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November 2020
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 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, or technology developments; 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. 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, 2019, its Quarterly Report on Form 10-Q for the quarter ended September 30, 2020, 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
defined patient biomarkers • Proven Management Team with deep business and scientific experience has built leading
private and public oncology biotech companies • Pharma Collaborations and Strategic Partnerships with Pfizer and GlaxoSmithKline,
including ~$3 billion in potential cash milestones • Strong Balance Sheet with Capital Efficient Model anticipated to fund operations into
2024 through multiple clinical catalysts over multiple programs • NASDAQ: IDYA
Leading Synthetic Lethality focused biotechnology company advancing transformative precision medicine therapies for cancer patients
• Synthetic lethality occurs when the simultaneous perturbation of two genes results in cell death
• Synthetic lethal genetic interactions with tumor-specific mutations may be exploited to develop anticancer therapies
• Large-scale screening for cancer-gene-specific synthetic lethal targets in human cells has progressed through advances in RNA interference and CRISPR-Cas9 editing
Synthetic Lethality
Synthetic Lethality provides a powerful approach to discover the next generation of precision medicine therapies for molecularly-defined patient populations, including MTAP-deletion (~15% of all solid tumors), BRCA/HRD, and high-MSI (16% CRC)
Reference: Charles Boone
Indication Biomarker Preclinical IND Enabling Phase 1 Phase 2 Status Collaboration
IDE397 MAT2A
PARG Solid Tumors Novel Biomarker In vivo Efficacy
Polθ Solid Tumors HRD In vivo Efficacy
WRN Solid Tumors High-MSI Chemistry SAR
DDT Solid Tumors Novel Biomarker Multiple DDT Targets and Biomarkers in Validation
IDEAYA’s Precision Medicine Oncology Pipeline
5
Precision Medicine Pipeline
(1) Pursuant to GSK Collaboration, Option and License Agreement: MAT2A and WRN: 50/50 US Profits + ex-US Royalties; Polθ: Global Royalties (2) Pursuant to CRUK Evaluation, Option and License Agreement, with ongoing Collaborative Research; IDEAYA controls all Commercial Rights (3) Pursuant to Pfizer Clinical Trial Collaboration and Supply Agreement; IDEAYA retains all IDE196 Commercial Rights
DDT = DNA Damage Target, WRN = Werner Helicase, Polθ = DNA Polymerase Theta, HRD = homologous recombination deficiency, MSI = microsatellite instability PKC = protein kinase C, MUM = metastatic uveal melanoma
(1)
(1)
(1)
(2)
Indication Biomarker Preclinical IND Enabling Phase 1 Phase 2 Status Collaboration
IDE196 PKC inhibitor
Ph2 Expansion in Skin Melanoma
MUM MEK Combo GNAQ/11 FPI (MUM) June 2020
Enrollment Ongoing (MUM)
MUM cMET Combo GNAQ/11 Targeting FPI (MUM) Late 2020 to Early 2021
(3)
(3)
6
• Validates IDEAYA Synthetic Lethality platform • Enhances collective leadership in Synthetic Lethality • Creates strategic combination opportunities
Transformative Strategic Partnership
• Targets: MAT2A, Pol Theta and Werner Helicase • Modalities: small molecule inhibitors & protein degraders • $100M cash upfront • $20M equity investment as direct private placement • $50M option exercise fee for MAT2A • 50/50 US profit share for MAT2A and Werner Helicase • 20% global development cost share for US profit share • Potential preclinical, clinical and sales milestones for each
licensed product • Royalties tiered high single-digit to sub-teen double digit %
Key Partnership Terms
DNA Polymerase Theta
• 50/50 US Profit Share and ex-US Royalties • 20% global development cost share • Cash payments upon preclinical, clinical and sales milestones
WRN Helicase
• Milestones and global royalties • Cash payments upon preclinical, clinical and sales milestones
• IDEAYA leads early clinical; GSK option to exclusive license • $50M Option Exercise Fee • 50/50 US Profit Share and ex-US Royalties • 20% global development cost share • Cash payments upon clinical and sales milestones
IDEAYA Form 8-K current report filed with the U.S. Securities and Exchange Commission on June 16, 2020
IDEAYA and GSK Strategic Partnership
7
Protein Degrader
Zejula™ PARP+
Patient Population
MTAP Deletion
Potential Combinations of IDEAYA SL + GSK Programs
IDEAYA Form 8-K current report filed with the U.S. Securities and Exchange Commission on June 16, 2020; GlaxoSmithKline Q2 2020 Earnings Presentation
Werner Helicase Dostarlimab (Ph 3) PD-1
+ MSI-H
8
Bioinformatics, including AI Algorithms
Dual CRISPR, CRISPR, siRNA
Small Molecule Chemistry
Protein Degrader Capabilities
• Potential 1st-in-class SL targets identified and validated, such as WRN, Pol Theta and PARG
• DECIPHER™ - Dual CRISPR SL Library in DDR in collaboration with UCSD
• PAGEO™ - Paralogous Gene Evaluation in Ovarian, in collaboration with Broad Institute
• Partnership Datasets • Public Databases
• Crystal structures for four SL programs obtained to enable SBDD
• Three SL programs advanced to in vivo efficacy in target genetic settings
• Potential best-in-class molecules discovered, including MAT2Ai, IDE397
• Protein degraders advancing for selected targets, including Pol Theta
Clinical Biomarker
Proteomics – Protein Expression Profiling
IDEAYA Synthetic Lethality Platform
cell lines and model systems • Analysis of human clinical
samples and correlation with clinical trial outcomes
Fully-Integrated Target, Biomarker, and Drug Discovery Capabilities
Partnership Datasets Cancer Dependency Map – Broad Institute Foundation Insights™ – Foundation Medicine
9
DECIPHER™ Dual CRISPR SL Library in DNA Damage Repair (2)
PAGEO™ Paralogous Gene Evaluation in Ovarian Cancer (1)
Public Databases IDEAYA data mining and analysis across data sets
Evaluation of SL targets in context of functionally redundant paralogous genes in ovarian cancer
Evaluation of DNA Damage Targets synthetic lethal with tumor suppressor or oncogenes
Novel Synthetic Lethality Platform and Data Integration • IDEAYA SL Platform integrates extensive proprietary and public data sets with orthogonal and complementary content • Bioinformatics enables identification and validation of synthetic lethal target / biomarker interactions across vast datasets • Robust SL interactions validated genetically (Dual CRISPR, paralogues, isogenic pairs, CRISPR/siRNA) and pharmacologically
(1, 2) IDEAYA Proprietary Libraries and Datasets – Strategic Collaborations with Broad Institute(1) and UC San Diego(2)
IDEAYA Team and Scientific Advisory Board
10
IDEAYA Executives & R&D Leadership
IDEAYA Scientific Advisory Board
Paul Stone, J.D. SVP, Chief Financial Officer
Michael Dillon, Ph.D. SVP, Chief Scientific Officer Head of Research
Mark Lackner, Ph.D. SVP, Head of Biology & Translational Sciences
Mick O’Quigley, M.B.A. VP, Development Operations
Paul Barsanti, Ph.D. VP, Head of Drug Discovery
Jason Throne, J.D. SVP, General Counsel
Alan D’Andrea, M.D. IDEAYA SAB Chair Harvard Medical School, Professor Director, Center of DNA Damage and Repair, Dana Farber
William Sellers, M.D. Broad Institute, Dana Farber, and Harvard, Professor Novartis, Former Head Oncology Research, SL Project Drive initiative
Frank McCormick, Ph.D. UCSF, Professor and former Director, Helen Diller Cancer Center Former President AACR; Founder and CSO, Onyx
Trey Ideker, Ph.D. UCSD, Professor, Co-Director Cancer Genomes & Networks Program, Research in Dual-CRISPR and SL interaction maps
Jeffrey Hager, Ph.D. Former Chief Technology Officer, IDEAYA
Elizabeth Swisher, M.D. University of Washington, Professor; Co-Leader, Breast and Ovarian Cancer Research Program, Seattle Cancer Care Alliance Principal Investigator on multiple PARP inhibitor trials
Brian Daniels, M.D. Bristol Myers Squibb, Former SVP Global Development & Medical Affairs
IDEAYA is Advancing the Next Generation of Synthetic Lethality Therapies
11
Rubraca (Clovis) Talzenna (Pfizer)
MAT2A MTAP-Deletion
WRN High-MSI
HRD = Homologous Recombination Deficiency, MSI = Microsatellite Instability
MTAP Deletion PrevalenceMTAP-MAT2A Synthetic Lethality Biology
MAT2A Inhibition is Synthetic Lethal with MTAP Deletion
12
MTAP Deletion Prevalence ~15% of all Solid Tumors
Data from The Cancer Genome Atlas in cBioPortal
Cancer Type N MTAP Deletions (%) Glioblastoma 592 41 Mesothelioma 87 32 Esophageal 95 28 Bladder 411 26 Pancreatic 184 22 Melanoma 448 16 Lung Cancer (NSCLC) 1053 15 Head and Neck 523 14 Sarcoma 255 10 Esophagogastric 514 10 Diffuse Glioma 513 9 Breast 1084 3 Ovarian 585 3 Adrenocortical 92 3 Thymic 123 3 Hepatocellular 369 3 Renal non-clear cell 348 2
MAT2A
SAM
PRMT5
MTAP
MTA accumulation partially inhibits PRMT5
Loss of methylation function of PRMT5 results in defects in RNA splicing, gene
expression and genome integrity
Inhibition of MAT2A results in reduction of SAM, starving PRMT5
of its substrate
Differentiated Profile vs Agios Compounds; Selective for MTAP-/- Cell Lines
IDE397 demonstrates greater in vivo efficacy at 5 to 10mg/kg
• More potent vs. AGI-25696 at 1/30th to 1/60th the dose in MTAP-deletion models
IDE397 has not caused liver injury or increased unconjugated bilirubin
• Liver injury not observed in tox studies • Not an inhibitor of UGT1A1
IDE397 has favorable physical properties, including solubility
• AG-270 observed non-linear exposure >200mg QD (GI absorption)
Targeting IND in December 2020
IDE397 vs Agios Compounds IDE397 is Selective for MTAP-/- Cell Lines
IDEAYA Data
In cr
ea se
d se
ns iti
vi ty
ID E3
97 tr
ea tm
en t
MTAP-/- cell lines are sensitive to IDE397 MTAP WT cell lines are insensitive Pharmacological inhibition correlates with MAT2A genetic knockdown
MTAP WT MTAP-/-
300
600
900
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Enhanced In Vivo Efficacy in MTAP-/- Engineered and Endogenous Models
HCT 116 MTAP-/- Model
100
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First dose Day 1
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-80
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20
100 mpk
300 mpk
IDE397 In Vivo Efficacy in HCT116 model at 1/20th to 1/60th of the dose, and in KP4 model at 1/30 of the dose of Agios MAT2A compound
Published AG-270 preclinical dose is typically 200 mg/kg QD
IDE397 PD Modulation in HCT116 model: IDE397 significantly reduces tumor SAM levels at 5 mg/kg
Dose-Dependent Efficacy in MTAP-/- Endogenous NSCLC Model IDE397 Demonstrates Monotherapy Tumor Regression
In Vivo Endogenous NSCLC MTAP-/- Model
IDEAYA Data
500
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Vehicle control 3 mg/kg IDE397 10 mg/kg IDE397 30 mg/kg IDE397
IDE397 In Vivo Efficacy is being evaluated in over 40 patient derived xenograft (PDX) models with homozygous MTAP deletions in solid tumors, including in NSCLC
PARG Synthetic Lethality Program
Pillay et al., Cancer Cell Mar 2019
March 2019
DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-ribose) Glycohydrolase Inhibitors
PARGi demonstrate cell viability effects in ovarian cell lines resistant to PARPi
PARG & DNA Replication VulnerabilitiesPARG Biology
PARG
IDB-PARG Potency
Cell Viability EC50 510 nM
• Extensive research in PARG biology and chemistry
• Multiple collaborations ongoing to refine patient selection biomarker strategy
IDEAYA has discovered potent PARG inhibitors SAR guided by structure-based drug design
PARG Inhibitor In Vivo PD and Efficacy DataPARG Drug Discovery Program
PARG Synthetic Lethality Program
17
Drug Discovery on Potential 1st in Class DDR Synthetic Lethality Target
IDEAYA PARG inhibitors demonstrate in vivo TGI in a model with a replication stress gene signature
Significant tumor PAR accumulation observed in vivo
IDEAYA Data IDEAYA Data
10
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7 14 21 28 0
500
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• IDB-PARG demonstrates differentiated activity relative to PARP inhibitor niraparib
• Targeting PARG development candidate in 2021
PARG Synthetic Lethality Program
Robust Monotherapy Activity Observed in Multiple PDX Models
IDEAYA Data
250
500
750
1000
PDX-1
250
500
750
1000
PDX-2
Project Drive: Werner is essential in MSI-high cancer cell lines
Werner Syndrome Helicase is Required for the Survival of Cancer Cells with Microsatellite Instability
IDEAYA Publication
• Discovery: multiple hit discovery campaigns using a range of screening formats and compound libraries completed
• Screening: robust suite of biochemical and biophysical assays to identify WRN inhibitors and differentiate false positives
• Structurally Enabled: crystal structure of WRN helicase domain solved
• Lead Series: identified a lead series with <10 nM IC50 potency in a Werner helicase biochemical assay
• >10,000x potency improvement obtained through ongoing SAR
Werner Helicase Drug DiscoveryWerner Helicase Biomarker
WRN
19
Candidate Biomarker: High-MSI (15% GI Cancers and 16% CRC) 1
IDB-WRN1 ATPase IC50 = ~30 µM
IDB-WRN2 ATPase IC50 < 10 nM
IDEAYA Data Project Drive
0
20
40
60
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WRN Inhibitors Phenocopy Genetic KnockdownWRN Inhibitor Cellular PD and Viability
WRN inhibitor
WRN siRNA
20
Candidate Biomarker: High-MSI (15% GI Cancers and 16% CRC) 1
IDEAYA Data
• PD-marker: dose dependent increase of DNA damage marker γH2AX demonstrated at 48 hours
• Cell viability: MSI-high specific cell viability effect observed across multiple cell lines; no effect in MSS cell lines
• Target Milestone: In vivo efficacy data in 2020
IDEAYA Data
Polθ Inhibitor In Vivo ActivityPolθ Inhibitor Cell Viability
PolQ
• Combination of Polθi with niraparib enhances activity of niraparib in DLD1 BRCA2-/- xenograft model
• Regressions observed for all animals dosed with combination in the study
Polθ Synthetic Lethality Program
IDEAYA Data
IDEAYA Polθ ATPase inhibitors show cell viability effects in DLD1 BRCA2-/- cell lines
Advancing preclinical research for small molecule inhibitors and protein degraders
IDEAYA Data
50
100
134% TGI
86% TGI
55% TGI
250
500
750
MUM Indication: Focus on Clinical Combinations
IDE196 + MEK – FPI June 2020
IDE196 + cMET – Target FPI Late 2020 / Early 2021
Pfizer Clinical Trial Collaboration and Supply Agreement
Metastatic Uveal Melanoma (MUM) IDE196 Combination Therapies
IDE196
• IDE196 Combination Therapies: MUM Indication Study goals are to identify tolerated combo dose and enhance clinical activity in MUM
– IDE196 BID Monotherapy in MUM (30 pts), ~73% Disease Control Rate & ~13% ORR (AACR 20191) – IDE196 + MEK inhibitor preclinical synergy demonstrated in uveal melanoma (AACR 20202) – IDE196 + cMET inhibitor preclinical synergy and retrospective analysis of human clinical samples support cMETi combination 3
IDE196 + MEK (binimetinib) – interim data anticipated 2021 IDE196 + cMET (crizotinib) – FPI anticipated late 2020 / early 2021
• IDE196 Monotherapy: GNAQ/GNA11 Basket Trial (Non-MUM) Phase 2 expansion in Skin Melanoma with 100% DCR and 1 confirmed PR (by RECIST V1.1) in first 4 evaluable patients Interim monotherapy data anticipated 2021; targeting to provide together with IDE196 / binimetinib combination interim data
22
GNAQ/11 Basket (Non-MUM): Evaluating Monotherapy
Ph2 Expansion in Skin Melanoma (July 2020)
In 4 evaluable Skin Melanoma patients observed 100% DCR and 1 confirmed PR by RECIST Guidelines (version 1.1)
GNAQ/GNA11 Basket Trial (Non-MUM) IDE196 Monotherapy
1 Novartis Data 2, 3 IDEAYA Data
23
IDE196 Monotherapy Confirmed PR by RECIST Guidelines (version 1.1) in Metastatic Skin Melanoma Patient with GNAQ Q209L Hotspot Mutation
Clinical Background CT Scan at Baseline and 20 Weeks
20 weeks
Baseline• Nivo, ipi, and pembro treatment through 2016 and 2017; progressed with liver metastases in 2018
• Restarted nivo in combination with radiation to liver lesions in 2018, and then T-VEC to cutaneous lesions in 2019
• Subsequent progression followed by adoptive T-cell therapy (TIL) May 2019; confirmed progression noted Feb 2020
• Started on IDE196 400mg BID Feb 2020
• PR (-31.1%) at 8 weeks, sustained at 20 weeks (-37%) with reduction in target liver lesion and inguinal lymph node
• Ongoing treatment with IDE196
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3.5
2.5
0
1
2
3
4
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6
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(Patients in 1,000’s)
US and EU5 ~3.5 K GNAQ/11 Metastatic Uveal Melanoma (MUM) ~2.5 K GNAQ/11 Other Solid Tumors (Hotspot)
0
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(Patients)
GNAQ/11: The Cancer Genome Atlas (TCGA), IDEAYA Analysis ROS1 Advanced NSCLC: Turning Point Therapeutics 11/2019 corporate presentation, prevalence estimates (160,000 US + 117,000 EU5) x 2% mutation rate HRASm HNSCC estimates: KURA Oncology 11/2019 corporate presentation (2,900-4,700 patients US) FGFR2 rearrangements in cholangiocarcinoma: Incyte 6/2019 press release (~2,000-3,000 patients US/EU/JPN) TRK fusion: LOXO 11/2018 corporate presentation Ex 99.2 (2,500-3,000 patients US) 4L GIST estimates: Deciphera 11/2019 corporate presentation (~2,100 patients US)
GNAQ/11 Hotspot Patients in US & EU5 Rare Oncology Indication Comparables
Indication Biomarker Preclinical IND Enabling Phase 1 Phase 2 Target Milestones Through 2021 Collaboration
IDE397 MAT2A
Solid Tumors MTAP IND December 2020 Phase 1 Initiation H1 2021
PARG Solid Tumors Novel Biomarker Development Candidate 2021
Polθ Solid Tumors HRD Development Candidate 2021
WRN Solid Tumors High-MSI Lead Optimization 2021
DDT Solid Tumors Novel Biomarker Multiple DDT Programs in Chemistry Optimization
IDEAYA’s Precision Medicine Oncology Pipeline
25
Precision Medicine Pipeline
= Target Program Milestone through 2021 (1) Pursuant to GSK Collaboration, Option and License Agreement: MAT2A and WRN: 50/50 US Profits + ex-US Royalties; Polθ: Global Royalties (2) Pursuant to CRUK Evaluation, Option and License Agreement, with ongoing Collaborative Research; IDEAYA controls all Commercial Rights (3) Pursuant to Pfizer Clinical Trial Collaboration and Supply Agreement; ; IDEAYA retains all IDE196 Commercial Rights
DDT = DNA Damage Target, WRN = Werner Helicase, Polθ = DNA Polymerase Theta, HRD = homologous recombination deficiency, MSI = microsatellite instability PKC = protein kinase C, MUM = metastatic uveal melanoma
(1)
(1)
(1)
(2)
Indication Biomarker Preclinical IND Enabling Phase 1 Phase 2 Target Milestones Through 2021 Collaboration
IDE196 PKC inhibitor
Interim Data 2021
Interim Data 2021
MUM cMET Combo GNAQ/11 cMET Combo Phase 1 and Phase 2 Expansion
Enrollment Ongoing
IDEAYA and GSK Strategic Partnership
IDEAYA and GSK Strategic Partnership
IDEAYA Synthetic Lethality Platform
IDEAYA Synthetic Lethality Platform
IDEAYA is Advancing the Next Generation of Synthetic Lethality Therapies
MAT2A Inhibition is Synthetic Lethal with MTAP Deletion
IDE397: MAT2A Development Candidate
IDE397: MAT2A Development Candidate
PARG Synthetic Lethality Program
PARG Synthetic Lethality Program
PARG Synthetic Lethality Program
Polq Synthetic Lethality Program
IDE196 Phase 1/2 Clinical Program Summary
IDE196 Monotherapy Confirmed PR by RECIST Guidelines (version 1.1) in Metastatic Skin Melanoma Patient with GNAQ Q209L Hotspot Mutation
IDE196 Potential Addressable Market Solid Tumors Having GNAQ/11 Hotspot Mutations
IDEAYA’s Precision Medicine Oncology Pipeline