NEW YORK – Tango Therapeutics on Wednesday said the US Food and Drug Administration cleared an investigational new drug application for its protein arginine methyltransferase 5 (PRMT5) inhibitor TNG462, allowing for the start of a trial involving patients with MTAP-deleted cancers.
PRMT5 is essential for cell survival. TNG462 binds to PRMT5 complexed with 5'-deoxy-5'-methylthioadenosine (MTA), which is produced in cancer cells with a methylthioadenosine phosphorylase (MTAP) deletion. Thus, Tango is betting that MTAP-deleted cancer cells will be vulnerable to PRMT5 inhibition by TNG462, while normal cells will remain unaffected. According to Tango, in vitro studies showed TNG462 was 45 times more potent in MTAP-deleted cancer cells than in normal cells.
Between 10 percent and 15 percent of all cancers are estimated to harbor an MTAP deletion. These alterations have been observed in non-small cell lung cancer, mesothelioma, pancreatic cancer, cholangiocarcinoma, and glioblastoma.
The Boston-based firm plans to begin a Phase I/II trial of TNG462 in MTAP-deleted NSCLC, mesothelioma, and cholangiocarcinoma in mid-2023. This trial will not include glioblastoma patients because while Tango's other PRMT5-targeted drug TNG908 crosses the blood-brain barrier, TNG462 does not. However, compared to TNG908, Tango claims that TNG462 is three times more selective for MTAP-deletions and 20 times more potent.
Meanwhile, the TNG908 program is also progressing. The FDA granted orphan drug designation to TNG908 for malignant glioma. The agency cleared Tango's IND for TNG908 last year, permitting it to begin a Phase I/II trial of the drug in MTAP-deleted malignant peripheral nerve sheath tumors, NSCLC, mesothelioma, and cholangiocarcinoma.