NEW YORK – Tango Therapeutics said on Wednesday that it is moving ahead with the development of two PRMT5 inhibitors, TNG462 and the preclinical candidate TNG456, but ending a third program, TNG908, after seeing Phase I/II trial results.
In an early readout from a Phase I/II trial of TNG462, the drug showed durable responses across several tumor types harboring MTAP deletions, including non-small cell lung and pancreatic cancer. However, most tumor types in the study did not yet have enough evaluable patients to report response rates. One tumor type that did have enough data was pancreatic cancer, where TNG462 demonstrated a 43 percent response rate among seven patients. Across all tumor types in the study, the median time on treatment is 24 weeks. Tango said the drug currently is being evaluated at three dose levels and that the firm will provide another update from the study in 2025.
The firm also plans to begin testing TNG462 with two RAS(ON) inhibitors from Revolution Medicines, RMC-6236 and RMC-980, and with AstraZeneca's EGFR inhibitor Tagrisso (osimertinib) and Merck's checkpoint inhibitor Keytruda (pembrolizumab). Boston-based Tango expects to begin enrollment in these studies in the first half of 2025.
Tango CEO Barbara Weber said in a statement that these forthcoming studies are "in preparation for registrational trials [of TNG462] in NSCLC and pancreatic cancer."
Meanwhile, in a separate Phase I/II trial in MTAP-deleted tumors, Tango's other PRMT5 inhibitor, TNG908, did not meet the pharmacokinetic exposure threshold for clinical efficacy in glioblastoma patients. The firm said cerebral spinal fluid exposure of the drug in three glioblastoma patients was about 30 percent of plasma exposure, below the threshold required for efficacy. There were no partial responses to TNG908 among glioblastoma patients in the trial.
TNG908 also showed lower efficacy and durability in other MTAP-deleted tumor types compared to TNG462. For example, the response rate among pancreatic cancer patients on the drug was 22 percent and the median time on treatment across all tumor types was 16 weeks. Based on these data, Tango said it decided to stop enrolling patients in the TNG908 trial to focus resources on advancing TNG462.
"Given the increased potency, selectivity, and predicted brain penetrance of TNG456, we expect central nervous system exposure to be in the range needed for meaningful efficacy in glioblastoma and brain metastases," Adam Crystal, president of R&D at Tango, said in a statement explaining the firm's decision to shift focus to TNG462. "While it's disappointing that, unlike in other solid tumors, TNG908 is not active in [glioblastoma], we believe this is due to lower-than-predicted central nervous system exposure."
Earlier this year, Tango also ended development of its USP1 inhibitor, TNG 348, due to liver toxicities reported in a Phase I/II trial in BRCA-mutant tumors.
Finally, the firm also said it is advancing its preclinical PRMT5 candidate, TNG456, in MTAP-deleted glioblastoma and in patients with brain metastases. It will evaluate the drug as a monotherapy and in combination with Ei Lilly's brain-penetrant CDK4/6 inhibitor Verzenio (abemaciclib) in a Phase I/II study that will begin in the first half of 2025.