TNG908 / 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

MTA-Cooperative PRMT5 Inhibitors Demonstrate Efficacy in MTAP-Deleted MPNST Models and Enhance Chemotherapy Response (SNO 2025) - "Furthermore, the combination of a PRMT5 inhibitor with doxorubicin or trabectedin had additive antiproliferative effects. In vivo, TNG908 and TNG462 demonstrated dose-dependent antitumor activity in MTAP-null MPNST PDX models WU-356 and WU-386, inducing tumor regressions at well-tolerated doses.CONCLUSIONTNG908 and TNG462 selectively inhibited MTAP-deleted MPNST cell growth in vitro and induced tumor regressions in vivo through PRMT5 inhibition and apoptosis induction. These findings support the therapeutic potential of MTA-cooperative PRMT5 inhibitors as a targeted treatment strategy for patients with MTAP-deleted MPNST."

Clinical • Brain Cancer • Neurofibrosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CASP3 • CDKN2A • MTAP

MTA-Cooperative PRMT5 Inhibitors Demonstrate Efficacy in MTAP-Deleted MPNST Models and Enhance Chemotherapy Response (WFNOS 2025) - "Furthermore, the combination of a PRMT5 inhibitor with doxorubicin or trabectedin had additive antiproliferative effects. In vivo, TNG908 and TNG462 demonstrated dose-dependent antitumor activity in MTAP-null MPNST PDX models WU-356 and WU-386, inducing tumor regressions at well-tolerated doses.CONCLUSIONTNG908 and TNG462 selectively inhibited MTAP-deleted MPNST cell growth in vitro and induced tumor regressions in vivo through PRMT5 inhibition and apoptosis induction. These findings support the therapeutic potential of MTA-cooperative PRMT5 inhibitors as a targeted treatment strategy for patients with MTAP-deleted MPNST."

Clinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • CASP3 • CDKN2A • 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

PARP inhibitor and PRMT5 inhibitor synergy is independent of BRCA1/2 and MTAP status in breast cancer cells. (PubMed, Sci Rep) - "This study investigates the effects of two classes of PRMT5 inhibitors, GSK3326595 and TNG908, on breast cancer cell lines with different BRCA1/2 statuses to evaluate their therapeutic potential and synergy with PARP inhibitors. These findings highlight the potential of combining PRMT5 inhibitors with PARP inhibitors in a wide range of cancers beyond BRCA1/2 and MTAP mutants. Further investigation is warranted to elucidate the underlying mechanisms of sensitization and the timing of cellular responses to PRMT5 inhibition."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • MTAP

Epigenetic silencing of MTAP defines a distinct class of PRMT5-inhibitor-sensitive cancers (AACR-NCI-EORTC 2025) - "This metabolic vulnerability renders MTAP-deficient tumors selectively sensitive to PRMT5 inhibitors such as TNG-462 and TNG-908. We identify promoter hypermethylation as a distinct mechanism of MTAP silencing, broadening the spectrum of MTAP-low tumors beyond genomic loss. These findings support integration of epigenetic biomarkers to refine patient selection and enhance response rates in PRMT5-targeted clinical trials."

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

TNG908-C101: Safety and Tolerability of TNG908 in Patients With MTAP-deleted Solid Tumors (clinicaltrials.gov) - P1/2 | N=192 | Active, not recruiting | Sponsor: Tango Therapeutics, Inc. | Trial completion date: Sep 2025 ➔ Dec 2025 | Trial primary completion date: Apr 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Brain Cancer • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • MTAP

MTA-Cooperative PRMT5 Inhibitors are Efficacious in MTAP-Deleted Malignant Peripheral Nerve Sheath Tumor Models. (PubMed, Clin Cancer Res) - "Clinical stage MTA-cooperative PRMT5 inhibitors TNG908 and TNG462 are efficacious in MPNST models in vitro and in vivo; therefore MTA-cooperative PRMT5 inhibitors are promising therapeutic agents for patients with MTAP-deleted MPNST."

Journal • Preclinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CDKN2A • MTAP

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

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

Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion. (PubMed, J Med Chem) - "We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials."

Journal • Oncology • MTAP

Exploring the Clinical Translation of Synthetic Lethality, PRMT5 Inhibitors in MTAP-Deleted Cancers: A Scoping Review (ISPOR-EU 2024) - P1/2 | "Notably, six oral PRMT5 inhibitors—MRTX1719, AG-270, AMI, LLY-238, HLCL-61, and EPZ015666 demonstrated significant antitumor activity in MTAP-deleted tumours in mouse xenograft models...Among the 25 clinical trials, two PRMT5 inhibitors, AMG193 (NCT05975073) and TNG908 (NCT05275478) are currently in Phase 1/2 trials targeting MTAP-null solid tumours. There is compelling evidence supporting the initial stages of drug development aimed at PRMT5 in MTAP-deleted cancers. Additional research is required to clarify molecular mechanisms and improve the clinical viability of this SL combination."

Clinical • Review • Synthetic lethality • Oncology • Solid Tumor • BRCA • MTAP

Discovery of a highly MTA-synergistic series of PRMT5 inhibitors for the treatment of MTAP-deficient tumors by virtual screening technology (EORTC-NCI-AACR 2024) - "TNG-908 & MRTX-1719) and leading to a greater degree of MTA-synergistic binding than for any clinical-stage chemical series. ConclusionsA characteristic, high degree of MTA-synergy has been demonstrated for compounds within a novel chemical series in vitro and in cellular contexts both by manipulating SAM and MTA concentrations through combination with small molecule inhibitors and extensive screening of MTAP wild type and deficient lineages. Optimization of the lead compounds toward selection of a development candidate is underway."

Oncology • MTAP

TNG908-C101: Safety and Tolerability of TNG908 in Patients With MTAP-deleted Solid Tumors (clinicaltrials.gov) - P1/2 | N=192 | Active, not recruiting | Sponsor: Tango Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Brain Cancer • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • MTAP

Tango Therapeutics Reports Third Quarter 2024 Financial Results and Provides Business Highlights (Businesswire) - P1/2 | N=192 | NCT05275478 | Sponsor: Tango Therapeutics, Inc. | "TNG908, an MTA-cooperative brain-penetrant PRMT5 inhibitor, is clinically active and well-tolerated across non-CNS cancers in the phase 1/2 clinical trial. In particular, there were a total of nine evaluable pancreatic cancer patients, two with partial responses (ORR 22%) and five with stable disease as best response to date. The five ongoing pancreatic cancer patients have been on study for an average of 24 weeks, the longest for 72 weeks. TNG908 did not demonstrate activity in glioblastoma (n=23 at active doses) likely because CNS exposure did not meet the required exposure threshold for clinical efficacy."

P1/2 data • Glioblastoma • Pancreatic Cancer

A novel, sensitive, and fast ultra-high-performance liquid chromatography tandem mass spectrometry method for TNG908 determination in dog plasma and pharmacokinetic study. (PubMed, Biomed Chromatogr) - "The validated assay was further applied to measure TNG908 in dog plasma after oral and intravenous administration and achieved success. The obtained pharmacokinetic parameters indicated low clearance of TNG908 (3.7 ± 0.8 mL/min/kg) and moderate oral bioavailability (>36.4%)."

Journal • PK/PD data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Tango Therapeutics Reports Second Quarter 2024 Financial Results and Provides Business Highlights (Businesswire) - "Enrollment in the dose expansion portion of the TNG908 phase 1/2 clinical trial is ongoing. Expansion cohorts are being enrolled in MTAP-deleted solid tumors in glioblastoma (GBM), non-small cell lung and pancreatic cancers at 600 mg BID....The dose expansion portion of the TNG462 phase 1/2 clinical trial is ongoing....A comprehensive update of the PRMT5 program, including clinical data from the ongoing phase 1/2 clinical trials of TNG908 and TNG462, is expected in 2H 2024."

P1/2 data • Trial status • Bladder Cancer • Cholangiocarcinoma • Glioblastoma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Sarcoma

Tango Therapeutics Reports First Quarter 2024 Financial Results and Provides Business Highlights (Businesswire) - "Dose expansion is expected to initiate in the TNG462 phase 1/2 clinical trial in 2Q 2024...A comprehensive update of the PRMT5 program, including clinical data from the ongoing phase 1/2 clinical trials of TNG908 and TNG462, is expected in 2H 2024."

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

PH020-2: an MTA-cooperative PRMT5 inhibitor with excellent selectivity and brain-penetration capability that targets MTAP-deleted tumors (AACR 2024) - "On this basis, MTA cooperative PRMT5 inhibitors (such as MRTX1719 and TNG908) have been designed to stabilize the binding of PRMT5 to MTA, but not SAM, resulting in further improvement of selectivity window. The data suggest that PH020-2 is an MTA-cooperative PRMT5 inhibitor with excellent brain-penetration that selectively targets MTAP-deleted tumors."

Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD34 • MTAP

MTAP loss alters the epigenetic landscape and demonstrates superior therapeutic sensitivity to concomitant PRMT5 and PARP inhibition in cholangiocarcinoma (AACR 2024) - P1/2 | "This renders selective targeting of MTAP null tumors with agents (MRTX1719, AMG193, TNG462, TNG908) targeting MTA bound PRMT5 (PRMT5:MTA), while sparing surrounding normal MTAP wild-type (WT) tissue...To address this pressing need, we co-treated CCA cell lines with MRTX1719 and PARP inhibitor olaparib...Similar differences in proportion of splicing events were also observed in MTAP loss CCA patient derived xenografts as compared to WT models. Collectively, these data implicate MTAP to be a crucial player in modulation of the chromatin and splicing events that may drive therapeutic response to PRMT5 inhibition."

Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • MTAP

Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivity (AACR 2024) - "CAAP1 or AKAP17A knockout in MTAP-deleted cancer cell lines sensitized the cells to PRMT5 inhibitors including the clinical stage MTA-cooperative inhibitors, TNG908 and TNG462, and the non-MTA-cooperative inhibitor, GSK3326595. S. Yoda and M. R. Tonini contributed equally."

Oncology • CDKN2A • MTAP

Evaluation of the impact of homozygous MTAP truncations on the activity and selectivity of MTA-cooperative PRMT5 inhibitors (AACR 2024) - P1/2 | "To benefit this large and diverse patient population, MTA-cooperative PRMT5 inhibitors, including TNG908 and TNG462, have been developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. Here, we present our initial functional genomics analysis of this important diagnostic biomarker using in vitro cDNA reconstitution approaches for MTAP activity combined with analysis of PRMT5 inhibitor sensitivity. Ultimately, these data may help refine patient enrollment on clinical trials to drive the maximum benefit for patients with MTAP-deleted cancers."

Oncology • CDKN2A • MTAP

Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers. (PubMed, J Med Chem) - "Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss."

Journal • Synthetic lethality • Brain Cancer • CNS Tumor • Oncology • MTAP

Tango Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Provides Business Highlights (Businesswire) - "Upcoming Milestones: Clinical data from the ongoing TNG908 phase 1/2 trial are expected in 2024....In March 2024, an oral presentation of the discovery and preclinical characterization of TNG348 will be presented at the ACS Spring Meeting, supporting the further development and ongoing phase 1/2 clinical trial of TNG348 as a single agent and in combination with olaparib....In April 2024, seven posters will be presented highlighting preclinical data from the Company’s clinical-stage precision oncology pipeline and synthetic lethality discovery platform. Ayushi Patel, Ph.D. from NYU Langone Health will present a minisymposium based on a Tango-NYU collaboration to study TNG260 in STK11 mutant non-small cell lung cancer in preclinical models."

P1/2 data • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Tango Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Provides Business Highlights (Businesswire) - "The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation (ODD) to TNG462 in December 2023 for the treatment of soft tissue sarcomas....Dose escalation is ongoing in the TNG462 phase 1/2 clinical trial in patients with MTAP-deleted solid tumors except GBM, as TNG462 is not brain penetrant in preclinical models....TNG462 has the same mechanism of action as TNG908, but with enhanced potency and selectivity in MTAP-deleted cell lines and patient-derived xenografts. In preclinical studies, TNG462 is 45X selective for MTAP-deleted cancer cells versus normal cells and ~30X more potent than TNG908."

Orphan drug • Preclinical • Trial status • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor