IDEAYA Biosciences has announced IDE892, a potential best-in-class MTA-cooperative PRMT5 inhibitor, initiates a phase 1/2 clinical combination study in MTAP-deleted pancreatic and lung cancers.
The first patient has been enrolled in its phase 1 clinical trial evaluating IDE892, methylthioadenosine (MTA)-cooperative inhibitor of PRMT5, in combination with IDE397, a potential first-in-class and best-in-class inhibitor of MAT2A, in MTAP-deleted solid tumours, with a focus on NSCLC and pancreatic cancer.
In preclinical studies, dual inhibition of PRMT5 and MAT2A with the combination of IDE892 and IDE397 resulted in potent anti-tumour activity in MTAP-deleted tumour models, including complete and durable responses at well-tolerated doses below those required for monotherapy activity.
Loss of MTAP leads to the accumulation of MTA and increased dependence on PRMT5 and MAT2A, two key enzymes involved in methylation and RNA splicing. In MTAP-deleted tumours, this biology establishes a robust synthetic lethal vulnerability that underpins the mechanistic rationale for combining IDE892 and IDE397.IDEAYA also entered into a clinical collaboration with Roche evaluating IDE892 in combination with RG6505, Roche’s phase 1 pan-RAS inhibitor, in MTAP-deleted pancreatic ductal adenocarcinoma (PDAC) to target the genetic co-alterations of MTAP and KRAS in this indication.
Next, IDEAYA is advancing a third proprietary programme for MTAP-deleted solid tumours targeting CDKN2A, the most common co-alteration of MTAP, through ongoing preclinical toxicology studies to support an investigational new drug (IND) application in the first half of 2027.
MTAP deletion is estimated to occur in approximately 15% of all solid tumours, including 15-20% of NSCLC and up to 40% of pancreatic cancer. There are no approved therapies for MTAP-deleted cancers, highlighting the significant unmet need and opportunity for new precision therapies for these patients.
