Slides
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NASDAQ: IDYA IDEAYA Biosciences Improving Lives Through Transformative Precision Medicine IDEAYA Investor R&D Day December 16, 2024
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Certain statements in this presentation and the accompanying oral commentary are forward-looking statements. These statements relate to future events or the future financial performance of IDEAYA Biosciences, Inc. (the “Company”) and involve known and unknown risks, uncertainties and other factors that may cause the actual results, levels of activity, performance or achievements of the Company or its industry to be materially different from those expressed or implied by any forward-looking statements. In some cases, forward-looking statements can be identified by terminology such as “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “potential” or other comparable terminology. All statements other than statements of historical fact could be deemed forward-looking, including the potentially addressable patient population for the Company’s programs, any expectations regarding the Company’s target discovery platform or new target validation efforts as creating opportunities for research and development initiatives; any projections of financial information, market opportunities, cash runway or profitability; any statements about historical results that may suggest trends for the Company's business; any statements of the plans, strategies, and objectives of management for development programs or future operations; any statements about the timing of preclinical research, clinical development, regulatory filings, manufacturing or release of data; any statements of expectation or belief regarding future events, potential markets or market size, technology developments, or receipt of cash milestones, option exercise fees or royalties; and any statements of assumptions underlying any of the items mentioned. The Company has based these forward-looking statements on its current expectations, assumptions, estimates and projections. While the Company believes these expectations, assumptions, estimates and projections are reasonable, such forward-looking statements are only predictions and involve known and unknown risks and uncertainties, many of which are beyond the Company's control. Such risks and uncertainties include, among others, the uncertainties inherent in the drug development process, including IDEAYA’sprograms’ early stage of development, the process of designing and conducting preclinical and clinical trials, the regulatory approval processes, the timing of regulatory filings, the challenges associated with manufacturing drug products, IDEAYA’sability to successfully establish, protect and defend its intellectual property, and other matters that could affect the sufficiency of existing cash to fund operations. These and other important factors may cause actual results, performance or achievements to differ materially from those expressed or implied by these forward-looking statements. The forward-looking statements in this presentation are made only as of the date hereof. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of the Company in general, see the Company's periodic filings with the Securities and Exchange Commission (the "SEC"), including its Annual Report on Form 10-K for the year ended December 31, 2023, and any current and periodic reports filed thereafter. Except as required by law, the Company assumes no obligation and does not intend to update these forward-looking statements or to conform these statements to actual results or to changes in the Company's expectations. This presentation concerns anticipated products that are under clinical investigation and which have not yet been approved for marketing by the U.S. Food and Drug Administration (FDA). It is currently limited by Federal law to investigational use, and no representation is made as to its safety or effectiveness for the purposes for which it is being investigated. Safe Harbor Statement 2
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3 IDEAYA Investor R&D Day Welcome and Introduction Yujiro S. Hata IDEAYA Biosciences President and Chief Executive Officer
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4 IDEAYA Investor R&D Day Welcome to our Participants and Guest Speakers Carol Shields, M.D. Wills Eye Hospital, Thomas Jefferson University Ramon Kemp, Ph.D. GSK Timothy Yap, MBBS, FRCP , PhD, BSc (Hons), PgDip (Onc) M.D. Anderson Cancer Center Amy Schefler, M.D. Retina Consultants of Texas, Weill Cornell Medical College, Houston Methodist Hospital & University of Texas Health Science Center at Houston Kornelia Polyak, M.D., Ph.D. Dana-Farber Cancer Institute, Harvard Medical School
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5 IDEAYA Investor R&D Day • Building Global Leader in Precision Medicine Oncology (Yujiro Hata, CEO) Welcome Guest Speakers; IDEAYA Vision & Strategy • Uveal Melanoma Roundtable (Carol Shields, Wills Eye Hospital, Amy Schefler, Retina Consultants of Texas, Darrin Beaupre, CMO) Treatment Paradigms in Neoadjuvant Uveal Melanoma • New paradigms to address tumor heterogeneity and drug resistance (Kornelia Polyak, Dana-Farber) • Mechanistic Rationale underpinning IDE161/Keytruda and IDE161/ADC Combination Opportunities (Tim Yap, MD Anderson) • IDEAYA and GSK Partnership (Ramon Kemp, GSK) IDE275/GSK959 (Phase 1) Werner Helicase Program Update • Development Candidate Updates (Mike White, CSO) IDE892 (PRMT5), IDE034 (B7H3/PTK7 Bispecific Topo-payload ADC), IDE251 (KAT6-7) • Closing Remarks, Preliminary 2025 Guidance, and Analyst Q&A (Yujiro Hata, CEO; Darrin Beaupre, CMO; Mike White, CSO) Agenda Topics
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6 Building Global Leader in Precision Medicine Oncology IDEAYA Vision, Strategy and Pipeline Yujiro S. Hata IDEAYA Biosciences President and Chief Executive Officer
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IDEAYA Vision & Strategy 7 Improving Lives through Transformative Precision Medicines IDEAYA First-in-Class Predictive Biomarkers Transformative Combinations (Neo)adjuvant Data Informatics Structural Biology Addressing the challenge of tumor heterogeneity
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8 Addressing Tumor Heterogeneity Through Transformative Combinations HRD/BRCA Solid Tumors*MTAP-Deletion Solid Tumors MSI-High Solid Tumors* IDEAYA Vision & Strategy kk IDE275 (GSK959) Werner + PD1 *Pursuant to GSK Collaboration IDE397 (MAT2A) + IDE892 (PRMT5) 8 IDE705 (GSK101) Pol Theta + Niraparib Addressing BRCA reversions: a key mechanism of PARP-acquired resistance Addressing PRMT5 resistance & bypass mechanisms in MTAP-deletion Targeting multiple MOA nodes to treat MSI-High solid tumors 8
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AI ML 9 IND engine: deep knowledge of target biology, drug MOA, and disease characteristics Internal capabilities support innovation across biological length scales Protein/ligand interactions IDEAYA Vision & Strategy: World Class R&D and Drug Discovery Enterprise Building Global Leader in Precision Medicine Oncology PIPELINE: 5 Clinical, 3 DCs, >3 Pre-Clinical • Ph3 – Darovasertib/PKC (potential 1st-in-class) • Ph2 – IDE397/MAT2A (potential 1st-in-class) • Ph1 – IDE161/PARG (potential 1st-in-class) • Ph1 – IDE705/Pol Theta (potential 1st-in-class) • Ph1 – IDE275/Werner (potential 1st-in-class) • DC – IDE034/B7H3-PTK7 ADC (potential 1st-in-class) • DC – IDE892/PRMT5 (potential best-in-class) • DC – IDE251/KAT6-7 (potential 1st-in-class) • PC – >3 potential 1st-in-class programs advancing COMBOS: Addressing Tumor Heterogeneity • PKC/cMET, GNAQ/11 (potential 1st-in-class), Pfizer • MAT2A/PRMT5, MTAP (potential 1st-in-class), Amgen • MAT2A/Topo-ADC, MTAP (potential 1st-in-class), Gilead • Pol Theta/PARP , HRD (potential 1st-in-class), GSK • Werner/PD1, MSI-High (potential 1st-in-class), GSK • PARG/PD1, MSI-High/MSS (potential 1st-in-class), Merck • PARG/Topo-ADC, Antigen (potential 1st-in-class) Tumor evolutionPatient populations Cell regulation
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10 Uveal Melanoma Roundtable Treatment Paradigms in Primary Uveal Melanoma Carol Shields, M.D. Amy Schefler, M.D. Darrin Beaupre, M.D., Ph.D.
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Enucleation, Proton Beam Therapy and Plaque Brachytherapy Proton Beam Enucleation of the Eye Conjunctiva Lateral Rectus Muscle Superior Rectus Muscle Superior Oblique Muscle Medial Rectus Muscle Inferior Rectus Muscle Superior Oblique Muscle Optic Nerve Synthetic Globe Sutures 1. 2. 3. 4. Adapted from SurgeryEncyclopedia.com 11
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-100.0 -80.0 -60.0 -40.0 -20.0 0.0 20.0 40.0 60.0 Darovasertib Neoadjuvant Therapy: Ph2 Company Sponsored & Ph2 IST UM Trials 12 61% (19 of 31) Observed Eye Preservation and 49% (24 of 49) with >30% Tumor Reduction* IDEAYA Data: Enrollment cut-off date of 13May24, and results as of 15Aug2024 (based on preliminary analysis of unlocked database for Ph2 company sponsored patients enrolled up to 13May2024); Ph2 IST as of 14May2024 [ASCO 2024 Oral Presentation] *Ocular tumor size measured by the product of diameters (longest basal diameter x tumor thickness); **Based on clinical data correlating ocular tumor shrinkage with eye preservation and vision from darovasertib treatment in UM. Clinical data provided in FDA briefing book for FDA Type C meeting Clinical Efficacy (n=49) Evaluable Patients, n 49 % Tumor Reduction, by Product of Diameters measurements, n, (%) ≥ 20% Reduction 29 (59%) ≥ 30% Reduction 24 (49%) Eyes Preserved in Enucleation Pts, n, (%) 19/31 (61%) Maximum % Change from Baseline* ^ = Eye Saved / Eye Eligible for Plaque + = Patient ongoing Treatment as of Cut-off Date = Enucleation – Ph2 Company Sponsored & IST UM Trials = Brachytherapy – Ph2 Company Sponsored ^^^^^ ^ ^ ^^ ^^ ^ ^ ^^ ^^+ + + + + + + + >20% Tumor Reduction Correlates with Eye Preservation and Vision Benefit** + + + + + + +++ + + ^ ^ ~59% (29 of 49) observed >20% Tumor Reduction ~49% (24 of 49) observed ≥ 30% Tumor Reduction 61% (19 of 31) Eye Preservation Rate Observed in Enucleation Patients ~82% (40 of 49) of UM Patients observed Tumor Shrinkage 43% of UM Patients have ongoing Daro Neoadjuvant Treatment + +
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13 Simulated Radiation Doses and Predicted Vision Loss after Plaque Brachytherapy Pre- & Post-Radiation Dose Reduction Simulations for 2 Patients Receiving Darovasertib*• 10 evaluable simulation subjects • Substantial reduction in projected radiation doses from baseline after treatment to critical eye structures (Median [Range]): Fovea: -20% [14%-41%] Optic Nerve: -35% [15%-54%] Optic Disc: -32% [16%-40%] • 60% (6 of 10) of patients show a lower predicted risk of Visual Acuity 20/200 or worse (legal blindness) post Plaque Brachytherapy [2] • 2 pre- and post- darovasertib radiation treatment simulations provided Darovasertib Treatment Results in Tumor Shrinkage, Radiation Reduction, and Improved Predicted Visual Outcomes* [1] Simulation is based on tumor size at baseline and post 3 cycles of darovasertib treatment as performed by independent radiation physicist [2] Risk reduction of Visual Acuity (VA) estimated using Vision Prognostication Tool algorithm; JAMA Ophthalmology, Aziz 2016 [3] Ocular tumor size measured by the product of diameters (longest basal diameter x tumor thickness); *2 UM patients enrolled in Phase 2 company-sponsored neoadjuvant UM study Baseline Simulation Month 3 Simulation Radiation Dose Reductions (Gy) Tumor & Plaque size reduced (brown outline) Critical Eye Structure Baseline (Gy) Month 3 (Gy) % Change Fovea 43.5 25.8 -41% Optic Nerve 40.9 19 -54% Optic Disc 50.3 30.2 -40% Baseline Simulation Month 6 Simulation Radiation Dose Reductions (Gy) Critical Eye Structure Baseline (Gy) Month 3 (Gy) % Change Fovea 20.0 7.5 -63% Optic Nerve 19.5 7.3 -63% Optic Disc 21.4 8.1 -62% Tumor & Plaque size reduced (orange outline) 64% reduction in tumor measurement by product of diameters [3] after 6 months of treatment 30% reduction in tumor measurement by product of diameters after 3 months of treatment
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14 CONFIDENTIAL Nomogram for Prediction of Visual Acuity > 20/200 at 1 and 3 Years*Predictive Factors for Visual Acuity Worse than 20/200 • Age at start of treatment • Largest Basal Diameter (mm) • Total Dose to Fovea (Gy) • Total Dose to Optic Disc (Gy) • Initial VA 20/50 or worse (Y/N) Risk Calculator for Vision Loss Post Plaque Brachytherapy in Uveal Melanoma Patients Evaluating Visual Acuity After Plaque Brachytherapy for Uveal Melanoma *Adapted from Aziz, JAMA Ophthalmology 2016: https://nakul.shinyapps.io/vision_calculator_150806/
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Enucleation Procedure Images courtesy of EyeWiki.org 15
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16 Pre & Post Darovasertib Treatment Radiation Plaque Planning and Vision Implications Reduced Radiation to Critical Structures & Potential Improvement in Vision*Plaque Treatment PlanBaseline & Post Baseline Measurements Phase 2 Darovasertib Neoadjuvant UM IST Results in Enucleation Patients Slides courtesy of Dr Rod O’Day and Lotte Fog Increased distance to critical structures and tumor enables smaller Ruthenium plaque (less radiation) Baseline Post Baseline Change Dose to nerve 78 Gy 13 Gy -83% Dose to fovea 157 Gy 59 Gy -62% 1-year probability of visual loss ~67% ~20% - 3-year probability of visual loss ~95% ~43% - Post-Baseline Plaque Size Requirements Baseline Plaque Size Requirements * Aziz et al., 2016 (Visual acuity of 20/200 or worse) Baseline Tumor Size Measurements Post Baseline Tumor Size Measurements • Distance to tumor from optic nerve and fovea increased by ~65% and ~163% respectively • Distance of tumor to optic nerve and fovea are 3.7 mm and 1.6 mm respectively Patient requires an Iodine plaque at Baseline
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CONFIDENTIAL17 Color & Fluorescein Angiography Evolution of Radiation Retinopathy Radiation Maculopathy BE Powell, Nature Eye 2022 Retinal hemorrhages, exudates & intraretinal microangiopathy Macular edema, capillary nonperfusion, microaneurysms & focal leakage of neo-vascular vessels
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18 Surveillance Guidelines for High vs Low Risk of Distant Metastasis CONFIDENTIAL Nature Reviews Clinical Oncology, Carvajal et al 2023
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19 Management of Primary Uveal Melanoma Based on Tumor Size CONFIDENTIAL Tumor Size Treatment Recommendations Largest diameter 5 – 19 mm and thickness < 2.5 mm • Brachytherapy plaque • Particle beam radiation Largest diameter ≤ 19 mm and thickness 2.5 – 10 mm • Brachytherapy plaque • Particle beam radiation • Enucleation Largest diameter > 19 mm (any thickness), or Thickness > 10 mm (any diameter), or Thickness > 8 mm with optic nerve involvement (any diameter) • Enucleation • Particle beam radiation • Stereotactic radiosurgery Adapted from Uveal Melanoma NCCN Guidelines V1.2024
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20 Tumor Heterogeneity Presenter: Kornelia Polyak, M.D., Ph.D.
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Intratumor heterogeneity Kornelia Polyak, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA, USA 21
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Marusyk et al. Cancer Cell 2020 Diversity is a hallmark of cancer … …and a driver of therapeutic resistance 22
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Quantitative measures of diversity in tumors • Cancer cells with unique identifiable features: “species” • Diversity of the tumor microenvironment • Topologic distribution of “species” Shannon index of diversity https://www.davidzeleny.net/anadat-r/doku.php/en:div-ind 23
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Phenotypic and genetic heterogeneity within breast tumors • CD44+ cells are more stem cell-like • CD24+ cells are more differentiated luminal epithelial cells • But, …. genetic divergence between the two populations within the same tumor Shipitsin et al. Cancer Cell, 2007 Park et al. JCI 120:636-644, 201024
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Intratumor diversity and treatment response Higher pre-treatment cellular genetic diversity is associated with therapeutic resistance Almendro et al. Cell Reports 2014 25
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Janiszewska et al. Nature Genetics, 2015 Mutation detection in situ STAR-FISH Specific to Allele PCR - FISH H1047H WT H1047R MUT CEP17 ERBB2 Nuclei 26
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Diversity changes and patient survival Both species diversity and its distribution tend to increase due to treatment Both increase and decrease in topologic genetic diversity is bad Changes in cellular genetic diversity do not predict long-term outcome Janiszewska et al. Nature Genetics, 2015 27
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Tumor topology - spatial distribution of genetically distinct cells WT: low clustering-no change (stroma) PIK3CAmut and PIK3CAmut +ERBB2amp: high decrease in clustering score ERBB2amp and ERBB2amp +WT: limited increase in clustering score Janiszewska et al. Nature Genetics, 2015 28
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Metzger et al. Cancer Disc, 2021 Neoadjuvant trial to test the impact of HER2 heterogeneity None of the HER2 heterogeneous cases had pCR 29
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HER2 heterogeneous: an area with ERBB2 amplification in >5% but <50% of tumor cells, or a HER2-negative area by FISH Li et al. JCI 2024 HER2 heterogeneous cases – limited transcriptomic response to treatment 30
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• Polyclonal tumors grow the fastest • IL11 and CCL5 drive tumor outgrowth Marusyk et al. Nature 2014 Functional relevance of intratumor heterogeneity: unique features of polyclonal tumors • Clonal expansion ≠ tumor outgrowth • Clonal interference 31
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Mechanistic drivers of intratumor heterogeneity IDEAYA combination Rx approaches Block source of bypass mutations PolQi (IDE705) + PARPi (Niraparib) Darovasertib + Crizotinib Block tissue- derived bypass pathway activation WRNi (IDE275) + Dostarlimab Block both tumor intrinsic and extrinsic drivers HRD tumors Metastatic uveal melanoma MSI-H tumors 32
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Mathematical modeling of polyclonal tumor growth Subclonal interactions and non-cell-autonomous drivers maintain intratumor diversity Marusyk et al. Nature 2014 33
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Intratumor heterogeneity and metastatic progression Janiszewska et al. Nature Cell Biol, 2019 Polyclonal tumors are more metastatic and promote polyclonal metastases by modifying the local and systemic microenvironments 34
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Can we decrease intratumor heterogeneity to improve treatment outcomes? Identify regulators of intratumor heterogeneity and modulate their activity Genetic heterogeneity is not easy to change, but evolution is driven by phenotypic diversity and this can be modulated An IDEAYA example: IDE397 (MAT2Ai) + PRMT5iMTA in MTAP-/- tumors 35
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KDM5 activity and cell-to-cell transcriptomic heterogeneity Cell-cell distance Gene A Gene B Cell1 Cell2 Distance Gene A Gene B Cell1 Cell2 Distance • KDM5i treatment decreases heterogeneity in KDM5i-sensitive cells • Fulvestrant-resistant (FULVR) cells more diverse than parental MCF7 cells • High KDM5B expression is associated with high transcriptomic heterogeneity in ER+ breast tumors Hinohara et. al. Cancer Cell, 2018 36
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KDMs and KATs are potential target classes to reverse tumor heterogeneity Epigenetic enzymes in general may regulate intratumor cellular transcriptomic heterogeneity The expression of several KDMs is associated with transcriptomic heterogeneity Hinohara et. al. Cancer Cell, 2018 • Histone demethylation facilitates histone acetylation • Histone acetylation opens chromatin to promote transcription 37
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• High intratumor heterogeneity in general is a poor prognostic marker • Polyclonal tumors have unique phenotypes • Cellular phenotypic heterogeneity can be modulated to improve outcomes • High degree of heterogeneity in both pre-existing and acquired resistance to therapeutic agents • Rationally designed combination therapies applied at the right time OVERALL SUMMARY 38
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39 Mechanistic Rationale underpinning IDE161/Keytruda and IDE161/ADC Combination Opportunities Timothy Yap, MBBS, FRCP, PhD, BSc (Hons), PgDip (Onc) MD Anderson
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PARG Inhibition by IDE161: MOA-driven mono and combination therapy opportunities PARG Inhibition is synthetic-lethal with replication stress IDE161 disrupts DNA replication fork fidelity Oncogene-induced replication stress confers PARG dependency 0 10 20 30 40 50 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Niraparib 45 mg/kg QD IDE161 100 mg/kg QD Vehicle QD; po PARP1 initiates DDR PARG resolves DDR • Replication stress promotes replication fork reversal • PARG supports replication fork restart Monotherapy in biomarker-enriched indications KEYTRUDA combination in biomarker-enriched indications Broad TOP1i-ADC combination opportunity across solid tumors PARG inhibition promotes death by mitotic catastrophe 0 2 4 6 CldU ratio (long/short arm) ✱✱✱ IDE161 - + Biomarker positive 0.0 0.5 1.0 1.5 2.0 Fork progression (kb/min) ✱✱✱✱ IDE161 - + Biomarker positive Fork speed Fork asymmetry IdU CldU 30m 30m DMSO/IDE161 48h Symmetrical Asymmetrical DMSO IDE161 0 25 50 75 100 125% population 0-2 3-4 5-6 7-8 9-10 >10 PCNA-RNAPII PLA foci IDE161 (hrs) 0 Biomarker positive 24 DMSOIDE161 IDE161 induces fork progression defects Transcription Replication RNAPII PCNA MCM2- 7 PCNA IDE161 increases TRCs IDE161 induces accumulation of PARylated PARP1 and stabilizes PAR-RECQ1 complexes Input IP: PAR RECQ1 Biomarker positive Biomarker negative Biomarker negative Biomarker positive DAPI γ-H2AX IDE161 treated - -IDE161 0 0.12 0.37 0 0.12 0.37 0 5 10 15 20 IDE161 concentration (µM) PARylated PARP1 Fold Change compared to DMSO 48h PARylated PARP1 - -IDE161 Biomarker positive Biomarker negative IDE161 induces pan-nuclear DNA damage Adapted from Harrison D. et al. Frontiers 2020 Adapted from Pillay et al. Cancer Cell , 201940
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IFI35 IFIT1 IFI6 IFIT3 IFNAR2 TRIM21 ICAM1 TRIM14 CD44 OAS1 MX2 USP18 HLA-E HERC5 SP100 HLA-B 41 IDE161 activates tumor cell-selective host defense signalingType 1 IFN response is the dominant gene expression program activated by IDE161 in preclinical tumor models IDE161 activates the innate immune response (Type 1 IFN) in tumors Ovarian CDX Day 14 Gene sets : Enriched in IDE161 30 mg/kg Depleted in IDE161 30 mg/kg Gene set enrichment analysis Ingenuity Pathway Analysis 0 1 2 Log2FC Treated/Veh Ovarian CDX tumors day 14 IDE161 vs. vehicle E2F targets G2M checkpoint IFN alpha IFN gamma -2 NES Hallmark Pathways Breast CDX tumors day 28 IDE161 vs. vehicle IFN alpha IFN gamma MYC targets E2F targets 0 5 10 15 20 25[IFN-β] pg/mL -IDE161 - - - - - 24 72 120 24 72 120 Biomarker positive Biomarker negative hrs OAS2 IFIT3 MX1 IRF7 STAT1 ISG15 0 2 4 6 12 14 16 Representative IFN-response genes Fold change biomarker positive biomarker negative 24 72 120 hrs IDE161 induces IRF3/7/9 innate-immune pathway response IDE161 induces IFN-β production and secretion Strong IFN signature within global proteome response to IDE161 Enrichment strength Log2 FC IDE161 vs DMSO NES Hallmark Pathways IDE161 Dose IFIT1 IFI6 ISG15 MX1 IRF9 STAT2 OAS1 STAT1 HLA-B CALR PDIA3 CD274 MR1 HLA-DMA HLA-C HLA-A HLA-F Antigen Presentation 10.0 1.0 0.1 10.0 1.0 0.1FDR-log10 FDR-log10 IFN Signaling IFN pathway protein enrichment FDR-log10 0 2 -2 0 2 IFN signaling IFN α/β signaling Immune system IFN gamma signaling Cytokine signaling Adaptive Immune Innate Immune REACTOME pathway enrichment FDR-log10 IFIT2 OASL
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Viral mimicry 0 10 20 30 0 1000 2000 3000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle QD Isotype control 10mg/kg BIW Anti-PD1 (RMP1-14) 10mg/kg BIW IDE161 100mg/kg QD Anti-PD1 (RMP1-14) + IDE161 IDE161 can promote ICI-mediated anti-tumor activity DNA repair intermediates can provoke innate immune pathway activation leading to enhanced adaptive immunity Runaway replication stress can be immunogenic via viral mimicry Slightly modified from da Costa et al. Nature Reviews Drug discovery, 2022 6/10 regressions Anti-PD1 combination benefit associated with enhanced immune cell tumor infiltration T cell receptor sequencing of clinical PBMC specimens provides evidence of adaptive immune response following IDE161 monotherapy 0 10 20 30 0 1000 2000 3000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Day 15 Day 22 0 10 20 30 40 50 Study Day Number of expanded clones on treatment Healthy repertoire 0 10 20 30 40 50 Individual patients Number of expanded clones at study Day 22 Healthy repertoire Individual mice (combination arm) 42
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IDE161 Combination With Pembrolizumab IDE161 Monotherapy Escalation and Expansion NCT05787587 module 2: focus on endometrial cancer; FPI December 2024 Clinical Evaluation of IDE161 Monotherapy & Pembrolizumab Combination 43 dMMR = deficient mismatch repair; EC = endometrial cancer; HR = homologous recombination; HRD = homologous recombination deficiency; MSI-H = microsatellite instability high; MSS = microsatellite stable; MTD = maximum tolerated dose; pMMR = proficient mismatch repair; RDE = recommended dose for expansion
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Potential transformative IDE161 combination benefit with TOP1i-ADCs PARG is required to repair TOP1 cleavage complexes IDE161 impairs resolution of TOP1 cleavage complexes Dual inhibition of TOP1 and PARG induces unresolvable DNA-protein crosslinks (Sun et al, Nat Comms, 2021) Potential for IDE161 as backbone combination partner for TOP1i payload-based ADCs 0 5000 10000 15000 20000 25000ECL counts relative to DMSO ✱✱✱ ✱✱✱ ✱✱ CPT DMSO IDE161 +IDE161 CPT DMSO IDE161 CPT CPT + IDE161 0 25 50 75 100% Population 0-500 500-2000 2000-6000 >6000 γ-H2AX mean intensity Top1cc accumulation and associated DNA damage 0.0 0.5 1.0 1.5 2.0fork speed (kb/min) IDE161 CPT - - - + + + - - ✱ ✱✱✱✱ ✱✱✱✱ Enhanced PAR accumulation Replication fork impairment 0 2000 4000 6000 8000 10000 0 10 20 30 TOP1cc mean intensity (a.u.) Relative frequency (%) DMSO IDE161 CPT (TOP1i) CPT + IDE161 ✱✱✱✱ ✱✱✱✱ Kruskal-Wallis test CPT = camptothecin, a topoisomerase I inhibitor TOP1 cleavage complex (TOP1cc) 44
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IDE161/ADC (Enhertu) combination test-of-conceptUnresolvable TOP1 lesions lead to complete responses Robust test-of-concept supports multi-pronged development strategy ADC antigen becomes the predictive biomarker Topotecan/IDE161 combination benefit 10 20 30 40 50 0 1000 2000 3000 Days on treatment Mean Tumor Volume (mm3) + S.E.M. Vehicle PO, QD Topotecan 1 mg/kg IP, 3d on/4d off IDE161 100 mg/kg PO, QD Topotecan + IDE161 10 20 30 40 50 -10 -5 0 5 10 15 20 % Body weight change Vehicle, PO, QD Topotecan 1 mg/kg IP, 3d on/4d off IDE161 100 mg/kg PO, QD Topotecan + IDE161 0 10 20 30 40 50 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle QD IDE161 100 mg/kg PO, QD Enhertu 10 mg/kg IV, QDx1 Enhertu + IDE161 0 20 40 60 80 0 1000 2000 3000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle QD Enhertu 10 mg/kg IV, QDx1 IDE161 100 mg/kg PO, QD Enhertu + IDE161 Colorectal HER2 LowNSCLC HER2+ SCLC HER2 Low 10 20 30 40 50 -20 -15 -10 -5 0 5 10 15 20 Days on treatment % Body weight change Vehicle QD Enhertu 10 mg/kg IV, QDx1 Enhertu + IDE161 5 10 15 20 25 -20 -15 -10 -5 0 5 10 15 20 Days on treatment % Body weight change Vehicle, PO Enhertu 10 mg/kg IV, QDx1 IDE 161 100 mg/kg PO, QD Enhertu + IDE161 20 40 60 80 -20 -15 -10 -5 0 5 10 15 20 Days on treatment % Body weight change Vehicle QD Enhertu 10 mg/kg IV, QDx1 Enhertu + IDE161 IDE161 100 mg/kg PO, QD 0 5 10 15 20 25 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle QD IDE161 100 mg/kg PO, QD Enhertu + IDE161 Enhertu 10 mg/kg IV, QDx1 Fam-trastuzumab deruxtecan/IDE161 combination benefit Potential for IDE161 as backbone combination partner for TOP1i payload-based ADCs 45
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46 GSK Partnership IDE275/GSK959 (Phase 1) Werner Helicase Program Update Ramon Kemp, Ph.D. GSK Vice President Head, Oncology EDL
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47 WRN helicase activity is specifically essential for survival of MSI-high/dMMR cancer cells IDE275/GSK959 WRN helicase inhibitor for precision cancer therapy 0 10 20 30 40 50 0 500 1000 1500 2000 2500 Days of treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle PO, QD IDE275 PO, QD untreated treated Anti-tumor response is specific for MSI-H endonucleases Adapted from van Wietmarschen et al., Nature, Vol 586, 2020 AATATATATATATATAT AT AT AT AT AT AT AT AT TA AT AT AT AT AT AT AT AT ATATATATATATATATT AT AT AT AT AT AT AT AT AT AT ATATATATATATATATATATAT AT AT ATATAT A AT AT AT AT AT AT AT AT ATATATATATATATATT AATATATATATATATAT AT AT AT AT AT AT AT AT T WRN (TA)n repeat Expanded (TA)n repeat MMR Cruciform formation Intact Genome Chromosome Shattering ATR WRN Normal MSI-H WRNi WRN resolves TA repeat 2° structures to prevent catastrophic DNA fragmentation in MMR-deficient cells Replication slippage DS DNA breaks WRNi: tumor-intrinsic DNA damage WRN helicase domain (not exonuclease domain) most critical as therapeutic target MSI-H 0 5 10 15 20 25 0 500 1000 1500 2000 2500 Days of treatment Mean Tumor volume (mm3) Vehicle PO, QD IDE275 PO, QD MSS Days of treatmentDays of treatment Mean Tumor Volume (mm3) Mean Tumor Volume (mm3)
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48 Supports clinical strategy to expand beyond MSI-H colorectal cancers Endometrial PDX 0 20 40 60 80 0 500 1000 1500 2000 Days of treatment Tumor Volume (mm3) Vehicle PO, QD WRNi PO, QD 0 20 40 60 80 0 500 1000 1500 2000 Days of treatment Tumor Volume (mm3) Vehicle PO, QD WRNi PO, QD 0 20 40 60 80 0 200 400 600 800 Days of treatment Tumor Volume (mm3) Vehicle PO, QD Gastric CDX Colorectal PDX Robust anti-tumor activity observed across MSI-H tumor types and in heavily pre-treated tumors 10/10 CR 4/10 CR 2/10 CR 0 10 20 30 40 0 300 600 900 1200 Days of treatment Tumor Volume (mm3) Vehicle PO, QD WRNi PO, QD Endometrial CDX 10/10 CR 2/10 CR 0 10 20 30 0 500 1000 1500 2000 Days of treatment Tumor Volume (mm3) Vehicle PO, QD WRNi PO, QD Treatment-relapsed CRC PDX 48 yo male treated with: • 1L FOLFOX • 2L XELIRI + bevacizumab • 3L nivolumab
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49 Response to IDE275/GSK959 across a panel of MSI-H in vivo xenograft models IDE275/GSK959 delivers single-agent tumor regression in multiple in vivo models GA2140IM95CR2518RL952SW48GA6894 474377 126 UT3617 175126 011R GA6806 23499 124R GA6875OV0250 381249 077R GA2421CR2502GA6208GA6209CR2528B RKO UT5318CR1245CR5046SW620UT5320 -100 0 100 200 300 400 500 Max Tumor Volume Response (%) Endometrial Carcinoma MSSMSI-H PR Colorectal Carcinoma Gastric Carcinoma • Clear patient selection biomarker: dMMR / MSI-H with validated clinical assays • Response unrelated to p53, BRAF, or KRAS mutational status • (PDX and CDX)
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50 A Phase 1/2 FTiH, open-label, multicenter, dose escalation and expansion study of the oral DNA Helicase Werner Inhibitor (WRNi) GSK4418959 alone or in combination with other anti-cancer agents in adult participants with Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI-H) solid tumors (SYLVER) • ≥18 years old • >3 months life expectancy • dMMR/MSI-H tumor • Advanced (unresectable/metastatic or recurrent) • Must have exhausted SOC PART 1: Monotherapy Dose Escalation Monotherapy GSK4418959 IND Approved: October 2024 • ≥18 years old • >3 months life expectancy • dMMR/MSI-H tumor • Advanced (unresectable/metastatic or recurrent) • Must have exhausted SOC PART 3: Combination Dose Escalation Combination GSK4418959 + anti PD-1 PART 2: Monotherapy Dose Expansion NCT06710847 50
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51 IDEAYA 2024 Development Candidates IDE034 (B7H3/PTK7 bispecific ADC with TOP1i payload) IDE892 (PRMT5MTA inhibitor) IDE251 (Dual KAT6/KAT7 inhibitor) Michael White, Ph.D. IDEAYA Biosciences
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52 IDE034 (B7H3/PTK7 bispecific ADC) Development Candidate
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IDE034 bispecific ADC potentially maximizes IDE161 combination opportunity blank 53 IDE034 program: fully human B7H3/PTK7 with TOP1i payloadBi-specific ADCs can enhance tumor-specificity (at a cost) CONFIDENTIAL Optimal safety window through • Enhanced tumor versus normal cell binding • Enhanced internalization efficiency • Potential for antigen synergy Estimated tumor-associated antigen expression Indication B7H3/PTK7 Double Positive % Lung 29.8% Colorectal 45.9% HNSCC 27.1% Ovarian 23.1% -4 -3 -2 -1 0 1 0 200000 400000 600000 800000 1000000 NSCLC Concentration (Log10, μg/mL) MFI B7-H3 monoAb PTK7 monoAb IDE034 0 3 6 24 0 5000 10000 15000 20000 NSCLC Time (hours) MFI B7-H3 monovalent Ab PTK7 monovalent Ab IDE034 Enhanced double-positive binding Enhanced double-positive internalization Efficacy cost from potential reduced payload delivery (tumor heterogeneity) mitigated by IDE161 synergy Heterodimeric Fc modification
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54 CONFIDENTIAL PDX-2 (double positive) PDX-3 (low double positive) PDX-4 (single positive) Excellent IDE034 anti-tumor activity in double-positive PDX 0 10 20 30 40 50 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle, IV IDE034, IV 0 10 20 30 40 0 500 1000 1500 2000 2500 3000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle, IV IDE034, IV 0 10 20 30 40 50 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle, IV IDE034, IV 0 10 20 30 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle, IV IDE034, IV 0 50 100 150 200 250 300 0 50 100 150 200 250 300 B7H3 PTK7 H score H score H score 0 50 100 150 200 250 300 B7H3 PTK7 B7H3 PTK7 B7H3 PTK7 H score 0 50 100 150 200 250 300 H score H score H score H score 0 50 100 150 200 250 300 0 50 100 150 200 250 300 0 50 100 150 200 250 300 0 50 100 150 200 250 300 PDX-1 (double positive)
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55 IDE892 (PRMT5MTA inhibitor) Development Candidate
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56 9p21.3 focal deletions confer multiple targetable vulnerabilities HIT1 HIT2 HIT3 Monotherapy opportunities in subsets of MTAP-/- tumors Combination opportunities for deep and durable responses broadly across MTAP -/- indications Program 3 on track for potential 2025 DC Cell cycle checkpoint Methionine salvage mRNA surveillance IFN signaling Lineage specification Fatty acid synthesis Chromatin remodeling Mitotic spindle integrity Co-deletion frequency with CDKN2A Co-deletion frequency with MTAP Gene co-deletion frequency distributions in 9p21.3 across 10,712 tumor samples Percent co-deletion
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-12 -10 -8 -6 -4 0 50 100 Compound Log[M] BRET ratio Clinical cmp 2 Clinical cmp 1 IDE892 57 IDE892 is a potent and selective MTA-cooperative PRMT5 inhibitor MTA/PRMT5 active site conformation is key to unlock MTAP-/- tumor-specific PRMT5 inhibition 0 10 20 30 40 50 0 50 100 Time (h) PRMT5 occupancy (%) In vitro target binding (+MTA) Biochemical inhibition Cellular target occupancy MTAP-selective cell killing -10 -8 -6 -4 0 50 100 IDE892 Log[M] Cell viability (%) HCT116 WT HCT116 MTAP-/- Cellular pathway modulation -10 -8 -6 -4 0 50 100 IDE892 Log[M] PRMT5 activity (%) Off-rate driven super-cooperative ligand binding in presence of MTA Potent cellular target occupancy Deep PRMT5 pathway suppression in MTAP-/- Highly selective cellular responses across CCLE -12 -10 -8 -6 -4 0 50 100 IDE892 Log[M] Substrate modification (%) H4R3-SDMA Total SDMA SmB-SDMA NCI-H838 t1/2 - MTA : 23 min t1/2 + MTA: > 100 hours IC50 < 10 nM IC50s < 10 nM MTA accumulation drives selective biological response MTAP CDKN2A CDKN2B CDKN2B- AS1 MTAP CDKN2A CDKN2B WDR77 PRMT5 CLINS1A RIOK1 Correlation of Cell Features and IDE892 AUC across >800 cancer cell lines Expression CNV RNAi(Surface plasmon resonance) (NanoBRET probe displacement) MTA K333 F334 E435
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0 10 20 30 40 50 60 70 80 90 0 500 1000 1500 2000 Days of treatment Mean Tumor Volume (mm3) ± S.E.M. Monotherapy Combination IDE892 (D1-D73) IDE397 (D45-73) Vehicle Reversal of monotherapy resistance IDE397 IDE892 0 50 100 150 Total Tumor SDMA (H-Score) 58 IDE892/IDE397 anti-tumor response is robust, on-target, and well-tolerated 0 7 14 21 28 35 42 0 500 1000 1500 2000 Days of treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle IDE397 3 mg/kg QD IDE892 IDE397 3 mg/kg QD +IDE892 0 7 14 21 28 35 42 -20 -10 0 10 20 30 Days of treatment Body Weight (% change from baseline, Mean ± SEM) Body Weights 0 50 100 150 200 250 Free-SDMA in plasma (ng/mL) Tumor naive Vehicle BID IDE397 3 mg/kg QD + IDE892 Tumor versus plasma SDMA 10 of 10 complete regressions CRs in combination (NCI-H838) Excellent anti-tumor activity Pathway-sparing in normal tissue Favorable human dose prediction supporting QD oral dosing
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59 IDE251 (dual KAT6/KAT7 inhibitor) Development Candidate
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IDEAYA SL target nomination platform highlights epigenetic vulnerabilities 60 Intersection of lineage dependency and somatic structural variants Three distinct paralog families define lysine acetyltransferases (HAT) landscape KAT CBP/p300 GCN5/PCAF Garraway and Sellers, 2006 Nature Reviews Cancer Lineage dependency and lineage survival oncogenes in human cancer e.g.: ESR1 (mammary), AR (prostate), MITF (melanocytic), TITF1/NKX2-1 (lung), TCF7L2 (colon), ASCL1 (neuroendocrine) Modified from White et al. Trends in PS 2024 Majority of strong lineage survival oncogenes are transcription factors Epigenetic enzymes that control gene promoter accessibility offer a strategy to drug transcription factor activity in cancer KAT family has established POC and can be further developed in meaningful patient populations De novo discovery pipeline for “lineage dependency” targets returns many lineage-specific transcription factors *HistoneDB 2.0 * Lineage addiction SL pipeline DelAmp Breast Lung Breast LungFG/GE FG/CNA FG/GE FG/CNA Chr 8KAT6A/8p11 CNV SL pipeline
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Potential for durable monotherapy with dual KAT6/7 inhibition 61 Maximize SL with 8p11 amplification and broaden opportunity to drug “lineage-addiction” Convergent transcriptional response to KAT6 vs KAT7 depletion Dual inhibitor design challenge KAT7 pocket (270 Å3) KAT6 pocket (614 Å3) Residue differences Substantial difference in binding site volume and residue identity BRPF1 BRPF2 BRPF1/2 -1.5 -1.0 -0.5 0.0 0.5 Dependency score Lineage-selective KAT6A/KAT7co- dependency KAT6i/KAT7i synergyShared binding partners and substrate sites reflect an intertwined MOA* FOXA2 NKX2.1 SOX2 Correlation Rank PGR SSTR2 ESR1 Pearson r Correlation Rank Pearson r BRPF1/2 Paralog relationshipLung Gene expression vs BRPF1 dependency Breast Gene expression vs BRPF1 dependency KAT6/7 shared scaffold dependencies associate with linage-specific transcription factors HSA model (cell viability) KAT5 KAT7 KAT8 AML Breast/Ovary Skin Pancreas n=30 n=126 n=74 Co-dependency p-val 0.9 0.005 n=67 Indication A Indication B Indication C Indication D HSA score0 20 40 Precision modulation of open chromatin in cancer KAT6i POC in 8p11/ER+ mBC HCC1428 – siKAT6A vs siKAT7 T47D – siKAT6A vs siKAT7 siKAT6A: T-statistic siKAT7: T-statistic siKAT6A: T-statistic siKAT7: T-statistic KAT6/KAT family DepMap CRISPR co- dependency analysis *Lalonde et al. Genes & Dev. 2013: Sheikh et al. Oncogene 2015; You et al. JCI 2016; Klein et al. Nat. Comm. 2019; MacPherson et al. Nature 2020; Wang et al. Science Trans. Med. 2021; Yan et al. Cancer Discovery. 2022; Kueh et al. Cell Reports 2023; Sharma et al. Cell Chem. Biol. 2023
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62 IDE251 is an equipotent KAT6/7 inhibitor with high selectivity vs KAT family Dual KAT6/7 inhibition deepens cellular response ATAC-seq DARs: 10-4 10-2 100 0 50 100 150 Concentration, μM FP response (%) KAT5 KAT6 KAT7 KAT8 KAT6/7 IC50s: < 1 nM IDE251 KAT family occupancy (NanoBRET) 10-4 10-2 100 0 50 100 Concentration, μM BRET ratio KAT5 KAT6 KAT7 KAT8 KAT6/7 IC50s: < 10 nM IDE251 KAT-family binding (Biophysical FP) Wide biochemical selectivity window Strong and selective cellular target binding 10-10 10-8 10-6 0 50 100 150 Concentration, log[M] % inhibition IC80 H3K23ac H3K14ac IDE251 on-target Kac modulation ER+ breast model IDE251DMSO TSS: transcriptional start site Robust chromatin modulation in gene promoter regions (ATAC-seq) Potent dual target inhibition and effective modulation of chromatin architecture Global expression response reflects coordinated KAT6/7 biology -40 -20 0 20 40 5 10 15 IDE251 DE t-stat -log (adj. p-val) Downregulated Upregulated q < 0.05 ESR1 IRX5 LGR4 FGFR1 WNT3A GATA3 CDKN2BATF5 BRPF3 DMSOKAT6iKAT7iIDE251 0 10 20 30 40% of cell population Senescence Apoptosis Sens/Apop Apoptotic response is enriched vs senescence in ER+ mBC IDE251 KAT6i CAMA1, 72h CAMA1, 6-72h time course, RNA-seq CAMA1 IDE251: T-statistic Linear regressionLoess regression Greater effect sizes with dual inhibition KAT6i: T-statistic Strong perturbation of luminal mBC expression program ~3000 WNT3A CD44 DMSO IDE251 DMSO IDE251
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63 Robust regressions observed in benchmark ER+ mBC CDX and PDX models 0 10 20 30 40 50 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle QD IDE251 low dose (0.1 X) QD IDE251 QD 0 50 100 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle QD IDE251 QD Clinical KAT6i (CRD) Drug off day 69 PDXST941 (HR+ mBC, 8p11 CN amp, ESR1 Y537S) CAMA1 (HR+ mBC, 8p11 CN amp) Vehicle0.1X QD0.3X QD1.0X QD CRD ~10X CRD 0 50 100 150% H3K14ac IDE251 KAT6i Vehicle0.1X QD0.3X QD 1.0X QD CRD ~10X CRD 0 50 100 150% H3K23ac IDE251 KAT6i Strong modulation of tumor H3K23ac and H3K14ac (day 3, CAMA1) Vehicle KAT6i IDE251 0.1X 0.3X 1.0X CAMA1 tumor samples Compelling monotherapy efficacy in aggressive preclinical models IDE251 demonstrates enhanced suppression of lineage survival genes relative to clinical KAT6i Representative leading-edge genes: PGR, GATA3, CCND1, IGFBP5, SOX9, AR, WNT3, WNT4, LRP5, AKT1, NCOR2 GOBP_MAMMARY_GLAND_DEVELOPMENT IDE251 vs. KAT6i Enrichment score(ES) Gene ranks NES=-1.85 P-value=0.0 FDR=0.03 Gene modulation in tumors is consistent with enhanced chromatin control by dual KAT6/7i Significantly downregulated genes on therapy (day 3) Significantly upregulated genes on therapy (day 3)
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0.1 1 10 100 100010000 0 50 100 150 Compound, nM % relative survival 0.1 1 10 100 100010000 0 50 100 150 Compound, nM % relative survival 0.1 1 10 100 100010000 0 50 100 150 Compound, nM % relative survival 64 Prostate & Testis Cervix Soft tissueHead & Neck SkinLung Eso/gastric Liver BladderThyroidPancreas OvaryBoneColonKidneyBreastUterus 0.2 0.4 0.6 0.8 1.0 1.2AUC IDE251 pan-cancer cell viability profile (5-day assay) Indications Pan-cancer profiling delivers expected and novel responder hypotheses 0 20 40 60 80 0 500 1000 1500 2000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle QD IDE251 QD 0 10 20 30 40 50 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle QD IDE251 QD KAT6i CRD NSCLC 8p11 CN amp Ovarian SOX17 high UXS1 CDKN2A EHMT2 KEAP1 TSC1 JADE1 Synthetic lethality rank T-statistic FDR < 0.10 Sens FDR < 0.10 Res -10 -5 0 5 10 15 MYC_targets E2F_targets Estrogen_Response PI3K_AKT_MTOR Signaling IC50 vs expression GSEA; Breast mBC CDK4/6i resistance PIK3CAmut KAT6i KAT6/7i IDE251 sensitizer screen NSCLC MEN1 UXS1 ING5 KAT7 GSK3B SPDEF AZIN1 Synthetic lethality rank T-statistic FDR < 0.10 Sens FDR < 0.10 Res -20 -10 0 10 20 IDE251 sensitizer screen mBC Lung 8p11 CN amp KAT6i KAT7i IDE251 Gastric TCF7L2 high KAT6i KAT7i IDE251 IC50 vs copy-number amp 8p11amp; multiple indications Lineage survival TFs; multiple indications HR+ mBC; CDK4/6i intrinsic and acquired resistance mBC CDK4/6i resistance ESR1mut 0.01 0.1 1 10 100 100010000 0 50 100 150 Compound, nM % relative survival KAT6i IDE251
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65 IDEAYA Investor R&D Day Closing Remarks, Preliminary 2025 Guidance, and Analyst Q&A Yujiro S. Hata IDEAYA Biosciences President and Chief Executive Officer
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AI ML 66 IND engine: deep knowledge of target biology, drug MOA, and disease characteristics Internal capabilities support innovation across biological length scales Protein/ligand interactions IDEAYA Vision & Strategy: World Class R&D and Drug Discover Enterprise Building Global Leader in Precision Medicine Oncology PIPELINE: 5 Clinical, 3 DCs, >3 Pre-Clinical • Ph3 – Darovasertib/PKC (potential 1st-in-class) • Ph2 – IDE397/MAT2A (potential 1st-in-class) • Ph1 – IDE161/PARG (potential 1st-in-class) • Ph1 – IDE705/Pol Theta (potential 1st-in-class) • Ph1 – IDE275/Werner (potential 1st-in-class) • DC – IDE034/B7H3-PTK7 ADC (potential 1st-in-class) • DC – IDE892/PRMT5 (potential best-in-class) • DC – IDE251/KAT6-7 (potential 1st-in-class) • PC – >3 potential 1st-in-class programs advancing COMBOS: Addressing Tumor Heterogeneity • PKC/cMET, GNAQ/11 (potential 1st-in-class), Pfizer • MAT2A/PRMT5, MTAP (potential 1st-in-class), Amgen • MAT2A/Topo-ADC, MTAP (potential 1st-in-class), Gilead • Pol Theta/PARP , HRD (potential 1st-in-class), GSK • Werner/PD1, MSI-High (potential 1st-in-class), GSK • PARG/PD1, MSI-High/MSS (potential 1st-in-class), Merck • PARG/Topo-ADC, Antigen (potential 1st-in-class) Tumor evolutionPatient populations Cell regulation
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• Darovasertib 2025 guidance will be provided at JPM 2025, based on enrollment and data maturity: Phase 2 Neoadjuvant UM clinical efficacy and safety data update (>75 patients from company-sponsored study) Phase 2 1L MUM median OS (~38 1L MUM patients) Registrational trial median PFS readout for potential accelerated approval in 1L HLA-A2-negative MUM • Targeting Ph1/2 IDE397 + Trodelvy combo clinical data update (efficacy and safety) in MTAP-deletion UC in 2025; multiple RECIST 1.1 responses observed in dose escalation • Targeting Ph1 IDE275 / GSK959 Werner Helicase presentation at medical conference with GSK in H1 2025, including potential best-in-class differentiation profile • ~$1.2 billion of cash with runway to at least 2028; ~$2 billion in potential GSK milestone payments* • 3 IND-filings targeted in 2025 to deliver 8 clinical programs, and to enable multiple wholly-owned combinations across pipeline in priority solid tumor-types: IDE892/PRMT5 (mid-2025); enable IDE397/MAT2A clinical combo in MTAP-deletion NSCLC IDE032/B7H3-PTK7 Bispecific Topo-payload ADC (H2 2025); enable IDE161/PARG clinical combo in lung & CRC IDE251/KAT6-7 (H2 2025); enable multiple potential combos across pipeline in lung and breast cancer 67 IDEAYA Investor R&D Day Preliminary 2025 Guidance and Analyst Q&A * Includes aggregate of $1.2 billion of cash, cash equivalents and marketable securities as of September 30, 2024 67