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NASDAQ: IDYA IDEAYA Biosciences NASDAQ: IDYA Improving Lives Through Transformative Precision Medicines IDEAYA 10-Year Anniversary Investor R&D Day September 8, 2025
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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 fro m 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 expect ations 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 timin g of preclinical research, clinical development, regulatory filings, manufacturing or release of data, including commercial readiness; any statements of expectat ion 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 substantial risks and uncertainties, many of which are beyond the Company's control that could cause the Company’s preclinical and clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the drug development process, including the Comp any’s programs’ 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, the Company’s ability to successfully establish, protect and defend its intellec tual 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 express ed 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, 2024, 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 fo r 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. 2 Safe Harbor Statement
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3 IDEAYA 10-Year Anniversary Investor R&D Day Welcome and Introduction Yujiro S. Hata IDEAYA Biosciences President and Chief Executive Officer
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4 IDEAYA 10-Year Anniversary Investor R&D Day Welcome to our Speakers and Participants Yujiro S. Hata CEO, IDEAYA Arun Singh, MD Director of Ophthalmic Oncology, Cleveland Clinic Darrin Beaupre, MD, PhD CMO, IDEAYA Mike White, PhD CSO, IDEAYA Jasgit Sachdev, MD SVP Clinical, IDEAYA
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IDEAYA 10-Year Anniversary Investor R&D Day Agenda 10-Year Anniversary & R&D Day Introduction Yujiro Hata, CEO 15 mins Darovasertib Ph2 Neoadjuvant UM PB Update Arun Singh, Cleveland Clinic; Darrin Beaupre, CMO 30 mins IDE849/DLL3 WCLC 2025 Ph1 Clinical Data Update Darrin Beaupre, CMO 20 mins TOP1 ADC + IDE161/PARG Combo WCLC 2025 Michael White, CSO 5 mins IDE397 + Trodelvy Combo Rationale in MTAP Michael White, CSO 10 mins IDE397 + Trodelvy Ph1 Clinical Data Update in MTAP Jasgit Sachdev, SVP Clinical Development 20 mins IDE892 a Potential Best-in-Class PRMT5 Inhibitor Mike White, CSO 5 mins AI/ML Drug Discovery Capabilities & Case Studies Mike White, CSO 15 mins Conclusion and Analyst Q&A IDEAYA Management 30 mins 150 Minutes: 120 Minutes Presentation & 30 Minutes Analyst Q&A 5
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IDEAYA Visionto Build Industry Leading Precision Medicine Oncology Company 6 Improving Lives through Transformative Precision Medicines, The First Decade SM = Small Molecule; ADC = Antibody Drug Conjugate; POLQ = Pol Theta; WRN = Werner Helicase; HRD = Homologous Recombination Deficiency; MSI = Microsatellite Instability; TOP1 = DNA Topoisomerase 1 Our mission is to advance the discovery, development, and commercialization of transformative precision medicines to address unmet medical needs in cancer Potential First-in-Class Pipeline 7 Clinical / IND Stage (6 SM & 1 ADC) 2 IND-Enabling (1 SM & 1 ADC) Biomarker Populations GNAQ/GNA11 MTAP-Deletion HRD/BRCA MSI-High Potential First-in-Class Combos PKC-cMET MAT2A-PRMT5 POLQ-PARP Structural Biology First-in- Class Predictive Biomarkers AI / ML Informatics Neoadjuvant- Adjuvant Transformative Combinations IDEAYA Vision DLL3 B7H3/PTK7 8P11 WRN-PD1 PARG-TOP1 MAT2A-TOP1
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Technological Breakthroughs in Oncology 7 IDEAYA Strategic Vision, The Next Decade 7 Golden Age of Cancer Biology Transformation of Life Sciences through AI Intersection of Therapeutics & Diagnostics (Neo)adjuvant therapies have potential to improve cancer survival Precision medicines Breakthroughs at the intersection of IT & life sciences Accelerated R&D productivity through AI First-in-class targets and unlocking the undruggable Molecular drivers of cancer to identify transformative combos
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8 AA = Accelerated Approval; SOC = Standard of Care IDEAYA Biosciences, The Next Decade Darovasertib & Commercial Readiness to Deliver Potential SOC in Uveal Melanoma Metastatic Uveal Melanoma 1L HLA-A201-negative AA topline results by YE2025 to Q1’26 Neoadjuvant Uveal Melanoma Ph3 Registrational trial initiated. US FDA Breakthrough Therapy Designation Adjuvant Uveal Melanoma Targeting Ph3 registrational trial initiation in 2026
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9 IDEAYA Biosciences, The Next Decade Next Strategic Growth Drivers to Build the Global Leader in Precision Oncology 9 AI = Artificial Intelligence Near Term (2-Years) Medium to Long Term (+2-Years) TOP1 ADC + DDR SM Combos MTAP Pioneer Early-Stage Disease First-in-Class AI Drug Discovery IDE849 DLL3 ADC IDE397/MAT2A Darova Neoadjuvant UM IDE574/KAT6-7 IDE034 B7H3/PTK7 Bispecific ADC IDE892/PRMT5 Darova Adjuvant UM MTAP Program 3 IDE161/PARG MTAP Program 3 Multiple (Neo)adjuvant Clinical Opportunities Multiple First-in-Class Programs
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10 IDEAYA Biosciences, The Next Decade Target ADC Monotherapy AA Paths & Rational Combos to Transform 1L/2L Settings 10 DDR = DNA Damage Repair; SM = Small Molecule; SOC = Standard of Care; 1L = First-Line; 2L = Second Line; AA = Accelerated Approval PD1/PDL1 IO Bispecifics IDE161/PARG Multiple DDR Programs ADC + IO SOC Combos to Pursue Earlier Stage Disease ADC + DDR SM Combos to Potentially Enhance Durability IDE849/DLL3 ADC in SCLC IDE034 B7H3/PTK7 Bispecific ADC Target ADC Monotherapy Accelerated Approval Paths in Later-Stage Settings 01 02 03
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11 IDEAYA Biosciences, The Next Decade 3-Pronged Combination Strategy to Establish Industry Leading MTAP Franchise 11 DDR = DNA Damage Repair IDE397/MAT2A Topoisomerase (Trop2 TOP1 ADC) Folate Target Multiple Nodes in MTAP Pathway to Address Resistance/Bypass IDE397/MAT2A IDE892/PRMT5 MTAP Co-Alterations CDKN2A RAS EGFR Leverage DDR Mechanisms in MTAP MTAP Program 3 Target IND 2026
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12 IDEAYA Biosciences, The Next Decade Our Differentiation is at Intersection of 1st-in-Class Biology, AI Drug Discovery, & SBDD 12 Potential First-in-Class Targets & Product Profiles: WRN POLQ PARG MAT2A KAT6/7 MTAP Program 3 Novel Target 1 Novel Target 2 AI Enabled Drug Discovery: IDE574/KAT6/7 MTAP Program 3 Novel Target 1 Novel Target 2 AI = Artificial Intelligence First-in-Class Cancer Biology AI Enabled Drug Discovery Structure Based Drug Design
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13 Darovasertib Neoadjuvant UM Plaque Brachytherapy Phase 2 Clinical Data Update Arun Singh, MD, Cleveland Clinic Darrin Beaupre, MD, PhD IDEAYA Biosciences Chief Medical Officer
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14 Uveal Melanoma Patient Journey Presentation to Metastasis Presentation Testing, Diagnosis, & Staging Primary UM Treatment Metastatic UM Treatment Uveal Melanoma is Treated by Specialists Across the Disease Spectrum • Metastatic surveillance by medical oncologists vs. ocular oncologists • Patients treated almost exclusively in academic setting EU Differences General Ophthalmologist Suspicion of UM Other Supporting Specialties • Radiologist / Pathologist: Interprets imaging and biopsies • IR*: Administers liver-directed therapy • NPs / PAs: Handle day-to-day patient management • Specialist: Continues to monitor for local recurrence *IR = Interventional Radiologist Sources: UptoDate; Blue Matter Market Research Ocular Oncologist or Retinal Specialist Clinical diagnosis and treatment Medical Oncologist Typically a melanoma specialist, responsible for metastatic treatment Radiation Oncologist Plaque Brachytherapy / other forms of Radiotherapy Progress to metastasis Medical Oncologist Manages surveillance Ocular Oncologist Enucleation and Plaque Brachytherapy procedures
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15 Uveal Melanoma Patient Journey Plaque Brachytherapy and Enucleation are the Most Common Treatments UM Treatment Paradigm Asymptomatic small tumors Symptomatic Tumors (~90%) Observation for evidence of growth Radiation Therapy (RT) • Plaque brachytherapy • Charged-particle • Photon stereotactic Surgery • Enucleation • Local tumor resection Long-term surveillance for local & metastatic recurrence Treatment Insights • Ocular Oncologist typically manage treatment decisions for primary UM, and involve radiation oncologists • Plaque brachytherapy is the preferred therapy for Medium sized UM • Enucleation is reserved for larger tumors (~20%) • Primary UM treatment is a “surgical” space, with no FDA approved (neo)adjuvant systemic therapies • Metastatic progression is common (~50% of patients), necessitating long-term surveillance • Responsibility for metastatic surveillance varies by practice; ophthalmologists often lead, though high-risk cases are referred to medical oncologists Progression to Metastatic Disease (~50% of Patients) Ophtha Sub-Specialist and/or MedOnc Ophthalmologist Sub-Specialist Primary decision-maker responsible for overall patient management and care Specialist consulted for treatment planning and delivery Sources: UptoDate; Blue Matter Market Research; AJCC Classification Uveal Melanoma, Shields, et al Rad Onc Standard of Care
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OptimUM-09: Ph2 Global Study in Primary Uveal Melanoma (UM) 16 Darovasertib as Neoadjuvant Therapy followed by Adjuvant Therapy ^ Enucleation Cohort (n~60[1]) Plaque Brachytherapy Cohort (n ~60[1]) Adjuvant Therapy[2] + Follow-Up Adjuvant Therapy[2] + Follow-Up Primary Local Therapy Treatment to Maximum Benefit up to 12[1] Months Treatment up to 6 Months Primary Endpoints • Safety • Cohort 1: Eye Preservation • Cohort 2: Decrease in Radiation Dose Secondary Endpoints • Useful Vision (1 yr) • Relapse Free Survival • Local (1 yr) • Distant (3 yr) Neoadjuvant Adjuvant Neoadjuvant Proof of Concept Adjuvant Proof of Concept ^ Clinicaltrials.gov: NCT05907954 [1] Planned sample size and treatment duration [2], adjuvant therapy allowed up to 6 months for patients who derived benefit from neoadjuvant darovasertib. Focus of today’s discussion is safety (n=39) and efficacy (n=21) evaluable subjects from PB cohort
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17 Treatment Related Adverse Events by Grade (n=39) Incidence >10% (n=39)Plaque Brachytherapy Cohort (n=39) • Subject discontinuation rate due to TRAEs = 4/39 (10.3%) • Dose reductions due to AEs (15.4%) • Treatment Related Serious Adverse Events = 1/39 (2.6%) Darovasertib is Well Tolerated in the Neoadjuvant Setting; Majority of TRAEs are Grade 1 & 2 OptimUM-09: Darovasertib Plaque Brachytherapy (PB) Cohort Safety Profile IDEAYA Data as of 23May2025 (based on preliminary analysis of unlocked database). TRAE = Treatment Related Adverse Event Grade 1 n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All Grades n (%) Number Of Subjects With Any Event 17 ( 43.6%) 15 ( 38.5%) 3 ( 7.7%) 1 ( 2.6%) 0 ( 0.0%) 36 ( 92.3%) Diarrhoea 21 ( 53.8%) 7 ( 17.9%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 28 ( 71.8%) Nausea 20 ( 51.3%) 2 ( 5.1%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 22 ( 56.4%) Fatigue 14 ( 35.9%) 2 ( 5.1%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 16 ( 41.0%) Vomiting 7 ( 17.9%) 1 ( 2.6%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 8 ( 20.5%) Rash Maculo-Papular 6 ( 15.4%) 1 ( 2.6%) 1 ( 2.6%) 0 ( 0.0%) 0 ( 0.0%) 8 ( 20.5%) Hypotension 1 ( 2.6%) 4 ( 10.3%) 1 ( 2.6%) 1 ( 2.6%) 0 ( 0.0%) 7 ( 17.9%) Dizziness 6 ( 15.4%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 6 ( 15.4%) Oedema Peripheral 5 ( 12.8%) 1 ( 2.6%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 6 ( 15.4%) Dermatitis Acneiform 6 ( 15.4%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 6 ( 15.4%) Alanine Aminotransferase Increased 3 ( 7.7%) 0 ( 0.0%) 2 ( 5.1%) 0 ( 0.0%) 0 ( 0.0%) 5 ( 12.8%) Aspartate Aminotransferase Increased 3 ( 7.7%) 0 ( 0.0%) 2 ( 5.1%) 0 ( 0.0%) 0 ( 0.0%) 5 ( 12.8%)
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Baseline Characteristics & ORR Definition 18 • Baseline Characteristics & ORR Definition • Median age 56 years (32-85 years) • Median apical height 7 mm (3-14 mm) • Median largest basal diameter 14 mm (7-21 mm) • Response criteria, >20% tumor shrinkage required for partial response, based on endpoint definition utilized for OptimUM-10 study** Reduction of Tumor Size By Product of Diameters in Efficacy Evaluable Subjects * (n=21) Plaque Brachytherapy Cohort (N=21) OptimUM-09: Ocular Tumor Reduction as Assessed by Product of Diameters * ≥ 3 cycles of darovasertib, baseline and on-treatment assessments, paired dosimetry and visual acuity score, includes subjects who discontinued due to disease progression or adverse events; ** If the longest basal diameter is not measurable, ORR will be based on Apical Height only; IDEAYA Data as of 22May2025 (based on preliminary analysis of unlocked database). 76% ORR (% of Subjects with >20% Ocular Tumor Shrinkage) Best % Change From Baseline 76% ORR (% of Subjects With >20% Ocular Tumor Shrinkage)
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19 Resolution of tumor associated retinal detachment following 12 cycles of neoadjuvant darovasertib• 62-years old male with UM involving right eye • Baseline: 6.2 mm apical height and 13.1 mm LBD • Post-darova: 2.3 mm apical height and 10.2 mm LBD • 71% reduction in product diameters (81.2 mm2 to 23.5 mm2) Tumor shrinkage with Darovasertib treatment leading to reduction in radiation dose and vision improvement International Society of Ocular Oncology (ISOO) 2025 Case Presentation Baseline End of Treatment Retinal detachment Resolution of retinal detachment • Predicted radiation dose 45 Gy to the optic disc and 83 Gy to the fovea • Delivered doses after darovasertib 34 Gy to the optic disc and 71 Gy to the fovea • 24% and 14% reduction in radiation doses to the optic disc and fovea, respectively. • On-treatment visual acuity improved from 20/25 to 20/12 accompanied by resolution of retinal detachment. • 3-year risk of ≤ 20/200 vision reduced from 59% to 41% Data presented at ISOO Meeting on 26Jul2025 and received best presentation award
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20 Subject Demonstrating Tumor Shrinkage After 10 Cycles of Neoadjuvant Darovasertib• 56-year old female • Baseline tumor size: Apical height= 4.9 mm, LBD= 14.7 mm who experienced a best response (by product of diameters) of -77% on neoadjuvant treatment • Radiation Dose reduction from baseline was -35% to Optic Disc and -40% to Fovea • With tumor shrinkage: • Distance of tumor to Optic Nerve increased from 11.5 mm to 13.2 mm (15% change from baseline) • Distance of tumor to fovea increased from 11 mm to 12.1 mm (10.2% change from baseline) • 3-year risk of <20/200 vision reduced from 36% to 13% after 3 cycles of darovasertib treatment Flattening of lesion after 10 Cycles of therapy Case Study 2: Neoadjuvant Darovasertib for UM Patient requiring Plague Brachytherapy Baseline End of Neoadjuvant Treatment 77% Reduction in Tumor Product of Diameters
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21 Vision Prognostication Tool in UM ^Eye Physics Software: PB Radiation Dose Prediction in UM Uveal Melanoma Plaque Brachytherapy Patients Predicted PB Radiation Dose and Vision Prognostication Software Tools Patient-specific risk can be calculated from 5 baseline variables prior to plaque brachytherapy to predict 3-year vision loss: 1) Age 2) Largest Basal Diameter 3) Dose to Fovea ^ Aziz et al; JAMAOphthalmol.2016;134(6):615-620; BCVA = Best Corrected Visual Acuity; VA = Visual Acuity Reduction of tumor size results in simulated XRT dose reduction End of Treatment Plaque Baseline Plaque Baseline modeling of plaque size and placement • Plaque placement and radiation dose to be delivered are planned by central review using Eye Physics software • Baseline and post treatment simulations are used to determine pre/post radiation dose using Eye Physics software Eye Physics Software Nomogram for Prediction of Visual Acuity better than or equal to 20/200 at 1 and 3 years 4) Dose to Optic Disc 5) Initial BCVA of 20/50 or worse
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OptimUM-10: Darovasertib Phase 3 Neoadjuvant Registrational Trial Design in Primary UM 22 Plaque Brachytherapy Cohort (n=400)* Enucleation Cohort (n=120) Follow-Up Follow-Up 1° Local Therapy (eg, enucleation, plaque) Primary Endpoints • PB Cohort: Vision Preservation (Proportion with BCVA ≥ 15 letters loss) • EN Cohort: Eye Preservation Rate Secondary Endpoints Darovasertib Neoadjuvant therapy versus immediate local therapy UM = Uveal Melanoma, PB = Plaque Brachytherapy, EN = Enucleation, BCVA = Best Corrected Visual Acuity, VA = Visual Acuity, ORR = Overall Response Rate 2:1 randomization PB Cohort: • Proportion with clinically significant macular edema • Proportion with VA 20/200 or worse • Radiation reduction PB & EN Cohorts: • ORR (>20% ocular tumor shrinkage by product of diameters) • No detriment to Event Free Survival (EFS) Population: Subjects With High Risk of Metastasis *Subjects with Moderate to High Risk of Visual Impairment 2:1 randomization OptimUM-10 Phase 3 Endpoints
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23 Tumor Shrinkage/Radiation Reduction Predicted to Improve Vision per OptimUM-09 Projected Radiation Reduction to Key Eye Structures (n=21) Tumor Shrinkage AND Radiation Reduction (n=21) OptimUM-10: Darovasertib Phase 3 Neoadjuvant Registrational Trial Data Supporting Primary Endpoint Primary Endpoints PB Cohort: Vision Preservation (Proportion with BCVA ≥ 15 letters loss) EN Cohort: Eye Preservation Rate Secondary Endpoints UM = Uveal Melanoma, BCVA = Best Corrected Visual Acuity, VA = Visual Acuity, RT = Radiation Therapy, ORR = Overall Response Rate PB Cohort: • Proportion with clinically significant macular edema • Proportion with VA 20/200 or worse • Radiation reduction PB & EN Cohorts: • ORR (>20% ocular tumor shrinkage by product of diameters) • No detriment to Event Free Survival (EFS) Goal with Neoadjuvant Tx: To reduce the loss of 3 lines of vision (15 letters, ETDRS) in treatment arm vs control arm in >20% of subjects Eye Structure Subjects with Any Dose Reduction Subjects with at least 20% Reduction Fovea 17/21 (81%) 7/21 (33%) Optic Disc 15/21 (71%) 8/21 (38%) Lens 16/21 (76%) 8/21 (38%) A 20% reduction in apex RT dose is known to correlate with improved visual outcomes* ≥20% Tumor Shrinkage Among All Subjects Reduction of Simulated Radiation Dose to Optic Disc/Nerve and/or Fovea Following Neoadjuvant Darovasertib in Subjects with Paired Dosimetry Product of diameters 16/21 (76%) Any reduction 18/21 (86% ) Apical height 13/21 (62%) ≥20% reduction to 1 or more structures 10/21 (48%) OptimUM-10 Ph3 Endpoints *Perez et al, Int J Radiat Oncol Biol Phys. 89(1):127-136, 2014; Kheir et al, Adv Radiat Oncol. 7(100869), 2022; Saconn et al, Int J Radiat Oncol Biol Phys. 78(3):844-848, 2010; Puusaari et al, Invest Ophthalmol Vis Sci. 45(10):3425-3434, 2004
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OptimUM-10: Darovasertib Phase 3 Neoadjuvant Registrational Trial Data Supporting Primary Endpoint 61% Eye Preservation Rate with Darovasertib Neoadjuvant Therapy from 2 separate multi-center trials: OptimUM-09 and Ph 2 IST 24 Primary Endpoints • Cohort 1: Vision Preservation (Proportion with BCVA ≥ 15 letters loss) • Cohort 2: Eye Preservation Rate Secondary Endpoints • Cohort 1: Proportion with clinically significant macular edema; Proportion with VA 20/200 or worse; Radiation reduction • Cohorts 1 & 2: ORR (>20% ocular tumor shrinkage by product of diameters); No detriment to Event Free Survival (EFS) Goal for Regulatory Success: Eye Preservation Rate Excluding a Lower CI Bound of 10% OptimUM-10 Ph3 Endpoints IDEAYA Data: Enrollment cut-off date of 13May24, and results as of 15Aug2024 (based on preliminary analysis of unlocked database for Phase 2 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 lower probability of severe vision loss from darovasertib treatment in UM; IST = Investigator Sponsored Trial; UM = Uveal Melanoma, BCVA = Best Corrected Visual Acuity, ORR = Overall Response Rate; CI = Confidence Interval *
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OptimUM-10: Darovasertib Phase 3 Neoadjuvant Registrational Trial Data Supporting Secondary Endpoints 25 Primary Endpoints • Cohort 1: Vision Preservation (Proportion with BCVA ≥ 15 letters loss) • Cohort 2: Eye Preservation Rate Secondary Endpoints UM = Uveal Melanoma, BCVA = Best Corrected Visual Acuity, ORR = Overall Response Rate, ME = Macular Edema; PB = Plaque Brachytherapy; XRT = Radiation Therapy *Aziz; JAMA Ophthalmol. 2016;134(6):615-620. doi:10.1001/jamaophthalmol.2016.0104 • Cohort 1: Proportion with clinically significant macular edema; Proportion with VA 20/200 or worse; Radiation reduction • Cohorts 1 & 2: ORR (>20% ocular tumor shrinkage by product of diameters); No detriment to Event Free Survival (EFS) • The most common cause of vision loss post PB is macular edema secondary to radiation therapy • Vision prognostic tool predicts 20/200 vision or worse (legal blindness)* Reduction in Predicted Risk of Severe Vision Loss at 3 years Following PB (Visual Acuity 20/200 or Worse) in Subjects with Paired Dosimetry [n/N (%)] Any reduction in risk 14/21 (66.7%) Subjects with ≥20% reduction in risk 8/21 (38.1%) Visual improvement observed during Darovasertib neoadjuvant UM therapy has potential to lower risk for legal blindness post PB Darovasertib can impact 4 of the 5 predictive factors for severe vision loss: • Baseline Vision • Dose to Fovea • Dose to Optic Disc • Tumor basal diameter Tumor Shrinkage/Radiation Reduction predicted to reduce ME & legal blindness per OptimUM-09 OptimUM-10 Ph3 Endpoints
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26 OptimUM-09: Vision Improvement Observed in Subset of UM Patients during Darovasertib Neoadjuvant Treatment Baseline: • 6.2 mm (Height) • 13.1 mm (Longest Basal Diameter) Post Therapy: • 2.3 mm (-63% Height) • 10.2 mm (-22% Longest Basal Diameter) PB= Plaque Brachytherapy; AP= Apical Height/Thickness, LBD= Longest Basal Diamter; *Aziz; JAMA Ophthalmol. 2016;134(6):615-620. doi:10.1001/jamaophthalmol.2016.0104 Baseline End of Therapy Measured Vision Improvement Observed during Darovasertib Neoadjuvant Treatment: • Any improvement in visual acuity score 13/20^# (65%) • Median letters gained: 6# • 8 of 20 subjects observed ≥ 5 letters gained at 2 consecutive visits ^ 1 subject missing visual acuity data, # best response
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OptimUM-10: Darovasertib Phase 3 Neoadjuvant Registrational Trial Data Supporting Secondary Endpoints 27 Primary Endpoints • Cohort 1: Vision Preservation (Proportion with BCVA ≥ 15 letters loss) • Cohort 2: Eye Preservation Rate Secondary Endpoints UM = Uveal Melanoma, BCVA = Best Corrected Visual Acuity, ORR = Overall Response Rate • Darovasertib targets the key driver Protein Kinase C in UM • For those that don’t respond (minority) they are taken immediately to primary therapy • Thus far in OptimUM-09 study few subjects have had either local relapse or metastasis • Superiority or non inferiority for EFS not required, overlapping confidence interval curves in Kaplan-Meier plot expected (if anything, more likely a potential for benefit will be seen) • Cohort 1: Proportion with clinically significant macular edema; Proportion with VA 20/200 or worse; Radiation reduction • Cohorts 1 & 2: ORR (>20% ocular tumor shrinkage by product of diameters); No detriment to Event Free Survival (EFS) No detriment in EFS expected with darovasertib neoadjuvant therapy OptimUM-10 Ph3 Endpoints
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28 Thanks to the KOLs (Global) that Provided Guidance to Develop the Phase 3 Neoadjuvant UM Trial (OptimUM-10) Investigator Institution Bill Harbour UT Southwestern, US Carol Shields Will Eye Hospital, US Arun Singh Cleveland Clinic, US Lauren Dalvin Mayo Clinic, US Prithvi Mruthyunjaya Stanford University, US Tom Aaberg Retina Specialists of Michigan, US Hatem Krema Princess Margaret CC, Canada Rod O’Day Royal Victorian Eye and Ear Hospital, Australia Mandeep Sagoo Moorfields Eye Hospital, United Kingdom KOLs = Key Opinion Leaders; OptimUM-10: NCT07015190
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Neoadjuvant Darovasertib Uveal Melanoma PB Data Update and Program Summary 29 • FDA Breakthrough Therapy Designation granted for Neoadjuvant Darovasertib in UM subjects requiring enucleation • ~76% of PB UM patients observed >20% ocular tumor shrinkage by product of diameters (response definitions utilized from OptimUM-10 Ph3 registrational study) • ~48% of PB UM patients achieved >20% reduction in simulated radiation dose to at least one key visual structure • 65% of UM patients observed any visual improvement during neoadjuvant darovasertib therapy with 40% achieving ≥ 5 letters gained at 2 consecutive visits • Results from a vision prognostication tool to predict 20/200 vision (legal blindness) in UM patients after PB therapy: 1) 67% of patients observed “any reduction” in risk of legal blindness, and 2) 38% of patients observed “> 20% reduction” in risk of legal blindness • Clinical data update in >90 neoadjuvant enucleation and PB eligible UM patients at ESMO 2025 • Initiated global Phase 3 randomized neoadjuvant UM trial (OptimUM-10) Orphan Drug Designation in UM*; Fast Track Designation in MUM; Breakthrough Therapy Designation** * Orphan Drugs benefit from certain tax credits and may be excluded from certain mandatory price negotiation provisions of the 2022 Inflation Reduction Act ** Breakthrough therapy designation for the neoadjuvant treatment of adult patients with primary uveal melanoma (UM) for whom enucleation has been recommended
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Uveal Melanoma - Growth Pattern Tumor Size Potential of Darovasertib Therapy to Impact Disease Outcome by Reducing Tumor Size Reduce Enucleations Reduce Radiation Toxicity Improve Vision Reduced Risk of Micrometastasis 30 Large Medium Small Potential practice changing paradigm not seen since 1915
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31 Phase 1 First-in-Human Study IDE849 (DLL3 TOP1 ADC) IASLC WCLC 2025 Clinical Data Update in Small Cell Lung Cancer Darrin Beaupre, MD, PhD IDEAYA Biosciences Chief Medical Officer
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1Affiliated Cancer Hospital of Shandong First Medical University, Jinan, China, 2Jilin Cancer Hospital, Changchun, China, 3The First Affiliated Hospital of Nanchang University, Nanchang, China, 4The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China, 5Beijing Cancer Hospital, Beijing, China, 6West China Hospital, Sichuan University, Chengdu, China, 7Zhejiang Cancer Hospital, Hangzhou, China, 8Harbin Medical University Cancer Hospital, Harbin, China, 9Shanghai Chest Hospital, Shanghai, China, 10Shanxi Provincial Cancer Hospital, Taiyuan, China, 11Fujian Provincial Cancer Hospital, Fujian, China, 12Yunnan Cancer Hospital, Kunming, China, 13Hunan Cancer Hospital, Changsha, China, 14Tianjin Medical University Cancer Institute & Hospital, Tianjin, China, 15Shengjing Hospital of China Medical University, Shengjing, China, 16Xiangya Hospital Central South University, Changsha, China, 17The First Hospital of China Medical University, Shenyang, China, 18Anhui Chest Hospital, Hefei, China, 19Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China, 20Sichuan Cancer Hospital & Institute, Chengdu, China, 21Fudan University Shanghai Cancer Center, Shanghai, China, 22 Jiangsu Hengrui Pharmaceuticals, Co., Ltd, Shanghai, China. A first-in-human phase 1 study of SHR-4849 (IDE849), a DLL3- directed antibody-drug conjugate, in relapsed SCLC Linlin Wang1, Ying Cheng2, Chunjiao Wu2, Xue Meng1, Yan Zhang1, Longhua Sun3, Jinhua Wen3, Qiming Wang4, Jian Fang5, Yan Zhang6, Li Zheng6, Zhengbo Song7, Baogang Liu8, Rong Qiao9, Wenzhong Su10, Xin Wang10, Yunjian Huang11, Runxiang Yang12, Lin Wu13, Peng Chen14, Caigang Liu15, Rongrong Zhou16, Qun Qin16, Funan Liu17, Mingfang Zhao17, Xuhong Min18, Shengxiang Ren19, Yang Wei20, Jie Chen21, Jian Zhang21, Peng Chen22, Yiru Wang22, Xiaoxia Lu22, Ke Ma22, Lulu Yang22 32
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wclc.iaslc.org Background • Small Cell Lung Cancer (SCLC) is a highly aggressive neuroendocrine carcinoma (NEC), with limited treatment options and poor prognosis in the second-line setting. • Delta-like ligand 3 (DLL3), a protein that inhibits Notch signaling, is highly expressed in SCLC and other NECs.1-4 • SHR-4849 (IDE849*) is an antibody-drug conjugate comprising a humanized anti-DLL3 IgG1 monoclonal antibody, linked to a DNA topoisomerase I inhibitor payload by a cleavable linker. • In preclinical studies,5 SHR-4849: ‒ Strongly inhibited the proliferation of human lung cancer cell lines with different DLL3 expression level; ‒ Demonstrated a robust bystander killing effect; ‒ Resulted in a dramatic and sustained inhibition of tumor growth in DLL3 expressing xenograft models. References: 1. Lung Cancer 2020;147:237-243. 2. Oncologist. 2022;27(11):940-951. 3. J Hematol Oncol. 2019;12(1):61. 4. Cell Oncol (Dordr). 2019;42(3):261-273. 5. 2024 AACR. Abstract 3146. *SHR-4849 is being developed as IDE849 by IDEAYA Biosciences, worldwide outside of greater China. 33
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wclc.iaslc.org 0.8 mg/kg 2.4 mg/kg 3.5 mg/kg 4.2 mg/kg Study design • A multicenter, open-label phase 1 study of SHR-4849 in advanced solid tumors (ClinicalTrials.gov, NCT06443489). Key eligibility criteria • Histologically or cytologically confirmed relapsed or metastatic SCLC and other NECs expressing DLL3; • Had progressive or recurrent disease after standard treatment(s); • ECOG PS of 0 or 1. Primary endpoints: • Safety; • MTD or MAD; • RP2D. Secondary endpoints: • Efficacy; • Pharmacokinetics; • Immunogenicity. Data cutoff: Jun 20, 2025 • During dose escalation, 1 DLT (grade 4 decreased platelet count) occurred at 4.2 mg/kg. • 2.4, 3.0, and 3.5 mg/kg SHR-4849 every 3 weeks were selected for further expansion. • Overall, 100 patients were treated: 0.8 mg/kg (N=1), 2.4 mg/kg (N=25), 3.0 mg/kg (N=29), 3.5 mg/kg (N=42), 4.2 mg/kg (N=3). • The median follow-up duration was 3.5 months (IQR, 1.4-5.8). ECOG PS, Eastern Cooperative Oncology Group performance status; BOIN, Bayesian optimal interval; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; MAD, maximum administered dose; RP2D, recommended phase 2 dose 5.0 mg/kg SHR-4849 was administered intravenously every 3 weeks. Accelerated Titration 3.5 mg/kg 3.0 mg/kg 2.4 mg/kg 34
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wclc.iaslc.org Baseline characteristics *Prior line of therapy for one patient in the 3.0 mg/kg dose group was missing. #Proportion of patients with prior immunotherapy was calculated in SCLC patients. 0.8 mg/kg (N=1) 2.4 mg/kg (N=25) 3.0 mg/kg (N=29) 3.5 mg/kg (N=42) 4.2 mg/kg (N=3) Total (N=100) Sex, n (%) Male 1 (100.0%) 17 (68.0%) 23 (79.3%) 27 (64.3%) 3 (100.0%) 71 (71.0%) Female 0 8 (32.0%) 6 (20.7%) 15 (35.7%) 0 29 (29.0%) Age, median (range), years 49 59 (36-73) 60 (44-75) 62 (33-75) 54 (52-64) 60 (33-75) ECOG PS, n (%) 0 0 1 (4.0%) 4 (13.8%) 0 0 5 (5.0%) 1 1 (100.0%) 24 (96.0%) 25 (86.2%) 42 (100.0%) 3 (100.0%) 95 (95.0%) Tumor Type, n (%) SCLC 1 (100.0%) 23 (92.0%) 28 (96.6%) 32 (76.2%) 3 (100.0%) 87 (87.0%) Other NECs 0 2 (8.0%) 1 (3.4%) 10 (23.8%) 0 13 (13.0%) Clinical stage IV, n (%) 1 (100.0%) 20 (80.0%) 28 (96.6%) 34 (81.0%) 3 (100.0%) 86 (86.0%) Brain metastases, n (%) 1 (100.0%) 6 (24.0%) 9 (31.0%) 7 (16.7%) 1 (33.3%) 24 (24.0%) Liver metastases, n (%) 1 (100.0%) 6 (24.0%) 10 (34.5%) 12 (28.6%) 1 (33.3%) 30 (30.0%) Prior lines of therapy, n (%)* 1 0 13 (52.0%) 14 (48.3%) 23 (54.8%) 1 (33.3%) 51 (51.0%) 2 0 7 (28.0%) 13 (44.8%) 12 (28.6%) 1 (33.3%) 33 (33.0%) ≥3 1 (100.0%) 5 (20.0%) 1 (3.4%) 7 (16.7%) 1 (33.3%) 15 (15.0%) Prior immunotherapy, n (%)# 1 (100.0%) 19 (82.6%) 19 (67.9%) 23 (71.9%) 1 (33.3%) 63 (72.4%) 35
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wclc.iaslc.org Pharmacokinetic profile TSC, tumor stasis concentration. • Following a single dose, systemic exposure of SHR-4849, total antibody, and payload increased proportionally with doses ranging from 2.4 to 4.2 mg/kg. • Across the 2.4 to 4.2 mg/kg doses, the mean half-life of the SHR-4849 ranged from 10.2 to 11.5 days. • A tumor stasis concentration of 3.0 μg/mL, derived from preclinical tumor growth inhibition modeling, justify the clinically effective dose range of 2.4 to 4.2 mg/kg. • Exposure of free plasma payload was low across the 2.4 to 4.2 mg/kg doses, with the mean half-life ranging from 4.4 to 5.2 days. 36
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wclc.iaslc.org Safety profile Total (N=100) Any TEAE 92 (92.0%) Grade ≥3 52 (52.0%) Any TRAE 92 (92.0%) Grade ≥3 48 (48.0%) Leading to dose reduction 15 (15.0%) Leading to treatment discontinuation 2 (2.0%) Serious 16 (16.0%) Leading to death 0 Data are n (%). TEAE, treatment-emergent adverse events; TRAE, treatment-related adverse events; WBC, white blood cell count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase. TRAEs occurring in ≥10% of patientsSummary 37
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wclc.iaslc.org Tumor response in SCLC 2.4 mg/kg 3.0 mg/kg 3.5 mg/kg 4.2 mg/kg Total (≥2.4 mg/kg) 2L Setting (n=10) All (n=19) 2L Setting (n=8) All (n=18) 2L Setting (n=16) All (n=31) 2L Setting (n=1) All (n=3) 2L Setting (n=35) All (n=71) ORR, n (%; 95% CI) 8 (80.0%; 44.4-97.5) 14 (73.7%; 48.8-90.9) 6 (75.0%; 34.9-96.8) 12 (66.7%; 41.0-86.7) 12 (75.0%; 47.6-92.7) 23 (74.2%; 55.4-88.1) 1 (100.0%; 2.5-100.0) 3 (100.0%; 29.2-100.0) 27 (77.1%; 59.9-89.6) 52 (73.2%; 61.4-83.1) Confirmed ORR, n (%; 95% CI) 7 (70.0%; 34.8-93.3) 11 (57.9%; 33.5-79.7) 2 (25.0%; 3.2-65.1) 4 (22.2%: 6.4-47.6) 11 (68.8%; 41.3-89.0) 16 (51.6%; 33.1-69.8) 1 (100.0%; 2.5-100.0) 3 (100.0%; 29.2-100.0) 21 (60.0%; 42.1-76.1) 34 (47.9%; 35.9-60.1) Response pending confirmation, n (%) 0 1 (5.3%) 4 (50.0%) 8 (44.4%) 0 1 (3.2%) 0 0 4 (11.4%) 10 (14.1%) DCR, n (%; 95% CI) 10 (100.0%; 69.2-100.0) 18 (94.7%; 74.0-99.9) 8 (100.0%; 63.1-100.0) 17 (94.4%; 72.7-99.9) 15 (93.8%; 69.8-99.8) 28 (90.3%; 74.2-98.0) 1 (100.0%; 2.5-100.0) 3 (100.0%; 29.2-100.0) 34 (97.1%; 85.1-99.9) 66 (93.0% 84.3-97.7) Tumor responses were assessed in all enrolled patients who received study treatment and had baseline and at least one post-baseline efficacy assessment. 2L: second-line; PR, partial response; SD, Stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate. DLL3 positivity was defined as H-score >0. 38
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wclc.iaslc.org Tumor response over time in SCLC 39
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wclc.iaslc.org Tumor response in SCLC with brain metastases 2.4 mg/kg (n=6) 3.0 mg/kg (n=4) 3.5 mg/kg (n=7) 4.2 mg/kg (n=1) Total (≥2.4 mg/kg) (n=18) ORR, n (%; 95% CI) 6 (100.0%; 54.1-100.0) 3 (75.0%; 19.4-99.4) 5 (71.4%; 29.0-96.3) 1 (100.0%; 2.5-100.0) 15 (83.3%; 58.6-96.4) Confirmed ORR, n (%; 95% CI) 5 (83.3%; 35.9-99.6) 2 (50.0%; 6.8-93.2) 4 (57.1%; 18.4-90.1) 1 (100.0%; 2.5-100.0) 12 (66.7%; 41.0-86.7) Response pending confirmation, n (%) 0 1 (25.0%) 0 0 1 (5.6%) DCR, n (%; 95% CI) 6 (100.0%; 54.1-100.0) 4 (100.0%; 39.8-100.0) 7 (100.0%; 59.0-100.0) 1 (100.0%; 2.5-100.0) 18 (100.0%; 81.5-100.0) 40
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wclc.iaslc.org PFS in SCLC Total (≥2.4 mg/kg) 2L Setting (n=42) All (n=86) Events, n (%) 8 (19.0%) 22 (25.6%) Median (95% CI), months NR (4.4-NR) 6.7 (4.4-NR) 3-month rate, % (95% CI) 93.3% (75.2-98.3) 83.3% (71.0-90.7) 6-month rate, % (95% CI) 59.0% (31.2-78.8) 55.3% (37.8-69.7) PFS, progression-free survival; NR, not reached. 41
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wclc.iaslc.org Conclusions • SHR-4849 (IDE849) demonstrated a tolerable and manageable safety profile in patients with relapsed SCLC. ― Common grade 3 or 4 TRAEs were hematological toxicities; ― Low incidence of TRAEs leading to treatment discontinuation (2.0%); ― No treatment-related deaths. • SHR-4849 at ≥2.4 mg/kg exhibited promising anti-tumor activity, especially in the second-line setting. ― All settings: ORR, 73.2%; DCR, 93.0%; ― Second-line setting: ORR, 77.1%; DCR, 97.1%; ― Patients with brain metastases: ORR, 83.3%; DCR, 100.0%. • Follow-up is ongoing to assess the long-term outcomes. 42
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43 TOP1 ADC + IDE161/PARG Combination Mechanistic Rationale IASLC WCLC 2025 Michael White, PhD IDEAYA Biosciences Chief Scientific Officer
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44 TOP1cc Cell death Cell prolif. TOP1i-induced DNA lesion From Sun et al, Nat Com, 2021 TOP1i Deparylation by PARG IDE161 (PARGi) TOP1cc accum. TOP1cc repair Dual inhibition of TOP1 and PARG amplifies accumulation of toxic TOP1cc PARG inhibition promotes death by mitotic catastrophe PARG inhibition is synthetic-lethal with DNA replication stress IDE161: Ph1 PARG Inhibitor; Broad Potential in Combination with TOP1i-ADCs PARP1 initiates DDR PARG resolves DDR Strong IDE161/topotecan combination activity across majority of cancer cell models linA linKlinJlinIlinHlinGlinFlinElinDlinClinB linNlinMlinL PANCAN N=433 Activity by indication (lineage distribution of cell viability EC50s): Munoz et al, AACR 2025
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4545 0 10000 20000 30000ECL counts relative to DMSO ✱✱✱ ✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ IDE161 (uM) 0 0.1 0 0.1 CPT (uM) 0 0 1 1 PAR accumulation TOP1 cleavage complex accumulation IDE161 Exacerbates Topotecan-Dependent Accumulation of TOP1cc and Drives Durable Tumor Regressions in Combination with TOP1i αTOP1cc antigen From Maskey et al., NAR, 2017 0 10 20 30 40 50 0 1000 2000 3000Mean Tumor Volume (mm3) + S.E.M. Days on treatment Small cell lung cancer Vehicle IDE161 Topotecan Combination 0 20 40 60 80 100 0 500 1000 1500 2000Mean Tumor Volume (mm3) ± S.E.M. Off treatment High grade serous ovarian cancer Vehicle IDE161 Topotecan Combo Robust combination benefit in CDX independent of HRD status Munoz et al, AACR 2025
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IDE161 Amplifies TOP1i-ADC Antitumor Activity 0 20 40 60 0 500 1000 1500 2000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Colorectal HER2 Low 0 10 20 30 40 0 500 1000 1500 2000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. NSCLC HER2+ SCLC HER2 Low 0 5 10 15 20 25 0 500 1000 1500 2000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Test-of-concept: Fam-Trastuzumab Deruxtecan + IDE161 Combination 0 10 20 30 40 -10 0 10 20 Days on treatment % Body weight change 0 20 40 60 -10 0 10 20 Days on treatment % Body weight change 0 5 10 15 20 25 -10 0 10 20 Days on treatment % Body weight change Munoz et al, AACR 202546 Vehicle IDE161 HER2-ADC Combination Vehicle IDE161 HER2-ADC Combination Vehicle IDE161 HER2-ADC Combination
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0 20 40 60 80 100 0 500 1000 1500 2000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. vehicle IDE161 IDE034 Combo 47 IDE034: B7H3/PTK7 Bispecific TOP1i ADCIDE849: Ph1 DLL3 TOP1i ADC IDE849 and IDE034: Clinical TOP1-ADC + PARGi Combination Opportunities 71 High affinity antibody Potent TOP1i payload Internalization-dependent cleavable linker Optimized DAR value of 8 High plasma stability The SCLC lineage survival oncogene, ASCL1, directly promotes DLL3 expression SHR-4849/ IDE849 Human IgG1 TOP1i: BLD1102 DAR=8 αPTK7αB7-H3 Enhanced tumor versus normal cell binding Enhanced internalization efficiency in double + Targets tumor initiating cells Substantial predicted double- positive disease population in lung, bowel, HNSCC, ovarian B7H3/PTK7 target cell binding NCI-H520 NSCLC (double positive) -4 -3 -2 -1 0 1 0 2×105 4×105 6×105 8×105 1×106 Concentration (Log10, μg/mL) MFI B7-H3 mono-Ab PTK7 mono-Ab IDE034-naked Isotype Dual tumor-antigen targeting to maximize tumor-specific PARGi combination benefit in multiple indications 85% SCLC are DLL3+ Amplify Anti-Tumor Activity to Enhance Both Rate of Response and Durability of Response 0 10 20 30 40 50 0 1000 2000 3000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Maskey et al. World Lung 2025 SCLC low DLL3 vehicle IDE161 IDE849 Combo ADC dose ADC dose B7H3low/PTK7high
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48 IDE397 + Trodelvy Combination Mechanistic Rationale in MTAP-Deletion Solid Tumors Michael White, PhD IDEAYA Biosciences Chief Scientific Officer
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49 MTAP-Deletion Confers Multiple Metabolic Dependencies on MAT2A IDE397 amplifies DNA repair liabilities installed by MTAP deletion One-carbon cycle/folate cycle connection maintains critical metabolite homeostasis MTAP Purines Nucleotide pool Reduced DNA repair (rate-limiting purine and pyrimidine salvage/synthesis) MTA PRMT5 Increased DNA damage (pre-mRNA splicing defects) MAT2A SAMSAM IDE397 X X Folate pathway MT-ase cofactor 9p21.3 deletion Salvage pathway Perturbation of SAM production Promotes Genomic Instability and Reduces DDR Capacity
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50 Disordered Methionine Metabolism Underpins IDE397 Combo Opportunity with TOP1i-ADCs MTAP WT MTAP-/- Metabolite profile IDE397 vs DMSO (Cytoscape nucleotide subcluster) green-decrease, red-increase; FDR< 0.05 Schematic adapted from Oster and Aqeilan, Cells 2020 R-Loop RNA Pol II DNA Polymerase TOP1 Perturbed Splicing Vehicle IDE397 3 mg/kgIDE397 10 mg/kg MRTX1719 12.5 mg/kgMRTX1719 50 mg/kg 0 1 2 3 4pKAP1 (Fold of vehicle, H-Score) ✱✱ ✱ ns ns α-folates and TOP1i among top IDE397 activity correlations across the CCLE IDE397 DMSO R-Loops (mutRNaseH1-GFP) NCI-H838 (72 hr) MTAP-/- Selective Depletion of Nucleotide Pools Concomitant with R-loop Mediated DNA damage MTAP-/- dependent metabolic perturbation by IDE397 IDE397 splicing perturbation is associated with R-loop accumulation and in vivo DNA damage response TOP1 activity is required to resolve R-loops 1488 drugs,737 cell lines NCI-H838 tumor PD (6 days) Rao et al, AACR 2025 IDE397 disconnects folate/Met cycles MTAP-/- IDE397 vs DMSO (24 hr) depletion accumulation anti-folate mTOR topoisomerase DNA synth. pyrimidine synth. 0.30 0.35 0.40 0.45 0.50spearman correlation
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51 Genome-Wide IDE397 CRISPR Enhancer Screens Highlight MTAP/MAT2A Support of DNA Damage Repair Capacity CL1: H838 CL2: H1437 CL3: H2170 Normalized drug score Synthetic lethality rank 3 MTAP-/- models Consensus SL interactions @ IC20 Rao et al, AACR 2025 GSEA- (MSigDB C2) Nucleotide/nucleoside transport (SLC29A1, SLC35E3) B12 transport (ABCD4) Polyamine transport and mTOR inhibition (ATP13A13, TSC2, NPRL2, DEPDC5) Met Hcy Methionine Cycle MTR-1P THF Folate Cycle Folate 5,10-meTHF 5-mTHF Pyrimidine Synthesis IDE397 Purine Synthesis SAH Methylation Reactions Purine Synthesis Transsulfuration Pathway Glutathione Synthesis Polyamine Metabolism DNA damage repair and R-loop resolution (FANCs, RAD51, RFC2, ERCC1, APEX1/2) Homocysteine generation (AHCY) Top enhancers map to 1-carbon cycle/folate pathway activityIDE397/gene interactions uncover key determinants of drug vulnerability MTAP-/- Genes ordered by guide enrichment Genes ordered by guide enrichment Genes ordered by guide enrichment
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52 Robust IDE397 + TOP1i Combination Benefit in MTAP-/- Urothelial CDX 0 10 20 30 40 50 60 70 80 -20 -10 0 10 20 Study Day Body Weight (% change from baseline ± SEM) IDE397/irinotecan combo is well tolerated Tumor transcriptomics (day 10) indicate IDE397 activation of DDR response -100 0 100 200 300 400 500 600 700 800 Change in tumor volume (%) Combination delivers durable anti-tumor activity Irinotecan Irinotecan +IDE397 Study day 74 (end of study) 0 10 20 30 40 50 60 70 80 250 500 750 1000 1250 Days on Treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle IDE397 Combination Irinotecan Rao et al, AACR 2025 On-Mechanism Augmentation of Anti-Tumor Response RT112/84 MTAP-/-
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53 Sacituzumab–Govitecan (TRODELVY®)/IDE397 Combination in MTAP-/- Cancer • De novo nucleotide synthesis is impaired upon loss of MTAP and MAT2A activity which limits replication and repair capacity • RNA splicing defects cause RNA polymerase stalling and R-loop accumulation which must be resolved by TOP1 to prevent mitotic catastrophe • Resulting genome stability is vulnerable to further insult by tumor- selective TOP1 inhibition 1Biomarkers of response to enfortumab vedotin (EV) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of the UNITE study; JCO.2023.41.6_suppl.450 2 Source: Han et al, Nature Communications 2021 • MTAP -/- tumors have a shorter PFS and OS with SOC agents like Enfortumab vedotin1 and CPI2 • IDE397 + TOP1 inhibitor has the potential to create a synthetic lethal pair that fully capitalizes on mechanistic vulnerabilities (genomic instability, replication stress) associated with MTAP loss • Tumor selective delivery of TOP1 inhibitor would maximize therapeutic index • Monotherapy clinical efficacy with IDE397 is also consistent with this mechanistic rationale
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54 Phase 1 First-in-Human Study of IDE397 + Trodelvy® Combination in MTAP-Deletion Urothelial Cancer Jasgit Sachdev, MD IDEAYA Biosciences Senior Vice President, Head of Clinical Development
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55 IDE397 Monotherapy & Trodelvy® Combination Dose Escalation/Expansion SchemaObjective: • Demonstrate higher ORR and DOR with the combination than seen with single agent Trodelvy® • Target population: 2nd line+, MTAP -/- UC and NSCLC • Trodelvy® observed single agent ORR of 23% in an EV-naïve UC population(TROPiCS-04) and 11% in EV treated population (RWD)*; ORR in NSCLC of 13%** Novel Combination Regimen for Subjects Who May Not Benefit from SOC Agents Clinical Testing of Trodelvy®+ IDE397 in MTAP -/- Urothelial and NSCLC Trodelvy® Combination Escalation DL1: Trodelvy® + IDE397 DL2: Trodelvy® + IDE397 DL3: Trodelvy® + IDE397 DL1 IDE397 Trodelvy® Combination Expansion Trodelvy® + IDE397 in UC RDE RDE DL2 IDE397 DL3 IDE397 DL4 IDE397 IDE397 Monotherapy Escalation Urothelial CancerDL5 IDE397 DL6 IDE397 NSCLC Trodelvy® + IDE397 in NSCLC * Benchmarks: SG monotherapy efficacy post EV N =82, ORR: 11%, DCR 31% : * Sternschuss, ESMO Open Vol 10, Issue 6, 2025; Reported ORR with SG of 23% in a predominantly EV naïve population (Phase 3 Tropics-04 trial ) **Benchmark ORR: Trodelvy 13.7%, EVOKE-01 trial: Paz-Ares et al JCO 2024; historical ORR for docetaxel 15-20%, DOR ~6 months RDE: Recommended Dose/s for Expansion IDE397 Monotherapy Expansion
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IDE397 + Trodelvy® Clinical Combo: Baseline Characteristics by Dose Level IDEAYA Data as of 29Aug2025 (based on preliminary analysis of unlocked database); IO = Immuno-Oncology Therapy; EV = Enfortumab Vedotin Baseline Characteristics Overall (n =19) Age (Years) Median (Range) 63 (45-78) ≥65 7 (36.8%) Sex Male (%) 14 (73.7%) ECOG PS 1 12 (63.2%) Prior Lines of Therapies Median (Range) 2 (1-3) ≥ 2 13 (68.4%) Prior Platinum 12 (63.2%) Prior IO 16 (84.2%) Prior Enfortumab 6 (31.6%) Majority of the patients have had prior platinum and IO and 32% had prior EV 56
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57 Treatment Related AEs at Combo Dose Level 1 (n=12) Manageable Safety Profile and Favorable Dose Delivery supported selection of DL1 as Expansion Dose 1 AE Profile: IDE397 15 mg QD + Trodelvy® 10 mg/kg (Dose Level 1) IDE397 Trodelvy All Grades n (%) Grade > 3 n (%) All Grades n (%) Grade > 3 n (%) Any Event 10 (83.3%) 5 (41.7%) 11 (91.7%) 7( 58.3%) Anemia 3 (25.0%) 3 (25.0%) 6 ( 50.0%) 5 (41.7%) Diarrhea 5 (41.7%) 0 (0.0%) 3 (25.0%) 0 ( 0.0%) Constipation 3 (25.0%) 0 (0.0%) 3 (25.0%) 0 (0.0%) Fatigue 4 (33.3%) 0 (0.0%) 3 (25.0%) 0 (0.0%) Nausea 4 (33.3%) 0 (0.0%) 4 (33.3%) 0 (0.0%) Peripheral Neuropathy 3 (25.0%) 0 ( 0.0%) 2 (16.7%) 0 ( 0.0%) White Blood Cell Decrease 2 (16.7%) 1 (8.3%) 2 ( 16.7%) 1 (8.3%) Neutropenia 1 (8.3%) 1 (8.3%) 2 (16.7%) 2 (16.7%) Neutrophil Count Decrease 1 (8.3%) 0 (0.0%) 2 (16.7%) 1 (8.3%) Alopecia 1(8.3%) 0 (0.0%) 2 (16.7%) 0 (0.0%) IDEAYA Data as of 29Aug2025 (based on preliminary analysis of unlocked database); 3 Treatment Related-SAEs reported: 1 subject with febrile neutropenia & colitis, 2 subjects with Grade ≥ 3 neutropenia
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58 Treatment Related AEs at Combo Dose Level 2 (n=7) Low rate of Grade ≥3 hematologic events; most are single events. No treatment related SAEs at Expansion Dose 2 AE Profile: IDE397 30 mg QD + Trodelvy® 7.5 mg/kg (Dose Level 2) IDE397 Trodelvy Preferred Term All Grade n (%) Grade ≥ 3, n (%) All Grade n (%) Grade ≥ 3, n (%) Any Event 6 (85.7%) 2 (28.6%) 5 (71.4%) 2 (28.6%) Anemia 3 (42.9%) 1 (14.3%) 3 (42.9%) 1 (14.3%) Alopecia 0 (0.0%) 0 (0.0%) 4 (57.1%) 0 (0.0%) Asthenia 1 (14.3%) 1 (14.3%) 1 (14.3%) 1 (14.3%) Decreased Appetite 1 (14.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Diarrhea 0 (0.0%) 0 (0.0%) 1 (14.3%) 1 (14.3%) Fatigue 1 (14.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Peripheral Neuropathy 1 (14.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Tinnitus 1 (14.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Stomatitis 1 (14.3%) 0 (0.0%) 1 (14.3%) 0 (0.0%) Rash pruritic 0 (0.0%) 0 (0.0%) 1 (14.3%) 0 (0.0%) IDEAYA Data as of 29Aug2025 (based on preliminary analysis of unlocked database); DL1 = Dose Level 1; DL2= Dose Level 2
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-80.00% -60.00% -40.00% -20.00% 0.00% 20.00% 40.00% Best Response by RECIST 1.1 59 33% ORR at Dose Level 1 (DL1) and 57% ORR at Dose Level 2 (DL2) by RECIST 1.1 IDE397 + Trodelvy® Urothelial Cancer MTAP-Deletion Patients (n=16) IDEAYA Data as of 29Aug2025 (based on preliminary analysis of unlocked database). Evaluable Patients: Treated with at least one dose of the combination and with ≥ 1 post-baseline scans. One patient not included as MTAP WT status by central IHC testing. # One patient confirmed response after the data cut-off. * Patient missed ~50% of dosing prior to 1 st scan; + Patient still on treatment as of cutoff date ^ Patient developed new lesions, CR = Complete Response, PR = Partial Response, cPR = confirmed PR, uPR = unconfirmed PR, SD = Stable Disease, PD = Progressive Disease; UC = Urothelial Cancer; 1 PR confirmed 27 days instead of 28 days or later after initial scan showing response ORR by RECIST 1.1, n (%) DL1 (9) 3 (33) DL2 (7) 4 (57) DCR, n (%) DL1 (9) 9 (100) DL2 (7) 5 (71) Historical Benchmark: Trodelvy monotherapy efficacy in UC post EV - Real World Data (n=82) ORR 11% DCR 31% Best Response by RECIST (% change from baseline) Sternschuss, ESMO Open Vol 10, Issue 6, 2025 Results from historical benchmark are not from a head-to-head clinical trials and the results from trials with different study protocols, conditions, patient populations and reporting standards. Caution should be exercised when comparing data across trials. + + cPR+^ ^ ^ cPR+ cPR+ cPR+ cPR+ # cPR+ DL1 = IDE397 15 mg QD + Trodelvy® 10 mg/kg DL2 = IDE397 30 mg QD + Trodelvy® 7.5 mg/kg Partial Response * uPR++^
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60 Spider Plot of IDE397 + Trodelvy Combo in MTAP Urothelial Cancer (n=16)• Median PFS in historical controls in a late line mUC population is around 2.5 months • IDE397 and Trodelvy combo mPFS and mDOR not yet reached • Preliminary duration of IDE397 + Trodelvy combination is trending positively vs. historical data Preliminary Durability with Deeper and More Rapid Responses vs. IDE397 Monotherapy IDE397 + Trodelvy® Urothelial Cancer Patients, Efficacy Evaluable Subjects IDEAYA Data as of 29Aug2025 (based on preliminary analysis of unlocked database). * Loriot et al, NEJM October 2023. Results from historical benchmark are not from a head-to-head clinical trials and the results from trials with different study protocols, conditions, patient populations and reporting standards. Caution should be exercised when comparing data across trials. Evaluable Patients: Treated with >= 1 dose of IDE397 + Trodelvy and with >= 1 post-baseline scans. One patient not included as central testing revealed MTAP intact status. EV = Enfortumab Vedotin mPFS in mUC after 1-2 prior lines of Rx* RECIST (% change from baseline) DL1 = IDE397 15 mg QD + Trodelvy® 10 mg/kg DL2 = IDE397 30 mg QD + Trodelvy® 7.5 mg/kg
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61 mUC Patient Treated with Combination of IDE397 + Trodelvy at Dose Level 2• 78-year old male with confirmed MTAP loss mUC, ECOG =1. Prior systemic therapy includes Gem + Cis, maintenance Avelumab and a clinical trial with a Nectin-4 ADC (same class as EV) • Baseline scans showed heavy disease burden with multiple liver metastases • Received combination of IDE397 30 mg QD + Trodelvy 7.5 mg/kg • PR at week 12 (-48% reduction in TL), confirmed at week 18 Confirmed Partial Response in Pre-Treated Nectin-4 ADC MTAP UC Patient Case Study 1: Combination of IDE397 30 mg QD + Trodelvy® 7.5 mg/kg Week 12 Baseline Reduction in target lesions by -48% at Week 12, confirmed at Week 18 MTAP -/- = Homozygous loss of Methylthioadenosine phosphorylase; UC = Urothelial Cancer; Gem + Cis = Gemcitabine + Cisplatin; EV: Enfortumab Vedotin; PR = Partial Response; mUC = metastatic Urothelial Cancer; TL= Target lesion
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62 mUC Patient Treated with Combination of IDE397 + Trodelvy at Dose Level 1• 52-year old male with confirmed MTAP loss mUC, ECOG =1. Prior systemic therapy for metastatic disease included EV+ Pembro followed by Gem+ Cis • Baseline scans showed multiple lung metastases bilaterally • Received combination of IDE397 15 mg QD + Trodelvy 10 mg/kg • Rapid PR at week 6 (-65% reduction in TL sum), along with complete disappearance of the largest TL Rapid and Deep Partial Response in Pre-Treated EV + PD1 MTAP UC Patient Case Study 2: Combination of IDE397 15 mg QD + Trodelvy® 10 mg/kg Week 6Baseline Complete resolution of lobulated right lower lobe lung mass at Week 6 MTAP -/- = Homozygous loss of Methylthioadenosine phosphorylase; UC = Urothelial Cancer; Gem + Cis = Gemcitabine + Cisplatin; EV: Enfortumab Vedotin; Pembro: Pembrolizumab PR = Partial Response; mUC = metastatic Urothelial Cancer; TL= Target lesion
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63 IDE397 + Trodelvy Combo Summary in MTAP-Deletion & Next Steps • High projected prevalence of MTAP-deletion in UC (~25-30%) and NSCLC (~15-20%) • 2 safe and efficacious expansion dose cohorts identified for IDE397 + Trodelvy® combo Manageable AE profile of 2 dose cohorts established Multiple PRs by RECIST 1.1 with higher preliminary efficacy vs. Trodelvy monotherapy • Trodelvy monotherapy: ~11% ORR in UC post EV, 23% ORR in EV naïve UC* • FPI achieved for IDE397 + Trodelvy® Combo in MTAP NSCLC in 3Q2025 • 57% ORR by RECIST 1.1 for IDE397 30mg QD + Trodelvy® 7.5 mg/kg Combo (Dose Level 2) Trending as the move-forward IDE397 + Trodelvy® combination dose • Determine RP2D for IDE397 + Trodelvy® Combo targeted by YE2025 Identify well tolerated IDE397 + Trodelvy® Combo Dose (achieved) Target ORR% “go/no-go”: Ideally >40% ORR with durability (>6 months mDOR) * Results from historical benchmark are not from a head-to-head clinical trials and the results from trials with different study protocols, conditions, patient populations and reporting standards. Caution should be exercised when comparing data across trials.
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64 IDE892 (IND-Filed), a Potential Best-in-Class PRMT5 Inhibitor, to Target MTAP-Deletion Solid Tumors Michael White, PhD IDEAYA Biosciences Chief Scientific Officer
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65 MTA/SAMMTA/SAM PRMT5 active conformation PRMT5 inactive conformation IDE397 Substrate peptide SAM PRMT5iMTA MTA % apparent target occupancy NSCLC MTAP-/- CDX model NCI-H838 0 10 20 30 40 50 60 0 500 1000 1500 2000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. 0 10 20 30 40 50 60 70 80 90 100 0 500 1000 1500 2000 Tumor Volume (mm3) Days on Study 100% tumor free Off Treatment IDE397/IDE892 Combination Opportunity: Amplify SL and Block Relapse vehicle IDE397 1/10th Ceff AMG193 1/10th Ceff TNG462 1/10th Ceff Combination vehicle 0 10 20 30 40 50 60 0 500 1000 1500 2000 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. BMS-504 ~1/10th Ceff vehicle IDE397 1/10th Ceff Combination IDE397 1/10th Ceff Combination Garbett et al, ENA 2025 Cooperative cellular target occupancy
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66 Tumor Transcriptomics Uncovers Candidate Monotherapy Bypass Mechanisms Blocked by Combination Therapy Day 7 and end-of- study tumors: bulk RNAseq fgsea 0 7 14 21 28 35 42 49 56 0 250 500 750 1000 1250 1500 1750 2000 Study Day Mean Tumor Volume (mm3) ± S.E.M. Vehicle IDE397 30 mg/kg BMS986504 100 mg/kg IDE397 3 mg/kg + BMS986504 12.5 mg/kg BMS986504 100mg/kg EoSBMS986504 100mg/kg Day7 Vehicle BMS986504 100 mg/kg SDMA IHC from end-of-study • Persistent PRMT5 inhibition in relapsed tumors • IDE397 maintains inhibition of epigenetic reprogramming and prevents MYC activation • BMS986504 maintains inhibition of mRNA splicing NCI-H838 MTAP-/- IDE397 30mpk BMS986504 100mpk End-of-Study BMS986504-specific REACTOME_MRNA_SPLICING ✓✕ End-of-Study IDE397-specific ZHONG_RESPONSE_TO_AZACITIDINE_AND_TSA_UP REACTOME_HATS_ACETYLATE_HISTONES PID_MYC_ACTIV_PATHWAY IDE397 30mpk BMS986504 100mpk ✕ ✕ ✕✓ ✓ ✓ Garbett et al, ENA 2025
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67 Biophysical Characterization Defines Optimization Parameters for PRMT5MTAi Maximize tumor-specific activity via MTA-cooperativity and SAM-antagonism Structural insights indicate inhibitors and metabolites can independently exchange in PRMT5 active site D419 K393 R421 “closed“ “open“ D419 K393 R421 Variable metabolite cooperativity among PRMT5i A-AB-A p-MTAP-/- = pseudo- MTAP-/- cellular MTA/SAM ratio p-WT = pseudo-WT cellular MTA/SAM ratio Modified SPR decodes metabolite binding cooperativity hi-SAM p-WT p-MTAP-/- hi-MTA hi-SAM p-WT p-MTAP-/- hi-MTA hi-SAM p-WT p-MTAP-/- hi-MTA hi-SAM p-WT p-MTAP-/- hi-MTA 0 25 50 75 100 125 150TRmax (%) IDE892 BMS-986504 TNG462 EPZ015666 (GSK3235025) DMSO baselineSAM/MTA co-operative competitiveBinding mode: A AAB Running buffer PRMT5iMTAs or PRMT5isDMSO, SAM/MTA -200 0 200 400 -10 0 10 20Binding level (RU) (1) (2) Time (s) A: DMSO, B: PRMT5iMTA A: 1:1 MTA/SAM, B: PRMT5iMTA Aubi et al, AACR 2025 ∆(2)-(1) TRmax
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0 10 20 30 40 50 60 0 500 1000 1500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. vehicle IDE892 IDE397 combo NSCLC 68 IDE892 Delivers Robust Selectivity Together with Exceptional IDE397 Combination Activity 0 10 20 30 40 50 60 0 250 500 750 1000 1250 1500 1750 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. 0 7 14 0 250 500 750 1000 1250 1500 1750 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. 0 10 20 30 40 50 60 70 80 0 250 500 750 1000 1250 1500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Only active in MTAP-/- (HCT116 isogenic pair) HCT116 WT HCT116 MTAP-/- IDE397 combination delivers CRs and reverses relapse NCI-H838 MTAP-/- vehicle IDE397 IDE892 combination vehicle IDE892 vehicle IDE892 IDE397 added IDE892 (D1-D73) + IDE397 (D45-D73) 0 10 20 30 40 50 60 0 200 400 600 800 1000 1200 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. NSCLC vehicle IDE892 0 10 20 30 40 50 60 0 500 1000 1500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Urothelial vehicle IDE892 IDE397 combination Strong mono and combination benefit in MTAP-/- PDX
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69 Computational (AI/ML) Drug Discovery Capabilities & Case Studies Michael White, PhD IDEAYA Biosciences Chief Scientific Officer
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70 Dovetailing Physics and AI to Augment Pace and Quality of Drug Discovery AI/ML and Physics-based methods deployed as force multipliers of IDEAYA MedChem expertise Accelerate sustainable delivery of FIC NCEs as an industry leader in computer-assisted drug discovery PARG WRN MAT2A POLθ Protein Folding Image Analysis FEP Dynamics Generative Design HDX ADME Predictions Design AI / ML Computational Physics and Biophysics Enable timely pursuit of the exceptionally challenging TPPs required to deliver transformational therapies (KAT6/7, MTAP program 3, early programs 1&2)
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71 Pre-existing resistance (persistence) From: Marusyk et al. Cancer Cell 2020 Intratumor heterogeneity- a hallmark of drug resistance Evolvability of de novo resistance • Attack truncal vulnerabilities • Disrupt adaptive phenotypic diversification • Eliminate tumor-persister/pluripotent progenitor cells Tumor heterogeneity is a Fundamental Challenge Confronting Drug Discovery Lysine Acetyltransferases are Emerging as an Important Drug Target Opportunity Shared support of cancer chromatin acetylation by KAT6A, KAT6B and KAT7 H3 H4 H3 KAT (MYST) Adapted from White et al. Trends in PS 2024; LaLonde et al. Genes&Dev. 2013 + other HATs *HistoneDB 2.0 * Lineage-survival oncogene networks Tumor initiating cell maintenance Evolution of drug-tolerant persister cells KAT7 pocket (270 Å3) KAT6 pocket (614 Å3) Residue differences Dual KAT6/7i opportunity: substantial discovery challenge Gupta et al, AACR 2025
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Free Energy Perturbation (FEP) Calculations Drove the Design of the First Reported Dual KAT6/7 Inhibitors 72 Predicted high-affinity high-polarity chemical space Initial compounds synthesized • Physics-based simulations can be applied to novel target classes and exploit dynamic protein differences without dependence on training data • FEP predicts ligand affinity across any protein target class using fundamental quantum principles Accelerated Design Prioritization: ~500 KAT6/7 innovative design ideas were evaluated by FEP with 20% prioritized for synthesis and characterization to ultimately deliver IDE574 synthesized deprioritized Predicted Ki Frequency (n) pKi exp pKi FEP
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73 Dual KAT6/7 Inhibition Delivers Robust PD Modulation and Cell Fate Control 10-4 10-2 100 0 50 100 KAT8 KAT5 KAT6 KAT7 FP response (%) IDE574, µM Biophysical target binding 10-4 10-2 100 0 50 100 KAT5 KAT6 KAT7 KAT8 BRET ratio IDE574, µM Cellular target binding 10-5 10-4 10-3 10-2 10-1 100 101 0 50 100 H3K23Ac H3K14Ac IDE574, µM %Ac inhibition Cellular target inhibition Unprecedented KAT selectivity CUT&RUN (cleavage under targets and release using nuclease) Enhanced target chromatin modulation by KAT6/7i vs KAT6i DMSO KAT6i KAT6/7i H3K9ac suppression at gene promoters H3K23ac LogFC -log10(FDR) -4 0 4 LogFC -log10(FDR) -4 0-8 4 H3K14ac H3Kac suppression by KAT6/7i vs KAT6i KAT6/7i- repressed protein modules Subcluster by Locally Weighted Cosine Distance Epigenetic Regulators Lineage Specification Metabolic Membrane dynamics Subcluster by Locally Weighted Cosine Distance Cell-cycle control Lineage Specification Epigenetic Regulators KAT6/7i-repressed protein modules CAMA1 RNAseq NCI-H2122 RNAseq FOXA1 motifs (ATACseq)GATA3 motifs (ATACseq) Superior cell fate modulation by KAT6/7i vs KAT6i “Hormone receptor– mediated epigenetic and transcriptional control of the G1/S cell-cycle” “Wnt/β-catenin, nuclear receptor TFs + epigenetic, chromatin, DNA repair” OpenAI + Custom RAG : Drug effect DMSO KAT6i KAT6/7i DMSO KAT6i KAT6/7i
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74 Single-Cell RNAseq Reveals Suppression of Adaptive Resistance by Dual KAT6/7i 10-2 10-1 100 101 102 103 104 0.0 0.2 0.4 0.6 0.8 1.0 KAT6/7i, nM % relative survival KAT7 supports persister cell expansion KAT6/7i prevents escape KAT6i KAT6/7i KAT6i selects for endocrine- independent cell state with drug- tolerant persister cell features Dual KAT6/7 inhibition prevents selection for endocrine- independence/drug resistance Gupta et al, AACR 2025 Top differential gene expression programs cluster 3 vs 0 Emergent subclonal adaptation to KAT6i is blocked by KAT6/7i (ST941C PDX-derived HR+ ESR1 Y537S mBC) Disruption of Tumor-Initiating Cell Populations and Inhibition of Epigenetic Evolution of Drug Tolerance UMAP-1 UMAP-2 DMSO KAT6/7i KAT6i UMAP-1 UMAP-2 Observed Cluster Frq * NS Leiden clusters DMSO1 nM10 nM50 nM400 nMDMSO1 nM10 nM50 nM400 nM 0.0 0.5 1.0 1.5CD44/CD24 ratio KAT6i IDE574 DMSO1 nM10 nM50 nM400 nMDMSO1 nM10 nM50 nM400 nM 0 10 20 30% CD44+/CD24+ cells KAT6i IDE574 DMSO1 nM10 nM DMSO1 nM10 nM 0 25 50 75 100% CD133+ cells KAT6i IDE574 DMSO1 nM10 nM DMSO1 nM10 nM 0 25 50 75 100% ALDH+ cells KAT6i IDE574 Tumor-initiating cell differentiation DTP marker: ALDH1 DTP marker: CD133 On/Off Clonogenic assay MDAMB231ST941C 14d on 14d on/10d off 14d on 14d on/10d off 0.0 0.2 0.4 0.6 0.8 1.0% colony forming efficiency KAT6i KAT6/7i Tumor-initiating cell stemness Drug-tolerant persister cell/tumor-initiating cell modulation 10-day viability
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75 Robust Monotherapy Activity and Broad Indication Opportunity 0 30 60 90 120 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle IDE574 (0.14X AUC, u) KAT6i (1X AUC, u) Off treatment 0 30 60 90 0 500 1000 1500 2000 2500 Days on treatment Mean Tumor Volume (mm3) ± S.E.M. Vehicle IDC-574 NSCLC 8p11 CN ampPDXST941 (HR+ mBC, ESR1 Y537S) fulvestrant-resistant tumor IDE574 long-duration viability assessments Priority indications – breast, lung, colon, ovary, eso/gastric Complete responses in ESR1 mutant mBC Durable control in NSCLC Indication-enriched sensitivity Vehicle IDE574 100 QD -2.0 -1.5 -1.0 -0.5 0.0 0.5 CD44 Log2FC Vehicle IDE574 100 QD -0.5 0.0 0.5 1.0 1.5 CD24 Log2FCDay 3 tumor PD: Veh 574 100 QD 0 50 100 150 % modulation H3K23ac Veh 574 100 QD 0 50 100 150 % modulation H3K14ac Day 3 tumor PD:
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76 Computer – Assisted Drug Discovery Supports IDEAYA’s Early-Stage Portfolio In vivo POC AI + Physics Critical End Points HARMONYTM Property Predictions Virtual Screening and ABFE Human PK Predictions Generative Chemical Design RoseTTAFold Image Analysis Automation Free Energy Perturbation PanDDA Crystallography Integration of AI- and physics-based predictions with measured data augments the pace and quality of discovery programs Hit ID Cellular POC
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77 Generative Design offers new ideas in orthogonal chemical and property space FEP delivers affinity predictions to rank prioritize generative design ideas. PanDDA workflow optimizes signal/ noise for rare hit detection among large crystallography screen data sets HDX provides insight into dynamic differences between highly similar structural domains Dovetailing computational Tools, AI and Biophysics for early portfolio success HARMONY Property predictions are dynamically trained on measured data to rapidly optimize accuracy within novel chemical space. Early Program 2 Hit MTAP Program 3 AI trained ADME models predict key readouts to drive lead optimization Early Program 1 Exemplar Early Hit Compound IC50 Similarity LLE Early Hit 2.6uM --- 3.9 Exemplar 13nM 0.63 5 Generative Design augments exploration of orthogonal space which is then evaluated by FEP Compound Target 1 KD Target 2 KD Early Hit >600uM >600uM Exemplar 2.8uM 120uM HDX data enables the generation of an advanced compound which is 40x selective over a paralog with 95% Identity Stability measured high med.low Stability predicted highmed.low Permeability measured Permeability predictedSolubility predictedSolubility measured high med.low Human Hepatocyte Extraction (%) Caco-2 Permeability (PappA-B) Kinetic Solubility (24h, pH7)
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78 Transforming Virtual-HTS with Physics + AI to Accelerate New Target Hit ID • Pioneering GPU-powered platform that enables physics-based virtual screening with unprecedented speed, accuracy and scale • Advanced ABFEP optimization independent of target class Absolute FEP calculations at the scale and speed required to train reliable ML models AI/Physics-supported virtual ligand screens that enable success with FIC targets • 6-12 month accelerated path to chemical starting points • Generalizable to novel/hard targets with no known ligands ∆G 0 (BIND) Hits Docking ABFEP Rapid automated workflows with iterative training against experimental data for optimized compound prioritization Ground truth dataAbsolute binding free energy Implementation of custom forcefields, machine-learning interatomic potentials, C-alpha protein restraints and confined binding pockets
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79 Conclusion and Analyst Q&A Yujiro S. Hata IDEAYA Biosciences President and Chief Executive Officer
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80 IDEAYA 10-Year Anniversary Investor R&D Day • IDEAYA is targeting to have 9 clinical stage programs by YE2025 Darovasertib (Ph3, PKC) IDE397 (Ph2, MAT2A) IDE849 (Ph1, DLL3 ADC) IDE275 (Ph1, WRN) IDE161 (Ph1, PARG) • Developing Darovasertib as potential SOC across Uveal Melanoma patient journey, including neoadjuvant, adjuvant, and 1L metastatic settings • Next clinical growth drivers advancing rapidly >70 patients of IDE849/DLL3 TOP1 ADC First-in-Human Ph1 Data Presented at WCLC 2025 MTAP Franchise: IDE397/MAT2A-Trodelvy® First-in-Human Ph1 Expansion Data at R&D Day 2025 • IND-Engine enabled by computational AI/ML drug discovery capabilities • ~$1.2 billion pro-forma cash balance* and planned runway into 2030 with Servier partnership • Upcoming Catalysts: ESMO Oct 2025: >90 patients of Neoadjuvant UM data as Proffered Paper Oral Presentation SMR Oct 2025: >40 patients of First-Reported 1L MUM Median Overall Survival Data as Oral Presentation YE25’ to Q1 26’ PFS Results: 1L HLA-A2-(-) MUM to enable potential US Accelerated Approval filing Conclusion IDE705 (Ph1, POLQ) IDE892 (IND-Filed, PRMT5) IDE034 (Targeting IND Q4 25, Bispecific B7H3/PTK7 ADC) IDE574 (Targeting IND Q4 25, KAT6/7) *Based on cash, cash equivalents and marketable securities of approximately $991.9 million as of June 30, 2025 and an upfront payment of $210 million pursuant to the license agreement with Servier
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IDEAYA Visionto Build Industry Leading Precision Medicine Oncology Company 81 Analyst Q&A SM = Small Molecule; ADC = Antibody Drug Conjugate; POLQ = Pol Theta; WRN = Werner Helicase; HRD = Homologous Recombination Deficiency; MSI = Microsatellite Instability; TOP1 = DNA Topoisomerase 1 Our mission is to advance the discovery, development, and commercialization of transformative precision medicines to address unmet medical needs in cancer Potential First-in-Class Pipeline 7 Clinical / IND Stage (6 SM & 1 ADC) 2 IND-Enabling (1 SM & 1 ADC) Biomarker Populations GNAQ/GNA11 MTAP-Deletion HRD/BRCA MSI-High Potential First-in-Class Combos PKC-cMET MAT2A-PRMT5 POLQ-PARP Structural Biology First-in- Class Predictive Biomarkers AI / ML Informatics Neoadjuvant- Adjuvant Transformative Combinations IDEAYA Vision DLL3 B7H3/PTK7 8P11 WRN-PD1 PARG-TOP1 MAT2A-TOP1