Tango Therapeutics Shifts Focus from TNG908 to More Promising Cancer Drug Candidates, TNG462 and TNG456

Tango Therapeutics (NASDAQ: TNGX) announced that it is stopping enrollment in its TNG908 clinical trial following disappointing results for glioblastoma, a highly aggressive brain cancer. Instead, Tango will concentrate on advancing two other small molecule PRMT5 inhibitors, TNG462 and TNG456, which target similar pathways but hold promise for more favorable outcomes.

TNG908’s Glioblastoma Setback

TNG908, designed as a brain-penetrant MTA-cooperative PRMT5 inhibitor, was initially developed to leverage synthetic lethality by selectively targeting MTAP-deleted tumors—a mutation found in about 10-15% of solid tumors. While TNG908 showed efficacy in non-CNS tumors like non-small cell lung cancer (NSCLC) and pancreatic cancer, its performance in glioblastoma patients was underwhelming. No partial responses were observed among 23 glioblastoma patients treated at active doses, with the median time on study lasting less than eight weeks.

In assessing the lack of CNS efficacy, Tango noted that cerebrospinal fluid (CSF) exposure was significantly lower than expected, reaching only 30% of plasma levels in patients, well below the threshold required for therapeutic effect in the brain.

Dr. Adam Crystal, President of Research and Development at Tango, said:

“We're disappointed that TNG908 hasn’t met our expectations for glioblastoma treatment... but we’re optimistic about TNG456, which we believe offers the potency, selectivity, and brain penetrance needed to meaningfully impact CNS cancers.”

The Shift to TNG462 and TNG456

Tango is now pivoting to its other pipeline assets, TNG462 and TNG456, both of which also target PRMT5 but demonstrate greater potential in trials to date.

See also: The Explosion of Therapeutic Modalities: Small Molecules, Biologics, and Everything in Between

TNG462, a selective PRMT5 inhibitor, has shown durable responses across multiple tumor types in an ongoing phase 1/2 trial, with particular promise in patients with cholangiocarcinoma, where 3 out of 7 showed confirmed partial responses. Tango plans to expand the trial and initiate several combination studies in early 2025, testing TNG462 with both standard therapies and innovative agents such as RAS(ON) inhibitors from Revolution Medicines.

Meanwhile, TNG456, a next-generation brain-penetrant PRMT5 inhibitor, is scheduled to enter clinical trials in early 2025. This candidate is designed to overcome the CNS exposure limitations seen in TNG908, with preclinical primate studies showing CSF exposure reaching up to 110% of plasma levels. Tango plans to study TNG456 as both a monotherapy and in combination with Eli Lilly’s CDK4/6 inhibitor Verzenio, focusing on glioblastoma, NSCLC, and other solid tumors.

“We’re confident that TNG456’s enhanced profile will enable us to pursue treatment for glioblastoma more effectively,” said Crystal. “We’ve seen promising preclinical synergy with Verzenio, and this approach aligns with our broader mission to explore novel synthetic lethal targets in cancer.”

Following the announcement, Tango’s shares dropped 26% to $3.81 in premarket trading, reflecting investor concerns about the challenges facing TNG908 and the need for stronger clinical data in the PRMT5 inhibitor space. Tango is among a growing group of companies pursuing this novel target, with Amgen, Bristol Myers Squibb, and AstraZeneca also making progress in PRMT5 therapies. Amgen recently set a high bar with first-in-human data from its PRMT5 inhibitor AMG 193, and Bristol Myers Squibb bolstered its efforts by acquiring Mirati Therapeutics.

With the discontinuation of TNG908, Tango Therapeutics is doubling down on TNG462 and TNG456, two candidates it hopes will push the boundaries of precision oncology. As the company repositions itself in a challenging market, these drugs represent Tango’s latest effort to harness synthetic lethality for a targeted attack on cancer, capitalizing on MTAP-deleted mutations while preserving healthy cells.

“We remain focused on delivering innovative treatments for patients with MTAP-deleted cancers, even as we navigate the inherent challenges of this field,” said Dr. Barbara Weber, President and CEO of Tango. "Our commitment is to advance TNG462 and TNG456 as viable therapeutic options, especially for those with limited options in aggressive cancers."

Topics: Clinical Trials