お知らせ • Mar 10
IDEAYA Biosciences Announces First-Patient-In for Phase 1 Trial of IDE892, Potential PRMT5 Inhibitor for MTAP-Deleted Solid Tumors, and Provides MTAP and CDKN2A Pipeline Update
Ideaya Biosciences, Inc. has enrolled the first patient in its Phase 1 clinical trial evaluating IDE892, an investigational MTA-cooperative PRMT5 inhibitor being developed for patients with MTAP-deleted solid tumors, including non-small cell lung cancer and pancreatic cancer. The trial will assess safety, tolerability, pharmacokinetics, and pharmacodynamics of IDE892 as a monotherapy agent and in combination with IDE397, Ideaya's MAT2A inhibitor, in mid-2026. Dual inhibition of IDE892 and IDE397 has demonstrated durable and well-tolerated tumor regressions in preclinical MTAP-deleted tumor models, including in NSCLC. IDE892 was designed to be a potential best-in-class PRMT5 inhibitor, with ~1,400-fold selective binding to MTA-PRMT5 versus SAM-PRMT5 complexes and observed single-digit nano-molar potency in endogenous MTAP-deleted cell lines, and greater than 50-fold potency differential in MTAP-deleted versus MTAP wild type HCT116 isogenic cell lines. In addition, IDE892 inhibited the arginine dimethylation of a key PRMT5 substrate involved in mRNA splicing, spliceosome protein SmB (SmB-SDMA), with pico-molar potency in MTAP-deleted cell lines with greater than 100-fold potency differential versus an MTAP wild type cell line. IDE892 has demonstrated monotherapy regressions in MTAP-deleted preclinical models, and durable complete responses in combination with IDE397. Loss of MTAP leads to the accumulation of methylthioadenosine (MTA) and increased dependence on PRMT5 and MAT2A, two key enzymes involved in methylation and RNA splicing. In MTAP-deleted tumors, this biology establishes a robust synthetic lethal vulnerability that underpins the mechanistic rationale for combining IDE892 and IDE397. In preclinical studies, dual inhibition of PRMT5 and MAT2A with the combination of IDE892 and IDE397 resulted in potent anti-tumor activity in MTAP-deleted tumor models, including complete and durable responses at well-tolerated doses below those required for monotherapy activity. Ideaya has also advanced its CDKN2A-deficiency program and is on track to select a potential first-in-class development candidate in H2 2026 with a target IND in H1 2027. Ideaya has demonstrated robust monotherapy efficacy with its CDKN2A lead in multiple preclinical models, including in a KRAS mutation pancreatic model. Ideaya plans to evaluate its CDKN2A-deficiency program preclinically as a monotherapy agent, and in combination with assets in its MTAP-deletion portfolio and potentially other RAS and KRAS targeted assets. CDKN2A-defiency is common in cancer, with a prevalence of over 80% in pancreatic cancer (M. Schutte, et al., Cancer Research, 1997; Ideaya analysis, TCGA) and is typically co-deleted in MTAP-deletion solid tumors and a common co-alteration with KRAS mutations, particularly in pancreatic cancer, creating rational combination opportunities with MTAP-deletion and KRAS targeted therapies, respectively. As part of Ideaya's strategic prioritization of its proprietary MTAP-deleted pipeline, including IDE397 and IDE892, and the advancement of its CDKN2A-deficiency program, the company has deprioritized its clinical combination activities with Trodelvy and will be concluding enrollment in the ongoing Phase 1/2 trials with Gilead. Based on preliminary data from these trials supporting the mechanistic rationale for the combination in MTAP-deleted cancers, Ideaya may evaluate additional combinations between IDE397 and other TOP1 payload ADCs in this setting, including IDE034, its B7H3/PTK7 bispecific TOP1 ADC. MTAP deletion is estimated to occur in 15–20% of non-small cell lung cancer, up to 40% of pancreatic cancer, and approximately 15% of all solid tumors, and is commonly co-deleted with CDKN2A due to the proximity of the two genes on chromosome 9p21. There are no approved therapies for patients with MTAP deletion, highlighting the significant unmet need and important new opportunities for precision therapies.