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Item 7. Management’s Discussion and Analysis

2022-03-18 compared with 2021-03-23 · 241 added, 152 removed, 234 unchanged (63% of the section changed)

Management’s Discussion and Analy sis of Financial Condition and Results of Operations

Management’s Discussion and Analysis of Financial Condition and Results of Operations

You should read the following discussion and analysis of our financial condition and results of operations together with our financial statements and the related notes included elsewhere in this report.

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Our approach integrates small molecule drug discovery with extensive capabilities in identifying and validating translational biomarkers to develop targeted therapies for select patient populations most likely to benefit.

We are applying these capabilities to develop a robust pipeline in precision medicine oncology, with a research and development focus in synthetic lethality—which represents an emerging class of precision medicine targets.

IDE397 – MAT2A Inhibitor Development Candidate

Our most advanced synthetic lethality research program targets methionine adenosyltransferase 2a, or MAT2A, for solid tumors with methylthioadenosine phosphorylase, or MTAP, deletions, a patient population estimated to represent approximately 15% of solid tumors.

Our MAT2A inhibitor development candidate is designated as IDE397.

We submitted an IND, to the FDA for IDE397, which is now effective.

We are initiating a Phase 1 clinical trial for evaluation of IDE397 as monotherapy, and are targeting First-Patient-In in the Phase 1 clinical trial in the first quarter of 2021.

Initial clinical development plans to evaluate IDE397 include a dose escalation portion of the Phase 1 clinical trial in which we plan to enroll patients having solid tumors with MTAP deletion identified by commercial or institutional next generation sequencing, or NGS, panels, and in some cases also confirmed by an MTAP immunohistochemistry, or IHC, assay.

Following and subject to satisfactory completion of the dose escalation portion of the Phase 1 clinical trial, we plan to enroll patients having solid tumors with MTAP deletion into one or more expansion arms focused on selected solid tumor indications.

We plan to obtain patient biopsies from the dose escalation and expansion portions of the clinical trial for translational research, including evaluation of certain pharmacodynamic, or PD, biomarkers, such as peripheral S-adenosyl methionine, or SAM, and tumor SAM as determined by liquid chromatography / mass spectroscopy, or LCMS, assays, and tumor symmetrical dimethyl arginine, or SDMA, as determined by enzyme linked immunosorbent assay, or ELISA, IHC assay and/or LCMS assay.

We have a program objective to obtain preliminary clinical PD data from the dose-escalation portion of the IDE397 monotherapy Phase 1 clinical trial in the second half of 2021.

We are continuing to advance certain preclinical activities to support IDE397 as a clinical candidate.

We are evaluating the efficacy of monotherapy IDE397 in over forty solid tumor patient derived xenograft, or PDX, models with homozygous MTAP deletions across a range of solid tumor types.

Preliminary results of this IDE397 MTAP-deletion PDX Panel Study show in vivo efficacy in multiple MTAP-null xenograft models, demonstrating tumor growth inhibition when MAT2A is pharmacologically inhibited with IDE397 as monotherapy, including in non-small cell lung cancer.

In this study, we observed > 75% Tumor Growth Inhibition, or TGI, in ~ 50% of models and across major solid tumor types.

We also observed tumor regressions, with > 100% TGI, in multiple PDX models and across multiple solid tumor types.

We are planning to present data summarizing the results of the IDE397 MTAP-deletion PDX Panel Study at the 2021 Annual Meeting of the American Association for Cancer Research, or AACR in April 2021.

We also plan to present preclinical data at AACR in April 2021 evaluating the effects of pharmacological inhibition of MAT2A, including analyses of genomic and metabolic effects in an isogenic cell pair and of proliferation effects in a panel of MTAP wild type and MTAP-deleted cell lines.

We have completed the good laboratory practice, or GLP, compliant toxicology studies with IDE397 in multiple species.

Preclinical combination tolerability and efficacy studies are ongoing to evaluate IDE397 in combination with GSK oncology assets , as well as other potential oncology agents, including taxanes .

We plan to lead research and development of IDE397 through early clinical development, in collaboration with GlaxoSmithKline pursuant to the Collaboration, Option and License Agreement, or the GSK Collaboration Agreement, with an affiliate of GlaxoSmithKline, GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO.

4), Limited, or GSK.

We are advancing our preclinical research for an inhibitor of poly (ADP-ribose) glycohydrolase, or PARG, for patients having tumors with a defined biomarker based on genetic mutations and/or molecular signatures.

One of our PARG inhibitor compounds, designated as IDB-PARG, has demonstrated dose-dependent in vivo efficacy as monotherapy with tumor regression or stasis in multiple PDX models and in multiple cell-derived xenograft, or CDX, models.

We observed tumor regressions (> 100% TGI) in multiple breast cancer PDX models with defined genetic and subtyping profiles.

We also observed tumor regressions and enhanced TGI relative to niraparib in multiple CDX models, including in vivo efficacy in a niraparib-resistant resistant CDX model.

We plan to present data at AACR in April 2021 summarizing the results of our preclinical studies evaluating the effects of pharmacological inhibition of PARG in a panel of homologous recombination deficient cell lines and in CDX and PDX models.

We are continuing to evaluate the efficacy of IDB-PARG as monotherapy across a panel of additional solid tumor PDX models with specific genetic alterations.

We entered into a strategic collaboration with the Broad Institute of MIT and Harvard, or Broad Institute, focused on synthetic lethality target and biomarker discovery.

Under our collaboration with the Broad Institute, we are evaluating pharmacological inhibition across a panel of cell lines using the Broad Institute’s PRISM platform to inform patient selection for potential clinical development of a PARG inhibitor.

PRISM is a high-throughput, multiplexed screening platform which we are using to evaluate our proprietary small molecule PARG inhibitor for activity against a curated panel of more than 750 genomically-characterized human cancer cell lines representing > 45 lineages.

We are also collaborating with the Broad Institute to evaluate paralogous CRISPR knockdown in selected cell lines in conjunction with pharmacological inhibition of PARG to inform patient selection and combination strategies in ovarian and breast cancer.

We have extended the option period during which IDEAYA has rights to exercise an option to certain license rights under the Evaluation, Option and License Agreement with Cancer Research UK and University of Manchester, or CRUK-UMann Agreement to September 2022.

The eighteen month extension of the option period was effected pursuant to the terms of the March 2020 amendment to the CRUK-UMann Agreement.

Subject to further preclinical studies, we are targeting to identify a PARG inhibitor development candidate in 2021.

Our small molecule drug discovery expertise includes discovery and development of small molecule inhibitors and protein degrader modalities.

We are applying these capabilities to develop a robust pipeline in precision medicine oncology, with a research focus in synthetic lethality – which represents an emerging class of precision medicine targets.

IDE397 – MAT2A Inhibitor Clinical Candidate

Our most advanced synthetic lethality product candidate is IDE397, a clinical-stage methionine adenosyltransferase 2a, or MAT2A, inhibitor being developed for solid tumors with S-methyl-5'-thioadenosine phosphorylase, or MTAP, deletions.

We are leading research and development of IDE397 through early clinical development, in collaboration with GSK pursuant to the GSK Collaboration Agreement.

Our initial clinical development plans to evaluate IDE397 include a dose escalation portion of the Phase 1 clinical trial.

We are enrolling patients having solid tumors with MTAP deletion identified by commercial or institutional next generation sequencing, or NGS, panels or by MTAP immunohistochemistry, or IHC, assay with confirmation by NGS.

We are currently enrolling patients into Cohort 6 of the dose escalation cohort of the Phase 1 clinical trial.

As of March 1, 2022, we have enrolled an aggregate total of 16 patients in the Phase 1 IDE397 clinical.

These patients collectively have various solid tumor types with MTAP-deletion, including NSCLC, pancreatic cancer, thymic cancer, adenoid cystic carcinoma, gastroesophageal cancer, and bladder cancer.

As of March 1, 2022, IDE397 has been generally well tolerated with mainly Grade 1/2 drug-related adverse events, and one patient who experienced drug-related Grade 3 asthenia that resolved after reducing the dose of IDE397.

There were no reported drug-related serious adverse events, no observed dose limiting toxicities, or DLTs, and IDE397 had not yet reached its maximum tolerated dose, or MTD.

Following and subject to satisfactory completion of the dose escalation portion of the Phase 1 clinical trial, we plan to enroll patients having solid tumors with MTAP deletion into one or more monotherapy expansion arms focused on one or more selected solid tumor indications.

We also plan to evaluate IDE397 in combination with one or more combination agents in patients having tumors with MTAP-deletion.

Potential solid tumors we are considering for future evaluation in one or more expansion arm(s) and/or combination arm(s) of the clinical trial evaluating IDE397 include NSCLC, head and neck cancer, bladder cancer, gastric cancer, pancreatic cancer and esophagogastric cancer, among others.

We have submitted a protocol amendment to the FDA to support cohort expansion as monotherapy in NSCLC, esophagogastric cancer and other indications, including potentially in one or more basket cohorts.

This amendment will also support evaluation of IDE397 combination therapies with taxanes and other potential combination agents, for example, in NSCLC, esophagogastric and/or pancreatic cancer.

Subject to satisfactory progression of the dose escalation portion of the Phase 1 clinical trial, we are targeting cohort expansion mid-year 2022.

The timing of the expansion and/or combination cohorts may be influenced by when we define the MTD.

The clinical trial design for the expansion portion of the Phase 1 clinical trial includes an aggregate of 150 or more patients across expansion cohorts.

We are obtaining patient biopsies for translational research from dose escalation cohorts and tumor biopsy backfill cohorts in the IDE397 Phase 1 clinical trial and we also plan to obtain patient biopsies from expansion cohorts in the clinic al trial.

We are evaluating pharmacodynamic, or PD, biomarkers, such as peripheral or plasma SAM and tumor SAM, as well as SDMA.

We observed dose-proportional pharmacokinetic exposures across dose ranges of Cohort 1 through Cohort 5 of the Phase 1 dose escalation.

The observed exposures at doses of Cohort 4 and Cohort 5 exceeded active exposure targets established from preclinical models.

We observed preliminary clinical activity with monotherapy in early dose escalation cohorts, including pharmacodynamic response in plasma SAM and tumor reductions in multiple patients with MTAP deleted advanced or metastatic solid tumors.

We observed a dose- and/or exposure-dependent pharmacodynamic modulation, reflected as a reduction in plasma SAM, a proximal pharmacodynamic marker, in evaluable plasma samples across dose ranges of Cohort 1 through Cohort 5 of the IDE397 Phase 1 dose escalation clinical trial, satisfying the clinical protocol threshold of approximately 60% or greater.

We have initiated tumor biopsy cohorts in the IDE397 Phase 1 clinical trial to evaluate tumor pharmacodynamic, or PD, biomarkers.

The clinical protocol threshold was established based on IDE397 preclinical in vivo efficacy data in MTAP-deletion xenograft models.

We observed robust, dose- and/or exposure-dependent pharmacodynamic modulation of symmetric dimethyl arginine, or SDMA, in evaluable tumor biopsies from Cohort 4 and Cohort 5.

We also observed tumor shrinkage in multiple patients in early dose escalation Cohorts 2 and 3 (n=3, n=2, respectively), including in a Cohort 2 NSCLC patient (approximately 15% reduction in target lesions) and in a Cohort 3 adenoid cystic carcinoma patient with a lung metastasis (approximately 11% reduction in target lesions), pursuant to RECIST v1.1 criteria.

Subject to initiation of an expansion cohort or establishing a MTD, we are targeting delivery of an IDE397 option data package to GSK mid-year 2022.

Delivery of the option data package would trigger an evaluation period for GSK to make a decision on whether to exercise its option to develop IDE397.

We have a program objective to obtain additional clinical PD data during dose escalation.

The GSK option data package comprises preclinical data and clinical data from the IDE397 monotherapy dose escalation study of the Phase 1 clinical trial, including safety and tolerability data, pharmacokinetic data and pharmacodynamic modulation of SAM and tumor SDMA.

The GSK option is exercisable within a certain period after we deliver the option data package.

Subject to GSK’s election to opt‐in and , if required, HSR clearance, we are entitled to receive a $50 million opt‐in payment from GSK.

If GSK exercises its option and makes the related $50 million payment to us, GSK would lead later-stage global clinical development.

We will be responsible for 20% of future development costs and GSK will be responsible for 80%.

Assuming GSK decides to exercise the option, we will be eligible to receive future development and regulatory milestones of up to $465 million.

If GSK decides to exercise the option and upon commercialization, we will also receive 50% of U.S.

net profits and tiered royalties on global non-U.S.

net sales ranging from high single digit to sub-teen double digit percentages, as well as certain commercial milestones of up to $475 million.

Our evaluation of IDE397 as a clinical candidate is supported by preclinical data.

We have evaluated the efficacy of IDE397 as monotherapy in over forty solid tumor patient derived xenograft, or PDX, models with homozygous MTAP deletions.

Results of this IDE397 MTAP-deletion PDX panel study were reported at AACR 2021 and showed in vivo efficacy in multiple MTAP-null xenograft models demonstrating tumor growth inhibition, or TGI, when MAT2A was pharmacologically inhibited with IDE397 as monotherapy.

In this study, we observed greater than 60% TGI, in approximately 75% of the models and greater than 75% TGI in approximately 50% of models, in each case across major solid tumor types.

We also observed tumor regressions, with greater than 100% TGI, in multiple PDX models and across multiple solid tumor types, including in NSCLC as well as in bladder and gastric cancer PDX models.

In NSCLC, data from the preclinical PDX Panel Study has shown greater than 60% TGI in 12 independent NSCLC PDX models out of 14 models evaluated, including in seven NSCLC adenocarcinoma PDX models out of nine evaluated and in five NSCLC squamous carcinoma PDX models out of five evaluated.

Tumor regressions were observed in three of five NSCLC squamous PDX models, including a complete response in one model.

Additionally, we have observed preclinical dose- and/or exposure-dependent modulation of selected PD biomarkers, including SDMA, ADMA and SAM, in these in vivo models, including in NSCLC and HCT-116 MTAP deletion cell derived xenograft, or CDX, models.

We also observed a correlation of in vivo efficacy with dose-dependent PD modulation in MTAP-deletion CDX model in NSCLC.

We have ongoing mechanistic studies, including evaluating various pathway constituents such as SAM, MTA, SDMA, ADMA and other downstream metabolic and gene expression changes in in vitro and in vivo models.

Through our participation in the DepMap (Cancer Dependency Map) consortium led by the Broad Institute of MIT and Harvard, or Broad Institute, and in collaboration with GSK, we have conducted a PRISM screen of a panel of over 800 cell lines for pharmacological sensitivity to IDE397.

This PRISM screen has identified differential selectivity across tumor lineages, potentially enabling additional biomarker discovery and clinical opportunity expansion for IDE397.

Preclinical tolerability and efficacy studies are ongoing with IDE397 and various potential combination agents.

Based on preliminary results, we have observed in vivo efficacy with enhanced TGI for IDE397 in combination with a taxane in a pancreatic cancer PDX model.

We have also demonstrated preclinical in vivo efficacy of IDE397 plus standard-of-care combination agents, including with paclitaxel in head and neck cancer PDX model.

We have also observed in vivo efficacy with enhanced TGI in CDX / PDX models for IDE397 in combination with other DNA Damage Response, or DDR, target inhibitors, and for IDE397 in combination with certain precision medicine target inhibitors in tumors having certain identified genetic alterations as co-alterations with MTAP.

We are advancing our preclinical research for an inhibitor of poly (ADP-ribose) glycohydrolase, or PARG, for patients having tumors with homologous recombination deficiencies, or HRD, and potentially other genetic and/or molecular signatures.

We are targeting to submit an IND for our development candidate, IDE161, in the fourth quarter of 2022, subject to satisfactory completion of ongoing preclinical and IND-enabling studies.

We are also continuing preclinical evaluation of additional compounds in the lead series as an additional potential development candidate or back-up compound.

We are evaluating the efficacy of our PARG inhibitors as monotherapy across a number of solid tumor CDX and PDX models with specific genetic alterations.

One of our PARG inhibitor compounds, designated as IDB-PARG, has demonstrated dose-dependent in vivo efficacy as monotherapy with tumor regression or stasis in multiple CDX models and PDX models, including in ovarian cancer, gastric cancer and breast cancer models.

In vivo studies in CDX and PDX models have shown evidence of differentiation from a PARP inhibitor, niraparib, including enhanced TGI relative to such PARP inhibitor and, in certain models, tumor regressions in models which are refractory to such PARP inhibitor.

We have also observed dose-dependent modulation of a PD biomarker, PAR, polymer chains across multiple in vivo CDX models, including in ovarian cancer, gastric cancer and breast cancer models.

We are preclinically evaluating and conducting IND-enabling studies for IDE161, our PARG inhibitor development candidate.

Such studies include evaluation of IDE161 as monotherapy in in vivo efficacy studies ongoing in multiple genetic settings, as well as in cell panel studies to validate and potentially identify new biomarker hypotheses.

We are supplementing our data set for indications and patient settings which are sensitive to pharmacological inhibition of our PARG inhibitors.

In January 2022, we exercised our option under the Evaluation, Option and License Agreement between IDEAYA and Cancer Research Technologies, also known as Cancer Research United Kingdom, or Cancer Research UK, and the University of Manchester, pursuant to which we hold exclusive worldwide license rights covering a broad class of PARG inhibitors.

We have an ongoing strategic collaboration with the Broad Institute focused on synthetic lethality target and biomarker discovery.

Through this collaboration with the Broad Institute, we are evaluating paralog CRISPR knockdown in selected cell lines in conjunction with pharmacological inhibition of PARG to inform patient selection and combination strategies in ovarian and breast cancer.

We own or control all commercial rights in our PARG program, subject to certain economic obligations pursuant to our exclusive, worldwide license with Cancer Research UK / University of Manchester.

We are progressing our program targeting DNA Polymerase Theta, or Pol Theta or POLQ, in collaboration with GSK, for patients having solid tumors with BRCA or other homologous recombination deficiency, or HRD, mutations.

Subject to further preclinical studies, we are, in collaboration with GSK, targeting to initiate IND-enabling studies for our Pol Theta small molecule Pol Theta ATPase domain inhibitor in the first half of 2022.

We have shown combination activity of our Pol Theta ATPase inhibitor with multiple PARP inhibitors, including niraparib.

We have demonstrated synergistic in vivo efficacy of a Pol T heta ATPase inhibitor with niraparib:

the combination of our Pol Theta ATPase inhibitor with niraparib enhanced the activity of niraparib in the DLD1 BRCA2-/- xenograft model.

Tumor regressions were observed for all animals in the study which were administered the combination.

We plan to continue further development of our POLQ program, including both protein degraders and small molecule inhibitors, in collaboration with GSK pursuant to the GSK Collaboration.

We have the potential to receive up to $20 million in aggregate milestone payments from GSK for certain milestones, which may occur as we, in collaboration with GSK, advance a Pol Theta helicase inhibitor from preclinical development into early Phase 1 clinical trials.

Werner Helicase

We are also continuing to advance our preclinical research in collaboration with GSK for an inhibitor targeting Werner Helicase, or WRN, for patients having tumors with high microsatellite instability, or MSI.

We have observed dose-dependent cellular viability effect and a dose-dependent cellular pharmacodynamic, or PD, response in multiple endogenous MSI high cell lines.

We have also demonstrated preliminary in vivo efficacy and PD response in a relevant MSI high model.

We have observed dose-dependent cellular viability effect and a dose-dependent cellular PD, response in multiple endogenous MSI high cell lines.

We have also demonstrated in vivo efficacy and PD response in a relevant MSI high model.

We observed Werner Helicase inhibitor in vivo efficacy in a CDX model with approximately 100% tumor growth inhibition.

We are, in collaboration with GSK, targeting nomination of a Werner Helicase inhibitor development candidate in 2023.

For this program, we plan to continue further development in collaboration with GSK pursuant to the GSK Collaboration Agreement.

We are progressing our program targeting DNA Polymerase Theta, or Pol Theta or POLQ, in collaboration with GSK for patients having solid tumors with BRCA or other homologous recombination deficiency, or HRD, mutations.

We have shown combination activity with multiple PARP inhibitors, including niraparib.

We have demonstrated synergistic in vivo

efficacy of a Pol Theta inhibitor with niraparib:

the combination of our Pol Theta inhibitor with niraparib enhanced the activity of niraparib in the DLD1 BRCA2-/- xenograft model.

Tumor regressions were observed for all animals in the study which were administered the combination, which was well tolerated.

We plan to continue further development of our POLQ program, including both protein degraders and small molecule inhibitors in collaboration with GSK pursuant to the GSK Collaboration Agreement, and are targeting selecting a development candidate for a Pol Theta small molecule inhibitor in 2021.

DNA Damage Target

We have initiated early preclinical research programs to identify small molecule inhibitors for multiple distinct DNA Damage Targets, or DDTs, for patients with solid tumors characterized by a proprietary biomarker or a gene signature.

We have the potential to receive up to $20 million in aggregate milestone payments from GlaxoSmithKline for certain milestones which may occur as we, in collaboration with GSK, advance a Werner Helicase inhibitor from preclinical into early Phase 1 clinical trials.

Other Synthetic Lethality Pipeline Programs

We have initiated early preclinical research programs to identify small molecule inhibitors for a target in the MTAP-synthetic lethality pathway, or MTAP-SL.

We believe an MTAP-SL inhibitor may be complementary to our IDE397 clinical candidate targeting MAT2A as a combination of two synthetic lethality therapeutics for patients selected based on tumors harboring MTAP deletion.

We have also initiated early preclinical research programs targeting multiple distinct DNA Damage Targets, or DDTs, for patients with solid tumors characterized by proprietary biomarkers or gene signatures.

We own or control all commercial rights in our MTAP-SL and DDT programs.

Synthetic Lethality Target and Biomarker Discovery Platform

Synthetic lethality continues to be our core research focus.

We have invested significantly and continue to invest in capabilities for identification and validation of new synthetic lethality targets.

For targets of interest, we advance our research to discover therapeutic drugs and relevant biomarkers.

IDE196 - PKC Inhibitor Clinical Candidate

We continue to execute on our ongoing Phase 1/2 clinical trial and preclinical research activities for our clinical candidate IDE196, a protein kinase C, or PKC, inhibitor for genetically-defined cancers having activating GNAQ or GNA11 hotspot mutations, including in metastatic uveal melanoma, or MUM, skin melanoma and other solid tumors.

Our clinical trial strategy is to pursue IDE196 combination therapies in MUM, including with binimetinib, a MEK inhibitor, and independently with crizotinib, a cMET inhibitor, each pursuant to our Clinical Trial Collaboration and Supply Agreement, or Pfizer Agreement, with Pfizer.

We have formed a joint development committee with Pfizer responsible for coordinating all regulatory and other activities under the Pfizer Agreement, including for both the IDE196/binimetinib combination arm of the clinical trial and the IDE196/crizotinib combination arm of the clinical trial.

If the clinical data from either or both of these combination studies is positive, we plan to enter into good faith negotiations with Pfizer to determine a regulatory submission strategy.

We are continuing to evaluate IDE196 as monotherapy in non-MUM cancers, including in skin melanoma, where we have met the clinical protocol criteria for an expansion cohort, based on observing one confirmed partial response in an initial four evaluable patients.

Based on preliminary IDE196 monotherapy clinical data and its mechanism of action, we anticipate IDE196 clinical activity independent of Human Leukocyte Antigen (HLA) status in GNAQ/11-mutation cancers.

IDE196 / Binimetinib Combination Therapy

In June 2020, we initiated a combination arm of our Phase 1/2 clinical trial to evaluate IDE196 in combination with binimetinib in patients having tumors harboring activating GNAQ or GNA11 hotspot mutations.

An initial dose escalation portion of this arm of the clinical trial is evaluating the safety and efficacy of IDE196 in combination with binimetinib at various dose combinations, initially in patients with metastatic uveal melanoma, or MUM.

Following our evaluation of tolerability and preliminary efficacy from the IDE196 / binimetinib combination arm of the clinical trial in MUM, we may also evaluate IDE196 / binimetinib combination therapy in patients having other solid tumors with activating GNAQ/11 hotspot mutations outside of uveal melanoma, such as skin melanoma.

We are continuing patient enrollment into the IDE196 / binimetinib combination arm under the clinical trial collaboration and supply agreement with Pfizer.

We initiated dose expansion in the IDE196 / binimetinib Phase 1/2 study in MUM, based on an observation of early clinical activity of the combination in MUM.

We are targeting to enroll a total of approximately 40 patients in the IDE196 / binimetinib combination arm in MUM.

We anticipate interim data from the IDE196 / binimetinib combination therapy arm of the Phase 1/2 clinical trial in MUM patients in 2021.

IDE196 / Crizotinib Combination Therapy

In September, 2020, we expanded the scope of our Pfizer Agreement to evaluate IDE196 and crizotinib as a combination therapy in patients having tumors harboring activating GNAQ or GNA11 hotspot mutations.

In December 2020, we initiated a combination arm of our Phase 1/2 clinical trial to evaluate IDE196 in combination with crizotinib in patients having tumors harboring activating GNAQ or GNA11 hotspot mutations.

An initial dose escalation portion of this arm of the clinical trial will be evaluating the safety and efficacy of IDE196 in combination with crizotinib at various dose combinations, initially in patients with metastatic uveal melanoma, or MUM.

Following our evaluation of tolerability and preliminary efficacy from the IDE196 / crizotinib combination arm of the clinical trial in MUM, we may also evaluate IDE196 / crizotinib combination therapy in patients having other solid tumors with activating GNAQ/11 hotspot mutations outside of uveal melanoma, such as skin melanoma.

We are continuing patient enrollment into the IDE196 / crizotinib combination arm under the clinical trial collaboration and supply agreement with Pfizer.

We identified cMET as a potential biomarker and a cMET inhibitor as potential combination agent though our translational research studies, or IDE196 cMET Translational Studies.

In these studies, we observed preclinical synergies between IDE196 and crizotinib in relevant cellular models under conditions simulating a tumor microenvironment in the liver, the site of approximately 90% of uveal melanoma metastases.

Additionally, we conducted a retrospective analysis of human clinical samples from the Novartis IDE196 Phase 1 clinical trial, which also independently supported cMET expression / activation as potential biomarker / combination agent.

We are planning to present data summarizing the results of the IDE196 cMET Translational Studies at AACR in April 2021.

IDE196 Monotherapy

Our ongoing monotherapy arm of the Phase 1/2 clinical trial was initiated in June 2019 to evaluate IDE196 in solid tumors harboring GNAQ or GNA11 hotspot mutations in a basket trial design.

We have invested significantly and continue to invest in capabilities for identification and validation of new synthetic lethality targets and biomarkers for patient selection.

For targets of interest, we advance our research to discover therapeutic drug candidates and to further qualify relevant biomarkers.

We are also continuing to invest in our capabilities to advance our research on newly identified synthetic lethality targets of interest, including to enable discovery of therapeutic drugs and relevant biomarkers.

These investments include both additional research personnel and capital investments, which will enhance our capabilities broadly, including in target validation, biological assay development, protein synthesis, structural biology, computational chemistry, and analytical chemistry, among other core functional areas.

In December 2021, we acquired our INQUIRE™ Chemical Library to enhance our synthetic lethality drug discovery platform INQUIRE is a proprietary, expert-curated small-molecule library of over 200,000 chemical compounds, which we believe will enhance our hit discovery capabilities across a broad range of novel synthetic lethality targets and historically difficult-to-drug target classes, such as helicases and endonucleases.

Darovasertib – PKC Inhibitor Clinical Candidate

Synthetic Lethality Combination Therapies Targeting Oncogenic Pathways

Darovasertib (IDE196) is a clinical-stage, potent and selective small molecule inhibitor of protein kinase C, or PKC, for genetically-defined cancers having GNAQ or GNA11 gene mutations.

PKC is a protein kinase that functions downstream of the GTPases GNAQ and GNA11.

We are clinically evaluating darovasertib in a Phase 1/2 clinical trial, designated as IDE196-001, in solid tumors harboring GNAQ or GNA11 hotspot mutations in a basket trial design, including in metastatic uveal melanoma, or MUM, and other solid tumor indications such as skin (cutaneous) melanoma.

Our clinical trial strategy in MUM is to pursue darovasertib as a combination therapy with crizotinib, an investigational cMET inhibitor, pursuant to the Pfizer Agreement.

We have formed a joint development committee with Pfizer responsible for coordinating all regulatory and other activities under the Pfizer Agreement.

If the clinical data from the combination study is positive, we plan to enter into good faith negotiations with Pfizer to determine a regulatory submission strategy.

We are targeting to obtain guidance from the FDA in mid-year 2022 on a clinical trial design for enabling a potential registrational trial in MUM.

We are planning to present additional interim clinical data in from the MUM Phase 2 darovasertib/crizotinib arm of the clinical trial in mid-year 2022.

The timing of the clinical data and FDA guidance may be influenced by data maturity, including for example, appropriate interim assessments of median duration of response, or DOR, and/or median progression free survival, or mPFS.

Subject to FDA guidance, we will evaluate darovasertib and Pfizer’s cMET inhibitor, crizotinib, as a combination therapy in MUM in a Phase 2 potential registration-enabling clinical trial pursuant to the Second Pfizer Agreement.

Based on preliminary darovasertib monotherapy clinical data and its mechanism of action, we anticipate darovasertib clinical activity independent of Human Leukocyte Antigen, or HLA, status in GNAQ/11-mutation cancers.

In coordination with St.

Vincent’s Hospital Sydney Limited, we plan to initiate an Investigator Sponsored Trial, or IST, to evaluate darovasertib in a neo-adjuvant and adjuvant setting in primary, non-metastatic uveal melanoma, or UM, patients.

Data from this potential clinical trial may offer proof of concept on our hypothesis that earlier treatment of UM patients with darovasertib, prior to tumor metastasis, may lead to improved patient outcomes.

We are also clinically evaluating darovasertib in combination with crizotinib in non-MUM cancers having GNAQ/11 mutations, with a current focus in skin melanoma, pursuant to the Pfizer Agreement.

We are also evaluating other potential expansion opportunities in oncology for darovasertib.

We are planning to evaluate, subject to preclinical validation, darovasertib in combination with crizotinib in cMET-driven solid tumors such as hepatocellular carcinoma, or HCC, or NSCLC in a Phase 1 clinical trial pursuant to the Third Pfizer Agreement.

We are preclinically studying darovasertib in combination with a KRAS inhibitor in certain solid tumors.

Darovasertib / Crizotinib Synthetic Lethality Combination Therapy

In December 2020, we initiated a combination arm of our Phase 1/2 clinical trial under the Pfizer Agreement to evaluate darovasertib in combination with crizotinib in patients having tumors harboring activating GNAQ or GNA11 hotspot mutations.

An initial dose escalation portion of this arm of the clinical trial evaluated the safety and efficacy of darovasertib in combination with crizotinib at various dose combinations.

We initiated a Phase 2 expansion cohort in June 2021 to evaluate darovasertib / crizotinib combination therapy in MUM.

We are continuing patient enrollment into the Phase 2 clinical trial to evaluate the darovasertib / crizotinib combination in MUM and in patients having other solid tumors with activating GNAQ/11 mutations, with a focus on GNAQ/11 skin melanoma.

As of March 1, 2022, we have enrolled an aggregate total of 53 MUM patients in the darovasertib / crizotinib arm of Phase 1/2 clinical trial.

In MUM, we reported preliminary clinical data from the Phase 2 expansion cohort evaluating darovasertib and crizotinib synthetic lethal combination in December 2021, based on a data and analyses cutoff on November 25, 2021.

The preliminary interim data included:

(i) 100% Disease Control Rate, or DCR:

16 of 16 evaluable patients with at least one post-baseline scan showed tumor shrinkage as determined by target lesion size reduction;

(ii) 31% Overall Response Rate, or ORR:

4 of 13 patients with at least two post-baseline scans had a confirmed partial response, or PR, as determined by RECIST 1.1 based on investigator or central review;

and no patients have come off-treatment prior to the second scan;

and (iii) 46% of patients (6

of 13) with at least two post-baseline scans observed greater than 30% tumor reduction, including one patient with an unconfirmed PR as determined by RECIST 1.1 .

The darovasertib and crizotinib combination therapy demonstrated a manageable side effect profile in MUM patients (n=22) as of the November 25, 2021 data cutoff, with predominantly Grade 1/2 drug-related adverse events.

As of November 25, 2021, one patient experienced a drug-related serious adverse event of diarrhea.

Eighteen patients experienced a drug-related adverse events, of which six patients experienced Grade 3 drug-related adverse events, and no patients observed Grade 4 or Grade 5 drug-related adverse events.

These preliminary clinical data provide clinical proof-of-concept for the darovasertib and crizotinib synthetic lethal combination treatment in MUM.

These data also inform potential expansion opportunities in other cMET-driven tumors.

These data are also consistent with the company’s translational research discovery that Phase 1 clinical response to darovasertib monotherapy associated with low cMET activity, as measured by gene signature score or cMET expression.

We identified cMET as a potential biomarker and a cMET inhibitor as potential combination agent though our darovasertib translational research studies, or darovasertib cMET Translational Studies.

In these studies, we observed preclinical synergies between darovasertib and crizotinib in relevant cellular models under conditions simulating a tumor microenvironment in the liver, the site of approximately 90% of uveal melanoma metastases.

Additionally, we conducted a retrospective analysis of human clinical samples from the Novartis darovasertib Phase 1 clinical trial, which also independently supported cMET expression / activation as potential biomarker / combination agent.

We presented data summarizing the results of certain darovasertib cMET translational studies at AACR in April 2021.

Darovasertib Monotherapy

The monotherapy arm of the Phase 1/2 clinical trial was initiated in June 2019 to evaluate darovasertib in solid tumors harboring GNAQ or GNA11 hotspot mutations in a basket trial design.

We have completed enrollment in the monotherapy arm of the Phase 1/2 clinical trial in MUM.

We are continuing enrollment of patients having other, non-MUM solid tumors harboring GNAQ or GNA11 hotspot mutations, such as skin melanoma.

Our development strategy in the monotherapy non-MUM GNAQ/11 arm of the clinical trial is focused on skin melanoma.

In the Phase 2 basket arm evaluating IDE196 as monotherapy in non-MUM solid tumors harboring GNAQ or GNA11 hotspot mutations (GNAQ/11), the clinical protocol criteria have been met for cohort expansion in cutaneous melanoma, or skin melanoma.

We are actively enrolling for this Phase 2 cohort expansion in skin melanoma.

Of 4 evaluable skin melanoma patients harboring GNAQ/11 hotspot mutations (excluding 1 non-evaluable) as of August 1, 2020, a 100% Disease Control Rate was observed, and one confirmed partial response (cPR) was determined by RESIST, or Response Evaluation Criteria in Solid Tumors, 1.1 guidelines, satisfying the protocol requirement of at least one RECIST response in the first Stage 1 cohort (n=9) in order to expand into a second Stage 2 cohort (n=15).

Following satisfaction of the clinical protocol criteria, we can enroll an additional 15 skin melanoma patients harboring GNAQ/11 mutations into the Stage 2 cohort expansion, for a total planned enrollment of 24 patients in the skin melanoma cohort.

As of March 15, 2020, we have enrolled a total of nine patients with solid tumors other than MUM, including seven patients with skin melanoma, into the Phase 2 monotherapy basket arm.

We have added and are continuing to access potential additional clinical trial sites to supplement enrollment into the Phase 2 basket arm of the IDE196 clinical trial.

We have established a relationship with Tempus and with CARIS, in each case through which we are accessing their network of clinical trial sites into which we can enroll qualifying patients having tumors harboring GNAQ/11 hotspot mutations.

We anticipate disclosing interim data from the monotherapy arm of our ongoing IDE196-001 Phase 1/2 basket trial in 2021, including in MUM and in GNAQ/11-mutation skin melanoma.

Preliminary clinical data from IDE196 monotherapy arm shows that IDE196 activity is independent of HLA status.

IDE196 Tolerability

IDE196 has been generally well tolerated in the Phase 1/2 clinical trial.

We plan to update further on tolerability in connection with an interim data updates for IDE196 / binimetinib combination therapy in MUM and for IDE196 monotherapy in MUM and in GNAQ/11 mutant skin melanoma.

IDE196 was initially developed by Novartis, and we obtained an exclusive, worldwide license to IDE196 from Novartis in September 2018.

Pursuant to our license agreement with Novartis, except for Novartis’ ongoing Phase 1 clinical trial, we control all future clinical development, and all commercial rights to IDE196, and may rely on and incorporate data previously submitted to the FDA by Novartis into our own regulatory submissions.

Novartis has completed enrollment in a Phase 1 clinical trial it is conducting to evaluate IDE196 in metastatic uveal melanoma.

We reported clinical data in April 2021 for darovasertib monotherapy in MUM patients enrolled across the IDEAYA and Novartis Phase 1/2 clinical trials.

At the time of data and analyses cutoff on April 13, 2021, an aggregate of 88 patients were evaluable for safety and an aggregate of 81 patients were evaluable for efficacy pursuant to RECIST 1.1.

In the MUM cohort of the monotherapy arm, as of April 13, 2021 data and analyses cutoff based on preliminary data from an unlocked database, we observed (i) a fifty-seven percent (57%) 1-Year overall survival (OS) in predominantly second line, third line and heavily pre-treated (out to 7 and 8 lines of prior treatment) MUM patients with ninety-five percent (95%) confidence interval (44%, 69%), (ii) a median OS of 13.2 months in predominantly second line, third line and heavily pre-treated (out to 7 and 8 lines of prior treatment) MUM patients with ninety-five percent (95%) confidence interval (10.7 months, not reached), and (iii) sixty-one percent (61%) (n=46) of MUM patients out of 75 evaluable had tumor reduction pursuant to RECIST 1.1guidelines, including 15 patients (20%) with greater than thirty percent (30%) target lesion reduction, including one confirmed complete response.

Preliminary clinical data from darovasertib monotherapy arm shows that darovasertib activity is independent of HLA status.

In the skin melanoma cohort, 80% (n=4) of evaluable patients (n=5) had tumor reduction per RECIST 1.1.

evaluation, including one confirmed partial response.

The overall safety profile of darovasertib monotherapy, as of the April 13, 2021 data and analyses cutoff, was consistent with prior experience and included primarily common low grade but manageable GI and skin toxicities.

Drug-related adverse events observed with darovasertib as monotherapy include:

serious adverse events of hypotension, nausea, vomiting, rash and liver toxicity;

and adverse events that occurred in greater than 10% of patients of nausea, vomiting, diarrhea, fatigue, rash, edema, and abdominal distention.

Darovasertib was initially developed as a monotherapy by Novartis, and we obtained an exclusive, worldwide license to darovasertib from Novartis in September 2018.

Pursuant to our license agreement with Novartis, except for Novartis’ ongoing Phase 1 clinical trial, we control all future clinical development, and all commercial rights to darovasertib, and may rely on and incorporate data previously submitted to the FDA by Novartis into our own regulatory submissions.

Novartis has completed enrollment in a Phase 1 clinical trial it is conducting to evaluate darovasertib in metastatic uveal melanoma.

Phase 1 monotherapy data from Novartis was presented at the American Association for Cancer Research, or AACR, in April 2019.

Regulatory / Potentially Registration-Enabling Clinical Trial

We plan to evaluate additional clinical tolerability and efficacy data from the ongoing darovasertib and crizotinib combination therapy Phase 2 portion of the clinical trial in MUM patients, as well as potential strategic partnering of the darovasertib program, prior to initiation of a potentially registrational clinical trial in MUM.

We are planning to obtain guidance from the FDA on a clinical trial design for enabling a potential registrational trial.

Subject to feedback and guidance from the FDA, we are considering scenarios for potential registrational clinical studies.

In one scenario, a single-arm Phase 2 clinical trial could comprise further enrollment of patients into the current single-arm Phase 2 clinical trial evaluating darovasertib and crizotinib as combination therapy in MUM.

In an alternative scenario, a randomized Phase 2 clinical trial could comprise a darovasertib and crizotinib combination arm as well as comparative arm in MUM.

The comparative agent could be, for example, darovasertib monotherapy.

In either approach, we believe there may be an opportunity for an accelerated approval based on the Phase 2 ORR as a primary endpoint, with a post-approval randomized Phase 3 as a confirmatory study based on a progression free survival, or PFS, and/or overall survival, or OS, as endpoints.

Other Potential Indications

We are continuing our preclinical evaluation of IDE196 in Sturge-Weber Syndrome, or SWS, a rare neurocutaneous disorder characterized by capillary malformations and associated with mutations in GNAQ.

Our preclinical evaluation will include potential feasibility for pediatric use.

Clinical Trial Collaboration and Supply Agreement for IDE196 Program

On March 11, 2020, we entered into the Pfizer Agreement with Pfizer Inc., pursuant to which Pfizer will supply us with their MEK inhibitor, binimetinib, to evaluate the combination in patients with tumors harboring activating GNAQ or GNA11 hotspot mutations.

On September 23, 2020, we expanded the scope of our clinical trial collaboration and supply agreement with Pfizer, pursuant to which Pfizer will supply us with their cMET inhibitor, crizotinib to evaluate IDE196 and crizotinib as a combination therapy in patients having tumors harboring activating GNAQ or GNA11 hotspot mutations.

For each of the IDE196/binimetinib and IDE196/crizotinib combination arms of the clinical trial, we have established a joint development committee, and there will be joint decision making and data sharing of the clinical trial results between the parties.

We will sponsor the clinical studies and Pfizer will provide the binimetinib and crizotinib drug supply.

If there is clinical data from the collaboration studies that could be used to obtain regulatory approvals or label changes, we will enter into good faith negotiations with Pfizer to determine a regulatory submission strategy.

We are preclinically evaluating potential expansion opportunities in oncology for darovasertib – including in cMET-driven solid tumors such as HCC or NSCLC.

In March 2022, we entered into the Third Pfizer Agreement, pursuant to which we plan to evaluate, subject to preclinical validation, darovasertib and Pfizer’s cMET inhibitor, crizotinib, as a combination therapy in cMET-driven tumors such as HCC or NSCLC in a Phase 1 clinical trial.

We will provide IDE196 and pay for the costs of this combination study;

Pfizer will provide crizotinib for this combination study at no cost to us.

We are also preclinically evaluating potential expansion opportunities in KRAS-driven solid tumors, evaluating darovasertib in combination with a KRAS inhibitor.

In addition, we are exploring potential expansion opportunities in GNAQ/11 rare diseases, such as Sturge Weber Syndrome, or SWS, and Port Wine Stain, or PWS.

2020 Public Offering and Sale of IDEAYA Common Stock

On June 22, 2020, we closed on an underwritten public offering, or the Offering, of 6,666,667 shares of our common stock at an offering price of $15.00 per share, pursuant to which we received gross proceeds of $100.0 million, before deducting underwriting discounts and commissions and other offering expenses.

On July 22, 2020, as part of the Offering, the Company sold and issued an additional 500,000 shares of common stock upon the exercise of the overallotment option by the underwriters for gross proceeds of $7.5 million before deducting underwriting discounts and commissions and other offering.

On July 22, 2020, as part of the Offering, we sold and issued an additional 500,000 shares of common stock upon the exercise of the overallotment option by the underwriters for gross proceeds of $7.5 million before deducting underwriting discounts and commissions and other offering.

We realized aggregate gross proceeds of $107.5 million from the Offering, including gross proceeds from the sale of shares in the base Offering and the sale of shares from exercise of the overallotment option, and before deducting underwriting discounts and commissions and other offering expenses payable by us.

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The common stock sold pursuant thereto was not registered under the Securities Act of 1933, as amended, or the Securities Act.

The closing of this private placement occurred on August 3, 2020, following HSR Clearance of the associated GSK Collaboration Agreement, described below, and satisfaction of other certain customary closing conditions, pursuant to which we received proceeds of $20.0 million.

On August 3, 2020, following HSR Clearance of the associated GSK Collaboration Agreement, we closed on the private placement of 1,333,333 shares of our common stock to Glaxo Group Limited, or GGL, an affiliate of GlaxoSmithKline, at a price per share of $15.00, which is equal to the public offering price per share in the Offering.

The common stock sold pursuant thereto was not registered under the Securities Act of 1933, as amended, or the Securities Act.

On August 3, 2020, following HSR Clearance of the associated GSK Collaboration Agreement, we closed on the private placement with GGL.

We received proceeds of $20.0 million from the sale of these shares in this private placement.

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Pursuant to the terms of the August 2020 Sales Agreement, we may offer and sell shares of our common stock, $0.0001 par value per share, having an aggregate offering price of up to $50,000,000 from time to time through Jefferies acting as agent.

Pursuant to the August 2020 Sales Agreement, Jefferies, as sales agent, receives a commission of 3.0% of the aggregate gross proceeds that the Company receives from each sale of its shares of common stock sold under the August 2020 Sales Agreement .

During the three months ended December 31, 2020, we sold 410,896 shares of our common stock for aggregate net proceeds of $6.6 million after deducting sales commission and other expenses at a weighted average sales price of approximately $16.92 per share under an at-the-market offering pursuant to the August 2020 Sales Agreement with Jefferies as sales agent.

Pursuant to the August 2020 Sales Agreement, Jefferies, as sales agent, receives a commission of 3.0% of the aggregate gross proceeds that we receive from each sale of its shares of common stock sold under the August 2020 Sales Agreement .

During the year ended December 31, 2020, we sold 410,896 shares of our common stock for aggregate net proceeds of $6.6 million after deducting sales commission and other expenses at a weighted average sales price of approximately $16.92 per share under an at-the-market offering pursuant to the August 2020 Sales Agreement with Jefferies as sales agent.

On January 20, 2021, we entered into a new Open Market Sale Agreement, or January 2021 Sale Agreement, with Jefferies, with respect to an at-the-market offering program under which we may offer and sell, from time to time at our sole discretion, shares of its common stock, par value $0.0001 per share (the “Common Stock”), having aggregate gross proceeds of up to $90.0 million through Jefferies as its sales agent.

Under the January 2021 Sale Agreement, we will pay Jefferies a commission equal to three percent (3.0%) of the aggregate gross proceeds from each sale of shares sold through Jefferies under the January 2021 Sale Agreement.

Subsequent to December 31, 2020, from January 2021 through March 22, 2021, we sold an additional 2,709,385 shares of our common stock for aggregate gross proceeds of $43.3 million at a weighted average sales price of approximately $15.97 per share under an at-the-market offering pursuant to the August 2020 and January 2021 Sales Agreements with Jefferies as sales agent.

During the year ended December 31, 2021, we sold an aggregate of 3,407,872 shares of our common stock for aggregate net proceeds of $57.3 million at a weighted average sales price of approximately $17.40 per share under the at-the-market offering pursuant to the August 2020 and January 2021 Sales Agreements with Jefferies as sales agent.

As of December 31, 2021, approximately $73.8 million of common stock remained available to be sold under the ATM facility.

In January 2022, we sold an aggregate of 2,173 shares of our common stock for aggregate net proceeds of $0.05 million at a weighted average sales price of approximately $24.01 per share under the at-the-market offering pursuant to the January 2021 Sales Agreements with Jefferies as sales agent.

2021 Public Offering and Sale of IDEAYA Common Stock

On July 12, 2021, we completed an underwritten public offering of 5,333,333 shares of our common stock at an offering price to the public of $17.25 per share, including 695,652 shares of common stock upon the exercise in full of the overallotment option by the underwriters, pursuant to which we received aggregate net proceeds of $86.0 million, after deducting underwriting discounts and commissions and other offering expenses.

Management / Leadership Team

We continue to enhance our leadership team with the addition of Matthew Maurer, M.D.

as Vice President, Head of Clinical Oncology and Medical Affairs in January 2021.

We continue to enhance our leadership team.

Michael White, Ph.D., joined as Senior Vice President and Chief Scientific Officer, in November 2021.

White was previously Chief Scientific Officer and Head of Tumor Biology at Pfizer, Inc.

and at UT Southwestern, where he was a Professor of Cell Biology and founding Director of the Cancer Intervention and Prevention Discovery Program.

Matthew Maurer, M.D.

joined us as Vice President, Head of Clinical Oncology and Medical Affairs in January 2021.

Maurer was previously with Bristol Myers Squibb, and was earlier an oncologist and Assistant Professor of Medicine at Columbia University College of Physicians and Surgeons.

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Kelley has over 25 years of experience in oncology drug research and development, including most recently as Chief Medical Officer of the Multiple Myeloma Research Consortium (MMRC), and previously at Bayer Healthcare Pharmaceuticals and Bayer-Schering Pharma, and at Bristol-Myers Squibb.

Corporate Update

We do not have any products approved for sale and have not generated any revenue since inception.

We have funded our operations through December 31, 2021 primarily through the sale and issuance of common stock, redeemable convertible preferred stock, and convertible promissory notes, including our initial public offering, or IPO, in May 2019, a follow-on underwritten public offering in June 2020, a direct private placement equity investment by GGL in June 2020, the sale and issuance of common stock under our at-the-market facility pursuant to the August 2020 and January 2021 Sales Agreements with Jefferies as sales agent, and through a follow-on underwritten public offering in July 2021.

Additionally, we received a non-dilutive upfront cash payment from GSK in July 2020 in connection with the GSK Collaboration Agreement.

Since our inception in June 2015, we have devoted substantially all of our resources to discovering and developing our product candidates.

We have incurred significant operating losses to date and expect that our operating expenses will increase significantly as we advance our product candidates through preclinical and clinical development;

seek regulatory approval, and prepare for, and, if approved, proceed to commercialization;

acquire, discover, validate and develop additional product candidates;

obtain, maintain, protect and enforce our intellectual property portfolio;

and hire additional personnel.

Certain program costs that contribute to our operating expenses will be reimbursed by GSK pursuant to the GSK Collaboration Agreement, including 100% of costs we incur for research we perform in connection with the Pol Theta program and 80% of the aggregate program costs incurred by us and GSK for research each of us performs for the Werner Helicase program, and if GSK exercises their exclusive option to obtain an exclusive license to continue development of and commercialize MAT2A products arising out of the MAT2A program, also the MAT2A program.

In addition, we expect to incur additional costs associated with operating as a public company.

Our net losses were $49.8 million and $34.5 million for the years ended December 31, 2021 and 2020, respectively.

As of December 31, 2021, we had an accumulated deficit of $176.7 million.

Our ability to generate product revenue will depend on the successful development, regulatory approval and eventual commercialization of one or more of our product candidates, ourselves, or for some programs, in collaboration with our strategic partners.

We are leading and solely responsible for preclinical, translational and clinical research and development, as applicable, for (i) the darovasertib monotherapy arm of our IDE196-001 clinical trial, (ii) our PARG program and (iii) our earlier pipeline programs, including our MTAP-SL program and our DNA Damage Target or DDT programs.

We are leading clinical development in the ongoing darovasertib / crizotinib combination arm of our IDE196-001 clinical trial, in each case in coordination with Pfizer pursuant to the Pfizer Agreement.

We are leading preclinical development and early-stage clinical development for evaluation of IDE397 in the ongoing IDE397-001 Phase 1 clinical trial, in coordination with GSK pursuant to the GSK Collaboration Agreement.

We are collaborating with GSK on preclinical research for our Pol Theta and Werner Helicase programs, pursuant to the GSK Collaboration Agreement.

Until such time as we can generate significant revenue from product sales, if ever, we expect to finance our operations through the sale of equity, debt financings, or other capital sources, including potential collaborations with other companies or other strategic transactions.

Adequate funding may not be available to us on acceptable terms, or at all.

If we fail to raise capital or enter into such agreements as and when needed, we may have to significantly delay, scale back or discontinue the development and commercialization of our product candidates.

As of December 31, 2021, we had cash, cash equivalents, and short-term and long-term marketable securities of $368.1 million.

We believe that our cash, cash equivalents, and short-term and long-term marketable securities will be sufficient to fund our planned operations for at least twelve months from the date of the issuance of our Annual Report on Form 10-K filed March 17, 2022.

These funds will support our efforts through potential achievement of multiple preclinical and clinical milestones across multiple programs.

Components of Operating Results

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To date, we have not generated any revenue from product sales, and we do not expect to generate any revenue from product sales for the foreseeable future.

Our revenue exclusively consists of collaboration revenue under the GSK Collaboration Agreement, including amounts that are recognized related to upfront payments and amounts due to us for research and development services.

Our revenue consists exclusively of collaboration revenue under the GSK Collaboration Agreement, including amounts that are recognized related to previously received upfront payments and amounts due and payable to us for research and development services.

In the future, revenue may include additional milestone payments, option exercise payments, profit sharing, and royalties on any net product sales under our collaborations.

We expect that any revenue we generate will fluctuate from period to period as a result of the timing and amount of license, research and development services, and milestone and other payments.

We expect that any revenue we generate will fluctuate from period to period as a result of various factors, such as the timing and amount of license, research and development services, and milestone and other payments.

The revenue we recognize or generate under

the GSK Collaboration Agreement may also fluctuate from period to period due to changes to prospective collaboration research budgets or changes to respective allocation of resources as between the parties and as between internal or external (e.g., CRO) sources, in each case on a program by program basis, as part of ongoing collaboration research management.

Operating Expenses

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Substantially all of our research and development expenses consist of expenses incurred in connection with discovery and development of our product candidates.

These expenses include certain payroll and personnel-related expenses, including salaries, employee benefit costs and stock-based compensation expenses for our research and product development employees, fees to third parties to conduct certain research and development activities on our behalf including fees to CMOs and CROs in support of manufacturing and clinical activity for IDE196, consulting costs, costs for laboratory supplies, costs for product licenses and allocated overhead, including rent, equipment, depreciation, information technology costs and utilities.

These expenses include certain payroll and personnel-related expenses, including salaries, employee benefit costs and stock-based compensation expenses for our research and product development employees, fees to third parties to conduct certain research and development activities on our behalf including fees to CMOs and CROs in support of manufacturing and clinical activity for IDE397 and darovasertib (IDE196), consulting costs, costs for laboratory supplies, costs for product licenses and allocated overhead, including rent, equipment, depreciation, information technology costs and utilities.

We expense both internal and external research and development expenses as they are incurred.

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A discussion regarding our financial condition and results of operations for fiscal year 2021 compared to fiscal year 2020 is presented below.

A discussion regarding our financial condition and results of operations for fiscal year 2019 compared to fiscal year 2018 can be found in “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in our Annual Report on Form 10-K filed with the SEC on March 24, 2020, which is available free of charge on the SEC’s website at http://www.sec.gov and at our investor relations website, https://ir.ideayabio.com/ .

A discussion regarding our financial condition and results of operations for fiscal year 2020 compared to fiscal year 2019 can be found in “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in our Annual Report on Form 10-K filed with the SEC on March 23, 2021.

Comparison of the Years Ended December 31, 2021 and December 31, 2020

The following table summarizes our results of operations for the periods indicated (in thousands):

Years Ended December 31,

Year Ended December 31,

Collaboration revenue

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General and administrative

Total operating expenses

Loss from operations

Interest income and other income (expense), net

Other income (expense)

Interest income and other income, net

Collaboration Revenue

Collaboration revenue increased by $19.5 million in the year ended December 31, 2020.

Collaboration revenue increased by $8.4 million, or 43%, during the year ended December 31, 2021 compared to the year ended December 31, 2020.

In July 2020, the GSK Collaboration Agreement became effective, and we started recognizing collaboration revenue, which consists of revenue from preclinical and Phase 1 monotherapy clinical research and development services under the MAT2A program as well as preclinical research services and the related license under the Pol Theta and WRN programs.

Revenue we recognize from satisfaction of performance obligations under the GSK Collaboration Agreement is impacted by our estimates of the remaining costs to complete our obligations, which may vary due to changes to prospective collaboration research budgets or changes to respective allocation of resources and in any case require significant judgment, and may cause fluctuation in the revenue recognized from period to period.

Collaboration revenue recognized in the year ended December 31, 2020 also included $3.0 million of revenue from the exercise by GSK of the material right associated with the option to license IDEAYA-owned technology under the MAT2A program to the extent necessary for preclinical activities.

Research and Development Expenses

Research and development expenses increased by $5.4 million, or 16%, from the year ended December 31, 2019 to the year ended December 31, 2020.

The increase in research and development expenses was primarily due to an increase in external clinical development expenses for IDE397 of $2.2 million related to manufacturing and clinical startup activities, an increase in external clinical development expenses for IDE196 of $0.1 million related to increased patient enrollment in our Phase 1/2 clinical trial to evaluate IDE196 in solid tumors, an increase in fees paid to CROs, CMOs and consultants of $5.2 million related to the advancement of our lead product candidates through preclinical studies, and an increase in software licenses, subscriptions and depreciation expense of $0.3 million.

The increase was partially offset by a decrease in costs for laboratory supplies used in support of our research programs of $1.5 million due to decreased laboratory operations as a result of COVID-19 restrictions, and a decrease in payroll expenses, including salaries, benefits and stock-based compensation expense of $1.1 million due to a decrease in our average research and development headcount for the year.

Research and development expenses increased by $18.5 million, or 47%, during the year ended December 31, 2021 compared to the year ended December 31, 2020.

The increase in research and development expenses was primarily due to increases of $8.0 million in personnel-related expenses, including salaries, benefits and stock-based compensation, related to an increase in headcount to support our growth, $6.6 million in fees paid to CROs, CMOs and consultants related to the advancement of our lead product candidates through preclinical and clinical studies, and $3.9 million in costs for laboratory supplies, facilities and software to support our research programs.

General and Administrative Expenses

General and administrative expenses increased by $5.2 million, or 53%, from the year ended December 31, 2019 to the year ended December 31, 2020.

The increase in general and administrative expenses was primarily due to an increase in payroll and personnel-related expenses, including salaries, benefits and stock-based compensation expense, of $2.8 million related to increased general and administrative headcount to support our growth, an increase in directors’ and officers’ liability insurance premiums of $1.0 million, an increase in legal patent expense of $0.4 million due to increased patent filings, an increase in consulting fees of $0.3 million related to human resources and information technology support, an increase in costs associated with the filing of a shelf registration statement on Form S-3 of $0.2 million, and an increase in software licenses of $0.2 million .

General and administrative expenses increased by $4.9 million, or 32%, during the year ended December 31, 2021 compared to the year ended December 31, 2020 .

The increase in general and administrative expenses was primarily due to increases of $3.7 million in personnel-related expenses, including salaries, benefits and stock-based compensation, related to an increase in headcount to support our growth, $0.5 million in software licenses, $0.3 million for consulting services related mainly to information technology support, and $0.3 million in directors’ and officers’ liability insurance premiums.

Interest Income and Other Income (Expense), Net

Interest income decreased by $1.4 million, or 63%, from the year ended December 31, 2019 to the year ended December 31, 2020, primarily due to a decrease in interest income on our cash, cash equivalents and marketable securities balances, as a result of the lower interest yields.

Interest income decreased by $0.3 million, or 40%, during the year ended December 31, 2021 compared to the year ended December 31, 2020, primarily due to lower cash, cash equivalents and marketable securities balances and lower interest rate yields.

Liquidity and Capital Resources;

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As of December 31, 2021, we had an accumulated deficit of $176.7 million.

Based on our current business plan, we believe that our existing cash, cash equivalents and marketable securities will be sufficient to fund our planned operations into 2024.

Based on our current business plan, we believe that our existing cash, cash equivalents and marketable securities will be sufficient to fund our planned operations for at least the next 12 months from the issuance date of this Annual Report on Form 10-K.

To date, we have not generated any product revenue.

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We will continue to require additional capital to develop our product candidates and fund operations for the foreseeable future.

We may seek to raise capital through private or public equity or debt financings, collaborati on or other arrangements with corporate sources, or through other sources of financing.

We may seek to raise capital through private or public equity or debt financings, collaboration or other arrangements with corporate sources, or through other sources of financing.

Adequate additional funding may not be available to us on acceptable terms or at all.

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These contracts generally provide for termination following a certain period after notice, and therefore we believe that our non-cancelable obligations under these agreements are not material.

Pursuant to the GSK Collaboration Agreement, subject to GSK’s exercise of the Option, we will be responsible for 20% of further development costs for the MAT2A program thereafter.

Pursuant to the GSK Collaboration Agreement, subject to GSK’s exercise of option to obtain an exclusive, sublicensable license to make, have made, use, sell, offer for sale and import MAT2A Compounds and MAT2A Products, we will be responsible for 20% of further development costs for the MAT2A program thereafter.

The cost-sharing percentages will be adjusted based on the actual ratio of U.S.

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We may opt out of 50% U.S.

net profit share and corresponding development cost share for the MAT2A program and/or WRN program.

net profit share and corresponding development cost share for the MAT2A program and/or the WRN program.

In September 2018, we entered into a license agreement with Novartis International Pharmaceuticals Ltd., or Novartis, to develop and commercialize Novartis’ LXS196 (also known as IDE196), a PKC inhibitor for the treatment of cancers having GNAQ and GNA11 mutations.

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Such milestones and royalties are dependent on future activity or product sales and are not provided for in the table above as the timing and amounts, if any, are not estimable.

We did not have during the periods presented, and we do not currently have, any off-balance sheet arrangements.

Adequate additional funding may not be available to us on acceptable terms or at all.

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– Risk Factors” for additional risks associated with our substantial capital requirements.

Off-Balance Sheet Arrangements

We have not entered into any off-balance sheet arrangements as defined in the rules and regulations of the SEC.

Summary Statement of Cash Flows

The following table sets forth the primary sources and uses of cash, cash equivalents, and restricted cash for each of the periods presented below (in thousands):

Years Ended December 31,

Year Ended December 31,

Net cash (used in) provided by:

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Cash Flows from Operating Activities

Net cash used in operating activities was $55.8 million for the year ended December 31, 2021.

Cash used in operating activities was primarily due to the use of funds in our operations to develop our product candidates resulting in a net loss of $49.8 million, adjusted for net non-cash charges of $11.8 million and changes in net operating assets and liabilities of $17.8 million.

Our non-cash charges consisted of $8.2 million in stock-based compensation, $1.9 million amortization of premium on marketable securities and $1.7 million in depreciation.

The net change in our operating assets and liabilities consisted primarily of decreases of $23.5 million in contract liabilities due to revenue recognized under the GSK Collaboration Agreement, $1.5 million in lease liabilities, $1.3 million in right-of-use assets and $0.8 million in accounts receivable from GSK for estimated program costs under the GSK Collaboration Agreement, partially offset by increases of $4.2 million in accrued and other liabilities d ue to CRO fees in support of research and manufacturing activities and $1.2 million in accounts payable.

Net cash provided by operating activities was $55.5 million for the year ended December 31, 2020.

Cash provided by operating activities was primarily due to an increase in contract liability of $83.8 million as a result of the up-front payment received from GSK, stock-based compensation expense of $3.6 million, an increase of accrued and other liabilities of $3.0 million due to fees to CROs in support of research and manufacturing activities and an increase in accrued payroll expenses due to increased headcounts, and depreciation and amortization expense of $1.4 million , partially offset by the use of funds in our operations to develop our product candidates resulting in a net loss of $34.5 million and an increase in accounts receivable of $1.9 million due to the estimated program costs for the fourth quarter of 2020 reimbursable by GSK under the GSK Collaboration Agreement.

Net cash used in operating activities was $39.3 million for the year ended December 31, 2019.

Cash used in operating activities was primarily due to the use of funds in our operations to develop our product candidates resulting in a net loss of $42.0 million, adjusted for the net amortization of premiums and discounts on marketable securities of $0.5 million and an increase in prepaid expenses and other assets of $2.0 million mainly due to advance payments for director’s and officers’ liability insurance premiums and fees for CROs, partially offset by depreciation and amortization expense of $1.2 million and stock-based compensation expense of $2.2 million, and an increase in accrued and other liabilities of $2.0 million mainly due to fees to CMOs and CROs in support of manufacturing and clinical activity for IDE196 and personnel-related expenses.

Cash Flows from Investing Activities

Net cash used in investing activities was $69.7 million for the year ended December 31, 2021, which consisted primarily of $315.0 million used to purchase marketable securities and $2.6 million used to purchase property and equipment, partially offset by $244.0 million provided by maturities of marketable securities and $4.0 million from sale of marketable securities.

Net cash used in investing activities was $146.2 million for the year ended December 31, 2020, which consisted primarily of $242.3 million used to purchase marketable securities and $0.5 million used to purchase property and equipment, partially offset by $96.6 million provided by maturities of marketable securities.

Net cash provided by investing activities was $2.3 million for the year ended December 31, 2019, which consisted primarily of $73.5 million provided by maturities of marketable securities and $18.1 million from sales of marketable securities , partially offset by $88.0 million used to purchase marketable securities and $1.4 million used to purchase property and equipment.

Cash Flows from Financing Activities

Net cash provided by financing activities was $145.5 million for the year ended December 31, 2021, which consisted primarily of $86.0 million of net proceeds from our follow-on offering, $57.3 million of proceeds from ATM offering, $1.5 million of proceeds from exercise of common stock options, and $0.7 million of proceeds from ESPP purchase .

Net cash provided by financing activities was $128.8 million for the year ended December 31, 2020, which consisted primarily of $100.7 million of net proceeds from our follow-on offering, $20.0 million of net proceeds from our private placement of common stock, $6.6 million of proceeds from ATM offering, $1.2 million of proceeds from exercise of common stock options, and $0.3 million of proceeds from ESPP purchase .

Net cash provided by financing activities was $50.6 million for the year ended December 31, 2019, which consisted primarily of $50.3 million of net proceeds from our IPO.

Critical Accounting Policies and Estimates

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Revenue Recognition

We follow Accounting Standards Codification Topic 606, Revenue from Contracts with Customers (“ASC 606”).

Under ASC 606, we recognize revenue when our customer obtains control of promised goods or services, in an amount that reflects the consideration which we expect to receive in exchange for those goods or services.

To determine revenue recognition for arrangements that we determine are within the scope of ASC 606, we perform the following five steps:

(i) identify the contract(s) with a customer;

(ii) identify the performance obligations in the contract;

(iii) determine the transaction price;

(iv) allocate the transaction price to the performance obligations in the contract;

and (v) recognize revenue when (or as) we satisfy a performance obligation.

We apply the five-step model to contracts when (1) parties have approved the contract and are committed to performing respective obligations, (2) we can identify each party’s rights regarding the goods or services to be transferred, (3) we can identify the payment terms for the goods or services to be transferred, (4) the contract has commercial substance, and (5) it is probable that we will collect the consideration we are entitled to in exchange for the goods or services we transfer to the customer.

At contract inception, we assess the goods or services promised within each contract and determine the performance obligations by assessing whether each promised good or service is distinct.

Goods or services that are not distinct are bundled with other goods or services in the contract until a bundle of goods or services that is distinct is created.

We then recognize as revenue the amount of the transaction price that is allocated to the respective performance obligations when (or as) the performance obligations are satisfied.

We constrain our estimate of the transaction price up to the amount (the “variable consideration constraint”) that a significant reversal of recognized revenue is not probable.

Licenses of intellectual property:

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The change in the estimated total costs and/or the timing of completion may materially impact an amount of subsequent revenue recognition and/or its timing.

Indemnification Agreements

We enter into standard indemnification arrangements in the ordinary course of business with vendors, clinical trial sites and other parties.

Pursuant to these arrangements, we indemnify, hold harmless and agree to reimburse the indemnified parties for losses suffered or incurred by the indemnified party.

The term of these indemnification agreements is generally perpetual any time after the execution of the agreement.

The maximum potential amount of future payments we could be required to make under these arrangements is not determinable.

We have never incurred costs to defend lawsuits or settle claims related to these indemnification agreements.

As a result, we believe the fair value of these agreements is not material.

JOBS Act Accounting Election

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 7. Management’s Discussion and Analysis