DDDR-10. TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors, including glioblastoma, with MTAP loss

Abstract MTAP deletions occur in 10-15% of all human cancers, providing one of the largest precision oncology patient populations. MTA-cooperative PRMT5 inhibitors leverage the well-characterized synthetic lethal relationship between PRMT5 inhibition and MTAP loss. TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 were the first MTA-cooperative PRMT5 inhibitors entered in clinical trials for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant in preclinical species. TNG456 is a clinical-stage, next-generation, highly potent and selective MTA-cooperative PRMT5 inhibitor designed for patients with MTAP-null cancers including gliomas and other tumors which frequently metastasize to the brain, such as NSCLC. In vitro, TNG456 is 55X selective for MTAP-null cancer cell lines over isogenic MTAP WT cell lines (compared to 15X for TNG908) and has marked selectivity for MTAP-null cancer cell lines independent of lineage in a large, diverse cell line panel. TNG456 is brain penetrant in preclinical species with a Kpuu range of 0.5-1.1 in non-human primates and dogs. Oral administration of TNG456 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in multiple cell line- and patient-derived xenograft models. TNG456 is currently enrolling patients with MTAP-null solid tumors, including glioblastoma, in a Phase 1/2 clinical study (NCT06810544). With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including glioblastoma and CNS metastases.