IDEAYA Biosciences has announced that the U.S. Food and Drug Administration (FDA) has cleared its investigational new drug (IND) application for IDE849, allowing the company to initiate a Phase 1 clinical trial in the United States. IDE849 (also known as SHR-4849) is a potential first-in-class delta-like ligand 3 (DLL3)-targeting antibody drug conjugate (ADC) with a topoisomerase I (Topo-I) payload designed to treat various solid tumors.
The South San Francisco-based precision medicine oncology company plans to evaluate IDE849 in small cell lung cancer (SCLC), neuroendocrine tumors (NETs), and other solid tumors with DLL3 upregulation. The company also intends to study the drug in combination with its PARG inhibitor IDE161 to potentially enhance treatment durability.
Promising Early Clinical Data
IDE849 is already being evaluated in an ongoing multi-site open-label Phase 1 clinical trial (NCT06443489) conducted by IDEAYA's partner, Jiangsu Hengrui Pharmaceuticals Co., Ltd. According to data collected through December 10, 2024, the drug has reached therapeutic dose levels where multiple partial responses have been observed.
"We are excited to advance IDE849, a potential first-in-class DLL3 TOP1 ADC, into a Phase 1 study in the U.S.," said Yujiro S. Hata, President and Chief Executive Officer of IDEAYA Biosciences. "DLL3 is upregulated in multiple solid tumor types, including small cell lung cancer, neuroendocrine tumors, non-small cell lung cancer, melanoma, among other solid tumors, highlighting the potential to have a pipeline in a single asset."
The safety profile from the ongoing trial appears promising, with treatment-related adverse events (TRAEs) predominantly Grade 1 or 2. The most common TRAEs observed were decreased white blood cell count, anemia, decreased neutrophil count, decreased platelet count, and nausea. Notably, the Phase 1 dose escalation is continuing with no reported drug-related discontinuations, and the maximum tolerated dose has not yet been reached.
Strategic Approach to Clinical Development
Dr. Darrin M. Beaupre, M.D., Ph.D., Chief Medical Officer at IDEAYA Biosciences, emphasized the strategic importance of IDE849: "IDE849 is a potential first-in-class DLL3 TOP1 ADC, a target antigen that has demonstrated preliminary monotherapy clinical validation in SCLC. In addition, IDE849 aligns with our strategy to develop rational combination therapies, particularly with our potential first-in-class Phase 1 PARG inhibitor IDE161."
Based on FDA guidance, IDEAYA will begin its U.S. Phase 1 study at a starting dose equivalent to one of the expansion doses currently being evaluated in Hengrui's ongoing Phase 1 study, where multiple confirmed partial responses have been observed according to RECIST 1.1 criteria.
Hengrui Pharmaceuticals is expected to present clinical efficacy and safety data on IDE849 from over 40 SCLC patients at a medical conference in Q3 2025. This data will include results from both the dose escalation phase and multiple expansion doses.
DLL3 as a Promising Target
DLL3 has emerged as a promising therapeutic target due to its upregulation in multiple solid tumor types while having limited extracellular expression in normal tissues. This characteristic potentially allows for targeted treatment with reduced off-target effects.
The target has been reported to be upregulated in SCLC, NETs, NSCLC, melanoma, and other solid tumors—many of which represent areas of significant unmet medical need. IDEAYA plans to evaluate IDE849 as a monotherapy in these tumor types through a multi-site global clinical trial.
Combination Strategy to Enhance Durability
In addition to monotherapy applications, IDEAYA is pursuing a combination strategy with IDE849. The company plans to evaluate IDE849 in combination with its Phase 1 PARG inhibitor, IDE161, in the second half of 2025.
IDEAYA is targeting to present preclinical combination mechanism and synergy efficacy data of IDE161/PARG with TOP1-payload based ADCs at a medical conference in the third quarter of 2025. The company believes this potential first-in-class combination could enhance the durability of its TOP1-payload based ADC pipeline, which includes both IDE849 and IDE034 (a B7H3/PTK7 Bispecific TOP1 ADC).
This approach aligns with IDEAYA's broader mission as a precision medicine oncology company committed to developing targeted therapeutics for patient populations selected using molecular diagnostics. The company's approach integrates capabilities in identifying and validating translational biomarkers with drug discovery to select patient populations most likely to benefit from its targeted therapies.
As IDE849 advances into clinical development in the United States, it represents an important addition to the emerging landscape of antibody-drug conjugates targeting solid tumors with specific molecular characteristics.
