TNG456 / Tango Therap - LARVOL DELTA

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors, including glioblastoma, with MTAP loss (SNO 2025) - P1/2 | "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 were the first MTA-cooperative PRMT5 inhibitors entered in clinical trials for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant in preclinical species. TNG456 is currently enrolling patients with MTAP-null solid tumors, including glioblastoma, in a Phase 1/2 clinical study (NCT06810544). With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including glioblastoma and CNS metastases."

Brain Cancer • Glioblastoma • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

Preclinical evaluation of the CNS penetration of a novel series of MTA-cooperative PRMT5 inhibitors including TNG456 (SNO 2025) - "In contrast, rodent terminal brain drug exposure models had limited utility. These data highlight the importance of integrating non-terminal preclinical models and physicochemical analysis to improve the safety and efficacy of CNS-targeted therapeutics."

Preclinical • Brain Cancer • Glioblastoma • Solid Tumor • MTAP

Preclinical evaluation of the CNS penetration of a novel series of MTA-cooperative PRMT5 inhibitors including TNG456 (WFNOS 2025) - "In contrast, rodent terminal brain drug exposure models had limited utility. These data highlight the importance of integrating non-terminal preclinical models and physicochemical analysis to improve the safety and efficacy of CNS-targeted therapeutics."

Preclinical • Brain Cancer • Glioblastoma • Solid Tumor • MTAP

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors, including glioblastoma, with MTAP loss (WFNOS 2025) - P1/2 | "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 were the first MTA-cooperative PRMT5 inhibitors entered in clinical trials for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant in preclinical species. TNG456 is currently enrolling patients with MTAP-null solid tumors, including glioblastoma, in a Phase 1/2 clinical study (NCT06810544). With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including glioblastoma and CNS metastases."

Brain Cancer • Glioblastoma • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • MTAP

Upcoming Milestone… TNG456 monotherapy phase 1/2 trial initial safety and efficacy data 2026 (The Manila Times)

P1/2 data • Glioblastoma

TNG456 is a potent, highly MTAP selective brain-penetrant PRMT5 inhibitor in development for glioblastoma, currently enrolling patients in a Phase 1/2 study. (The Manila Times) - "...the FDA granted Orphan Drug Designation (ODD) to TNG456 for the treatment of malignant glioma."

Enrollment status • Orphan drug • Glioblastoma

Tango Therapeutics Announces First Patient Dosed in TNG456 Phase 1/2 Trial in Patients With MTAP-deleted Glioblastomas and Other Solid Tumors (GlobeNewswire) - "Tango Therapeutics, Inc...today announced that the first patient has been dosed in the TNG456 Phase 1/2 trial in patients with MTAP-deleted solid tumors, with a focus on glioblastoma (GBM). TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor....We are currently enrolling patients with TNG456 monotherapy in dose escalation focused on GBM."

Trial status • Glioblastoma

Tango Therapeutics Reports First Quarter 2025 Financial Results and Provides Business Highlights (GlobeNewswire) - "TNG456: The Company plans to begin enrolling a Phase 1/2 clinical trial evaluating TNG456 in patients with MTAP-deleted solid tumors, focused on glioblastoma in 2Q 2025."

Trial status • Glioblastoma

Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors (AACR 2025) - "To benefit this large patient population, MTA-cooperative PRMT5 inhibitors, including TNG908, TNG462, and TNG456 were developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. Previously, we reported that homozygous loss of only the terminal exon (exon 8), an event reported to occur in only 0.5% of MTAP-deleted tumors, is insufficient for complete loss of MTAP activity in preclinical assays. Here, we report initial evidence for the clinical impact of MTAP truncations, as opposed to complete deletion, on the activity of MTA-cooperative PRMT5 inhibitors."

Clinical • Oncology • CDKN2A • MTAP

TNG462, an MTA-cooperative PRMT5 inhibitor, demonstrates strong efficacy in combination with clinically relevant targeted therapies in MTAP-null preclinical models (AACR 2025) - "This supports our clinical development plans for TNG462, which include targeted combinations with two RAS(ON) inhibitors, RMC-6236 and RMC-9805 from Revolution Medicines, as well as the EGFR inhibitor osimertinib from AstraZeneca...Significant efficacy was observed in preclinical models with the combination of TNG462 and CDK4/6 inhibitors, supporting a potential development path in GBM for our next generation CNS penetrant PRMT5 inhibitor, TNG456, with abemaciclib...However, TNG462 monotherapy at a clinically relevant dose achieved comparable benefits to the combination. Collectively, these findings strongly support evaluating TNG462 in combination with other targeted therapies in clinical trials for patients with cancers that exhibit MTAP loss."

Combination therapy • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • KRAS • MAT2A • MTAP

Preclinical evaluation of CNS drug penetration of a novel series of MTA-cooperative PRMT5 inhibitors including TNG456 (AACR 2025) - "This research highlights the importance of integrating non-terminal preclinical models and physicochemical analysis to improve the safety and efficacy of CNS-targeted therapeutics. In addition, utility of rodent terminal brain drug exposure models and the importance of deriving unbound free brain drug exposures will be discussed."

Preclinical • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor • MTAP

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors with MTAP loss (AACR 2025) - "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 are clinical-stage MTA-cooperative PRMT5 inhibitors for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant. Oral administration of TNG456 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in multiple cell line- and patient-derived xenograft models. With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including gliomas and CNS metastases."

Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

Safety and Tolerability of TNG456 Alone and in Combination With Abemaciclib in Patients With Solid Tumors With MTAP Loss (clinicaltrials.gov) - P1/2 | N=191 | Recruiting | Sponsor: Tango Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Malignant Glioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Tango Therapeutics to Highlight Preclinical Data on Precision Oncology Pipeline with Five Posters at the American Association for Cancer Research (AACR) Annual Meeting 2025 (GlobeNewswire) - "Tango Therapeutics...announced that five abstracts have been accepted as poster presentations at the American Association for Cancer Research (AACR) Annual Meeting 2025....'The data we are presenting at this year’s AACR meeting highlights important preclinical analyses of our PRMT5 programs that underscore the potential of these molecules as both standalone treatments and as key combination partners in MTAP-deleted cancers, including in combination with KRAS-inhibitors'..."

Preclinical • Solid Tumor

Tango Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Highlights (GlobeNewswire) - "Upcoming Milestones: TNG456 phase 1/2 trial enrollment expected to begin 1H 2025; TNG260 clinical data update expected in 2025."

P1/2 data • Trial status • Oncology • Solid Tumor

Tango Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Highlights (GlobeNewswire) - "Investigational New Drug (IND) application for TNG456, a next-generation brain-penetrant MTA-cooperative PRMT5 inhibitor, cleared by FDA. Phase 1/2 enrollment expected to begin 1H 2025; Data update from ongoing TNG462 monotherapy trial expected in 2025 with focus on pancreatic and lung cancer."

P1/2 data • Trial status • Lung Cancer • Pancreatic Cancer

Safety and Tolerability of TNG456 Alone and in Combination With Abemaciclib in Patients With Solid Tumors With MTAP Loss (clinicaltrials.gov) - P1/2 | N=191 | Not yet recruiting | Sponsor: Tango Therapeutics, Inc.

Monotherapy • New P1/2 trial • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Malignant Glioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

Tango Therapeutics Reports Third Quarter 2024 Financial Results and Provides Business Highlights (Businesswire) - "TNG456 is a next-generation brain-penetrant MTA-cooperative PRMT5 inhibitor that is 55X selective for MTAP deletion with 20 nM potency....The Company expects to begin enrolling patients in the planned phase 1/2 trial during 1H 2025....The TNG260 phase 1/2 clinical trial is ongoing, evaluating safety, pharmacokinetics, pharmacodynamics and efficacy of TNG260 in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors with an STK11 loss-of-function mutation....TNG260 clinical data expected in 2025."

New P1 trial • P1/2 data • Breast Cancer • Cervical Cancer • Endometrial Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer