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Item 1. Business

2022-03-18 compared with 2021-03-23 · 378 added, 298 removed, 558 unchanged (55% of the section changed)

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We are establishing a broad pipeline of clinical and preclinical programs directed to synthetic lethality targets.

We are also investing in and enhance our capabilities for identification and validation of new synthetic lethality targets.

We are also investing in and enhancing our capabilities for identification and validation of new synthetic lethality targets.

For targets of interest, we plan to discover therapeutic drugs and relevant biomarkers.

Our most advanced synthetic lethality product candidate is IDE397, a clinical-stage methionine adenosyltransferase 2a, or MAT2A, inhibitor for patients with solid tumors having methylthioadenosine phosphorylase, or MTAP, deletions – a patient population estimated to represent approximately 15% of solid tumors.

We have clearance from the U.S.

Food and Drug Administration, or FDA, to initiate a Phase 1 clinical trial designated as IDE397-001 to evaluate IDE397 under an investigational new drug application, or IND, and are targeting initial dosing of our first patient in the first quarter of 2021.

We are enrolling patients into a Phase 1 clinical trial designated as IDE397-001 to evaluate IDE397 under an investigational new drug application, or IND.

We are leading 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 currently enrolling patients having tumors with MTAP deletion into Cohort 6 of the dose escalation portion of the IDE397 Phase 1 clinical trial.

We have completed enrollment in Cohorts 1 through 5 without observing a dose limiting toxicity, or DLT, during the DLT window that begins following the first dose of IDE397.

As considered across evaluated cohorts, we observed dose-proportional pharmacokinetic exposures and robust, dose- and/or exposure-dependent pharmacodynamic modulation of S-adenosyl methionine, or SAM, in plasma samples and of symmetric dimethyl arginine, or SDMA, in tumor biopsy samples.

We have several preclinical synthetic lethality research programs in our pipeline advancing toward the clinic.

We are targeting poly (ADP-ribose) glycohydrolase, or PARG, for patients having tumors with a defined biomarker based on genetic mutations and/or molecular signatures.

We own or control all commercial rights in our PARG program, and are targeting to designate a development candidate in 2021.

We own or control all commercial rights in our PARG program.

We are targeting DNA Polymerase Theta, or Pol Theta or POLQ, in collaboration with GSK, for solid tumors with homologous recombination deficiency, or HRD, including BRCA mutations.

We are targeting to designate a development candidate for Pol Theta in 2021.

We are also targeting Werner Helicase, or WRN, in collaboration with GSK, in tumors with high microsatellite instability, or MSI high.

Additionally, we have multiple wholly-owned early preclinical research programs targeting distinct DNA Damage Targets, or DDTs, for patients with solid tumors characterized by a proprietary biomarker or a gene signature.

Our product candidate IDE196 is a clinical-stage protein kinase C, or PKC, inhibitor for genetically-defined cancers having GNAQ or GNA11 gene mutations, which we in-licensed from Novartis and are clinically evaluating in a Phase 1/2 clinical trial designated as IDE196-001.

Our clinical trial strategy in metastatic uveal melanoma, or MUM, is to pursue IDE196 combination therapies, 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 are continuing patient enrollment in the IDE196/binimetinib combination arm, which initiated Phase 1 dose escalation in June 2020.

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

We initiated the IDE196/crizotinib combination arm in December 2020, and enrollment in this arm of the clinical trial is ongoing.

Additionally, 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.

Additionally, we have multiple wholly-owned early preclinical research programs targeting MTAP synthetic lethality, or MTAP-SL, target distinct DNA Damage Targets, or DDTs, for patients with solid tumors characterized by a proprietary biomarker or a gene signature.

Another clinical-stage product candidate, darovasertib or IDE196, is a protein kinase C, or PKC, inhibitor that we are evaluating as a synthetic lethal combination therapy in patients having genetically-defined cancers having GNAQ or GNA11 gene mutations.

Darovasertib, which we in-licensed from Novartis, is being clinically evaluated in a Phase 1/2 clinical trial designated as IDE196-001.

Our current clinical strategy includes evaluation of darovasertib in metastatic uveal melanoma, or MUM patients, adjuvant primary uveal melanoma, or UM patients, and in skin melanoma patients having tumors with GNAQ or GNA11, or GNAQ/11, mutations.

We are evaluating darovasertib in a Phase 1/2 clinical trial in combination with crizotinib, an investigational cMET inhibitor, pursuant to our Clinical Trial Collaboration and Supply Agreement, or Pfizer Agreement, with Pfizer in MUM and in skin melanoma patients having tumors with GNAQ/11 mutations.

We have expanded our relationship with Pfizer.

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

We also plan to evaluate, subject to preclinical validation, darovasertib and Pfizer’s cMET inhibitor, crizotinib, as a combination therapy in other cMET-driven tumors such as non-small cell lung cancer, or NSCLC, and/or in hepatocellular carcinoma, or HCC, in a Phase 1 clinical trial pursuant to a third Clinical Trial Collaboration and Supply Agreement, or the Third Pfizer Agreement, or collectively with the Pfizer Agreement and the

Second Pfizer Agreement, the Pfizer Agreements .

We are planning to initiate evaluation of darovasertib in adjuvant UM patients through an investigator sponsor clinical trial, or IST.

We are preclinically evaluating potential expansion opportunities in oncology for darovasertib, including in combination with a cMET inhibitor in certain cMET-driven solid tumors, and in combination with a KRAS inhibitor in certain KRAS-driven solid tumors.

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.

We have assembled a team of cancer biologists, drug discovery chemists, translational biologists and drug development professionals with broad experience at leading oncology organizations.

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We are also guided by a renowned scientific advisory board made up of key scientific and clinical thought leaders.

Our objective is to develop and commercialize innovative precision medicine drugs that indirectly or directly target the genetic drivers of cancer in order to provide solutions for defined patient populations.

Our objective is to develop and commercialize innovative precision medicine drugs that indirectly or directly target the genetic drivers of cancer in order to provide therapies for defined patient populations.

The principal components of our strategy are to:

Continue to efficiently develop our clinical-stage product candidates, IDE397, an orally available small molecule inhibitor of MAT2A, and IDE196, an orally available small molecule inhibitor of PKC.

Continue to efficiently develop our clinical-stage product candidates, IDE397, an orally available small molecule inhibitor of MAT2A, and darovasertib, an orally available small molecule inhibitor of PKC.

We are currently conducting a Phase 1 clinical trial evaluating IDE397 in patients with tumors having MTAP-deletion.

We are conducting a Phase 1/2 tissue-type agnostic basket trial evaluating IDE196 in patients with solid tumors harboring GNAQ or GNA11 hotspot mutations, including metastatic uveal melanoma and other solid tumors such as cutaneous melanoma.

We are also conducting a Phase 1/2 trial evaluating darovasertib as a combination therapy with crizotinib in patients with MUM and in skin melanoma with tumors harboring GNAQ or GNA11 mutations.

We are planning to initiate evaluation of darovasertib in adjuvant primary UM through an IST, and are preclinically evaluating multiple potential expansion opportunities, including in cMET-driven solid tumors, and KRAS-driven solid tumors.

Advance our preclinical pipeline of small molecule product candidates in synthetic lethality into clinical development.

Our synthetic lethality pipeline includes multiple preclinical research programs, including our PARG and Pol Theta programs, for which in each case we are targeting to identify a development candidate in 2021.

We are also continuing to invest in our broader portfolio of synthetic lethality programs, including programs targeting WRN and certain DNA Damage Targets.

Our synthetic lethality pipeline includes multiple preclinical research programs, including our maturing PARG and Pol Theta programs.

We are also continuing to invest in our earlier, broader portfolio of synthetic lethality programs, including programs targeting WRN, MTAP-SL and certain DNA Damage Targets.

Broaden our pipeline of targeted therapies and apply our core capabilities to establish a leading franchise in the field of synthetic lethality.

We are continuing our target identification and validation activities for advancing new synthetic lethality targets and associated biomarkers.

We continue to invest in core functional capabilities, including in drug discovery, bioinformatics and translational biology.

Collaborate with leaders in the field of diagnostics to enable the identification of defined patient populations for our product candidates.

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We have entered into a strategic partnership and collaboration with GSK for our synthetic lethality programs targeting MAT2A, Pol Theta and Werner Helicase pursuant to the GSK Collaboration Agreement.

We have also entered into the Pfizer Agreement for evaluation of IDE196 combinations with each of binimetinib and crizotinib.

We have also entered into the Pfizer Agreements for evaluation of darovasertib combinations with crizotinib in MUM, other GNAQ/11 solid tumors and in cMET-driven solid tumors.

We will selectively evaluate strategic collaborations for our targeted product candidates with biopharmaceutical partners whose research, development, commercial, marketing, and geographic capabilities complement our own.

We are applying our capabilities and approach to develop a portfolio of targeted therapeutics for defined patient populations, with a focus in synthetic lethality.

Our precision medicine pipeline includes clinical-stage assets IDE397, a MAT2A inhibitor being evaluated in a Phase 1 clinical trial in patients with solid tumors having MTAP deletion, and IDE196, a PKC inhibitor being evaluated in a Phase 1/2 clinical trial in patients harboring GNAQ/11 hotspot mutations.

Pursuant to GSK Collaboration, Option and License Agreement

Pursuant to CRUK/Manchester Agreement

Pursuant to Pfizer Agreements

Our precision medicine pipeline includes clinical-stage assets IDE397, a MAT2A inhibitor being evaluated in a Phase 1 clinical trial in patients with solid tumors having MTAP deletion, and darovasertib, a PKC inhibitor being evaluated in a Phase 1/2 clinical trial in patients harboring certain GNAQ/11 mutations.

Our pipeline also includes preclinical research programs directed to synthetic lethality targets PARG, Pol Theta, Werner Helicase, and certain DNA Damage Targets, the profiles of which are summarized below.

All data and status are as of March 15, 2021, unless otherwise noted.

All data and the status of each program are as of March 1, 2022, unless otherwise noted.

IDE397 (MTAP Gene Deletion)

We are developing our synthetic lethality product candidate, IDE397, a clinical stage MAT2A inhibitor for patients with solid tumors having MTAP deletions, which represents approximately 15% of all solid tumors.

We have clearance from the FDA to initiate a Phase 1 clinical trial designated as IDE397-001 to evaluate IDE397 under an IND and are targeting initial dosing of our first patient in the first quarter of 2021.

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

We have initiated a Phase 1 clinical trial designated as IDE397-001 to evaluate IDE397 in patients with solid tumors having MTAP deletion.

We are currently enrolling into Cohort 6 of the dose escalation portion of the clinical trial and have not yet observed a DLT in prior Cohorts 1 through Cohort 5.

We are targeting monotherapy cohort expansion and initiation of combination cohorts in the second or third quarter of 2022, or mid-year 2022.

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

We are targeting delivery of an IDE397 option data package to GSK mid-year 2022, subject to initiation of an expansion cohort or establishing the MTD.

Delivery of the option data package would trigger an evaluation period for GSK to make an opt‐in decision.

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.

We observed preliminary clinical pharmacodynamic, or PD, response in early cohorts of the dose-escalation portion of the IDE397 monotherapy Phase 1 clinical trial including SAM, tumor SAM and SDMA.

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

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

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We are advancing our preclinical-stage synthetic lethality PARG program for patients having tumors with a defined biomarker based on genetic mutations and/or molecular signatures.

Subject to further preclinical studies, we are targeting to designate a development candidate for our PARG program in 2021.

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

We are targeting submission of 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 own or control all commercial rights in our PARG program, subject to certain economic obligations pursuant to our exclusive, worldwide license to certain PARG inhibitors, including IDE161, with Cancer Research UK and University of Manchester.

Pol Theta Program (HRD, including BRCA)

We are also pursuing our preclinical synthetic lethality Pol Theta program, in collaboration with GSK, for solid tumors with homologous recombination deficiency, or HRD, including BRCA mutations.

Subject to further preclinical studies, we are targeting to designate a development candidate for our Pol Theta program in 2021.

We are pursuing our preclinical synthetic lethality Pol Theta program, in collaboration with GSK, for solid tumors with HRD, including BRCA mutations.

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

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

We plan to continue further research and development of our Pol Theta program in collaboration with GSK pursuant to the GSK Collaboration Agreement.

WRN Program (MSI-High)

We are also progressing our synthetic lethality Werner Helicase program, in collaboration with GSK, for patients with tumors having high microsatellite instability, or MSI high.

We are progressing our synthetic lethality Werner Helicase program, in collaboration with GSK, for patients with MSI-high tumors.

We observed Werner Helicase inhibitor in vivo efficacy in a cell derived xenograft, or CDX, model with approximately 100% tumor growth inhibition, and are, in collaboration with GSK, targeting nomination of a Werner Helicase inhibitor development candidate in 2023.

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 Werner Helicase inhibitor from preclinical development into early Phase 1 clinical trials.

We plan to continue further research and development of our Werner Helicase program in collaboration with GSK pursuant to the GSK Collaboration Agreement.

DNA Damage Targets (Defined Biomarkers)

We have initiated early preclinical research programs targeting multiple distinct DNA Damage Targets, or DDTs, for patients with solid tumors characterized by a defined biomarker based on genetic mutations and/or molecular signatures.

We own or control all commercial rights in our DNA Damage Target programs.

We have initiated early preclinical research programs targeting multiple distinct DDTs for patients with solid tumors characterized by a defined biomarker based on genetic mutations and/or molecular signatures.

We own or control all commercial rights in our DDT programs.

Synthetic Lethality Target and Biomarker Discovery Platform

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We own or control all commercial rights in programs directed to targets identified in on our synthetic lethality and biomarker discovery platform.

IDE196 (GNAQ or GNA11 Mutations)

We are evaluating IDE196, a clinical stage PKC inhibitor, in our ongoing Phase 1/2 clinical basket trial in patients having tumors harboring GNAQ or GNA11 mutations.

In metastatic uveal melanoma, or MUM, we are pursuing IDE196 combination therapies, including with binimetinib, a MEK inhibitor, and independently with crizotinib, a cMET inhibitor, each pursuant to the Pfizer Agreement.

In the IDE196/binimetinib combination arm, we continue to enroll patients and have initiated dose expansion in the IDE196/binimetinib Phase 1/2 study in MUM.

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

We are also evaluating IDE196 as monotherapy in non-MUM solid tumor indications, such as skin melanoma.

We are targeting interim data from the IDE196 monotherapy arm in solid tumors, including in MUM and GNAQ/11-mutation skin melanoma, in 2021.

We currently own or control all commercial rights in our IDE196 program, subject to certain economic obligations pursuant to our exclusive, worldwide license to IDE196 with Novartis.

Darovasertib (GNAQ or GNA11 Mutations)

We are evaluating darovasertib, a clinical stage PKC inhibitor, in our ongoing Phase 1/2 clinical basket trial in patients having tumors harboring GNAQ or GNA11 mutations, such as MUM and skin melanoma, and plan to initiate an IST to evaluate darovasertib in adjuvant primary UM.

In metastatic uveal melanoma, or MUM, we are enrolling patients into a Phase 2 arm of the clinical trial evaluating IDE196 in combination with crizotinib, a cMET inhibitor, pursuant to the Pfizer Agreement.

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

We are planning to present additional interim clinical data from the 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.

We are preclinically evaluating potential expansion opportunities in cMET-driven solid tumors and KRAS-driven solid tumors.

We have expanded our relationship with Pfizer with additional agreements which will support clinical evaluation, subject to FDA guidance, of darovasertib and Pfizer’s cMET inhibitor, crizotinib, as a combination therapy in a planned MUM Phase 2 potential registration-enabling clinical trial pursuant to the Second Pfizer Agreement, and, subject to preclinical validation and FDA guidance, in other cMET-driven tumors such as HCC or NSCLC in a planned Phase 1 clinical trial pursuant to the Third Pfizer Agreement.

We currently own or control all commercial rights in our darovasertib program, subject to certain economic obligations pursuant to our exclusive, worldwide license to darovasertib with Novartis.

Therapies Based on Synthetic Lethality

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Our synthetic lethality pipeline is complemented by a robust target and biomarker discovery platform.

For each synthetic lethality target, we are simultaneously pursuing identification and validation of both a therapeutic and tumor-associated biomarker(s) for patient selection.

For each synthetic lethality target, we are simultaneously pursuing identification and validation of both therapeutic and tumor-associated biomarker(s) for patient selection.

In addition to these programs, we are actively identifying and validating novel synthetic lethality targets through our internal research as well as through collaborations with academic and clinical institutions, including the University of California, San Diego, the Broad Institute of MIT and Harvard, or Broad Institute, and Cancer Research UK.

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Cancer targets based on synthetic lethality are ideal for precision medicine approaches because each product candidate inherently has a tumor-associated genetic biomarker to facilitate patient selection.

MAT2A Inhibitors in Tumors Containing MTAP Deletion – Program Update

MAT2A Inhibitors in Tumors Containing MTAP Deletion

Our most advanced synthetic lethality product candidate is IDE397, a clinical stage MAT2A inhibitor for patients with solid tumors having MTAP deletions.

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Because of this enhanced dependence, loss of MTAP results in synthetic lethality when MAT2A is pharmacologically inhibited.

The prevalence of MTAP deletions is estimated to be approximately 15% of all human tumors, translating to an estimated addressable population in major market countries, consisting of the US, EU5 and Japan, for patients having solid tumors with MTAP deletion to be approximately 75 ,000 annually.

In China, the estimated addressable population for esophageal cancer with MTAP deletion is about 30,000 annually, and for NSCLC with MTAP deletion is about 20,000 annually.

We have clearance from the FDA, to initiate a Phase 1 clinical trial designated as IDE397-001 to evaluate IDE397 under an IND.

We are targeting initial dosing of our first patient 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 or by MTAP immunohistochemistry, or IHC, assay with confirmation by NGS.

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 one or more 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 symmetric dimethylarginine, 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, such as taxanes.

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

PARG Inhibitors in Tumors with Defined Biomarker – Program Update

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.

The prevalence of MTAP deletions is estimated to be approximately 15% of all human tumors, translating to an estimated addressable population in major market countries, consisting of the US, EU5 (composed of Germany, Italy, Spain, France and the UK) and Japan, for patients having solid tumors with MTAP deletion to be approximately 75,000 annually.

In China, the estimated addressable population for esophageal cancer with MTAP deletion is about 30,000 annually, and for non-small cell lung cancer, or NSCLC , with MTAP deletion is about 20,000 annually.

We are leading 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 the ongoing 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 portion 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, or SAEs, no observed DLTs, and IDE397 had not yet reached its MTD.

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.

We are obtaining patient biopsies from the dose escalation and expansion portions of the clinical trial for translational research, including evaluation of certain pharmacodynamic biomarkers, such as peripheral or plasma SAM, tumor SAM, and 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, modulation of tumor SDMA, and tumor size 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.

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

We have obtained tumor biopsy cohorts in the IDE397 Phase 1 clinical trial to evaluate tumor pharmacodynamic biomarkers, including SDMA.

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.

In an interim analysis, IDE397 showed exposure-dependent reduction of SDMA in target tumor types – including in biopsies from patients having pancreatic cancer (Cohorts 3 and 4) and NSCLC (Cohort 5).

Treatment with IDE397 in a Cohort 5 patient resulted in a 95% reduction of tumor SDMA in NSCLC as measured by immunohistochemistry (IHC) score.

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 (~15% reduction in target lesions) and in a Cohort 3 adenoid cystic carcinoma patient with a lung metastasis (~11% reduction in target lesions) , pursuant to RE C IST v1.1 criteria .

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

Following initiation of an expansion cohort or establishing a MTD, we plan to submit an option data package to GSK, which would trigger an evaluation period for GSK to make a decision on whether to exercise its option to develop IDE397.

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

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 its option and upon commercialization, we will also be entitled to 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% tumor growth inhibition, or 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 > 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.

We observed preclinical in vivo efficacy of IDE397 plus standard-of-care combination agents, including with paclitaxel in head and neck cancer.

Additional preclinical combination tolerability and efficacy studies are ongoing, in collaboration with GSK, to evaluate IDE397 in combination with potential oncology agents.

Additionally, we have observed preclinical dose-dependent modulation of selected pharmacodynamic biomarkers, including SDMA, ADMA and SAM, in these in vivo models, including in NSCLC and HCT-116 MTAP deletion 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, 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 tumor growth inhibition for IDE397 in combination with a taxane in a pancreatic cancer PDX model.

We have also observed 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 tumor growth inhibition 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.

P ARG Inhibitors in Tumors with Defined Biomarker

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.

PARG is a novel target in a clinically validated biological pathway.

PARG functions as a regulator of DNA repair in the same biochemical pathway as PARP.

PARG functions as a regulator of DNA repair in the same biochemical pathway as poly (ADP-ribose) polymerase, or PARP.

In particular, PARG hydrolyzes poly (ADP-ribose), or PAR, chains that are polymerized by PARP enzymes, completing the PAR cycle.

Small molecule inhibitors of PARG result in a dose dependent increase in cellular PAR after DNA damage.

Depletion of certain base-excision repair components sensitizes cancer cells to pharmacological PARG inhibition in vitro .

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 been observed to show dose-dependent in vivo efficacy as monotherapy with tumor regression or stasis in multiple PDX models and in multiple CDX models.

We observed tumor regressions (greater than 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 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.

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

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 t umor r egressions ( > 100% TGI) in multiple breast cancer PDX models with defined genetic and subtyping profiles .

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

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 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 preclinically evaluating our PARG inhibitors as monotherapy in in vivo efficacy studies ongoing in multiple genetic settings.

We are also evaluating cell panel studies to validate and potentially identify new biomarker hypotheses, and supplementing our data set for indications and patient settings which are sensitive to pharmacological inhibition of our PARG inhibitors.

Among other efforts, we are collaborating with several academic and research institute investigators, including UCSF (S.

Bandyopadhyay), the Broad Institute of MIT and Harvard, or Broad Institute, and Cancer Research UK / University of Manchester (C.

Taylor), to evaluate cellular sensitivity in cell panels and to evaluate in vivo efficacy in relevant animal models.

We amended 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, in March 2020 to expand our research collaboration with Cancer Research UK / University of Manchester.

The expanded collaborative research includes evaluation of an IDEAYA proprietary small molecule PARG inhibitor in multiple in vitro and in vivo ovarian cancer xenograft models.

This research is also evaluating replication stress signature as a potential patient selection biomarker.

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.

Pol Theta Inhibitors in Tumors with Homologous Recombination Deficiency – Program Update

Pol Theta Inhibitors in Tumors with Homologous Recombination Deficiency

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.

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We also have established an independent research approach based on a protein degradation.

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:

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

We have observed 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.

WRN Inhibitors in Tumors with High Microsatellite Instability – Program Update

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.

WRN Inhibitors in Tumors with High Microsatellite Instability

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

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WRN is a protein having several functional domains, and we have shown that the helicase functional domain of WRN is responsible for this synthetic lethal interaction, as reflected in our publication in Cell Press - iScience, Werner Syndrome Helicase is Required for the Survival of Cancer Cells with Microsatellite Instability (March 2019).

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 pharmacodynamic response in multiple endogenous MSI high cell lines.

We have also observed in vivo efficacy and PD response in a relevant MSI high model, including approximately 100% TGI observed in a MSI high CDX model.

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

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We have established a comprehensive platform to computationally and empirically identify high value synthetic lethal pairs in defined patient populations.

This platform integrates across parallel data sets, each including orthogonal content based on particular screening efforts.

This platform integrates synthetic lethality relationship data across parallel data sets, each including orthogonal content based on particular screening efforts.

These screens include evaluation of curated, genetically defined and preselected model cell sets indicative of targeted patient populations.

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These integrated, comprehensive analysis efforts allow us to determine synthetic lethality target / biomarker pairs with the strongest signals across the data sets.

Potential therapeutic targets are ranked based on several factors, including the strength of the synthetic lethal interaction, potential drugability , potential clinical development path, and potential market opportunity.

Potential therapeutic targets are ranked based

on several factors, including the strength of the synthetic lethal interaction, potential drugability, potential clinical development path, and potential market opportunity.

The most promising therapeutic targets are validated empirically.

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PAGEO™ Paralogous Gene Evaluation in Ovarian Cancer and Dep Map Consortium – Broad Institute

On October 21, 2020, we entered into a strategic collaboration with the Broad Institute of MIT and Harvard focused on synthetic lethality target and biomarker discovery.

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

This collaboration will use the large-scale CRISPR paralog screening platform developed at the laboratory of William R.

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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.

Therapies Directly Targeting Oncogenic Pathways

IDE196 Overview – PKC Inhibitor for Patients having Tumors with GNAQ or GNA11 Mutations

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

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.

Synthetic Lethality Combination Therapies Targeting Oncogenic Pathways

Darovasertib Overview – PKC Inhibitor for Patients having Tumors with GNAQ or GNA11 Mutations

Darovasertib is a potent and selective small molecule inhibitor of 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 initiated a Phase 1/2 clinical trial IDE196-001 in June 2019 to evaluate IDE196 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 or colorectal cancer.

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 the Pfizer Agreement.

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.

We initiated a Phase 1/2 clinical trial IDE196-001 in June 2019 to evaluate darovasertib in solid tumors harboring GNAQ or GNA11 hotspot mutations in a basket trial design, including in 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, a 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 also evaluating darovasertib in combination with crizotinib in non-MUM cancers having GNAQ/11 mutations, with a current focus in skin melanoma.

We also plan to initiate evaluation of darovasertib in adjuvant primary UM through an IST.

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.

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

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.

Scientific Rationale and Opportunity

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Inactivation of PKC by specific inhibitors or reduction in protein expression using RNA all highlight the essential role of PKC in cells with GNAQ or GNA11 mutations.

Activating mutations in GNAQ or GNA11 are found in approximately 90% of uveal melanoma patients, resulting in a dependency on PKC activity which we believe may sensitize these tumors to the effects of IDE196.

Uveal melanoma is a cancer of the eye and the most common primary intraocular malignancy in adults.

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However, approximately 50% of uveal melanoma patients treated in this manner will eventually develop metastatic disease, most commonly in the liver.

We have estimated the addressable population in major market countries, consisting of the US, the five major countries in Europe, or EU5, and Japan, for patients having solid tumors with GNAQ or GNA11 mutations to include an annual incidence of about 3,500 in metastatic uveal melanoma.

For solid tumor indications other than metastatic uveal melanoma, we believe about 2,500 patients annually have tumors with GNAQ or GNA11 “hotspot” mutations that are potentially pathogenic, based on the loci of such mutations relative to the loci of mutations in uveal melanoma.

Thus, the addressable population in such major market countries is estimated to be about 6,000 patients having metastatic uveal melanoma or other solid tumors with potentially pathogenic GNAQ or GNA11 “hotspot” mutations.

We have estimated the addressable population in major market countries, consisting of the US, the twenty-eight countries in Europe, or EU28, and Japan, for patients having solid tumors with GNAQ or GNA11 mutations to include an annual incidence of about 4,200 in metastatic uveal melanoma.

For skin melanoma in the US, EU28 and Japan, we believe about 1,300 patients annually have tumors with GNAQ or GNA11 “hotspot” mutations that are potentially pathogenic, based on the loci of such mutations relative to the loci of mutations in uveal melanoma.

We believe the opportunity for treatment of adjuvant primary UM in the US, EU28 and Japan will add an additional 1,600 annual addressable patients.

Thus, the total addressable population for MUM, skin melanoma and adjuvant UM in such major market countries is estimated to be about 7,100 patients.

Patients with metastatic uveal melanoma have a very poor prognosis, and there are no FDA-approved therapies for this disease.

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The poor prognosis associated with metastatic disease and the lack of effective therapies highlight the need for novel therapeutic approaches that specifically target metastatic uveal melanoma.

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 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 Pfizer Agreement.

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 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.

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, w e observed preclinical synerg ies between I DE196 and crizotinib in relevant cell ular models under conditions simulating a tumor microenvironment in the liver, the site of approximately 90% of uveal melanoma metastases .

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 combination arm of the 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 translational research studies, or darovasertib cMET Translational Studies .

In these studies, w e observed preclinical synerg ies between darovasertib and crizotinib in relevant cell ular 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 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 IDE196 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 into the monotherapy Phase 2 basket arm of the clinical trial.

The company’s 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 RECIST, 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, 2021, 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 assess 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 toRECIST 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 indicates that darovasertib activity is independent of HLA status.

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

evaluation, including one confirmed PR.

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 gastrointestinal 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 darovasetib, 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

In an end of Phase 1 meeting with the FDA in the fourth quarter of 2019, the FDA indicated that our proposed single-arm Phase 2 portion of the IDE196 001 Phase 1/2 clinical trial may be adequate to support a new drug application, or NDA, seeking Accelerated Approval for IDE196 monotherapy in MUM.

The FDA indicated that such a single-arm, potentially registration enabling part of the Phase 1/2 clinical trial could target enrollment of 60 evaluable MUM patients with the primary endpoint of overall response rate, or ORR, as determined by blinded independent central review, or BICR, supported by BICR determined duration of response, or DOR, as a secondary endpoint.

We initiated 13-week good laboratory practice-, or GLP-, compliant toxicology studies in two species in November 2019, in support of an FDA requirement that results of these studies be submitted prior to enrollment of more than approximately 50 patients in the potentially registrational arm that will support a marketing application.

We have completed the 13-week preclinical toxicology studies of IDE196 in two species.

We plan to evaluate clinical tolerability and efficacy data from each of the ongoing IDE196 monotherapy Phase 1 portion of the clinical trial in MUM patients and the IDE196 combination therapy Phase 1/2 portions of the clinical trial in MUM patients, as well as potential strategic partnering of the IDE196 program, prior to initiation of a potentially registrational clinical trial in MUM.

We will provide updated guidance on timing for a potential NDA submission for IDE196 in MUM after making such decision on a potential registrational pathway in MUM.

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 to seek 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 and are evaluating the potential for clinical 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.

SWS is associated with a somatic, activating hotspot mutation in GNAQ through which PKC may mediate disease pathology, as reported by Shirley et al., NEJM (2013).

SWS is physiologically characterized by facial birthmark (e.g., a port-wine stain), neurological abnormalities (e.g., seizures) and glaucoma.

SWS, also known as encephalofacial angiomatosis, is a neurocutaneous disorder that occurs as a sporadic congenital condition.

It is understood to affect the skin in the distribution of the ophthalmic branch of the trigeminal nerve and is associated with venous-capillary abnormalities of the leptomeninges.

In January 2020, we entered into a Sponsored Research Agreement with Boston Children’s Hospital for preclinical evaluation of the role of PKC in SWS.

Under the agreement, we are collaborating with and support research at Boston Children’s Hospital in the laboratory of Dr.

Joyce Bischoff, Ph.D., Research Associate, Department of Surgery and Professor, Harvard Medical School, who is Principal Investigator of the research studies.

The preclinical research is evaluating IDE196 in vitro to assess whether pharmacological inhibition of PKC in endothelial cells having GNAQ mutations will restore normal cell function, as well as in vivo to assess whether pharmacological inhibition of PKC can regulate blood vessel size in murine models that recapitulate enlarged vessels seen in SWS capillary malformations.

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

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.

Impact of COVID-19 Pandemic on IDE397-001 Phase 1 Clinical Trial and IDE196-001 Phase 1/2 Clinical Trial

We continue to monitor the COVID-19 pandemic and its potential impact on the ongoing IDE397 and IDE196 clinical programs and timing of clinical data results.

Generally, initiation of clinical trial sites, patient enrollment and ongoing monitoring of enrolled patients, including obtaining patient computed tomography (CT) scans, may be impacted for IDEAYA clinical trials evaluating IDE397 and IDE196;

We continue to monitor the COVID-19 pandemic and its potential impact on the ongoing IDE397 and darovasertib, clinical programs and timing of clinical data results.

Generally, initiation of clinical trial sites, patient enrollment and ongoing monitoring of enrolled patients, including obtaining patient computed tomography, or CT, scans, may be impacted for our clinical trials evaluating IDE397 and darovasertib;

the specific impacts are currently uncertain.

For the IDE196 clinical program, GNAQ/11 patients enrolled in the ongoing Phase 1/2 clinical trial and sites affected by COVID-19 restrictions are adapting to logistical constraints on activities, such as travel and site visits.

For example, patients are continuing on IDE196 therapy, which is an oral drug and is being shipped to and self-administered by patients at home.

For these clinical programs, patients enrolled in the ongoing clinical trials and sites affected by COVID-19 restrictions are adapting to logistical constraints on activities, such as travel and site visits.

For example, patients are continuing on therapy, which are oral drugs and are being shipped to and self-administered by patients at home.

Patients are being monitored through a combination of telemedicine visits and local visits.

COVID‐19 infection rates have fluctuated over the course of the pandemic in several states in which our clinical trial sites are located.

Additionally, enrollment into the IDE397 and/or IDE196 clinical trials, including the Phase 1 dose escalation arm for IDE397 as monotherapy or the Phase 2 expansion arm for IDE196 as a monotherapy in non-MUM solid tumors having GNAQ or GNA11 hotspot mutations, may be delayed by circumstances resulting from the COVID-19 pandemic, including for example, as a result of increases in COVID-19 infection rates in several states in which our clinical trial sites are located, and by clinical site-specific policies and practices related to COVID-19.

COVID‐19 infection rates have fluctuated over the course of the pandemic in the countries and states in which our clinical trial sites are located.

Additionally, enrollment into these clinical trials, including the Phase 1 dose escalation arm for IDE397 as monotherapy or the Phase 2 expansion arm for darovasertib and crizotinib combination therapy in MUM and other solid tumors having GNAQ or GNA11 hotspot mutations, may be delayed by circumstances resulting from the COVID-19 pandemic, including for example, as a result of increases in COVID-19 infection rates in the states in which our clinical trial sites are located, and by clinical site-specific policies and practices related to COVID-19.

The specific impact on enrollment into these clinical trials is currently uncertain.

Enrollment into the combination arm evaluating IDE196 and binimetinib and/or the combination arm of IDE196 and crizotinib , in each case as combination therapy in MUM and non-MUM solid tumors having GNAQ or GNA11 hotspot mutations, may be delayed by circumstances resulting from the COVID-19 pandemic, including for example, by clinical site-specific policies and practices related to COVID-19.

The specific impact on enrollment into these combination arm s of the Phase 1/2 clinical trial is currently uncertain.

We plan to continue to use third-party service providers, including clinical research organizations, or CROs, and clinical manufacturing organizations, or CMOs, to carry out our preclinical and clinical development and manufacture and supply of our preclinical and clinical materials to be used during the development of our product candidates.

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We face competition with respect to product candidates in our pipeline, and will face competition with respect to future product candidates, from segments of the pharmaceutical, biotechnology and other related markets that pursue targeted approaches to addressing activating genetic and other molecular alterations in cancer.

For IDE397, our MAT2A inhibitor for patients with solid tumors having MTAP deletions, Agios Pharmaceuticals, or Agios, is clinically evaluating a small molecule MAT2A inhibitor designated as AG270 in patients having tumors with MTAP deletion.

For IDE397, Servier Pharmaceuticals, LLC, or Servier, is clinically evaluating a small molecule MAT2A inhibitor designated as AG270 in patients having tumors with MTAP deletion.

AG270 was originally developed by Agios Pharmaceuticals, or Agios, which sold its commercial, clinical and research-stage oncology portfolio, including AG270, to Servier in April 2021.

Agios presented initial data from its Phase 1 clinical trial evaluating AG270 in patients having tumors with MTAP deletion at the AACR/NCI/EORTC conference in October 2019.

We believe that Agios has no current ongoing clinical trials to evaluate AG270 as monotherapy;

We believe that Servier has no current ongoing clinical trials to evaluate AG270 as monotherapy;

their current clinical development efforts include evaluation of AG270 in combination with taxanes in selected tumor indications.

We believe that IDE397 is more potent, more selective and has enhanced physical properties, collectively contributing to a differentiated target product profile relative to an Agios compound AGI-25696, which we believe to be representative of a series of Agios compounds including AG270.

Agios has entered into an agreement with Servier Pharmaceuticals, LLC, or Servier, to sell its commercial, clinical and research-stage oncology portfolio, including AG270, to Servier.

Agios has announced that it currently expects to complete the transaction at the end of the first quarter or in the beginning of the second quarter of 2021.

For our preclinical pipeline of synthetic lethality therapeutics, potential competition includes established companies as well as earlier-stage emerging biotechnology companies.

Multiple companies have been involved with research and development of PARP inhibitors, such as Lynparza, Rubraca, Zejula, and Talzenna.

Additionally, several other early-stage companies, including Anticancer Bioscience, Artios, Cyteir, FoRx Therapeutics, KSQ, MetaboMed, NeoMed, Repare, Ribon, and Tango are performing research in synthetic lethality.

For IDE196, our small molecule inhibitor targeting PKC in genetically-defined solid tumors having GNAQ or GNA11 mutations, we are not aware of other companies actively developing clinical-stage therapeutics directed to PKC as a target.

Also, we are not aware of any approved therapies for metastatic uveal melanoma.

Some companies are conducting research and development of potential therapies for metastatic uveal melanoma based on other targets and approaches.

For example, Immunocore is developing IMCgp100, or tebentafusp, as monotherapy for metastatic uveal melanoma in a current Phase 3 clinical trial for patients with the HLA-A2 allele.

Immunocore has disclosed in regulatory filings that of the approximately 5,000 to 6,000 estimated new cases of primary uveal melanoma per annum, there is an estimated addressable patient population of 1,000 patients per annum which have metastatic uveal melanoma that are HLA-A*02:01-positive and will be eligible for treatment with tebentafusp.

Immunocore recently announced that a Phase 3 clinical trial of tebentafusp in MUM has met the predefined boundaries for statistical significance of the primary endpoint of overall survival in an interim analysis conducted by an independent data monitoring committee.

Immunocore also announced that the FDA granted Breakthrough Therapy Designation, or BTD, to tebentafusp for the treatment of HLA-A*02:01-positive adult patients with unresectable uveal melanoma or MUM.

Multiple established companies have been involved with research and development in synthetic lethality, such as AstraZeneca (Lynparza), Pfizer (Talzenna), GSK (Zejula) and Roche.

Additionally, several other early-stage companies, including Mirati Therapeutics, Zai Labs, Breakpoint Therapeutics, Ryvu Therapeutics, Foghorn Therapeutics, Silicon Therapeutics (acquired by Roivant Sciences), Anticancer Bioscience, Artios, Cyteir, FoRx Therapeutics, KSQ, MetaboMed, NeoMed, Vividion Repare, Ribon, and Tango are performing research in synthetic lethality.

For darovasertib, we are not aware of other companies actively developing clinical-stage therapeutics directed to PKC as a target for solid tumors.

MingSight is developing a PKC beta inhibitor in chronic lymphocytic leukemia and diabetic macular edema, both in Phase 1 studies.

Varian Biopharmaceuticals is advancing a preclinical-stage atypical PCK iota inhibitor, including as a dermatologic gel formulation for potential topical treatment of Basal Cell Carcinoma, or BCC.

We are aware of other companies that are conducting research and development of potential therapies for metastatic uveal melanoma based on other targets and approaches.

For example, Immunocore is developing Tebentafusp, also known under its branded name as Kimmtrak.

Kimmtrak was approved by the FDA in January 2022 for the treatment of HLA-A*02:01-positive unresectable or metastatic uveal melanoma patients.

Intellectual Property

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We are seeking and maintaining patent protection in the United States and key foreign jurisdictions.

As of January 15, 2021, we own or exclusively in-license patents and patent applications, comprising approximately 32 distinct patent families, protecting our technology across our pipeline.

Excluding applications that we are not currently prosecuting, our portfolio consists of six issued U.S.

As of February 1, 2022, we own or exclusively in-license patents and patent applications, comprising approximately 45 distinct patent families, protecting our technology across our pipeline.

Excluding applications that we are not currently prosecuting, our portfolio consists of 10 issued U.S.

patents, approximately 33 pending U.S.

applications, 11 pending applications under the Patent Cooperation Treaty, or PCT, 19 issued foreign patents and approximately 48 pending foreign applications in approximately 29 foreign jurisdictions, including without limitation countries included in major markets in North America, Europe, and Asia, each having a nominal expiration ranging from 2035 to 2040.

applications, 12 pending applications under the Patent Cooperation Treaty, or PCT, 32 issued foreign patents and approximately 88 pending foreign applications in approximately 43 foreign jurisdictions, including without limitation countries included in major markets in North America, Europe, and Asia, each having expiration dates ranging from 2035 to 2042.

Of these, we own approximately 42 distinct patent families, including approximately 30 pending U.S.

patent applications and 11 PCT applications, nominally expiring in 2038 to 2041.

patent applications and 12 PCT applications, nominally expiring between 2038 and 2042.

The nominal expiration of our patents and patent applications does not account for any applicable patent term adjustments or extensions.

As of January 15, 2021, the portion of our portfolio for IDE196, which we have in-licensed from Novartis, consists of four issued U.S.

As of February 1, 2022, the portion of our portfolio for IDE196, which we have in-licensed from Novartis, consists of four issued U.S.

patents, approximately 23 issued foreign patents, approximately two pending U.S.

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These in-licensed patents and applications are directed to composition of matter, pharmaceutical compositions and methods of treatment, including treatment of uveal melanoma.

These in-licensed patents nominally expire from 2035 to 2038, without taking into account any applicable patent term adjustments or extensions.

These in-licensed patents expire between 2035 and 2038, without taking into account any applicable patent term adjustments or extensions.

In addition, the IDE196 portfolio also includes one pending U.S.

patent application and three PCT applications solely owned by IDEAYA directed to methods of treatment for certain dosing regimens, for certain solid tumors having mutations in GNAQ or GNA11, or for certain EGFR mutant tumors in NSCLC.

These solely owned patents nominally expire in 2040, without taking into account any applicable patent term adjustments or extensions.

patent application and two PCT applications solely owned by IDEAYA directed to methods of treatment, including dosing regimens, for patients having solid tumors, including tumors having mutations in GNAQ or GNA11.

These solely owned patents expire between 2040 and 2041, without taking into account any applicable patent term adjustments or extensions.

In addition, the IDE196 portfolio includes two U.S.

provisional patent applications which are jointly owned with Pfizer directed to methods of treatment for certain combination treatments.

As of February 1, 2022, the portion of our portfolio for programs in our synthetic lethality pipeline consists of U.S.

patent applications directed to composition of matter, pharmaceutical compositions and/or methods of treatment of cancer for each of our MAT2A (MTAP), PARG (BER), POLQ (HR) and WRN (high MSI) programs, which we own.

patent applications directed to composition of matter, pharmaceutical compositions and/or methods of treatment of cancer for each of our MAT2A (MTAP), PARG (HRD), POLQ (HR), WRN (high MSI), and DDR1 programs, which we own.

This portion of our portfolio also includes pending U.S.

and foreign applications directed to composition of matter, pharmaceutical compositions and methods of treatment of cancer for our PARG (BER) program, which are owned by Cancer Research UK and University of Manchester, for which we have the exclusive option to obtain an exclusive in-license.

and foreign applications directed to composition of matter, pharmaceutical

compositions and methods of treatment of cancer for our PARG (HRD) program, which we have exclusively in-licensed from Cancer Research UK and University of Manchester .

Strategic Relationships

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We have an in-license agreement for our PARG program with Cancer Research UK and University of Manchester.

For IDE196, our clinical stage PKC program, we have an in-license agreement with Novartis, and have established a clinical trial and supply agreement in support of our clinical evaluation of IDE196 in combination with binimetinib, and independently, in combination with crizotinib.

For darovasertib, our clinical stage PKC program, we have an in-license agreement with Novartis, and have established a clinical trial collaboration and supply agreements in support of our clinical evaluation of darovasertib in combination with binimetinib, and independently, in combination with crizotinib.

For our PARG, DDT1 and DDT2 programs, our small molecule compounds are being discovered and/or developed internally with our own resources, as supplemented by certain service providers such as CROs.

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We have also established a collaborative relationship with Ventana (Roche Diagnostics) for development of molecular diagnostics for various research programs.

We have established certain development manufacturing and service relationships with CMOs for IDE397 and IDE196.

We have established certain development manufacturing and service relationships with CMOs for IDE397 and darovasertib.

We have an agreement with STA Pharmaceutical Hong Kong Limited for the synthesis of the API and formulation for IDE397, and with Bioduro for the manufacturing of IDE397 drug product.

We have an agreement with STA Pharmaceutical Hong Kong Limited for the synthesis of the API and formulation for IDE196, and for the manufacturing of IDE196 drug product.

We have establish ed arrangements with CMOs as well for packaging, labeling and distribution of IDE397 and IDE196.

We also have established clinical services relationship with Parexel International (IRL) Limited as a CRO to support our conduct of clinical trials for our IDE397 program, and with Icon Clinical Research Limited as a CRO to support our conduct of clinical trials for our IDE196 program.

We have an agreement with STA Pharmaceutical Hong Kong Limited for the synthesis of the API and formulation for darovasertib, and for the manufacturing of IDE196 drug product.

We have established arrangements with CMOs as well for packaging, labeling and distribution of IDE397 anddarovasertib.

We also have established clinical services relationship with CROs to support our conduct of clinical trials for our IDE397 program and our darovasertib program.

In addition to these existing strategic license relationships, existing and planned development manufacturing and service arrangements, and existing and planned clinical services arrangements, we have various existing agreements and relationships with service providers, such as CROs, which are enabling execution of various research and development activities for each of our pipeline programs.

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GSK’s exercise of the Option may be subject to HSR Clearance therefor at such time of exercise, and following exercise and HSR Clearance, GSK has agreed to pay us an option exercise payment of $50.0 million.

GSK may initiate, or request that we initiate, a Phase 1 combination clinical trial for a MAT2A product and GSK’s Type I PRMT inhibitor (GSK3368715) product, or the MAT2A Combination Trial, prior to GSK’s exercise of the Option.

We will be responsible for the costs of research and early clinical development activities that we conduct for the MAT2A program prior to GSK’s exercise of the Option (including during any interim waiting period for HSR Clearance for such Option exercise, if applicable), excluding the costs of conducting the MAT2A Combination Trial.

GSK will be solely responsible for costs of the conduct of the MAT2A Combination Trial, except for supply of the MAT2A product therefor, to be provided by us at our own cost.

In January 2022, we and GSK entered into an Amendment No.

2 to the GSK Collaboration Agreement which amended certain elements of the Option Data Package, including conforming to GSK’s waiver of rights relating to the MAT2A Combination Trial.

In January 2022, GSK waived its rights under the GSK Collaboration Agreement to initiate, or request that we initiate, prior to GSK’s exercise of the Option, a Phase 1 combination clinical trial for a MAT2A product and GSK’s Type I PRMT inhibitor (GSK3368715) product, or the MAT2A Combination Trial.

Accordingly, we have no further obligation under the GSK Collaboration Agreement to supply MAT2A product for the MAT2A Combination Trial at our own cost.

Subject to GSK’s exercise of the Option (and HSR Clearance thereof, if applicable), GSK will lead later stage global clinical development for the MAT2A program, with IDEAYA responsible for 20% and GSK responsible for 80% of further development costs.

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to global profits for MAT2A products, as measured three and six years after global commercial launch thereof.

Subject to GSK’s exercise of the Option (and HSR Clearance thereof, if applicable), we will be eligible to receive future development and regulatory milestones of up to $465.0 million, and commercial milestones of up to $475.0 million, with respect to each MAT2A product.

Subject to GSK’s exercise of the Option (and HSR Clearance thereof, if applicable), we will be eligible to receive future development and regulatory milestones of up to $465.0 million.

If GSK decides to exercise its option and upon commercialization, we will also be entitled to receive commercial milestones of up to $475.0 million, with respect to each MAT2A product.

Additionally, we are entitled to receive 50% of U.S.

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We will be eligible to receive future development and regulatory milestones of up to $485.0 million, with respect to each POLQ product, including as applicable, for multiple POLQ products that target certain alternative protein domains or are based on alternative modalities.

Included within such development and regulatory milestones, 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.

Additionally, we are eligible to receive up to $475.0 million of commercial milestones with respect to each POLQ product.

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We will be eligible to receive future development milestones of up to $485.0 million, with respect to each WRN product, including as applicable, for multiple WRN products that are based on alternative modalities.

Included within such development and regulatory milestones, we have the p otential to receive up to $20 million in aggregate milestone payments from G SK for certain milestones, which may occur as we, in collaboration with GSK, advance a WRN product from preclinical development in to early Phase 1 clinical trials.

Additionally, we will be eligible to receive up to $475.0 million of commercial milestones with respect to each WRN product.

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The GSK Collaboration Agreement contains various representations, warranties, covenants, dispute resolution mechanisms, indemnities and other provisions generally customary for transactions of this nature.

Exclusive License Agreement with Novartis for IDE196 (PKC)

On September 19, 2018, we entered into a license agreement with Novartis to develop products based on Novartis’ small molecule PKC inhibitors, including Novartis’ LXS196 oncology product candidate, which we have renamed as IDE196.

Exclusive License Agreement with Novartis for Darovasertib (PKC)

Under the license agreement, Novartis granted to us a worldwide, exclusive, sublicensable license to research, develop, manufacture, and commercialize certain defined compounds and products, including IDE196 and certain other PKC inhibitors as well as companion diagnostic products, collectively referred to as the licensed products, for any purpose.

The license grant is subject to Novartis’ retained rights to complete its ongoing Phase 1 clinical trial of IDE196.

Novartis also agreed to transfer to us certain materials and know-how relating to the licensed products or arising from the ongoing Phase 1 clinical trial of IDE196.

We are solely responsible for the manufacturing and commercialization of the licensed products, subject to Novartis’ rights under the ongoing clinical trial of IDE196.

We have certain obligations to supply IDE196 and licensed products for compassionate use, named patient and similar programs in connection with the ongoing clinical trial.

Novartis also agreed to transfer to us certain materials and know-how relating to the licensed products or arising from the ongoing Phase 1 clinical trial of darovasertib.

We are solely responsible for the manufacturing and commercialization of the licensed products, subject to Novartis’ rights under the ongoing clinical trial of darovasertib.

We have certain obligations to supply darovasertib and licensed products for compassionate use, named patient and similar programs in connection with the ongoing clinical trial.

We are obligated to use commercially reasonable efforts to develop one licensed product and to commercialize and obtain regulatory approval for at least one licensed product in the United States and in specified European countries.

All inventions, know-how, data and results resulting from our activities under the license agreement, including activities relating to our own clinical trials, will be exclusively owned by us.

All inventions, know-how, data and results resulting from Novartis’ activities connected with Novartis’ ongoing Phase 1 clinical trial for IDE196 will be exclusively owned by Novartis, and subject to the license to us.

All inventions, know-how, data and results resulting from

Novartis’ activities connected with Novartis’ ongoing Phase 1 clinical trial for IDE196 will be exclusively owned by Novartis, and subject to the license to us.

Ownership of all other inventions and know-how will be determined according to U.S.

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Upon termination by Novartis for material breach or for our insolvency, or upon termination by us without cause, at Novartis’ written request and in return for consideration that will be negotiated at such time, we will grant to Novartis a perpetual, irrevocable, worldwide, sublicensable, nonexclusive or exclusive license, under all patent rights and know-how controlled by us that are related to and actually used as of the date of termination in the development, manufacture, and commercialization of licensed products, for Novartis to develop, manufacture, and commercialize the licensed products.

Clinical Trial Collaboration and Supply Agreement with Pfizer for IDE196 (PKC)

Clinical Trial Collaboration and Supply Agreements with Pfizer for Darovasertib (PKC)

In March 2020, we entered into the Pfizer Agreement, pursuant to which the parties will work on combination studies, as portions of the Company’s Phase 1/2 clinical trial in MUM and other solid tumors harboring activating GNAQ or GNA11 hotspot mutations.

The combination study specifically pertains to the clinical evaluation of our IDE196 clinical candidate in combination with Pfizer’s MEK inhibitor, binimetinib.

In September 2020, we expanded the scope of our Pfizer Agreement to also evaluate IDE196 and Pfizer’s cMET inhibitor, crizotinib, as an additional, independent combination therapy.

Under the agreement, we are sponsor of the combination studies, and will provide IDE196 and pay for the costs of the combination studies.

The combination study specifically pertains to the clinical evaluation of our darovasertib clinical candidate in combination with Pfizer’s MEK inhibitor, binimetinib.

In September 2020, we expanded the scope of our Pfizer Agreement to also evaluate darovasertib and Pfizer’s cMET inhibitor, crizotinib, as an additional, independent combination therapy.

Under the agreement, we are sponsor of the combination studies, and will provide darovasertib and pay for the costs of the combination studies.

Pfizer will provide binimetinib and crizotinib for the combination studies at no cost to us.

We and Pfizer will jointly own clinical data from the combination studies and will also jointly own inventions, if any, relating to the combined use of IDE196 and binimetinib, or independently, to the combined use of IDE196 and crizotinib.

We and Pfizer will jointly own clinical data from the combination studies and will also jointly own inventions, if any, relating to the combined use of darovasertib and binimetinib, or independently, to the combined use of darovasertib and crizotinib.

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

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If Pfizer terminates the agreement because of our material breach, we will be required to reimburse Pfizer certain manufacturing costs for the binimetinib or crizotinib supplied under the agreement.

We have further expanded the scope of our relationship with Pfizer, entering into additional agreements to facilitate evaluation of darovasertib in combination with crizotinib in MUM and in other cMET-driven tumor indications.

On March 11, 2022 and effective March 9, 2022, we and Pfizer entered into a second Clinical Trial Collaboration and Supply Agreement, or the Second Pfizer Agreement, pursuant to which we may, subject to FDA feedback and guidance, evaluate darovasertib and Pfizer’s cMET inhibitor, crizotinib , as a combination therapy in MUM in a planned Phase 2 potential registration-enabling clinical trial.

Pursuant to the Second Pfizer Agreement, we are the sponsor of the planned combination trial and we will provide darovasertib and pay for the costs of the combination trial;

Pfizer will provide crizotinib for the planned combination trial at no cost to us.

We and Pfizer will jointly own clinical data from the planned c ombination trial and all inventions relating to the combined use of IDE196 and crizotnib .

We and Pfizer will form a joint development committee responsible for coordinating all regulatory and other activities under the Second Pfizer Agreement.

Separately, on March 11, 2022 and effective March 9, 2022, we and Pfizer also entered into a third Clinical Trial Collaboration and Supply Agreement, or the Third Pfizer Agreement, pursuant to which we may, subject to preclinical validation and FDA feedback and guidance, evaluate darovasertib and Pfizer’s cMET inhibitor, crizotinib, as a combination therapy in cMET-driven tumors such as NSCLC and/or HCC in a Phase 1 clinical trial.

Pursuant to the Third Pfizer Agreement, we are the sponsor of the planned combination trial and we will provide darovasertib and pay for the costs of the combination trial;

Pfizer will provide crizotinib for the planned combination trial at no cost to us.

We and Pfizer will jointly own clinical data from the planned combination trial and all inventions relating to the combined use of darovasertib and crizotnib.

We and Pfizer will form a joint development committee responsible for coordinating all regulatory and other activities under the Third Pfizer Agreement.

Exclusive Option and License Agreement with Cancer Research UK

On April 28, 2017, we entered into an evaluation, option and license agreement with Cancer Research UK and University of Manchester, which was amended on April 24, 2019 and on March 3, 2020, for the development and commercialization of licensed products comprising pharmaceutical preparations of PARG inhibitors for all therapeutic uses.

On April 28, 2017, we entered into an Evaluation, Option and License agreement, or CRUK/Manchester Agreement, with Cancer Research UK and University of Manchester, which was amended on April 24, 2019 and on March 3, 2020, for the development and commercialization of licensed products comprising pharmaceutical preparations of PARG inhibitors for all therapeutic uses

Under this agreement, Cancer Research UK and University of Manchester have granted to us, and we have in turn granted to Cancer Research UK and University of Manchester, non-exclusive, sublicensable, royalty-free licenses to carry out non-clinical research during the research term, currently ending in March 2021.

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Cancer Research UK and University of Manchester retain certain rights under the licensed intellectual property for academic, non-commercial research and teaching.

In the March 2020 second amendment to the evaluation, option and license agreement, the parties reduced the license fee due at exercise of our option, extended the research period to March 2021, and also extended the option period, during which IDEAYA has rights to exercise an option to certain license rights.

The expanded collaborative research includes evaluation of an IDEAYA proprietary small molecule PARG inhibitor in multiple in vitro and in vivo ovarian cancer xenograft models.

In the March 2020 second amendment to the CRUK/Manchester Agreement, the parties reduced the license fee due at exercise of our option, extended the research period to March 2021, and also extended the option period, during which IDEAYA has rights to exercise an option to certain license rights.

The expanded collaborative research included evaluation of an IDEAYA proprietary small molecule PARG inhibitor in multiple in vitro and in vivo ovarian cancer xenograft models.

This research is also evaluating replication stress signature as a potential patient selection biomarker.

The extended option period was for up to four additional years from March 2020, including an initial one year period to March 2021 and an additional eighteen month extension to September 2022, which has now been elected pursuant to our certification of ongoing program research activities.

Thereafter, we can elect three additional six-month extensions, contingent upon both our certification of ongoing research activities and payment of certain extension fees, which together with the reduced license fee would equal the original license fee.

During the option period, no party shall grant to any third party any rights or licenses under Cancer Research UK background intellectual property that specifically relate to PARG or under our intellectual property covering inventions made in the performance of the research program.

Upon option exercise, we will gain sole control and responsibility for the research, development, manufacture, and commercialization of the licensed PARG inhibitors.

In January 2022, we exercised our option under the CRUK/Manchester Agreement, pursuant to which we hold exclusive worldwide license rights covering a broad class of PARG inhibitors.

Following our option exercise, we gained sole control and responsibility for the research, development, manufacture, and commercialization of the licensed PARG inhibitors.

Cancer Research UK has also agreed to transfer its know how relating to the research, development or manufacturing of the licensed PARG inhibitors to us.

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Each party is the sole owner of any intellectual property it develops solely under the agreement, and the parties will be joint owners of any jointly developed intellectual property.

Each party grants the other a non-exclusive, fully-paid, royalty free, irrevocable, sublicensable, perpetual license to its rights in such jointly created intellectual property to make, use and sell inventions claimed in the joint patents, except for those joint patents exclusively licensed to us under the agreement if we exercise our option.

Before our exercise of the option, Cancer Research UK is responsible for the prosecution and maintenance of Cancer Research UK background patents specifically relating to PARG, while we are responsible for the prosecution and maintenance of patents covering inventions developed under the agreement as project intellectual property.

Cancer Research UK and U niversity of Man chester have the first right to enforce the patents covering inventions developed under the agreement as project intellectual property and we have the right to participate in such actions.

In the event we exercise the option, we will assume Cancer Research UK ’s prosecution and maintenance responsibilities for the Cancer Research UK background patents specifically relating to PARG and we obtain the first right to enforce such patents as well as the patents covering inventions developed under the agreement as project intellectual property, and Cancer Research UK will have the right to participate.

In either case, we pay all expenses associated with prosecution and maintenance and each party bears its own costs for enforcement.

If we choose not to exercise the option, or if we abandon the patents covering inventions developed under the agreement as project intellectual property, Cancer Research UK will thereafter be responsible for prosecuting and maintaining such patents.

If we abandon such patents, Cancer Research UK and U niversity of Man chester will be responsible for paying the expenses associated with the prosecution and maintenance of such patents.

In addition to paying an upfront fee of £100,000, if we exercise the option we additionally agree to pay Cancer Research UK (a) a one-time fee of £250,000, (b) subject to completion of certain clinical and regulatory milestones, payments of up to £19.5 million per indication, (c) subject to certain sales milestones, payments of up to £9 million per indication, and (d) low single-digit tiered royalty payments based on aggregate worldwide net sales of all products, payable on a product-by-product and country-by-country basis until the later of the last-to-expire patent covering such product in such country and the ten year anniversary of the first commercial sale of such licensed product in such country.

Each party grants the other a non-exclusive, fully-paid, royalty free, irrevocable, sublicensable, perpetual license to its rights in such jointly created intellectual property to make, use and sell

inventions claimed in the joint patents, except for those joint patents exclusively licensed to us under the agreement following our exercise of the option.

We are obligated to use reasonable efforts to research a PARG inhibitor during the research term, and to develop a PARG inhibitor for the treatment of a cancer indication if we exercise the option.

Each party is the sole owner of any intellectual property it develops solely under the agreement, and the parties will be joint owners of any jointly developed intellectual property.

Before our exercise of the option, Cancer Research UK was responsible for the prosecution and maintenance of Cancer Research UK background patents specifically relating to PARG, while we were responsible for the prosecution and maintenance of patents covering inventions developed under the agreement as project intellectual property.

Cancer Research UK and University of Manchester had the first right to enforce the patents covering inventions developed under the agreement as project intellectual property and we had the right to participate in such actions.

Following our exercise of the option, we have assumed Cancer Research UK’s prosecution and maintenance responsibilities for the Cancer Research UK background patents specifically relating to PARG and we obtained the first right to enforce such patents as well as the patents covering inventions developed under the agreement as project intellectual property, and Cancer Research UK will have the right to participate.

We pay all expenses associated with prosecution and maintenance and each party bears its own costs for enforcement.

If we abandon the patents covering inventions developed under the agreement as project intellectual property, Cancer Research UK will thereafter be responsible for prosecuting and maintaining such patents.

If we abandon such patents, Cancer Research UK and University of Manchester will be responsible for paying the expenses associated with the prosecution and maintenance of such patents.

In addition to an upfront fee of £100,000 and a one-time option exercise fee of £250,000, each of which have been paid, we have certain potential milestone-dependent financial obligations, including:

(a) subject to completion of certain clinical and regulatory milestones, payments of up to £19.5 million per broad disease classification block – for example, in oncologic diseases, up to £13.0 million aggregate for a first achievement of such clinical and regulatory milestones and up to £6.5 million aggregate for a second achievement of such clinical and regulatory milestones;

(b) subject to certain sales milestones, payments of up to £9 million per broad disease classification block – for example, in oncologic diseases, up to

£6.0 million aggregate for a first achievement of such sales milestones and up to £3.0 million aggregate for a second achievement of such sales milestones;

and (c) low single-digit tiered royalty payments based on aggregate worldwide net sales of all products, payable on a product-by-product and country-by-country basis until the later of the last-to-expire patent covering such product in such country and the ten year anniversary of the first commercial sale of such licensed product in such country.

The royalty payments are subject to reductions for payment obligations in the event third-party licenses are required to develop or commercialize the product or if the product is not covered by certain patents.

If we exercise the option, we also agreed to pay to Cancer Research UK percentages in the low to mid-teens of sublicense revenue we receive for a sublicense of intellectual property derived from certain intellectual property developed under the agreement or Cancer Research UK background patents specifically relating to PARG.

If the agreement expires because we do not exercise the option or if the agreement is terminated due to our material breach, then we are eligible to receive a percentage of sublicensing revenue that Cancer Research UK receives for licensing such intellectual property.

The agreement will expire at the end of the Option Period if we do not exercise the option, or upon expiration of all payment obligations if we do exercise the option.

Either party may terminate the agreement for the other party’s insolvency or material breach that remains uncured for thirty days.

In addition, Cancer Research UK and University of Manchester may terminate the agreement with thirty days advance written notice if we become an affiliate of or transfer rights to a party with a business in tobacco products.

If we elect not to exercise the option, or if the agreement is terminated by Cancer Research UK and University of Manchester pursuant to any of their termination rights, then Cancer Research UK and University of Manchester will have exclusive, worldwide rights to project intellectual property.

Following our exercise of the option, if we sublicense certain intellectual property developed under the agreement or Cancer Research UK background patents specifically relating to PARG, we will also have an obligation to pay to Cancer Research UK low double digit percentage of sublicense revenue we receive, if any.

If the agreement is terminated due to our material breach, then we are eligible to receive a percentage of sublicensing revenue that Cancer Research UK receives for licensing intellectual property.

If the agreement is terminated by Cancer Research UK and University of Manchester pursuant to any of their termination rights, then Cancer Research UK and University of Manchester will have exclusive, worldwide rights to project intellectual property.

If we terminate the agreement for material breach, then the licenses we receive upon exercise of the option survive, and our payment obligations will be reduced.

If we exercise the option, the licenses we receive upon exercise of the option survive expiration of the agreement.

Following our exercise of the option, the licenses we receive upon exercise of the option survive expiration of the agreement.

Sales and Marketing

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These points may be prior to submission of an IND, at the end of Phase 2, and before an NDA is submitted.

Meetings at other times may

be requested.

Meetings at other times may be requested.

These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and for the sponsor and the FDA to reach agreement on the next phase of development.

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The FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality and purity.

Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review.

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The resubmitted application also is subject to review before the FDA accepts it for filing.

Under the Prescription Drug User Fee Act, or PDUFA, the FDA has agreed to certain performance goals in the review of NDAs through a two-tiered classification system, standard review and priority review.

According to the current PDUFA performance goals for new molecular entity NDAs, the FDA endeavors to review and act on applications within ten months of the 60-day filing date under standard review, and within six months of the 60-day filing date under priority review.

The FDA may refer an application for a novel drug to an advisory committee.

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The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA will inspect the facility or facilities where the product is manufactured.

Before approving an

NDA, the FDA will inspect the facility or facilities where the product is manufactured.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

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A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form.

A Complete Response Letter usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical data, such as an additional pivotal Phase 3 clinical trial or other significant and time-consuming

requirements related to clinical trials, nonclinical studies or manufacturing.

If a Complete Response Letter is issued, the sponsor must resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application.

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Marketing approval may be withdrawn for non-compliance with regulatory requirements or if problems occur following initial marketing.

The Pediatric Research Equity Act, or PREA, requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration.

Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver.

The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The sponsor or FDA may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations.

A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin.

The FDA must send a non-compliance letter to any sponsor that fails to submit the required assessment or keep a deferral current, or fails to submit a request for approval of a pediatric formulation.

Pediatric Use

Even when not pursuing a pediatric indication, under the Pediatric Research Equity Act, or PREA, an NDA or supplement thereto must contain data that is adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

With the enactment of the Food and Drug Administration Safety and Innovation Act in 2012, sponsors must also submit pediatric trial plans prior to the assessment data.

Those plans must contain an outline of the proposed pediatric trials the sponsor plans to conduct, including trial objectives and design, any deferral or waiver requests, and other information required by regulation.

The FDA must then review the information submitted, consult with the sponsor, and agree upon a final plan.

The FDA or the sponsor may request an amendment to the plan at any time.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

Separately, in the event the FDA issues a Written Request for pediatric data relating to a drug product, an NDA sponsor who submits such data may be entitled to pediatric exclusivity.

Pediatric exclusivity is another type of non-patent marketing exclusivity which, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing exclusivity.

Orphan Drug Designation

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States or, if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making a drug product available in the United States for this type of disease or condition will be recovered from sales of the product.

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States or, if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making the drug product available in the United States for the disease or condition will be recovered from sales of the product in the United States.

Orphan designation must be requested before submitting an NDA.

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Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or inability to manufacture the product in sufficient quantities.

The designation of such drug also entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers.

applications to market the same drug for the same indication for seven years, except in limited circumstances, such as a subsequent product showing of clinical superiority to the product with orphan exclusivity.

The designation of such drug also entitles a party to financial incentives such as opportunities for grant funding, tax credits for certain clinical trial costs and user-fee waivers.

However, competitors, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.

Orphan exclusivity also could block the approval of one of our product candidates for seven years if a competitor obtains approval of the same drug as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease.

Orphan exclusivity also could block the approval of one of our product candidates for seven years if a competitor obtains approval of the same drug for the same rare disease or condition before we do.

In addition, if an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.

Exclusive marketing rights in the United States may also be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

Expedited Development and Review Programs

The FDA has a fast track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria.

Specifically, new drugs are eligible for Fast Track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

Unique to a fast track product, the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

Any product submitted to the FDA for approval, including a product with a fast track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

A product is eligible for priority review if it has the potential to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis or prevention of a disease compared to marketed products.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug designated for priority review in an effort to facilitate the review.

The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.

In addition, a product may be eligible for accelerated approval.

Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

New drug products are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

Fast track designation applies to the combination of the product and the specific indication for which it is being studied.

The sponsor of a fast track product has opportunities for frequent interactions with the review team during product development and, once an NDA is submitted, the product may be eligible for priority review.

A fast track product may also be eligible for rolling review, where the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

A product intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review.

A product can receive breakthrough therapy designation if preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product, including involvement of senior managers.

After an NDA is submitted for a product, including a product with a fast track designation and/or breakthrough therapy designation, the NDA may be eligible for priority review.

A product is eligible for priority review if it has the potential to provide a significant improvement in the treatment or prevention of a serious disease or condition compared to marketed products.

If the drug contains a new molecular entity, priority review designation means the FDA’s goal is to take an action on the marketing application within six months of the 60-day filing date, compared with ten months under standard review.

Additionally, products studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate and well-controlled post-marketing clinical studies to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit.

In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

Fast track designation, priority review and accelerated approval do not change the standards for approval but may expedite the development or approval process.

The Food and Drug Administration Safety and Innovation Act, or FDASIA, established a category of drugs referred to as “breakthrough therapies” that may be eligible to receive breakthrough therapy designation.

A sponsor may seek FDA designation of a product candidate as a “breakthrough therapy” if the product is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance.

The breakthrough therapy designation is a distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met.

If a product is designated as breakthrough therapy, the FDA will work to expedite the development and review of such drug.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

We expect to pursue breakthrough therapy designation for IDE196 and may explore some of these opportunities for our other product candidates as appropriate.

We expect to pursue breakthrough therapy designation for darovasertib and may explore some of these opportunities for our other product candidates as appropriate.

Post-approval Requirements

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Later discovery of previously unknown problems with a product may result in restrictions on the product or even complete withdrawal of the product from the market.

After approval, some types of changes to the approved product, such as adding new indications, certain manufacturing changes and additional labeling claims, are subject to further FDA review and approval.

After approval, some types of changes to the approved product, such as adding new indications, certain manufacturing changes and additional

labeling claims, are subject to further FDA review and approval.

Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP regulations and other laws and regulations.

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Failure to comply with the applicable U.S.

requirements at any time during the product development process, approval process or after approval, may subject an applicant or manufacturer to

administrative or judicial civil or criminal sanctions and adverse publicity.

requirements at any time during the product development process, approval process or after approval, may subject an applicant or manufacturer to administrative or judicial civil or criminal sanctions and adverse publicity.

FDA sanctions could include refusal to approve pending applications, withdrawal of an approval, clinical holds on post-approval clinical trials, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, mandated corrective advertising or communications with doctors, debarment, restitution, disgorgement of profits, or civil or criminal penalties.

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A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.

During the exclusivity period, the FDA may not approve or even accept for review an abbreviated new drug application, or ANDA, or an NDA submitted under Section 505(b)(2), or 505(b)(2) NDA, submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.

During the exclusivity period, the FDA may not approve or even accept for review an abbreviated new drug application, or ANDA, or an NDA submitted under Section 505(b)(2) of the FDCA, or 505(b)(2) NDA, submitted by another company for another drug that contains the same active moiety.

However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.

The FDCA alternatively provides three years of marketing exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug.

The FDCA alternatively provides three years of marketing exclusivity for a change to a previously approved drug, such as a new indication or condition of use, submitted in an NDA, or supplement to an existing NDA if one or more new clinical investigations, other than bioavailability or bioequivalence studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application.

This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for drugs containing the active agent for the original indication or condition of use.

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However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Pediatric exclusivity is another type of marketing exclusivity available in the United States.

Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA.

The issuance of a written request does not require the sponsor to undertake the described clinical trials.

In addition, orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity, except in certain circumstances.

Other types of non-patent exclusivity include seven-year orphan drug exclusivity and six-month pediatric exclusivity (each discussed above).

FDA Regulation of Companion Diagnostics

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These diagnostics, often referred to as companion diagnostics, are regulated as medical devices.

In the United States, the FDCA and its implementing regulations, and other federal and state statutes and regulations govern, among other things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling, storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance.

In the United States, the FDCA and its implementing

regulations, and other federal and state statutes and regulations govern, among other things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling, storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance.

Under the FDCA, medical devices are classified into one of three classes – Class I, Class II or Class III – depending on the degree of risk associated with each medical device and the extent of control needed to provide reasonable assurances with respect to safety and effectiveness.

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Class III devices include devices deemed by the FDA to pose the greatest risk such as life-supporting or life-sustaining devices, or implantable devices, in addition to new devices deemed not substantially equivalent following the 510(k) process.

The safety and

effectiveness of Class III devices cannot be reasonably assured solely by the General Controls and Special Controls.

The safety and effectiveness of Class III devices cannot be reasonably assured solely by the General Controls and Special Controls.

Therefore, these devices are generally subject to the premarket approval, or PMA, application process, which is generally more costly and time-consuming than the 510(k) process.

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If the use of a companion diagnostic is essential to the safe and effective use of a drug or biologic product, then the FDA generally will require approval or clearance of the diagnostic contemporaneously with the approval of the therapeutic product.

On August 6, 2014, the FDA issued a final guidance document addressing the development and approval process for “In Vitro Companion Diagnostic Devices.” According to the guidance, for novel product candidates such as ours, a companion diagnostic device and its corresponding drug or biologic candidate should be approved or cleared contemporaneously by the FDA for the use indicated in the therapeutic product labeling.

On August 6, 2014, the FDA issued a final guidance document addressing the development and approval process for in vitro companion diagnostic devices.

According to the guidance, for novel product candidates such as ours, a companion diagnostic device and its corresponding drug or biologic candidate should be approved or cleared contemporaneously by the FDA for the use indicated in the therapeutic product labeling.

The guidance also explains that a companion diagnostic device used to make treatment decisions in clinical trials of a drug generally will be considered an investigational device, unless it is employed for an intended use for which the device is already approved or cleared.

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In addition, PMAs for certain devices must generally include the results from extensive preclinical and adequate and well-controlled clinical trials to establish the safety and effectiveness of the device for each indication for which FDA approval is sought.

In particular, for a diagnostic, the applicant must demonstrate that the diagnostic produces reproducible results when the same sample is tested multiple times by multiple users at multiple laboratories.

In particular, for a diagnostic, the applicant must demonstrate that the diagnostic produces reproducible

results when the same sample is tested multiple times by multiple users at multiple laboratories.

As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the QSR, which imposes elaborate testing, control, documentation and other quality assurance requirements.

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Once granted, PMA approval may be withdrawn by the FDA if compliance with post approval requirements, conditions of approval or other regulatory standards is not maintained or problems are identified following initial marketing.

PMA approval is not guaranteed, and the FDA may ultimately respond to

a PMA submission with a not approvable determination based on deficiencies in the application and require additional clinical trials or other data that may be expensive and time-consuming to generate and that can substantially delay approval.

PMA approval is not guaranteed, and the FDA may ultimately respond to a PMA submission with a not approvable determination based on deficiencies in the application and require additional clinical trials or other data that may be expensive and time-consuming to generate and that can substantially delay approval.

If a companion diagnostic is the subject of a de novo classification request in lieu of a PMA, the FDA is required to classify the device within 120 days following receipt of the de novo submission.

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The Centralized Procedure is optional for products containing a new active substance not yet authorized in the EEA, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU;

National MAs, which are issued by the competent authorities of the Member States of the EEA and only cover their respective territory, are available for products not falling within the mandatory scope of the Centralized Procedure.

Where a product has already been authorized for marketing in a Member State of the EEA, this National MA can be recognized in another Member State through the Mutual Recognition Procedure.

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The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial authorization of the reference product in the EU.

therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

The 10-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those 10 years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Pediatric Investigation Plan

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Medicinal products designated as orphan drugs pursuant are eligible for incentives made available by the EU and its Member States to support research into, and the development and availability of, orphan drugs.

Companion Diagnostics

Companion D iagnostics

In the EEA, in vitro medical devices are required to conform with the essential requirements of the EU Directive on in vitro diagnostic medical devices (Directive No.

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The conformity assessment of in vitro diagnostic medical devices can require the intervention of an accredited EEA Notified Body.

If successful, the conformity assessment concludes with the drawing up by the manufacturer of an

EC Declaration of Conformity entitling the manufacturer to affix the CE mark to its products and to sell them throughout the EEA.

If successful, the conformity assessment concludes with the drawing up by the manufacturer of an EC Declaration of Conformity entitling the manufacturer to affix the CE mark to its products and to sell them throughout the EEA.

On April 5, 2017, the European Parliament passed the In Vitro Device Regulation, or IVDR, which repeals and replaces Directive No 98/79/EC.

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Since its enactment, there have been judicial, executive and Congressional challenges to certain aspects of the ACA.

For example, the Tax Cuts and Jobs Acts of 2017, or the Tax Act, included a provision, effective January 1, 2019, that repealed the tax-based share responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all of part of a year that is common referred to the “individual mandate.” On December 14, 2018, a U.S.

District Court Judge in the Northern District of Texas ruled that the individual mandate is a critical and inseverable feature of the ACA, and therefore, because it was repealed as part of the Tax Act, the remaining provisions of the ACA are invalid as well.

On December 18, 2019, the U.S.

Court of Appeals for the 5th Circuit upheld the District Court’s decision that the individual mandate was unconstitutional but remanded the case back to the District Court to determine whether the remaining provisions of the ACA are invalid as well.

Supreme Court is currently reviewing the case, although it is unclear how the Supreme Court will rule.

It is also unclear how other efforts, if any, to challenge, repeal or replace the ACA will impact the law.

Other legislative changes have been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to providers of 2% per fiscal year, which was temporarily suspended from May 1, 2020 through March 31, 2021, and reduced payments to several types of Medicare providers.

Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted legislation designed, among other things, to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement methodologies for drug products.

Individual states in the United States have also

become increasingly active in implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures and, in some cases, mechanisms to encourage importation from other countries and bulk purchasing.

On June 17, 2021, the U.S.

Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Prior to the U.S.

Supreme Court’s decision, President Biden issued an executive order initiating a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare.

It is unclear how other healthcare reform measures enacted by Congress or implemented by the Biden administration, if any, will impact our business .

Other legislative changes have been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to providers of 2% per fiscal year, which was temporarily suspended from May 1, 2020 through March 31, 2022 and a 1% reduction from April 1, 2022 through June 30, 2022, and reduced payments to several types of Medicare providers.

designed, among other things, to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement methodologies for drug products.

Individual states in the United States have also become increasingly active in implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures and, in some cases, mechanisms to encourage importation from other countries and bulk purchasing.

Other Healthcare Laws

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fines up to the greater of €20 million (£17.5 million) or 4% of global turnover.

The relationship between the United Kingdom and the EU in relation to certain aspects of data protection law remains unclear, and it is unclear how United Kingdom data protection laws and regulations will develop in the medium to longer term, and how data transfers to and from the United Kingdom will be regulated in the long term.

Currently there is a four to six-month grace period agreed in the EU

and United Kingdom Trade and Cooperation Agreement, ending June 30, 2021 at the latest, whil e the parties discuss an adequacy decision.

The relationship between the

United Kingdom and the EU in relation to certain aspects of data protection law remains unclear, and it is unclear how United Kingdom data protection laws and regulations will develop in the medium to longer term, and how data transfers to and from the United Kingdom will be regulated in the long term.

Currently there is a four to six-month grace period agreed in the EU and United Kingdom Trade and Cooperation Agreement, ending June 30, 2021 at the latest, whil e the parties discuss an adequacy decision.

However, it is not clear whether (and when) an adequacy decision may be granted by the European Commission enabling data transfers from EU member states to the United Kingdom long term without additional measures.

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We believe the variety of experiences, backgrounds and perspectives of our employees bring to their work every day makes IDEAYA stronger and more successful.

Currently, females make up 37% of our workforce, 17% of our executive team, and 25% of our board of directors.

As of December 31, 2021, females make up 43% of our workforce, 17% of our executive team, and 25% of our board of directors.

As of December 31, 2021, we had a total of 81 employees.

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We consider our relationship with our employees to be good.

Corporate Information

We were founded in June 2015 as a Delaware corporation.

Our principal executive offices are located at 7000 Shoreline Court, Suite 350, South San Francisco, California 94080, and our telephone number is (650) 443-6209.

Our website address is www.ideayabio.com.

We file electronically with the Securities and Exchange Commission (“SEC”) our annual reports on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended.

Our SEC filings are available to the public on the SEC’s website at www.sec.gov.

At our corporate website, www.ideayabio.com, we make available free of charge a variety of information for investors, including copies of these reports, and any amendments to these reports, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC.

The information on, or that can be accessed through, our website is not part of this report and is not incorporated by reference herein.

We have included our website address as an inactive textual reference only.

We also use our website as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD.

We use IDEAYA Biosicences, Inc.®, the IDEAYA logo, and other marks as trademarks in the United States and other countries.

This Annual Report on Form 10-K contains references to our trademarks and service marks and to those belonging to other entities.

Solely for convenience, trademarks and trade names referred to in this Annual Report on Form 10-K, including logos, artwork and other visual displays, may appear without the ® or ™ symbols, but such references are not intended to indicate in any way that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these trademarks and trade names.

We do not intend our use or display of other entities’ trade names, trademarks or service marks to imply a relationship with, or endorsement or sponsorship of us by any other entity.

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 1. Business