IDEAYA Biosciences Inc

Previous wording

The following discussion and analysis of our financial condition and results of operations should be read in conjunction with our financial statements and related notes appearing elsewhere in this Quarterly Report on Form 10-Q. Some of the information contained in this discussion and analysis or set forth elsewhere in this Quarterly Report on Form 10-Q, including information with respect to our plans and strategy for our business, includes forward-looking statements that involve risks and uncertainties. As a result of many factors, including those factors set forth in the “Risk Factors” section of this Quarterly Report on Form 10-Q, our actual results could differ materially from the results described, in or implied, by these forward-looking statements. Please also see the section of this Quarterly Report on Form 10-Q titled “Forward-Looking Statements.”

Current wording

The following discussion and analysis of our financial condition and results of operations should be read in conjunction with our financial statements and related notes appearing elsewhere in this Quarterly Report on Form 10-Q. Some of the information contained in this discussion and analysis or set forth elsewhere in this Quarterly Report on Form 10-Q, including information with respect to our plans and strategy for our business, includes forward-looking statements that involve risks and uncertainties. As a result of many factors, including those factors set forth in the “Risk Factors” section of this Quarterly Report on Form 10-Q, our actual results could differ materially from the results described, in or implied, by these forward-looking statements. Please also see the section of this Quarterly Report on Form 10-Q titled “Note Regarding Forward-Looking Statements.”

Previous wording

We are a precision medicine oncology company committed to the discovery and development of targeted therapeutics for patient populations selected using molecular diagnostics. Our approach integrates small molecule drug discovery with extensive capabilities in identifying and validating translational biomarkers to develop targeted therapies for select patient populations that are most likely to benefit from these targeted therapies. Our small molecule drug discovery expertise includes discovery and development of small molecule therapeutics. We are applying these capabilities to develop a robust pipeline in precision medicine oncology.

Current wording

We are a precision medicine oncology company committed to the discovery and development of targeted therapeutics for patient populations selected using molecular diagnostics. Our approach integrates small molecule drug discovery with extensive capabilities in identifying and validating translational biomarkers to develop targeted therapies for select patient populations that are most likely to benefit from these targeted therapies. Our small molecule drug discovery expertise includes discovery and development of small molecule therapeutics. We are applying these capabilities and approach to develop a robust pipeline in precision medicine oncology.

Previous wording

Our clinical pipeline includes five potential first-in-class clinical-stage product candidates – darovasertib (PKC), IDE397 (MAT2A), IDE161 (PARG), IDE705 / GSK101 (Pol Theta Helicase), and IDE275 / GSK959 (Werner Helicase). We own or control all commercial rights of the three most-advanced of these product candidates: darovasertib, IDE397, and IDE161. In July 2024, we entered into an Option and License Agreement with Biocytogen Pharmaceuticals (Beijing) Co., Ltd., or Biocytogen, pursuant to which Biocytogen granted to us an option for an exclusive worldwide license to develop and commercialize products in connection with a potential first-in-class B7H3/PTK7 topo-I-payload bispecific antibody drug conjugate program for which we are targeting a development candidate in the fourth quarter of 2024. We also have multiple earlier-stage preclinical programs. We are targeting development candidate nominations in the fourth quarter of 2024 for multiple new targets, or NTs, including a development candidate to treat MTAP-deletion solid tumors to enable a potential wholly-owned clinical combination with IDE397, and we are separately targeting a development candidate for a potential first-in-class program in the KAT6 pathway. We have established selective, value-accretive collaborations with leading pharmaceutical companies to support our clinical development activities.

Current wording

Our clinical pipeline includes six potential first-in-class clinical-stage product candidates – darovasertib (PKC), IDE397 (MAT2A), IDE849 (DLL3), IDE275 / GSK959 (Werner Helicase), IDE161 (PARG), and IDE705 / GSK101 (Pol Theta Helicase). We own or control all commercial rights of three of these product candidates: darovasertib, IDE397, and IDE161, and own or control all commercial rights outside of greater China for IDE849. We are also advancing several development candidates, including IDE892, a potential best-in-class MTA-cooperative PRMT5 inhibitor for which we are targeting an investigational new drug, or IND, filing in mid-year 2025; IDE034, a potential first-in-class B7H3/PTK7 topoisomerase-I-inhibitor-payload bispecific antibody drug conjugate, or BsADC, program for which we are targeting an IND filing in the second half of 2025; and IDE574, a potential first-in-class KAT6/7 dual inhibitor program for which we are targeting an IND filing in the second half of 2025. We also have multiple earlier-stage preclinical programs. We have established selective, value-accretive collaborations with leading pharmaceutical companies to support our clinical development activities.

Previous wording

Darovasertib– PKC Inhibitor Clinical Candidate in Uveal Melanoma and GNAQ/11 Melanomas

Current wording

Darovasertib – PKC Inhibitor Clinical Candidate in Uveal Melanoma (UM)

Previous wording

We have enrolled over 150 patients as of October 31, 2024, and have opened multiple clinical sites, including international sites, in our potential registration-enabling Phase 2/3 clinical trial, designated as IDE196-002. The purpose of the clinical trial is to evaluate darovasertib in combination with crizotinib, Pfizer’s investigational cMET inhibitor, in patients having metastatic uveal melanoma, or MUM, with human leukocyte antigen-, or HLA-A*02:01 negative, or HLA-A2(-), serotype, as part of a second Clinical Trial Collaboration and Supply Agreement, or Second Pfizer agreement, with Pfizer.

Current wording

We have enrolled over 300 patients as of May 5, 2025, and have opened multiple clinical sites, including international sites, in our potential registration-enabling Phase 2/3 clinical trial, designated as IDE196-002. The purpose of the clinical trial is to evaluate darovasertib in combination with crizotinib, Pfizer’s investigational cMET inhibitor, in patients having metastatic uveal melanoma, or MUM, with human leukocyte antigen-, or HLA-A*02:01 negative, or HLA-A2(-), serotype, as part of a second Clinical Trial Collaboration and Supply Agreement, or the Second Pfizer Agreement, with Pfizer.

Previous wording

We are planning to enroll additional HLA-A*02:01 positive, or HLA-A2(+), patients as an independent clinical strategy to address HLA-A2(+) MUM patients, in our ongoing Phase 2 clinical trial, designated as IDE196-001.

Current wording

We are enrolling additional HLA-A*02:01 positive, or HLA-A2(+), patients as an independent clinical strategy to address HLA-A2(+) MUM patients, in our ongoing Phase 2 clinical trial, designated as IDE196-001.

Previous wording

We are also supporting evaluation of darovasertib as single-agent neoadjuvant and adjuvant therapy in primary UM in an ongoing investigator-sponsored clinical trial, or IST, captioned as “Neoadjuvant / Adjuvant trial of Darovasertib in Ocular Melanoma”, or NADOM, led by St. Vincent’s Hospital in Sydney with the participation of Alfred Health and the Royal Victorian Eye and Ear Hospital in Melbourne.

Current wording

We are also supporting evaluation of darovasertib as single-agent neoadjuvant and adjuvant therapy in primary uveal melanoma, or UM, in an ongoing investigator-sponsored clinical trial, or IST, captioned as “Neoadjuvant / Adjuvant trial of Darovasertib in Ocular Melanoma,” or NADOM, led by St. Vincent’s Hospital in Sydney with the participation of Alfred Health and the Royal Victorian Eye and Ear Hospital in Melbourne.

Previous wording

We have enrolled over 75 patients as of October 31, 2024, in our Phase 2 clinical trial, designated as IDE196-009, evaluating darovasertib as single-agent neoadjuvant and adjuvant therapy in patients having primary uveal melanoma, or UM, with ongoing enrollment and multiple clinical sites open. In September 2024, we announced interim clinical data from the ongoing Phase 2 company-sponsored trial and provided a regulatory update on a registrational trial based on a Type C meeting held with the U.S. Food and Drug Administration, or FDA.

Current wording

In September 2024, we announced interim clinical data from the ongoing Phase 2 Company-sponsored trial and provided a regulatory update on a potential Phase 3 registration-enabling clinical trial in neoadjuvant UM patients based on a Type C meeting held with the U.S. Food and Drug Administration, or FDA. In April 2025, we provided a further regulatory update on the potential Phase 3 registrational trial design for darovasertib in neoadjuvant UM patients based on a Type D meeting held with the FDA. Based on the Type D meeting, we currently project approximately 520 patients will be randomized 2:1 to receive darovasertib or control in two cohorts. The two cohorts include enucleation-eligible UM patients (n=120) and plaque brachytherapy, or PB,-eligible UM patients (n=400). Primary endpoints, which are supportive of full approval based on the FDA Type D Meeting, include eye preservation rate for enucleation patients and proportion of patients with best corrected visual acuity 15-letter loss from time of randomization and time of completion of PB for the PB cohort, with event-free survival (EFS) as a required secondary endpoint for both cohorts. Commencement of the Phase 3 registration-enabling trial for darovasertib in neoadjuvant UM is targeted for the first half of 2025.

Previous wording

In September 2024, we provided another clinical data update in which we observed encouraging clinical activity in our Phase 2 company-sponsored trial. Collectively with the IST trial, the clinical efficacy data from the Phase 2 company-sponsored trial substantiate clinical proof of concept for the use of darovasertib in the neoadjuvant uveal melanoma setting. The Phase 2 company-sponsored trial used a data cutoff date of August 15, 2024, with an enrollment cutoff date of May 13, 2024.

Current wording

In September 2024, we provided a clinical data update in which we observed encouraging clinical activity in our Phase 2 Company-sponsored trial. Collectively with the IST trial, the clinical efficacy data from the Phase 2 Company-sponsored trial substantiate clinical proof of concept for the use of darovasertib in the neoadjuvant uveal melanoma setting. The Phase 2 Company-sponsored trial used a data cutoff date of August 15, 2024, with an enrollment cutoff date of May 13, 2024.

Previous wording

We evaluated 31 enucleation and 18 plaque brachytherapy UM patients who were treated with darovasertib neoadjuvant therapy in the Phase 2 company-sponsored and IST trials. We observed approximately 59%, or 29 of the 49 total evaluable patients, with greater than or equal to 20% ocular tumor shrinkage by product of diameters and approximately 49%, or 24 of the 49 total evaluable patients, with greater than or equal to 30% ocular tumor shrinkage by product of diameters. We also observed an approximately 61% eye preservation rate in enucleation patients. We found evidence predicting visual preservation by reducing the amount of radiation associated with plaque brachytherapy.

Current wording

We evaluated 31 enucleation and 18 plaque brachytherapy UM patients who were treated with darovasertib neoadjuvant therapy in the Phase 2 Company-sponsored and IST trials. We observed approximately 59%, or 29 of the 49 total evaluable patients, with greater than or equal to 20% ocular tumor shrinkage by product of diameters and approximately 49%, or 24 of the 49 total evaluable patients, with greater than or equal to 30% ocular tumor shrinkage by product of diameters. We also observed an approximately 61% eye preservation rate in enucleation patients. We found evidence predicting visual preservation by reducing the amount of radiation associated with plaque brachytherapy. We observed a manageable AE profile from the Phase 2 Company-sponsored trial. In 38 patients, 11% of patients experienced a Grade 3 or higher AE and 5% of patients experienced a serious AE rate. We also observed a discontinuation rate of 3%. The most common AEs observed included diarrhea, nausea, vomiting and fatigue.

Previous wording

We are pursuing a clinical strategy for darovasertib to broadly address uveal melanoma, alternatively referred to as ocular melanoma, in both primary and metastatic settings. Greater than 90% of uveal melanoma patients have tumors harboring GNAQ or GNA11 mutations. There are no FDA-approved systemic therapies for primary UM, as either neoadjuvant or adjuvant therapies. There are likewise no FDA-approved therapies for patients having MUM with HLA-A02:01 negative, or HLA-A2(-), serotype. These primary UM patients and HLA-A2(-) MUM patients collectively represent approximately 85% of all ocular melanoma patients. We have a separate, independent clinical strategy to address HLA-A02:01 positive, or HLA-A2(+), MUM patients.

Current wording

We are pursuing a clinical strategy for darovasertib to broadly address UM, alternatively referred to as ocular melanoma, in both primary and metastatic settings. Greater than 90% of UM patients have tumors harboring GNAQ or GNA11 mutations. There are no FDA-approved systemic therapies for primary UM as either neoadjuvant or adjuvant therapies. There are likewise no FDA-approved therapies for patients having MUM with HLA-A02:01 negative, or HLA-A2(-), serotype. These primary UM patients and HLA-A2(-) MUM patients collectively represent approximately 85% of all ocular melanoma patients. We have a separate, independent clinical strategy to address HLA-A02:01 positive, or HLA-A2(+), MUM patients.

Previous wording

The potentially addressable patient population for MUM is estimated to include an annual incidence of approximately 4,500 patients across the United States, or U.S., and Europe. (Neo)Adjuvant UM represents a significant expansion opportunity for darovasertib – with a potential annual incidence of approximately 12,000 patients aggregate in North America, Europe and Australia.

Current wording

The potentially addressable patient population for MUM is estimated to include an annual incidence of approximately 4,500 patients across the United States and Europe. (Neo)Adjuvant UM represents a significant expansion opportunity for darovasertib – with a potential annual incidence of approximately 12,000 patients aggregate in North America, Europe and Australia.

Previous wording

We own or control all commercial rights in our darovasertib program in uveal melanoma, including in MUM and in primary UM, subject to certain economic obligations pursuant to our exclusive, worldwide license to darovasertib with Novartis.

Current wording

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

Previous wording

The protocol of the Phase 2/3 clinical trial design incorporates guidance and feedback following our Type C meeting with the FDA in March 2023. This protocol includes an integrated Phase 2/3 open-label study-in-study design in first-line MUM patients with an HLA-A2(-) serotype. The clinical trial design employs a Phase 2 portion with median progression free survival, or PFS, as a primary endpoint for potential accelerated approval. Patients enrolled in Phase 2 will continue on treatment within the same study and will be considered, together with additional enrolled patients, to evaluate overall survival, or OS, as the primary endpoint of the Phase 3 portion of the clinical trial to support a potential confirmational approval.

Current wording

The protocol of the Phase 2/3 clinical trial design incorporates guidance and feedback following our Type C meeting with the FDA in March 2023. This protocol includes an integrated Phase 2/3 open-label study-in-study design in first-line MUM patients with an HLA-A2(-) serotype. The clinical trial design employs a Phase 2 portion with median progression free survival, or PFS, as a primary endpoint for potential accelerated approval. Patients enrolled in Phase 2 will continue on treatment within the same study and will be considered, together with additional enrolled patients, to evaluate OS as the primary endpoint of the Phase 3 confirmatory portion of the clinical trial to support a potential full approval.

Previous wording

In the Phase 2 portion of the clinical trial, approximately 230 patients will be randomized on a 2:1 basis for treatment with the darovasertib and crizotinib combination in the treatment arm or investigators choice in the control arm, selected from (a) a combination of ipilimumab (ipi) and nivolumab (nivo), (b) PD1-targeted monotherapy or (c) dacarbazine. The treatment arm of the Phase 2 portion of the clinical trial includes a nested study to confirm the move forward combination dose for the integrated Phase 2/3 clinical trial – including cohorts at the Phase 2 expansion doses of (i) darovasertib 300 mg BID + crizotinib 200 mg BID and (ii) darovasertib 200 mg BID + crizotinib 200 mg BID. Under the nested study design, patients enrolled in the cohort at the move forward dose will be included within the Phase 2/3 registrational clinical trial. The Phase 2 portion of the clinical trial contemplates an efficacy and safety data set of approximately 200 patients randomized 2:1 with the treatment arm at the move forward dose to support a potential accelerated approval based on median PFS by blinded independent central review, or BICR, as a primary endpoint. Accelerated approval is intended to allow for earlier approval of drugs that treat serious conditions and fill an unmet medical need based on a demonstration of effectiveness on a surrogate endpoint.

Current wording

In the Phase 2 portion of the clinical trial, approximately 260 patients will be randomized on a 2:1 basis for treatment with the darovasertib and crizotinib combination in the treatment arm or investigators choice in the control arm, selected from (a) a combination of ipilimumab (ipi) and nivolumab (nivo), (b) PD1-targeted monotherapy or (c) dacarbazine. The treatment arm of the Phase 2 portion of the clinical trial includes a nested study to confirm the move forward combination dose for the integrated Phase 2/3 clinical trial – including cohorts at the Phase 2 expansion doses of (i) darovasertib 300 mg BID + crizotinib 200 mg BID and (ii) darovasertib 200 mg BID + crizotinib 200 mg BID. Under the nested study design, patients enrolled in the cohort at the move forward dose will be included within the Phase 2/3 registrational clinical trial. The Phase 2 portion of the clinical trial contemplates an efficacy and safety data set of approximately 200 patients randomized 2:1 with the treatment arm at the move forward dose to support a potential accelerated approval based on median PFS by blinded independent central review, or BICR, as a primary endpoint. Accelerated approval is intended to allow for earlier approval of drugs that treat serious conditions and fill an unmet medical need based on a demonstration of effectiveness on a surrogate endpoint.

Previous wording

Patients enrolled in Phase 2 at the selected dose would continue on treatment and be included in the Phase 3 study analysis, supplemented by enrollment of approximately 120 additional patients into the Phase 3 portion of the clinical trial, with 2:1 randomization on the same basis as the Phase 2 portion. Efficacy data from the Phase 3 could support potential approval using median OS as a primary endpoint.

Current wording

Patients enrolled in Phase 2 at the selected dose would continue on treatment and be included in the Phase 3 study analysis, supplemented by enrollment of approximately 120 additional patients into the Phase 3 portion of the clinical trial, with 2:1 randomization on the same basis as the Phase 2 portion. Efficacy data from the Phase 3 could support potential full approval using median OS as a primary endpoint.

Previous wording

We also expanded our relationship with Pfizer in May 2023 under an Amendment No. 1 to the Second Pfizer Agreement to support the Phase 2/3 registrational trial to evaluate darovasertib and crizotinib as a combination therapy in MUM. Under the as-amended Second Pfizer Agreement, Pfizer will provide us with a first defined quantity of crizotinib at no cost, as well as an additional second defined quantity of crizotinib at a lump-sum cost. Under Amendment No. 1 to the Second Pfizer Agreement, we also terminated the Third Pfizer Agreement.

Current wording

In May 2023, we expanded our relationship with Pfizer to support the Phase 2/3 registrational trial to evaluate darovasertib and crizotinib as a combination therapy in MUM by entering into Amendment No. 1 to the Second Pfizer Agreement. Under Amendment No. 1 to the Second Pfizer Agreement, Pfizer will provide us with a first defined quantity of crizotinib at no cost, as well as an additional second defined quantity of crizotinib at a lump-sum cost.

Previous wording

We are planning to enroll additional HLA-A2(+) MUM patients as an independent clinical strategy to address HLA-A2(+) MUM patients, in our ongoing Phase 2 clinical trial, designated as IDE196-001. This strategy demonstrates our commitment to fully address the high unmet medical need in MUM. Such clinical trial data from darovasertib and crizotinib combination treatment in HLA-A2(+) MUM could support publication and potential inclusion in NCCN Clinical Practice Guidelines in Oncology.

Current wording

We are enrolling additional HLA-A2(+) MUM patients as an independent clinical strategy to address HLA-A2(+) MUM patients, in our ongoing Phase 2 clinical trial, designated as IDE196-001. This strategy demonstrates our commitment to fully address the high unmet medical need in MUM. Such clinical trial data from darovasertib and crizotinib combination treatment in HLA-A2(+) MUM could support publication and potential inclusion in NCCN Clinical Practice Guidelines in Oncology.

Previous wording

Darovasertib – Orphan Drug Designation in UM and Fast Track Designation in MUM

Current wording

Darovasertib – Orphan Drug Designation in UM, Fast Track Designation in MUM and Breakthrough Therapy Designation in Neoadjuvant UM

Previous wording

In April 2022, the FDA designated darovasertib as an Orphan Drug in UM, including primary and metastatic disease under 21 C.F.R Part 316. Under an Orphan Drug designation, darovasertib may be entitled to certain tax credits for qualifying clinical trial expenses, exemption from certain user fees and, subject to FDA approval of a New Drug Application, or NDA, for darovasertib in UM, eligibility for seven years of statutory marketing exclusivity. As an FDA-designated Orphan Drug, darovasertib may also be excluded from certain mandatory price negotiation provisions of the 2022 Inflation Reduction Act, if approved.

Current wording

In April 2022, the FDA designated darovasertib as an Orphan Drug in UM, including primary and metastatic disease. Under an Orphan Drug designation, darovasertib may be entitled to certain tax credits for qualifying clinical trial expenses, exemption from certain user fees and, subject to FDA approval of a New Drug Application, or NDA, for darovasertib in UM, eligibility for seven years of statutory marketing exclusivity during which the FDA is prohibited from approving a subsequent same drug for the same rare disease or condition except in limited circumstances, such as a subsequent drug that demonstrates clinical superiority. As an FDA-designated Orphan Drug, darovasertib may also be excluded from certain mandatory price negotiation provisions of the 2022 Inflation Reduction Act, if approved for a single indication only.

Previous wording

Darovasertib – Phase 2 Trials in Neoadjuvant and Adjuvant Therapy in Uveal Melanoma (UM)

Current wording

Darovasertib – Phase 2 Trials in Neoadjuvant and Adjuvant Therapy in UM

Previous wording

We have initiated and achieved double-digit patient enrollment in our company-sponsored Phase 2 clinical trial designated as IDE196-009, with ongoing enrollment and multiple clinical sites open. The purpose of the clinical trial is to evaluate single-agent darovasertib as neoadjuvant treatment of primary UM prior to primary interventional treatment of enucleation or radiation therapy and also as adjuvant therapy following the primary treatment. An amendment to the study protocol was submitted to the FDA in July 2024 to enable dosing of darovasertib therapy up to 12 months.

Current wording

We enrolled 95 patients as of December 31, 2024 in our Phase 2 clinical trial, designated as IDE196-009, evaluating darovasertib as single-agent neoadjuvant and adjuvant therapy in patients having primary UM with ongoing enrollment and multiple clinical sites open. The purpose of the clinical trial is to evaluate single-agent darovasertib as neoadjuvant treatment of primary UM prior to primary interventional treatment of enucleation or radiation therapy and also as adjuvant therapy following the primary treatment. An amendment to the study protocol was submitted to the FDA in July 2024 to enable dosing of darovasertib therapy up to 12 months.

Previous wording

We are additionally supporting evaluation of darovasertib as (neo)adjuvant therapy in primary UM in the ongoing NADOM IST. Pursuant to an as-amended protocol for the NADOM study, uveal melanoma patients who would otherwise undergo enucleation are instead treated with single agent darovasertib as neoadjuvant treatment for up to six months or maximum benefit. This reflects an increase in potential treatment duration versus the initial approach of one month neoadjuvant therapy, following which these patients will undergo a primary interventional treatment. Patients will subsequently be treated with darovasertib for up to six months as follow-up adjuvant therapy after the primary interventional treatment.

Current wording

We are additionally supporting evaluation of darovasertib as (neo)adjuvant therapy in primary UM in the ongoing NADOM IST. Pursuant to an as-amended protocol for the NADOM study, UM patients who would otherwise undergo enucleation are instead treated with single agent darovasertib as neoadjuvant treatment for up to six months or maximum benefit. This reflects an increase in potential treatment duration versus the initial approach of one month neoadjuvant therapy, following which these patients will undergo a primary interventional treatment. Patients will subsequently be treated with darovasertib for up to six months as follow-up adjuvant therapy after the primary interventional treatment.

Previous wording

A Type C meeting was held with the FDA for the clinical trial design of a potential Phase 3 registration-enabling clinical trial in neoadjuvant UM patients. For the potential Phase 3 clinical trial, we currently project approximately 400 patients will be randomized for treatment with darovasertib in the treatment arm or the control arm, with potential modifications pending further feedback from the FDA. Based on the currently targeted clinical trial design, there will be two cohorts enrolled, including plaque brachytherapy eligible UM patients and enucleation eligible UM patients. For the plaque brachytherapy cohort, the randomization will be darovasertib followed by plaque brachytherapy versus plaque brachytherapy alone. For the enucleation cohort, the randomization will be with or without darovasertib as neoadjuvant therapy.

Current wording

A Type C meeting was held with the FDA in September 2024 and a Type D meeting was subsequently held in April 2025 for the clinical trial design of a potential Phase 3 registration-enabling clinical trial in neoadjuvant UM patients. For the potential Phase 3 clinical trial, we currently project approximately 520 patients will be randomized 2:1 for treatment with darovasertib in the treatment arm or the control arm. Based on the currently targeted clinical trial design, there will be two cohorts enrolled, including enucleation eligible UM patients and plaque brachytherapy eligible UM patients. For the enucleation cohort, the randomization will be with or without darovasertib as neoadjuvant therapy. For the plaque brachytherapy cohort, the randomization will be darovasertib followed by plaque brachytherapy versus plaque brachytherapy alone.

Previous wording

Based on FDA guidance and information provided in our FDA briefing book, we expect that time to vision loss will be the primary endpoint for plaque brachytherapy UM patients. Eye preservation rate will be the primary endpoint for enucleation UM patients for the target registrational trial design in neoadjuvant UM. The FDA briefing book noted an objective to exceed lower bound of 10% eye preservation rate with a 95% confidence interval for this primary endpoint. No detriment to Event-Free-Survival, or EFS, in the treatment arms will be a secondary endpoint.

Current wording

Based on guidance and information provided in the FDA Type D meeting, we expect that eye preservation rate (exceed lower bound of 10% eye preservation rate with a 95% confidence interval) will be the primary endpoint for enucleation UM patients. Proportion of patients with best corrected visual acuity 15-letter loss from time of randomization and time of completion of PB will be the primary endpoint for plaque brachytherapy UM patients. Vision detriment will be measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Best-Corrected Visual Acuity (BCVA) of>15-letters lost. No detriment to Event-Free-Survival, or EFS, in the treatment arms will be a required secondary endpoint. No detriment is defined as overlapping confidence intervals.

Previous wording

Pending ongoing discussions with the FDA, we are evaluating potential surrogate and composite endpoints to support earlier approval scenarios. The registrational study will enroll UM patients with a high risk for metastatic disease. Based on the FDA meeting, there is a potential for consideration of a broad indication label in neoadjuvant UM for subjects with low, intermediate and high risk for metastatic disease. We anticipate approximately two years of data maturity to initial readout for no detriment to EFS in the treatment arms for this high-risk patient population based on preliminary projections. 300mg BID darovasertib was noted in the FDA briefing book as the move-forward dose for the registrational trial. We are currently finalizing the trial protocol and are targeting to initiate the study in the first half of 2025.

Current wording

The registrational study will enroll UM patients with a high risk for metastatic disease. Patients with moderate to high risk for vision loss will also be enrolled in the plaque brachytherapy eligible UM cohort. Based on the FDA meeting, there is a potential for consideration of a broad indication label in neoadjuvant UM for subjects with low, intermediate and high risk for metastatic disease. We anticipate approximately 18 months of data maturity from the last patient enrolled to an initial readout for no detriment to EFS in the treatment arms. 300mg BID darovasertib will be the move-forward dose for the registrational trial. Commencement of the Phase 3 registration-enabling trial for darovasertib in neoadjuvant UM is targeted for the first half of 2025.

Previous wording

We are enrolling patients into a Phase 1/2 clinical trial designated as IDE397-001 to evaluate IDE397 for patients having certain tumors with MTAP gene deletion. We are proceeding with enrollment of MTAP-deletion patients into a monotherapy Phase 1/2 expansion cohort with an initial focus on high priority solid tumor types, including urothelial cancer, or UC, and non-small cell lung cancer, or NSCLC. We have selected a move-forward Phase 1/2 expansion dose for IDE397 monotherapy in MTAP-deletion UC and NSCLC, based on adverse event profile and preliminary clinical efficacy observed, including multiple partial responses by RECIST 1.1. The estimated U.S. MTAP-deletion annual incidence in UC and NSCLC is approximately 48,000 patients.

Current wording

We have enrolled patients into a Phase 1/2 clinical trial, designated as IDE397-001, to evaluate IDE397 for patients having certain tumors with MTAP gene deletion, with an initial focus in MTAP-deletion urothelial cancer, or UC, and non-small cell lung cancer, or NSCLC. We are proceeding with enrollment of MTAP-deletion patients into a monotherapy Phase 1/2 expansion cohort with an initial focus on high priority solid tumor types, including UC and NSCLC. We have selected a move-forward Phase 2 expansion dose for IDE397 monotherapy, based on AE profile and preliminary clinical efficacy observed, including multiple partial responses by RECIST 1.1.

Previous wording

We are also advancing multiple preclinical stage MTAP-deletion programs to enable wholly-owned combinations with IDE397, including a program targeting a development candidate nomination in the second half of 2024. We own all rights, title, and interest in and to IDE397 and the MAT2A program, including all worldwide commercial rights thereto.

Current wording

We own all right, title and interest in and to IDE397 and the MAT2A program, including all worldwide commercial rights thereto.

Previous wording

June 21, 2024, we reported an overall response rate of approximately 39% (one complete response and six partial responses by RECIST 1.1 evaluation), which included two unconfirmed partial responses (one UC patient that had a 100% tumor reduction in the target lesion at the last CT-scan assessment and one adenocarcinoma squamous NSCLC patient which were both confirmed in the Company's October 2024 update). We also observed a disease control rate of 94%, including one complete response, six partial responses and ten stable disease by RECIST 1.1 evaluation. In addition, we observed tumor shrinkage in 14 of the 18 evaluable patients. 11 of the evaluable patients are still on treatment and five of the seven responses by RECIST 1.1 evaluation remain in response. We also reported a ctDNA molecular response, or MR, rate of 81%, representing 13 of 16 reportable patients with 50% or greater ctDNA reduction (several quality control failures of patient samples precluded the other patients from MR analysis).

Current wording

In July 2024, we announced clinical data for the IDE397 Phase 1/2 monotherapy expansion dose demonstrating preliminary clinical efficacy in heavily pre-treated MTAP-deletion UC and NSCLC patients. The patients evaluated had a median of two prior lines of therapy, ranging from one to seven prior lines of treatment. The reported Phase 1/2 clinical data were based on 18 evaluable MTAP-deletion patients, including seven UC patients, four adenocarcinoma squamous NSCLC patients, and seven squamous NSCLC patients at the expansion dose of 30 mg once-a-day, or QD, of IDE397. In the interim update for 18 evaluable patients, with a data analysis cutoff date of June 21, 2024, we reported an overall response rate of approximately 39% (one complete response and six partial responses by RECIST 1.1 evaluation), which included two unconfirmed partial responses (one UC patient that had a 100% tumor reduction in the target lesion at the last CT-scan assessment and one adenocarcinoma squamous NSCLC patient which were both confirmed in our October 2024 update). We also observed a disease control rate of 94%, including one complete response, six partial responses and 10 stable disease by RECIST 1.1 evaluation. In addition, we observed tumor shrinkage in 14 of the 18 evaluable patients. 11 of the evaluable patients are still on treatment and five of the seven responses by RECIST 1.1 evaluation remain in response. We also reported a ctDNA molecular response, or MR, rate of 81%, representing 13 of 16 reportable patients with 50% or greater ctDNA reduction (several quality control failures of patient samples precluded the other patients from MR analysis).

Previous wording

Regarding safety data, we also reported a favorable AE profile at the 30 mg QD expansion dose. Approximately 5.6% of patients experienced a Grade 3 or higher drug-related AE at the 30 mg QD dose, represented by one instance of Grade 3 asthenia, and no drug-related SAEs were observed. We observed no drug-related AEs leading to discontinuations, and one non-evaluable patient discontinued due to rapid clinical progression of cancer fatigue and drug-unrelated adverse events in the first cycle of treatment. We anticipate that the favorable AE profile and dosing convenience of a 30 mg QD tablet has the potential to enable long-term dosing and combination development.

Current wording

Regarding safety data, we also reported a favorable AE profile at the 30 mg QD expansion dose. Approximately 5.6% of patients experienced a Grade 3 or higher drug-related AE at the 30 mg QD dose, represented by one instance of Grade 3 asthenia, and no drug-related SAEs were observed. We observed no drug-related AEs leading to discontinuations, and one non-evaluable patient discontinued due to rapid clinical progression of cancer fatigue and drug-unrelated AEs in the first cycle of treatment. We anticipate that the favorable AE profile and dosing convenience of a 30 mg QD tablet has the potential to enable long-term dosing and combination development.

Previous wording

In October 2024, we announced Phase 1 expansion data for IDE397 in MTAP-deletion UC and NSCLC patients in a late breaker abstract oral presentation at the 36 th edition of the EORTC-NCI-AACR Symposium, or ENA 2024, in Barcelona, Spain. The patients evaluated had a median of two to three prior lines of therapy, ranging from one to seven prior lines of treatment. The reported clinical data were based on 27 evaluable MTAP-deletion patients, including 10 UC patients, nine adenocarcinoma NSCLC patients, and eight squamous NSCLC patients at the expansion dose of 30 mg QD of IDE397. In the update of 27 evaluable patients, with a data analysis cutoff date of August 22, 2024, we reported an overall response rate of approximately 33% (one complete response and eight partial responses by RECIST 1.1 evaluation). Nine of nine responses were confirmed by RECIST 1.1, including four UC patients, of which one was a complete response, three squamous NSCLC patients, and two adenocarcinoma NSCLC patients. Two patients were confirmed after the data cutoff date. We also observed an overall response rate by RECIST 1.1 evaluation by solid tumor type. For MTAP-deletion urothelial cancer patients, the confirmed overall response rate was 40%, or 4 out of 10 patients, for MTAP-deletion squamous NSCLC patients, the confirmed overall response rate was approximately 38%, or 3 out of 8 patients, and for MTAP-deletion adenocarcinoma NSCLC patients, the confirmed overall response rate was approximately 22%, or 2 out of 9 patients. In addition, we observed a disease control rate of 93%, including one complete response, eight partial responses and 16 stable disease by RECIST 1.1 evaluation, reflecting 25 of 27 evaluable patients with stable disease or better. Of the 27 evaluable patients, 15 are still on treatment. The median duration of treatment has not been reached and is greater than 6.2 months. The median time to response is approximately 2.7 months. The median duration of response and median progression free survival data is still immature. Three UC patients were on treatment greater than 250 days, four squamous NSCLC patients were on treatment greater than 200 days, and three adenocarcinoma NSCLC patients were on treatment greater than 200 days. We also reported a ctDNA MR rate of 81%, representing 17 of 21 reportable patients with 50% or greater ctDNA reduction and approximately 33%, representing 7 of 21 reportable patients, with a deep 90% or greater ctDNA reduction (several quality control failures of patient samples precluded the other patients from MR analysis). All 17 MRs were rapid occurring at the first ctDNA sample analysis.

Current wording

In October 2024, we announced Phase 1 expansion data for IDE397 in MTAP-deletion UC and NSCLC patients in a late breaker abstract oral presentation at the 36th edition of the EORTC-NCI-AACR Symposium, or ENA 2024, in Barcelona, Spain. The patients evaluated had a median of two to three prior lines of therapy, ranging from one to seven prior lines of treatment. The reported clinical data were based on 27 evaluable MTAP-deletion patients, including 10 UC patients, nine adenocarcinoma NSCLC patients, and eight squamous NSCLC patients at the expansion dose of 30 mg QD of IDE397. In the update of 27 evaluable patients, with a data analysis cutoff date of August 22, 2024, we reported an overall response rate of approximately 33% (one complete response and eight partial responses by RECIST 1.1 evaluation). Nine of nine responses were confirmed by RECIST 1.1, including four UC patients, of which one was a complete response, three squamous NSCLC patients, and two adenocarcinoma NSCLC patients. Two patients were confirmed after the data cutoff date. We also observed an overall response rate by RECIST 1.1 evaluation by solid tumor type. For MTAP-deletion UC patients, the confirmed overall response rate was 40%, or 4 out of 10 patients, for MTAP-deletion squamous NSCLC patients, the confirmed overall response rate was approximately 38%, or 3 out of 8 patients, and for MTAP-deletion adenocarcinoma NSCLC patients, the confirmed overall response rate was approximately 22%, or 2 out of 9 patients. In addition, we observed a disease control rate of 93%, including one complete response, eight partial responses and 16 stable disease by RECIST 1.1 evaluation, reflecting 25 of 27 evaluable patients with stable disease or better. Of the 27 evaluable patients, 15 are still on treatment. The median duration of treatment has not been reached and is greater than 6.2 months. The median time to response is approximately 2.7 months. The median duration of response and median progression free survival data is still immature. Three UC patients were on treatment greater than 250 days, four squamous NSCLC patients were on treatment greater than 200 days, and three adenocarcinoma NSCLC patients were on treatment greater than 200 days. We also reported a ctDNA MR rate of 81%, representing 17 of 21 reportable patients with 50% or greater ctDNA reduction and approximately 33%, representing 7 of 21 reportable patients, with a deep 90% or greater ctDNA reduction (several quality control failures of patient samples precluded the other patients from MR analysis). All 17 MRs were rapid occurring at the first ctDNA sample analysis.

Previous wording

We continued to report favorable AE profile at the 30 mg QD expansion dose. Approximately 18% of patients experienced a Grade 3 or higher drug-related AE at the 30mg QD dose and no drug-related SAEs were observed. No drug-related AEs leading to discontinuations were observed. We anticipate that the favorable AE profile and dosing convenience of a 30 mg QD tablet has the potential to enable long-term dosing and combination development, including with MTA-cooperative PRMT5 inhibitors and topoisomerase payload antibody-drug conjugates, or ADCs.

Current wording

We continued to report favorable AE profile at the 30 mg QD expansion dose. Approximately 18% of patients experienced a Grade 3 or higher drug-related AE at the 30 mg QD dose, and no drug-related SAEs were observed. No drug-related AEs leading to discontinuations were observed. We anticipate that the favorable AE profile and dosing convenience of a 30 mg QD tablet has the potential to enable long-term dosing and combination development, including with MTA-cooperative PRMT5 inhibitors and topoisomerase payload ADCs.

Previous wording

We are separately collaborating with Gilead Sciences, Inc., or Gilead, to clinically evaluate IDE397 and Trodelvy (sacituzumab-govitecan-hziy), Gilead’s Trop-2 directed ADC combination, in patients having MTAP-deletion UC, in our Phase 1 clinical trial pursuant to a Clinical Study Collaboration and Supply Agreement, or Gilead CSCSA, with Gilead. A first patient was dosed for the Phase 1 trial in June 2024.

Current wording

We are collaborating with Gilead Sciences, Inc., or Gilead, to clinically evaluate IDE397 in combination with Trodelvy (sacituzumab govitecan-hziy), Gilead’s Trop-2 directed antibody drug conjugate, or ADC, in patients having MTAP-deletion UC, in our Phase 1 clinical trial pursuant to a Clinical Study Collaboration and Supply Agreement, or CSCSA, with Gilead.

Previous wording

In October, we reported the first preliminary clinical case study of the IDE397 and Trodelvy combination in MTAP-deletion UC at ENA 2024, including a partial response by RECIST 1.1 in a patient case report with a genetic co-alteration of MTAP-deletion and a FGFR3-TACC3 fusion, and rapid and deep first-evaluation MRs with ctDNA reduction of greater than 95% observed. The partial response reported at ENA 2024 has confirmed by RECIST 1.1. We are targeting to initiate the IDE397 and Trodelvy Phase 1/2 combination expansion in MTAP-deletion UC patients in the fourth quarter of 2024.

Current wording

In October 2024, we reported the first preliminary clinical case study of the IDE397 and Trodelvy combination in MTAP-deletion UC at ENA 2024, including a partial response by RECIST 1.1 in a patient case report with a genetic co-alteration of MTAP-deletion and a FGFR3-TACC3 fusion, and rapid and deep first-evaluation MRs with ctDNA reduction of greater than 95% observed. The partial response reported at ENA 2024 has confirmed by RECIST 1.1.

Previous wording

We are collaborating with Amgen to clinically evaluate IDE397 in combination with AMG 193, the Amgen investigational MTA-cooperative PRMT5 inhibitor, in patients having tumors with MTAP deletion, in an Amgen-sponsored clinical trial pursuant to our Clinical Trial Collaboration and Supply Agreement with Amgen, or the Amgen CTCSA.

Current wording

We were collaborating with Amgen to clinically evaluate IDE397 in combination with AMG 193, the Amgen investigational MTA-cooperative PRMT5 inhibitor, in patients having tumors with MTAP-deletion, in an Amgen-sponsored clinical trial pursuant to our Clinical Trial Collaboration and Supply Agreement with Amgen, or the Amgen CTCSA. In February 2025, we and Amgen mutually agreed to wind down the IDE397 and AMG 193 clinical combination study and will not pursue dose expansion.

Previous wording

In August 2023, Amgen initiated and dosed a first patient in the IDE397 /AMG 193 combination study, following FDA authorization to proceed with the clinical trial. This Phase 1/2 clinical trial (NCT: 05975073) will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of IDE397 in combination with AMG 193, with an initial focus for expansion in NSCLC patients and an estimated enrollment of approximately 180 patients. Enrollment is ongoing in the dose escalation portion of this Phase 1/2 clinical trial [and are targeting an expansion in MTAP-deletion NSCLC in late 2024 to early 2025]. We presented a preclinical poster presentation on the antitumor activity by combinatorial inhibition of MAT2A and PRMT5 in MTAP-deleted tumors at ENA 2024.

Current wording

In October 2024, we presented a preclinical poster presentation on the antitumor activity by combinatorial inhibition of MAT2A and PRMT5 in MTAP-deleted tumors at ENA 2024. We are targeting to enable our wholly-owned clinical combination of IDE397 and IDE892, our potential best-in-class MTA-cooperative PRMT5 inhibitor development candidate, in the second half of 2025 in MTAP-deletion NSCLC.

Previous wording

We discovered IDE275 (GSK959), our Werner Helicase, or WRN, inhibitor clinical development candidate, and evaluated IDE275 (GSK959) in preclinical studies in collaboration with GSK. IDE275 (GSK959) targets WRN for patients having tumors with high MSI.

Current wording

We discovered IDE275 (GSK959), our Werner, or WRN, Helicase inhibitor clinical development candidate and evaluated IDE275 (GSK959) in preclinical studies in collaboration with GSK. IDE275 (GSK959) targets WRN for patients having tumors with MSI-High.

Previous wording

WRN protein is a RecQ enzyme involved in the maintenance of genome integrity. Germline loss of function mutations in WRN lead to premature aging and pre-disposition to cancer. MSI is a change in the DNA content of a tumor cell in which the number of repeats of microsatellites, short repeated sequences of DNA, differ as cells divide. High MSI is present in about 15% of gastrointestinal tumor cancers, including in approximately 22% of stomach adenocarcinoma and 16% of colorectal cancer. Tumors with high MSI are routinely assessed in multiple diagnostic profiling tests.

Current wording

WRN protein is a RecQ enzyme involved in the maintenance of genome integrity. Germline loss of function mutations in WRN lead to premature aging and pre-disposition to cancer. Microsatellite instability is a change in the DNA content of a tumor cell in which the number of repeats of microsatellites, short repeated sequences of DNA, differ as cells divide. MSI-High is present in about 15% of gastrointestinal tumor cancers, including in approximately 22% of stomach adenocarcinoma and 16% of colorectal cancer. Tumors with MSI-High are routinely assessed in multiple diagnostic profiling tests.

Previous wording

We have demonstratedin vivo efficacy with tumor regression and PD response in a relevant high MSI model. We have observed selectivity of our Werner Helicase inhibitor and validation of the synthetic lethal relationship to tumors with high MSI over tumors with MSS based on a lack ofin vivo pharmacological response in relevant MSS xenograft models.

Current wording

We, in collaboration with GSK, have demonstrated preclinical in vivo efficacy with tumor regression and PD response in a relevant MSI-High model. We have observed selectivity of our Werner Helicase inhibitor and validation of the synthetic lethal relationship to tumors with MSI-High over tumors with MSS based on a lack of in vivo pharmacological response in relevant MSS xenograft models.

Previous wording

We, in collaboration with GSK, received IND clearance for IDE275 (GSK959), a potential first-in-class WRN inhibitor, in October 2024 to enable first-in-human clinical evaluation of IDE275 (GSK959) for patients having tumors with high MSI. GSK will lead clinical development for the Werner Helicase program. GSK is responsible for 80% of global research and development costs and we are responsible for 20% of such costs. GSK holds a global, exclusive license to develop and commercialize the Werner Helicase Inhibitor DC.

Current wording

We, in collaboration with GSK, received IND clearance for IDE275 (GSK959), a potential first-in-class WRN inhibitor, in October 2024 to enable first-in-human clinical evaluation of IDE275 (GSK959) for patients having tumors with MSI-High. GSK initiated a Phase 1/2 clinical trial for IDE275 (GSK959), following FDA allowance to proceed with the clinical trial. GSK will lead clinical development for the Werner Helicase program. GSK is responsible for 80% of global research and development costs, and we are responsible for 20% of such costs. GSK holds a global, exclusive license to develop and commercialize the Werner Helicase Inhibitor DC.