1st patient dosed in trial of PRMT5 inhibitor for glioblastoma
Phase 1/2 study to evaluate treatment in solid tumors with MTAP deletion
The first participant has been dosed in a Phase 1/2 trial investigating TNG456, a PRMT5 inhibitor to treat people with advanced solid tumors with MTAP deletion, including glioblastoma.
The trial (NCT06810544) is evaluating the safety, pharmacological properties, and antitumor activity of Tango Therapeutics‘ TNG456 given alone or in combination with abemaciclib, a medication used in the treatment of certain types of breast cancer. TNG456 is being tested as a single therapy in people with glioblastoma and is enrolling patients at two sites in the U.S.
“Dosing the first patient in the TNG456 Phase 1/2 trial marks a significant step for us and for patients with MTAP-deleted [glioblastoma],” Adam Crystal, MD, PhD, president of research and development at Tango Therapeutics, said in a company press release.
Deletion of the MTAP gene is a frequent genetic alteration observed in a wide range of solid tumors, including glioblastoma, the most common and aggressive primary brain tumor in adults. The gene encodes the enzyme methylthioadenosine phosphorylase, which plays a critical role in several essential cellular processes.
This MTAP deletion creates a specific vulnerability in cancer cells by reducing the activity of PRMT5, an enzyme crucial for gene regulation and DNA repair. This dependency sensitizes cancer cells to further suppression of PRMT5, making them particularly susceptible to TNG456, an oral, brain-penetrant PRMT5 inhibitor.
‘Substantial number’ of patients stand to benefit
“People with [glioblastoma] currently have few treatment options and a five-year survival rate below 10%. 45% of [glioblastoma] is MTAP-deleted, thus a substantial number of patients have the potential to benefit from TNG456,” Crystal said.
In preclinical studies, TNG456 was shown to be highly selective for MTAP deletions and 55 times more potent in MTAP-deleted cancer cells than in normal cells. It was also able to reach the brain, meaning it “has the potential to be sufficient for meaningful efficacy in [glioblastoma],” Crystal said.
The Phase1/2 trial is expected to enroll up to 191 people with MTAP-deleted solid tumors and is now focusing on people with glioblastoma receiving TNG456 alone.
The trial includes a Phase 1 part in which people with MTAP-deleted solid tumors receive TNG456 alone or in combination with oral abemaciclib, at escalating doses. This ongoing phase aims to determine the maximum tolerated dose — the highest effective dose that does not cause unacceptable or severe side effects — and the recommended dose for the Phase 2 part.
Abemaciclib is primarily approved for breast cancer under the brand name Verzenio, but is also being investigated for its potential role in glioblastoma.
In the Phase 2 part of the study, patients will be grouped by tumor type and receive TNG456 at the selected dose, also alone or in combination. The main goal of this part is to assess the treatment’s anti-tumor activity at 18 weeks (about four months).
