc
Slide 33: 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 34: 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 35: Advancement of highly selective CBP degraders
| ADVANCEMENT OF HIGHLY SELECTIVE CBP DEGRADERS 35 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 36: CBP degrader demonstrates CBP-dependent cell killing
| HIGHLY SELECTIVE DEGRADER OF CBP DEMONSTRTES 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 Cmpd [nM] HT29 (CBP/EP300 WT) RFO (EP300 mutant) % C el
Slide 37: 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 38: 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 39: Advancement of highly selective EP300 degraders
| ADVANCEMENT OF HIGHLY SELECTIVE EP300 DEGRADERS 39 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 40: 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 41: 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 42: 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 43: 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 44: 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 45: TFs are compelling drug targets but historically difficult
| 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 46: 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 47: 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 48: 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 Uveal Melanoma BRG1 Mutated Cancers, e.g. , NSCLC & Bladder Undiscl
Slide 49: 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 50: Appendix
APPENDIX FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex
Slide 51: FHD-286 Phase 1 combination study for AML
FHD-286 FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM subunits of the BAF complex PHASE 1 COMBINATION STUDY FOR AML FHD-286 is a Potent, Selective, Allosteric, Small Molecule Inhibitor of the BRG1 and BRM Subunits of the BAF Complex
Slide 52: Significant unmet need remains in R/R AML
| SIGNIFICANT UNMET NEED REMAINS IN R/R AML REGARDLESS OF GENOMIC ALTERATIONS 52 30% FHD-286 OPPORTUNITY 30% FHD-286 OPPORTUNITY US: ~ 11,500 patients G6: ~ 16,800 patients FIT UNFIT INTENSIVE CHEMO (IC) VEN/HMA Epidemiology: DRG 2022 AML Report; Market Shares: Cerner Enviza CancerMPact Treatment Ar
Slide 53: Phase 1 dose escalation patient characteristics
| PHASE 1 MONOTHERAPY DOSE ESCALATION PATIENT CHARACTERISTICS Highly Relapsed and Refractory, Abnormal Karyotype, and Poor Genetic Risk Factors 2.5 mg QD N=5 5 mg QD N=16 7.5 mg QD N=13 10 mg QD N=6 Total N=40 Age (years) Median (min, max) 73.0 (61, 84) 67.5 (43, 80) 66.0 (25, 75) 45.0 (27, 79) 65.5
Slide 54: Phase 1 dose escalation safety summary
| PHASE 1 MONOTHERAPY DOSE ESCALATION SAFETY SUMMARY 2.5 mg QD N=5 5 mg QD N=16 7.5 mg QD N=13 10 mg QD N=6 Total N=40 Any grade TRAE 5 (100) 15 (93.8) 10 (76.9) 4 (66.7) 34 (85.0) Dry mouth 0 8 (50.0) 3 (23.1) 0 11 (27.5) Increased blood bilirubin 0 4 (25.0) 3 (23.1) 2 (33.3) 9 (22.5) ALT increased
Slide 55: Grade 3 or higher treatment-related adverse events
| PHASE 1 MONOTHERAPY DOSE ESCALATION SAFETY SUMMARY 2.5 mg QD N=5 5 mg QD N=16 7.5 mg QD N=13 10 mg QD N=6 Total N=40 Grade ≥3 TRAEs 1 (20.0) 9 (56.3) 8 (61.5) 2 (33.3) 20 (50.0) Increased blood bilirubin 0 2 (12.5) 2 (15.4) 1 (16.7) 5 (12.5) Hypocalcemia 1 (20.0) 1 (6.3) 0 1 (16.7) 3 (7.5) Differe
Slide 56: FHD-286 reduces leukemogenic potential in transplant model
| FHD-286 SIGNIFICANTLY REDUCES LEUKEMOGENIC POTENTIAL IN IN VIVO TRANSPLANT MODEL LEUKEMOGENIC POTENTIAL TRANSPLANT MODEL 109 1010 1.5 mg/kg FHD-286 (n=4) Vehicle (n=4) mtNPM1 + FLT3-ITD Luc/GFP AML PDX Total Bioluminescent Flux (p/s) Post 5-weeks of Rx 0.0104 Veh icl e 1.5 m g/k g FHD28 6 15 20 25
Slide 57: CD11b+ increases and CD34+ decreases associated with differentiation
| • Mature differentiated cells are functionally specialized and compose the majority of cells in the body • Cancer cells often revert to a more stem-like state in order to gain self-renewal and resistance phenotypes • CD34 is a marker of hematopoietic stem cells that can differentiate into CD11b+ m
Slide 58: Robust differentiation effect in AML preclinical models
| ROBUST DIFFERENTIATION EFFECT OBSERVED IN AML PRE-CLINICAL MODELS DAY 14 SAMPLE (EVI-1 MUT) MORPHOLOGIC CHANGES OBSERVED IN PATIENT DERIVED CELL MODELS TREATED WITH FHD-286 FHD-286 CAUSES DIFFERENTIATION IN AML CELL LINES 0 10 20 30 0 10 20 30 40 50 nM, FHD-286, 7 days % d iff er en tia te d ce ll
Slide 59: 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 60: 50/50 U.S. economics on two programs
| 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 61: 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 62: 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 63: Breakdowns in 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 64: 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 65: 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 66: 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 67: 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 68: 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 69: Proven leadership team
| PROVEN LEADERSHIP TEAM 69 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 70: 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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