Tango Therapeutics Announces Positive TNG462 Data and PRMT5 Development Update

Tango Therapeutics, Inc., a clinical-stage biotechnology firm, has provided an update on its PRMT5 program following positive results from the dose escalation and early dose expansion phases of the TNG462 phase 1/2 clinical trial. The company has decided to advance TNG462 into full development. Another drug, TNG908, which is an MTA-cooperative brain penetrant PRMT5 inhibitor, showed clinical activity and was well-tolerated in non-CNS solid tumors like NSCLC and pancreatic cancer. However, it did not meet the necessary pharmacokinetic exposure for clinical efficacy in glioblastoma (GBM). Therefore, Tango Therapeutics is introducing TNG456, a next-generation brain-penetrant PRMT5 inhibitor with greater potency and selectivity for GBM, NSCLC, and other selected solid tumors. Enrollment for TNG908 will be halted to focus resources on TNG462 and TNG456.

Adam Crystal, President of Research and Development at Tango Therapeutics, emphasized the promising results of TNG462, which has shown activity, durability, and tolerability in the ongoing phase 1/2 clinical trial. Patients have remained on treatment for a median of 24 weeks. Additionally, TNG456 is expected to enter clinical trials in the first half of next year, with anticipated enhanced brain exposure for efficacy in GBM and brain metastases. While TNG908 did not perform as hoped in GBM, the company remains dedicated to finding effective treatments for this condition.

Barbara Weber, President and CEO of Tango Therapeutics, highlighted that TNG462 has shown strong clinical activity, durability, and safety across multiple tumor types in the trial. The company plans to rapidly advance TNG462 into further development, including clinical evaluations as a monotherapy and in combination with both targeted and standard care agents starting in the first half of 2025. Tango has also entered into a clinical collaboration with Revolution Medicines to conduct the first combination trials of an MTA-cooperative PRMT5 inhibitor with RAS(ON) tri-complex inhibitors, which could significantly impact the treatment landscape for pancreatic cancer.

The TNG462 trial began dose escalation in July 2023, with dose expansion cohorts starting in June 2024. As of October 2024, 59 patients were enrolled, with 39 evaluable patients across 13 histologies at active doses. TNG462 has shown activity and good tolerance across various tumor types, including NSCLC and pancreatic cancer, with a median treatment time of 24 weeks. The drug continues to demonstrate tumor shrinkage over time, with a median response time of 16 weeks.

Although exact objective response rates (ORR) for most cancer types are yet to be determined, partial responses were observed in 3 out of 7 cholangiocarcinoma patients. TNG462 exhibited a favorable safety profile, with thrombocytopenia as the dose-limiting toxicity. Other adverse events like nausea, vomiting, diarrhea, and fatigue were mostly mild. Current evaluations of TNG462 cover daily doses of 200 mg, 250 mg, and 300 mg, particularly for NSCLC and pancreatic cancer, with the next clinical update expected in 2025.

Tango's development strategy for TNG462 includes combination trials with RAS(ON) inhibitors RMC-6236 and RMC-9805 from Revolution Medicines, osimertinib from AstraZeneca, and pembrolizumab from Merck, with plans to begin enrollment in the first half of 2025. Tango is also exploring combinations with standard chemotherapy for NSCLC and pancreatic cancer as potential first-line treatments and is preparing for multiple registrational studies in collaboration with the FDA.

TNG908, a blood-brain barrier penetrant PRMT5 inhibitor, began dose escalation in August 2022, with dose expansion cohorts starting in April 2024. By October 2024, 103 patients had been enrolled, including 70 non-CNS patients across 24 histologies and 33 glioblastoma patients. While TNG908 showed activity and tolerability in non-CNS solid tumors, it did not meet the efficacy threshold in glioblastoma. Consequently, enrollment for TNG908 will be stopped to fully support the development of TNG462.

TNG456, a novel brain-penetrant PRMT5 inhibitor, is 55 times more selective for MTAP deletion and shows greater potency in preclinical studies. With significant brain exposure predicted for efficacy in glioblastoma and brain metastases, TNG456 will be evaluated in glioblastoma, NSCLC, and other solid tumors both as a monotherapy and in combination with the brain-penetrant CDK4/6 inhibitor abemaciclib from Lilly. Tango plans to begin patient enrollment for TNG456 in the first half of 2025.