Abstract
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) with standard of care therapies, demonstrating the significant need for the development of novel therapeutics. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that is selectively active in MTAP-deleted cells by leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors have MTAP loss due to a co-deletion event with the proximal tumor suppressor gene, CDKN2A. In preclinical in vitro studies, TNG908 was 15-fold more potent in MTAP-deleted cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is neither a substrate for P-glycoprotein nor Breast Cancer Resistant Protein (BCRP) efflux transporters. Consistent with these favorable attributes, TNG908 demonstrated in vivo brain penetration in multiple preclinical models, including non-human primates and mice. TNG908 on-target pharmacodynamic activity was determined by dose-dependent decreases in SDMA-modified protein levels in a GBM subcutaneous xenograft model. TNG908 demonstrated dose-dependent antitumor activity in multiple hyper- and hypomethylated GBM subcutaneous models, including cell lines and patient-derived xenograft models. Despite 6-fold reduced Kpuu in rodents (Kpuu ~0.15) relative to non-human primates (Kpuu 0.9), oral administration of TNG908 drove near tumor stasis and increased median survival by 3-fold in a highly aggressive murine GBM orthotopic model. In summary, TNG908 is a potent, brain-penetrant, MTA-cooperative PRMT5 inhibitor that drives strong antitumor activity in preclinical models of MTAP-deleted GBM. TNG908 is currently enrolling patients with MTAP-deleted tumors including glioblastoma in a Phase I/II clinical trial (NCT05275478).