Tango missteps in PRMT5
The company abandons TNG908, but is still all in on the troubled target.
The company abandons TNG908, but is still all in on the troubled target.
With Amgen’s PRMT5 inhibitor AMG 193 recently disappointing the pressure was on Tango Therapeutics to deliver something special with its similarly acting contenders. But Tango has fallen short, on Wednesday discontinuing its lead project, TNG908, following lacklustre data in glioblastoma, and switching to a next-generation PRMT5 blocker, TNG462.
One difference is that TNG908 was designed to cross the blood-brain barrier, while TNG462 is not. Tango also unveiled a brain-penetrant follow-on, TNG456, but this is well behind, with clinical development not due to start until next year.
Investors sent the company’s stock down 40% on Wednesday morning. Tango is uniquely exposed to PRMT5, with two of its three disclosed pipeline projects hitting this target; if the problem turns out to be the target not the molecule the company’s prospects look bleak.
Tango’s pipeline
| Project | Description | Status | Note |
|---|---|---|---|
| TNG908 | PRMT5 inhibitor (brain penetrant) | Ph1/2 in MTAP-deleted solid tumours | Project discontinued Nov 2024 after disappointing in glioblastoma |
| TNG462 | PRMT5 inhibitor (not brain penetrant) | Ph1/2 in MTAP-deleted solid tumours | ORR 43% (3/7) in cholangiocarcinoma; plans to combine with RMC-6236, RMC-9805, Tagrisso & Keytruda, starting H1 2025 |
| TNG260 | CoREST complex inhibitor | Ph1/2 in STK11-mutated solid tumours + Keytruda | Data due 2025 |
| TNG456 | PRMT5 inhibitor (brain penetrant) | Preclinical | Ph1/2 to start H1 2025 |
Source: OncologyPipeline, company presentation & releases.
As well as Amgen, others in this space include Bristol Myers Squibb, which gained MRTX1719 through its purchase of Mirati, and Astrazeneca, which took AZD3470 into the clinic last year.
TNG908 was in a phase 1/2 trial in various MTAP-deleted solid tumours, including NSCLC, pancreatic cancer and glioblastoma.
Tango claimed on Wednesday that TNG908 showed activity in multiple non-CNS tumours; however, among 31 evaluable patients receiving active doses of 400-600mg twice daily the ORR was just 13%, with four partial responses.
Data in pancreatic cancer appear to be the most robust, with two responses among nine patients. This 22% ORR looks favourable compared with the 9% (2/23) produced by Amgen’s AMG 193 in pancreatic patients at the recent ESMO meeting.
But, among 23 glioblastoma patients receiving active doses of TNG908, there were no responses. Tango suggested that not enough drug was getting into the brain, according to cerebrospinal fluid samples from three patients.
In addition, nausea and fatigue were seen in around 40% of patients receiving 600mg twice daily.
TNG462 focus
So it’s full steam ahead for the next-gen TNG462. Tango also released some phase 1/2 data on this project on Wednesday, citing a 43% ORR in cholangiocarcinoma, though this came from just seven patients.
The company said there weren’t enough evaluable patients to “accurately estimate ORR for most cancer types” so the next update from this study, in 2025, will be closely watched.
Tango also has plans to combine TNG462 with other agents, including AstraZeneca’s Tagrisso and Merck’s Keytruda – and, more surprisingly, Revolution Medicines’ pan-KRAS and G12D-selective inhibitors, RMC-6236 and RMC-9805 respectively. According to Tango, nearly all MTAP-deleted pancreatic cancers have a co-occurring RAS mutation.
TNG462 will also be given alongside chemo in first-line NSCLC and pancreatic cancer, where the group is planning registrational studies.
However, Amgen recently began a phase 2 trial in MTAP-deleted NSCLC. Tango, already lagging, is now even further behind with a questionable mechanism.
1038
