IDE-275 / Ideaya Biosci, GSK - LARVOL DELTA

An innovative and reversible WRN helicase inhibitor, GSK4418959 (IDE275), emerges as a promising clinical candidate for MSI-H cancers (AACR 2025) - "One of these models was an MSI-H CRC PDX from a patient that had failed 3 previous lines of therapy, including the immune checkpoint inhibitor Nivolumab. These findings demonstrate GSK4418959 (IDE275)'s potent and selective preclinical activity against MSI-H cancer models, indicating its potential as a promising clinical treatment for MSI-H cancer patients, including those that have failed existing therapies. All studies were conducted according to GSK's Policy on the Care, Welfare and Treatment of Animals and reviewed by the Institutional Animal Care and Use Committee at GSK or by the ethical review process at the institution where the work was performed."

Clinical • IO biomarker • MSI-H • Microsatellite Instability • Oncology • MSI • WRN

Discovery of GSK4418959 (IDE275): A novel, non-covalent, reversible Werner Helicase inhibitor and a new potential therapeutic for the treatment of MSI-H cancers (AACR 2025) - "Importantly, no response is observed in analogous microsatellite stable (MSS) models, exemplifying the precision effect of the WRN inhibition mechanism. GSK4418959 will be investigated as a potential treatment for patients with MSI-H cancer, including those who have been treated with and failed at least one line of checkpoint immunotherapy for their advanced disease."

MSI-H • Microsatellite Instability • Oncology • MSI • WRN

Patient selection, target engagement and pharmacodynamic markers of WRN inhibitor GSK4418959 (IDE275) (AACR 2025) - "DNA damage markers such as gH2AX and pKAP1 were strongly induced both in vitro and in vivo. Immunohistochemistry (IHC) results suggested dose- and time-dependent induction of these markers in MSI-H xenograft models by GSK4418959 (IDE275), providing evidence to support their use in monitoring drug response in clinical settings."

Clinical • PK/PD data • Microsatellite Instability • Oncology • MSI • WRN

First-in-human, phase 1/2 study of GSK4418959, an oral Werner DNA helicase inhibitor, alone or combined with other anticancer agents in adults with advanced mismatch repair-deficient or microsatellite instability-high solid tumors (SYLVER) (AACR 2025) - P1/2 | "Tumor responses will be assessed per RECIST 1.1. Planned enrollment is approximately 133 patients in the US, Australia, Japan, South Korea, Spain, Belgium and the Netherlands, with potential to expand to additional countries for later stages of the study.Disclosures: This study (NCT06710847) is sponsored by GSK.NCT number: NCT06710847Third-party medical writing support: Writing and editorial support, funded and coordinated by GSK, was provided by Tafara T.R. Kunota, PhD, and Mary C. Wiggin of Ashfield MedComms, an Inizio company."

Clinical • dMMR • Metastases • Mismatch repair • MSI-H • P1/2 data • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

Preclinical characterization of GSK4418959 (IDE275): A potent, selective, and highly efficacious WRN inhibitor for MSI-H tumors across multiple cancer types (AACR 2025) - "One notable model is an MSI-H CRC PDX derived from a patient who had failed three prior lines of therapy, including the immune checkpoint inhibitor Nivolumab. Furthermore, GSK4418959 (IDE275) also demonstrated combinatorial effects with existing standard-of-care therapies to benefit MSI-H cancer patients. These findings underscore GSK4418959 (IDE275)'s potency and highly selective activity against MSI-H cancer models in preclinic, highlighting its potential as a promising treatment option for MSI-H cancer patients in clinical setting, both as in monotherapy for those unresponsive to current cancer treatments and in combination with existing therapies for enhanced clinical benefit.All studies were conducted according to GSK's Policy on the Care, Welfare and Treatment of Animals and reviewed by the Institutional Animal Care and Use Committee at GSK or by the ethical review process at the institution where the work was performed."

IO biomarker • MSI-H • Preclinical • Gastric Cancer • Microsatellite Instability • Oncology • Solid Tumor • HER-2 • MSI • WRN

IDEAYA Announces Oral Presentation at the New Drugs on the Horizon Series at AACR 2025 for IDE275 (GSK959), a Phase 1 Werner Helicase Inhibitor (PRNewswire) - "IDEAYA Biosciences...today announced the publication of abstracts for an oral presentation in the New Drugs on the Horizon series, and three poster presentations on IDE275 (GSK959) at the American Association for Cancer Research (AACR) Annual Meeting, taking place April 25-30, 2025, in Chicago, Illinois. IDE275 (GSK959), a potential best-in-class Werner Helicase (WRN) inhibitor, has demonstrated selective preclinical efficacy in the high microsatellite instability (MSI-H) solid tumor setting, and is advancing in a Phase 1 dose escalation trial in partnership with GSK."

Clinical • Preclinical • Microsatellite Instability • Solid Tumor

IDEAYA Biosciences, Inc. Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Update (PRNewswire) - "Data highlighting IDE275's differentiated potential best-in-class profile will be presented with GSK at a medical conference in the first half of 2025...First patient dosed in the Phase 1 trial evaluating IDE161 in combination with KEYTRUDA in patients with MSI-High and microsatellite stable (MSS) endometrial cancer. Targeting Phase 1 expansion in 2025...Targeting clinical combination(s) of IDE161 with TOP1i ADCs in solid tumors in 2025."

Clinical • New trial • P1 data • Endometrial Cancer • Microsatellite Instability • Solid Tumor

IDEAYA Announces Agenda for Investor R&D Day Webcast on December 16, 2024 (PRNewswire) - "The presentations by IDEAYA management and key opinion leaders will showcase scientific insights and clinical development opportunities across IDEAYA's precision medicine oncology pipeline. In addition, IDEAYA will highlight its next-generation precision medicine pipeline programs, including IDE275 / GSK959, a potential first-in-class and best-in-class Phase 1 Werner Helicase inhibitor, IDE892, a potential best-in-class MTA-cooperative PMRT5 inhibitor, IDE034, a potential first-in-class B7H3/PTK7 topo-I-payload bispecific antibody drug conjugate (BsADC), and a potential first-in-class lysine acetyltransferase 6/7 (KAT6/7) development candidate."

Clinical • Oncology • Solid Tumor

IDEAYA Biosciences Announces IND-Clearance for Werner Helicase Development Candidate IDE275 (GSK959) for a Phase 1 Study in MSI-High Solid Tumors (PRNewswire) - "IDEAYA Biosciences, Inc...announced the clearance of an investigational new drug (IND) application with the U.S. Food and Drug Administration (FDA) for the initiation of a Phase 1 clinical trial to evaluate IDE275 (GSK959), a potential first-in-class and best-in-class Werner Helicase (WRN) inhibitor....Phase 1 clinical trial will enroll patients having tumors characterized by MSI-High....Initiation of the Phase 1 trial for IDE275 is projected in the fourth quarter of 2024....IDEAYA is eligible to receive a $7 million milestone payment upon acceptance of the IND by the U.S. Food and Drug Administration (FDA), and a potential additional $10 million milestone payment upon initiation of Phase 1 clinical dose expansion."

IND • New P1 trial • Microsatellite Instability • Oncology • Solid Tumor

On-target mutations drive resistance to WRN helicase inhibitors in microsatellite unstable colorectal cancer (EORTC-NCI-AACR 2024) - "Results were validated in cell and patient-derived xenograft models treated with multiple WRN inhibitors, and drug cross-resistance studies are ongoing. This study indicates that on-target WRN mutations are a key driver of drug resistance, provides a platform to evaluate drug cross-resistance, and can inform potential resistance mechanisms observed in WRNi clinical trials."

Late-breaking abstract • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI • WRN

Novel WRN helicase inhibitors selectively target microsatellite unstable cancer cells (AACR 2024) - "Efficacy was also confirmed in patient-derived organoids and PDX models refractory to immunotherapy. The discovery of potent and selective covalent WRN inhibitors provides proof-of-concept for targeting MSI cancers and provides tools to unlock the molecular dissection of the WRN biology and MSI synthetic lethality."

IO biomarker • Oncology • WRN

Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells. (PubMed, Cancer Discov) - "Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft (PDX) models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic-lethal targeting of WRN in MSI cancer and tools to dissect WRN biology."

IO biomarker • Journal • Oncology • WRN

IDEAYA Biosciences, Inc. Reports Fourth Quarter and Full-Year 2023 Financial Results and Provides Business Update (PRNewswire) - "The Phase 1 trial (NCT05787587) is evaluating the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of IDE161 in patients having tumors with homologous recombination deficiency (HRD)....The Phase 1 expansion trial continues to enroll in HRD solid tumor types, including ER+ HER-breast, colorectal, endometrial, and prostate cancers. Clinical program update(s) are expected in 2024. IDEAYA is also validating IDE161 combination opportunities preclinically and is targeting identification of potential combination(s) in 2024....IDEAYA, in collaboration with GSK, selected a Werner Helicase inhibitor for further development and IDEAYA earned a $3.0 million milestone from GSK in connection with IND-enabling studies....The companies are targeting IND submission in 2024."

IND • P1 data • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Estrogen Receptor Positive Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Prostate Cancer • Solid Tumor

IDEAYA Biosciences, Inc. Reports Third Quarter 2023 Financial Results and Provides Business Update (PRNewswire) - The IDEAYA Investor R&D Day will include participation from GSK and a key opinion leader that will showcase scientific insights and clinical development opportunities across IDEAYA's synthetic lethality pipeline, including IDE397 (MAT2A) in Phase 2, IDE161 (PARG) in Phase 1, GSK101/IDE705 (Pol Theta Helicase) in Phase 1, and the Werner Helicase program for which an IND submission is planned for 2024. In addition, IDEAYA will highlight its next generation initiatives in MTAP-deletion, including a wholly-owned program where a development candidate nomination is targeted in 2024, further advancing IDEAYA's multi-pronged strategy."

Clinical • IND • Oncology

IDEAYA Biosciences Announces Development Candidate Nomination of a Werner Helicase Inhibitor in Collaboration with GSK and Investor R&D Day (PRNewswire) - "IDEAYA Biosciences...announces selection of a Werner Helicase Inhibitor Development Candidate (DC) and Investor R&D Day. The Werner Helicase Inhibitor DC is a potent, selective, small molecule inhibitor of the helicase domain of Werner protein. IDEAYA is collaborating with GSK on IND-enabling studies to support the clinical evaluation of the Werner Helicase Inhibitor DC for patients having tumors characterized by high microsatellite instability (MSI-High)....'Our Werner Helicase Inhibitor DC has demonstrated robust in vivo efficacy in multiple MSI-High cancer models'.....IDEAYA and GSK are targeting an Investigational New Drug (IND) submission to the U.S. Food and Drug Administration (FDA) in 2024....IDEAYA earned a $3 million milestone from GSK in connection with IND-enabling studies and has the potential to earn up to an additional $17 million aggregate milestone payments through early Phase 1."

Financing • IND • Pipeline update • Preclinical • Microsatellite Instability • Solid Tumor

IDEAYA Announces Presentations at AACR Annual Meeting 2023 for Potential First-in-Class Synthetic Lethality Programs IDE397 (MAT2A), IDE161 (PARG) and Werner Helicase (PRNewswire) - "IDEAYA Biosciences...announced publication of abstracts at the 2023 Annual Meeting of the American Association for Cancer Research (AACR). IDEAYA will present data for its potential first-in-class synthetic lethality programs IDE397, a Phase 1/2 methionine adenosyltransferase 2a (MAT2A) inhibitor, IDE161, a Phase 1/2 poly (ADP-ribose) glycohydrolase (PARG) inhibitor, and Werner Helicase, for which a development candidate is targeted in 2023. ...'We are excited to present foundational preclinical data supporting our clinical-stage IDE397 and IDE161 programs and our preclinical Werner Helicase program. These data include fundamental mechanistic, biological and pharmacological insights which inform our ongoing or future clinical development plans for these programs'."

Preclinical • Breast Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor