IDEAYA Biosciences (IDYA) Study Update summary

Clinical background and rationale

• IDE397 is a first-in-class MAT2A inhibitor targeting MTAP-deleted solid tumors, especially lung and urothelial cancers, where MTAP deletion prevalence is high and no FDA-approved therapies exist.

• MTAP deletion creates vulnerabilities in tumor cells that can be exploited by MAT2A inhibition, leading to synthetic lethality and tumor cell death.

• IDE397 demonstrates high selectivity and potency in MTAP-null cells, with a favorable selectivity window compared to other PRMT5 inhibitors.

• Preclinical studies identified squamous non-small cell lung cancer as an optimal monotherapy proof-of-concept indication due to consistent MTA accumulation and PRMT5 pathway suppression.

• Combination strategies with PRMT5 inhibitors (AMG 193) and TROP2 ADC (Trodelvy) are being pursued to maximize efficacy and overcome resistance.

Market opportunity and unmet need

• MTAP-deletion occurs in ~48,000 new NSCLC and urothelial cancer cases annually in the U.S., with no FDA-approved therapies for these tumors.

• MTAP-deletion prevalence is >25% in urothelial cancer and >15% in NSCLC, representing a significant patient population.

• IDE397 targets MAT2A, addressing vulnerabilities in MTAP-deleted tumors, which are present in ~15% of all solid tumors.

Phase II clinical data and patient outcomes

• In the phase II expansion, 18 evaluable patients (7 urothelial, 4 adeno NSCLC, 7 squamous NSCLC) received 30mg IDE397; most were heavily pretreated with a median of 2 prior therapies.

• IDE397 at 30mg achieved plasma exposures above preclinical efficacy thresholds and induced pronounced, sustained reductions in plasma SAM, confirming target engagement.

• The safety profile was favorable, with ~5.6% grade ≥3 drug-related AEs, no drug-related serious events or discontinuations, and most AEs being low grade.

• 78% of patients experienced tumor shrinkage; the overall response rate was 39% (1 CR, 6 PRs, 2 pending confirmation), and the disease control rate was 94% (1 CR, 6 PRs, 10 SD).

• Median duration of treatment, response, and progression-free survival not yet reached; 11 of 18 patients remain on treatment.